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What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Introduction
Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5
BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12
Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24
To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850).
Methods
Study design and patient eligibility
This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL).
With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis.
Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP).
The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial.
Treatment protocol and response assessment
As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents.
For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician.
Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment.
Table 2. Patients’ characteristics.
Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician.
Correlative studies
CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed.
Statistical analysis
The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019.
Results
Patients’ characteristics
Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis.
Safety and feasibility
Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment.
Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses.
Table 3A All adverse events at least possibly related to the BV-R-CHP regimen.
Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen.
Efficacy
In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown.
In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95).
CD30 expression as determined by immunohistochemistry and response to therapy
While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry.
Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma
Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx.
Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22).
Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin.
Discussion
There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active.
Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17
We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33
Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors.
Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1).
The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients.
We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38
Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials.
This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559).
BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities. | 750 MILLIGRAM/SQ. METER, QD, CYCLE OF 21 DAYS | DrugDosageText | CC BY-NC | 32414850 | 19,809,418 | 2021-06-01 |
What was the dosage of drug 'DOXORUBICIN'? | Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Introduction
Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5
BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12
Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24
To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850).
Methods
Study design and patient eligibility
This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL).
With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis.
Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP).
The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial.
Treatment protocol and response assessment
As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents.
For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician.
Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment.
Table 2. Patients’ characteristics.
Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician.
Correlative studies
CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed.
Statistical analysis
The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019.
Results
Patients’ characteristics
Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis.
Safety and feasibility
Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment.
Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses.
Table 3A All adverse events at least possibly related to the BV-R-CHP regimen.
Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen.
Efficacy
In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown.
In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95).
CD30 expression as determined by immunohistochemistry and response to therapy
While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry.
Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma
Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx.
Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22).
Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin.
Discussion
There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active.
Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17
We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33
Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors.
Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1).
The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients.
We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38
Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials.
This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559).
BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities. | 50 MILLIGRAM/SQ. METER, QD, CYCLE OF 21 DAYS | DrugDosageText | CC BY-NC | 32414850 | 19,809,418 | 2021-06-01 |
What was the dosage of drug 'PREDNISONE'? | Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas.
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Introduction
Brentuximab vedotin (BV) is an immunoconjugate consisting of a CD30-directed antibody linked to the anti-microtubule agent auristatin.1 BV is highly active in relapsed and refractory (r/r) classical Hodgkin lymphoma and in CD30-expressing T-cell lymphomas.2,3 In the frontline setting, BV combined with chemotherapy has been recently approved for advanced classical Hodgkin lymphoma and CD30-positive (CD30+) T-cell lymphomas based on results of randomized trials showing benefit of the BV-containing arms.4,5
BV targets the cell membrane protein CD30 that is expressed not only by classical Hodgkin lymphoma and some T-cell lymphomas, but at various frequencies also by B-cell non-Hodgkin lymphomas including up to 80% of primary mediastinal B-cell lymphomas (PMBCL).6-9 PMBCL is a mature large B-cell lymphoma of thymic origin which usually presents with mediastinal masses. It occurs predominantly in young adults and represents about 5% of aggressive B-cell lymphomas.10 While previous classifications considered it as a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now thought of as a distinct clinicopathological entity with clinical features and also a molecular signature that share similarities with those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defining PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12
Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratification. 15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell transplant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been disappointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24
To test the tolerability and make a preliminary assessment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850).
Methods
Study design and patient eligibility
This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measurable disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biopsy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II portion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma subtype (PMBCL, DLBCL, and GZL).
With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to minimize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I subjects accrued at the phase II dose were included in the efficacy analysis.
Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP).
The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial.
Treatment protocol and response assessment
As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial rituximab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents.
For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hematologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
The use of granulocyte-colony stimulating factor (G-CSF) was allowed as per institutional policy. Consolidative radiation therapy was permitted after completion of all systemic therapy and only after end-of-treatment imaging at the discretion of the treating physician.
Figure 1. CONSORT diagram. GZL: gray zone lymphoma; cHL: classical Hodgkin lymphoma; EOT: end of treatment.
Table 2. Patients’ characteristics.
Treatment response was assessed by imaging with fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) using the revised response criteria for malignant lymphoma described by Cheson et al.25 Computed tomography scans were performed after cycles 2 and 4 to monitor for interim response. End-of-treatment imaging was performed 3-5 weeks after completion of systemic therapy using FDG-PET/CT. Consolidative radiation following end-of-treatment response assessment was permissible at the discretion of the treating physician.
Correlative studies
CD30 expression was determined on the diagnostic tissue biopsies using immunohistochemistry though visual inspection by two independent pathologists. The gene expression analysis (Lymph3Cx) was performed on archival formalin-fixed, paraffinembedded tissue from pre-treatment biopsies. The tissue was examined by a hematopathologist for adequate tumor amount and nucleic acids were extracted from formalin-fixed paraffinembedded scrolls or unstained slides. The Lymph3Cx assay was previously described and validated to aid in the molecular distinction of PMBCL versus DLBCL.26 The gene expression assay on the diagnostic tissue was performed in a blinded fashion, and once the assignment of diagnosis by Lymph3Cx was made, a correlation with investigator-based diagnosis (PMBCL vs. DLBCL vs. GZL) was performed.
Statistical analysis
The overall response rate and complete response rate with a two-sided 95% exact confidence intervals (95% CI) were calculated using the Clopper-Pearson method. Two-year progression-free and overall survival rates were estimated using the Kaplan-Meier method. The median follow-up was estimated by the reverse Kaplan-Meier method.27 The data cut-off for analysis was January 1, 2019.
Results
Patients’ characteristics
Thirty-three patients gave consent to enrollment in the trial (Figure 1). One of these patients was subsequently reclassified from having GZL to having classical Hodgkin lymphoma and was taken off the study before starting therapy. Thus, 32 patients were enrolled and received at least one cycle of therapy. One patient withdrew from the study after cycle 1 to receive R-CHOP therapy closer to home. The characteristics of the patients evaluable for toxicity (n=31) are presented in Table 2. The median age was 37 years (range, 18-76), 50% of the patients were female, 42% had stage III/IV disease and 17% were classified in high-intermediate or high International Prognostic Index (IPI) risk group.28 Using traditional clinicopathological criteria, 23 patients had a diagnosis of PMBCL, six were diagnosed as having DLBCL, and two as having GZL. For the PMBCL cohort, 91% of patients had large mediastinal masses over 7.5 cm in maximal transverse diameter and 35% had stage III/IV disease. Two patients were removed from the study (1 patient because of non-compliance and 1 in complete remission because of a regimen violation). Therefore, a total of 29 patients were evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-RCHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using protons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis.
Safety and feasibility
Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in combination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (maximum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxicities were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treatment after cycle 4 because of sepsis and grade 3 cardiomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropathy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the follow- up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treatment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after completing study treatment. One patient died of progressive lymphoma 40 months after completing study treatment.
Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associated thromboses.
Table 3A All adverse events at least possibly related to the BV-R-CHP regimen.
Table 3B Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen.
Efficacy
In the combined phase I/II cohort with 29 evaluable patients, the overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving a complete response and 14% (95% CI: 4-32) achieving a partial response according to FDG-PET/CT imaging at the end of treatment. All four patients with a partial response had a diagnosis of PMBCL and had a low or low-intermediate IPI risk classification. Only two of the four patients with a partial response ultimately progressed. At a median follow-up of 30 months (95% CI: 26-46), four patients (14%) progressed: three with PMBCL and one with GZL. The 2-year progression-free survival rate was 85% (95% CI: 66-94) and the 2-year overall survival was 100% (Figure 2). Of three patients who were not evaluable per study criteria, two remain progression-free at last followup and the status of one patient is unknown.
In the PMBCL cohort of 22 evaluable patients with a median follow-up of 30 months (95% CI: 23-46), the 2- year progression-free survival rate was 86% (95% CI: 62-95) with a 2-year overall survival of 100% (Figure 2). Of the three PMBCL patients who progressed, two had bulky advanced stage disease with expression of CD30 ≤10% and one had bulky stage I disease with CD30 expression of 1%. There was no statistically significant difference in progression-free survival between the PMBCL patients who received consolidative radiation therapy (n=13) and those who did not (n=9) (P=0.95).
CD30 expression as determined by immunohistochemistry and response to therapy
While all cases expressed CD30 in at least 1% of the lymphoma B cells in the tumor biopsy by immunohistochemistry, it was challenging to capture CD30 expression as a single metric since there was great heterogeneity of CD30 expression patterns, as depicted in Figure 3. Additionally, given the 100% overall response rate and low number of relapses, we could not make any conclusions about correlations between efficacy of the BV-containing regimen and CD30 expression as determined by immunohistochemistry.
Gene expression analysis to improve diagnostic accuracy of primary mediastinal B-cell lymphoma
Of 29 evaluable patients with CD30+ B-cell lymphoma, 26 had a pre-treatment biopsy available (11 excisional biopsies and 15 core needle biopsies). Of the 26 samples, five core needle biopsies did not have adequate tumor content or amounts of extractable RNA for the Lymph3Cx assay. The biopsies of the remaining 21 patients (11 excisional and 10 core needle biopsies) were tested. All three subtypes of CD30+ B-cell lymphomas as assessed by investigator assessment were tested in blinded fashion by the Lymph3Cx assay and comprised 14 cases of PMBCL, six of DLBCL, and one case of GZL. Of 14 patients with PMBCL by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9 which were consistent with a molecular diagnosis of PMBCL (mPMBCL) by gene expression; two patients scored in the indeterminate category (0.1 to 0.9); and one patient scored as having a molecular diagnosis of DLBCL (< 0.1) (Figure 4). None of the CD30+ B-cell lymphoma samples that were felt to be DLBCL by investigator assessment scored as having a molecular diagnosis of PMBCL by Lymph3Cx.
Figure 2. Survival curves for patients who received the BV-R-CHP treatment regimen. (A, B) Progression-free survival (A) and overall survival (B) of all evaluable patients enrolled in the trial (n=29). (C, D) Progression-free survival (C) and overall survival (D) of evaluable patients with primary mediastinal B-cell lymphoma (PMBCL) (n=22).
Figure 3. Examples of different CD30 staining patterns by immunohistochemistry in three representative patients with primary mediastinal B-cell lymphoma enrolled on the trial. (A) Heterogeneous staining pattern with strong and dim staining in different areas of the same tumor. (B) Focal staining in one area of the tumor. (C) Diffuse staining throughout the tumor. The antibodies used were CD20 (ready to use, DAKO) and CD30 (ready to use, Leica) and they were detected using a chromogenic substrate, diaminobenzene (Leica). An original magnification x200 was used for all images. H&E: hematoxylin & eosin.
Discussion
There is a strong rationale for replacing vincristine with BV in the standard R-CHOP regimen for the treatment of CD30+ aggressive B-cell lymphomas. BV specifically delivers the antimicrotubule agent auristatin to CD30-expressing cells, which could result in improved efficacy from BV and reduced toxicity due to the omission of vincristine. While BV displayed only limited clinical activity as monotherapy in aggressive r/r B-cell lymphomas, it has not been widely studied in the frontline setting or in combination with chemotherapy.24,29 In our phase I/II study, we showed that a frontline regimen using BV at a dose of 1.8 mg/kg in combination with R-CHP for patients with CD30+ B-cell lymphomas has an acceptable toxicity profile and is highly active.
Our study included a heterogeneous group of B-cell lymphomas, but the majority of the patients had a clinicopathological diagnosis of PMBCL. For many reasons, this is a challenging population to study in a frontline setting. PMBCL is a rare and clinically heterogeneous lymphoma. Patients with this type of lymphoma often present with an acute onset of pulmonary symptoms necessitating urgent therapy which may lead to a selection bias in nonrandomized studies. While several frontline treatment approaches are effective in PMBCL, there are unique challenges in this population of patients. DA-EPOCH-R is a highly active dose-intense regimen, but it requires central venous access, use of growth factors, frequent blood testing, and inpatient admission at some institutions. RCHOP is easier to administer, but the excellent outcomes in PMBCL are achieved using consolidative radiation therapy, which may cause long-term toxicities.14,16,30,31 While a recently published phase III trial comparing R-CHOP versus DA-EPOCH-R in DLBCL included a small cohort of PMBCL cases (n=35), it was not statistically powered to detect the differences in this lymphoma subtype.17
We recognize that it is difficult to compare regimens across different trials, but outcomes within the PMBCL cohort in our study are comparable to previously published results for patients treated with R-CHOP with radiotherapy or dose-intense regimens such as DAEPOCH- R.14-16,19,30,32 For lymphoma subtypes other than PMBCL, the numbers of patients were too small to make any efficacy conclusions regarding BV-R-CHP. One of two patients with GZL relapsed after achieving a complete response and none of the five patients with CD30+ DLBCL relapsed, which is encouraging. Interestingly, preliminary results from another phase II trial (ClinicalTrial.gov identifier: NCT01925612) using BV-R-CHOP in DLBCL (without any requirement for CD30 staining) documented an overall response rate of 97% in the initial 30 evaluable patients. None of the CD30+ DLBCL patients in the preliminary report relapsed, but the median follow-up of 5 months was short.33
Regarding toxicity of the BV-R-CHP regimen, there were no study-related deaths. With the caveats about cross-trial comparisons of studies, the rate of grade 3 or 4 hematologic and non-hematologic toxicities was similar or lower compared to the rates reported for R-CHOP.17,34 When compared to the DA-EPOCH-R arm from the recently published randomized trial in DLBCL, there appears to be less toxicity with BV-R-CHP in our study.17 However, one limitation of this comparison is the younger median age of patients in our cohort. Neuropathy is of particular concern with a BV-containing regimen and was closely monitored in our study. While peripheral sensory neuropathy was reported in 61% of patients, no patient experienced grade 3 or 4 neuropathy. This lack of severe peripheral neuropathy may again relate to the young age of our patients and the fact that our BV-containing regimen did not contain additional vinca alkaloids, in contrast to some of the other BV-containing combinations used frontline.4,33 There were no unexpected opportunistic infections using the combination of rituximab and BV. The administration of G-CSF was not consistent across the participating institutions in our study, but over 20% of patients did not require G-CSF at all or its use was limited to one or two cycles. However, considering that 23% of patients experienced febrile neutropenia, empiric use of G-CSF should be considered in patients being treated with BV-R-CHP. With regard to long-term toxicities, one patient developed acute myeloid leukemia 2 years after completing the trial therapy and radiation. It is not possible to determine the association between the protocol treatment and her leukemia, but the fact that the patient’s mother died of acute myeloid leukemia and the patient had normal cytogenetics (rare in secondary leukemias) is suggestive of other contributing factors.
Figure 4. Correlation of Lymph3Cx results with standard clinicopathological diagnoses made by the investigators. DLBCL: diffuse large B-cell lymphoma; GZL: gray zone lymphoma; PMBCL: primary mediastinal B-cell lymphoma. Patients who progressed are labeled by an arrow. Of 14 patients with PMBCL diagnosed by investigator assessment alone, 11 patients (79%) had Lymph3Cx probability scores >0.9, which were consistent with a molecular diagnosis of PMBCL by gene expression analysis, two patients (14%) scored in the indeterminate category (0.1 to 0.9), and one patient (7%) scored as having DLBCL (< 0.1).
The high rate of thrombosis in the PMBCL cohort is of special interest. Thromboses were found in over one third of PMBCL patients and approximately 50% were diagnosed prior to initiation of therapy. This high risk of thrombosis in PMBCL patients was described with similar frequency in retrospective studies and is not likely to be related to BV-R-CHP.19,35 This finding warrants further investigations about screening, the potential contribution of central lines to thrombosis, and any possible role for prophylactic anticoagulation in PMBCL patients.
We also attempted to define clinical and pathological factors which would correlate with outcomes of patients receiving BV-R-CHP therapy for CD30+ B-cell lymphomas. IPI risk group, which is well-established as a prognostic factor for outcomes of frontline treatments in DLBCL, did not clearly correlate with complete response rate, progression-free survival or overall survival in our study. This could be due to the small number of patients in the high or high-intermediate IPI risk category. Furthermore, the majority of our patients had PMBCL and the utility of the IPI has some limitations as most patients are young and present with limited stage disease. For our ancillary studies, we planned an analysis of CD30 expression by immunohistochemistry and correlation with outcomes as there is controversy over the impact of CD30 status on the efficacy of BV.33,36,37 However, this proved difficult because of the very low number of relapses and heterogeneity of CD30 staining patterns in neoplastic cells (Figure 3). Additional studies beyond a simple determination of the percentage of CD30+ cells by immunohistochemistry and visual assessment will need to be applied and other groups have attempted this with some success.37,38
Among 21 patients who had pre-treatment tissue analyzed by LymphC3x, we found that there was discordance between the protocol-specified standard clinicopathological diagnosis of PMBCL and the gene expression- based method. These findings are thought-provoking since, in small trials of PMBCL, even a few misclassified patients may have a great impact on interpretation of the results. We believe that developing objective diagnostic criteria based on quantitative methods, such as gene expression signatures, will be an important step in designing treatment strategies for B-cell lymphoma patients with mediastinal lesions and for comparing results across PMBCL trials.
This trial is limited by the small number of evaluable patients and diagnostic heterogeneity. However, the entities included are rare, and we involved three institutions to enroll 32 patients. One of the challenges when interpreting the clinical efficacy and progression-free/overall survival data of patients treated with the BV-R-CHP regimen is the fact that consolidative radiation was used in about 50% of all patients enrolled on this trial. The protocol was designed in 2011-2012 when R-CHOP followed by consolidative radiation therapy was utilized by most centers for PMBCL patients. Therefore, the protocol allowed investigators to use consolidative radiotherapy after completion of BV-R-CHP. It is important to note that the end-of-treatment response assessment was performed before radiation. Interestingly, there were no statistically significant differences in progression-free or overall survival between patients who received consolidative radiation and those who did not. There were no clear differences in patients’ characteristics between those who received consolidative radiotherapy and those who did not other than institutional practice differences. Of the four patients who did not achieve metabolic complete response on end-of-treatment imaging, two received consolidative radiation therapy and two did not. Longer follow-up will be necessary to determine whether there are any long-term toxicities of radiation in the study participants (with the majority of patients having received proton radiation). Of note, an ongoing randomized trial in patients with PMBCL may allow us to determine whether consolidative radiation therapy after frontline chemoimmunotherapy is necessary in patients who achieve metabolic complete response after systemic treatment (ClinicalTrial.gov identifier: NCT01599559).
BV in combination with R-CHP with or without consolidative radiation therapy is a feasible and active frontline treatment in patients with CD30+ B-cell lymphomas. The safety profile of this regimen, ease of administration and preliminary efficacy data appear promising. The next generation of trials in CD30+ B-cell lymphomas and PMBCL should take into consideration the clinical and biological heterogeneity of these lymphomas. Ultimately, developing treatment regimens that will be tailored to unique tumor and patient characteristics will result in improved outcomes and will minimize treatment-related toxicities. | ORAL OR EQUIVALENT IV DOSE IN A CYCLE OF 21 DAYS; 100MG OR EQUIVALENT DOSE DAILY | DrugDosageText | CC BY-NC | 32414850 | 19,809,418 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | BISOPROLOL, DIAMORPHINE, FUROSEMIDE | DrugsGivenReaction | CC BY-NC | 32434290 | 20,992,015 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | BISOPROLOL, DIAMORPHINE, FUROSEMIDE | DrugsGivenReaction | CC BY-NC | 32434290 | 20,992,015 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Low birth weight baby'. | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | BISOPROLOL, BUPIVACAINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, DIAMORPHINE, FUROSEMIDE, MAGNESIUM, OXYTOCIN, PHENYLEPHRINE HYDROCHLORIDE, POTASSIUM CHLORIDE, ROPIVACAINE, TINZAPARIN | DrugsGivenReaction | CC BY-NC | 32434290 | 20,960,163 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | BISOPROLOL, BUPIVACAINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, DIAMORPHINE, FUROSEMIDE, MAGNESIUM, OXYTOCIN, PHENYLEPHRINE HYDROCHLORIDE, POTASSIUM CHLORIDE, ROPIVACAINE, TINZAPARIN | DrugsGivenReaction | CC BY-NC | 32434290 | 20,945,322 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | BISOPROLOL, BUPIVACAINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, DIAMORPHINE, FUROSEMIDE, MAGNESIUM, OXYTOCIN, PHENYLEPHRINE HYDROCHLORIDE, POTASSIUM CHLORIDE, ROPIVACAINE, TINZAPARIN | DrugsGivenReaction | CC BY-NC | 32434290 | 20,945,322 | 2021-08 |
What was the administration route of drug 'CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE'? | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | Transplacental | DrugAdministrationRoute | CC BY-NC | 32434290 | 20,960,163 | 2021-08 |
What was the administration route of drug 'ROPIVACAINE'? | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | Transplacental | DrugAdministrationRoute | CC BY-NC | 32434290 | 20,960,163 | 2021-08 |
What was the dosage of drug 'MAGNESIUM'? | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | MATERNAL EXPOSURE DURING PREGNANCY: UNK | DrugDosageText | CC BY-NC | 32434290 | 20,960,163 | 2021-08 |
What was the dosage of drug 'POTASSIUM CHLORIDE'? | Anesthetic management of a parturient with Shone's syndrome -a case report with review of literature.
Shone's syndrome is a rare complex congenital cardiac condition, characterized by a supra-valvular mitral ring, parachute deformity of the mitral valve, aortic stenosis, and coarctation of the aorta.
A 26-year-old parturient with partial Shone's syndrome presented to our delivery unit in pulmonary edema. She underwent a scheduled cesarean section performed under a combined spinal-epidural anesthetic at 33 weeks. She had multidisciplinary input from the cardiac, obstetric, and anesthetic teams, which led to a good outcome. A review of the five published case reports of Shone's syndrome in pregnancy is presented along with key findings.
Our case report and the review highlight the successful use of combined spinal-epidural anesthetic and provides guidance to the multidisciplinary team on the varied presentation and the optimum management of women with Shone's syndrome during the peripartum period.
Heart disease remains one of the most common causes of maternal mortality. Shone’s syndrome (SS) was first described in 1963 by John Shone – a pediatric cardiologist [1]. It is characterized by:
1) Left ventricular (LV) inflow tract obstruction in the form of a supra-valvular mitral valve (MV) ring or a parachute MV
2) LV outflow tract obstruction in the form of aortic stenosis (AS), which may be supra-valvular, valvular with a bicuspid aortic valve (BAV), or sub-valvular
3) Aortic abnormalities in the form of hypoplasia of the aortic arch or coarctation of aorta (Co-A).
The lesions encountered in SS are represented in Fig. 1.
It has an incidence of 0.67% in adults with congenital heart disease and the most common lesions seen in this syndrome are congenital MV stenosis (93%), Co-A (75%), and AS (71%) [2]. It can exist in a complete form (all lesions present), or more frequently in a partial or incomplete form (LV inflow obstruction and any one of the other abnormalities) [2]. The syndrome is extremely rare in pregnancy. We describe our anesthetic management for a parturient with repaired but with residual SS who underwent an uneventful Cesarean section (C-section).
Case Report
Written informed consent was obtained from the patient. A 26-year-old primigravida with a body mass index (BMI) of 25.71 kg/m2 (weight 70 kg, height 165 cm) presented to our delivery suite in Manchester at 32-weeks with a 2-week history of dyspnea on exertion, orthopnea, and palpitations. She was known to have SS. Her syndrome consisted of a supra-valvular mitral ring, a parachute MV, mild LV outflow tract obstruction with Co-A, and a BAV. The mitral ring, LV outflow tract obstruction, and the Co-A were repaired at the age of three by open heart surgery, which was followed by a dual chamber pacemaker insertion for complete heart block. The BAV and the parachute MV were not repaired. This was followed by balloon dilatation of the aorta for re-coarctation at the age of 12. She remained asymptomatic following this till the end of the second trimester of pregnancy.
On presentation to our unit, she had a heart rate (HR) of 100 beats/min, blood pressure (BP) of 136/88 mmHg, respiratory rate (RR) of 28 breaths/min with oxygen saturations (SpO2) 90–92% on room air. Auscultation revealed bilateral crepitations along with a mid-diastolic murmur and a diagnosis of acute pulmonary edema was made. Arterial blood gas (ABG) revealed a pH – 7.48, partial pressure of carbon dioxide (pCO2) – 23.5 mmHg, partial pressure of oxygen (pO2) – 90.76 mmHg, base excess of 4 mmol/L with a lactate of 3 mmol/L. Her hemoglobin was 12.2 g/dl, serum potassium (K+) was 3.6 mmol/L, and serum magnesium (Mg+) was 0.65 mmol/L. Her N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels were 1,020 pg/ml. Her chest X-ray was suggestive of pulmonary edema and electrocardiogram (ECG) showed a sinus tachycardia with P mitrale.
She was transferred to the coronary care unit and the treatment instituted included oxygen, intravenous (IV) furosemide 20 mg, 5 mg of IV diamorphine, and oral bisoprolol 2.5 mg. Fluid balance was monitored using strict input and output monitoring with a urinary catheter, and oral potassium chloride and IV magnesium were supplemented to maintain K+ > 4 mmol/L and Mg+2 > 0.7 mmol/L.
Pacemaker check revealed an appropriately functioning dual chamber DDD device. Cardiotocography as part of fetal monitoring revealed a normal trace. A trans-thoracic echocardiogram (TTE) revealed:
1) A BAV with mild AS with a velocity of 2.5 m/s across the valve and a mean gradient of 25 mmHg
2) A normal LV size (LV diastolic diameter of 4.4 cm), with an ejection fraction of 48%, with mildly impaired systolic function
3) Parachute MV with chordal attachment to single papillary muscle, MV area of 1.12 m2, mean gradient of 8 mmHg across MV, moderate MV stenosis with mild-moderate regurgitation
4) Severely dilated left atrium (LA-volume/body surface area of 49 ml/m2)
5) A normal aortic root, with a normally functioning repair (velocity across the aorta was 2.4 m/s) with no diastolic tail
6) A mildly dilated well-functioning right ventricle (base RV of 4.3 cm and mid RV of 3.8 cm with preserved RV fractional area of change > 40%), mild tricuspid regurgitation (vena contracta width of 3 mm, max velocity of 3.4 m/s) with estimated mean pulmonary artery (PA) pressure of 56 mmHg with a moderately dilated right atrial volume of 67 ml.
Her case was discussed at the multi-disciplinary cardiology, obstetric, anesthetic team meeting. In view of her on-going symptoms, limited mobility, and detection of a severely dilated LA and raised PA pressure on TTE, the team decided to administer tinzaparin 4500 IU subcutaneously for thromboprophylaxis.
Despite medical management for the next 72 h, she complained of dyspnea on minimal exertion. She required 2 L of oxygen to maintain saturations of 97% (94% on air) but was able to lie almost flat without significant difficulty. A repeat ABG on oxygen, revealed a pH – 7.42, pCO2 – 30.5 mmHg, pO2 – 93.33 mmHg, base excess of 2 mmol/L with a lactate of 1.6 mmol/L. As thromboembolism remains one of the most common direct causes of death in pregnancy in the United Kingdom (UK), on a risk-benefit basis, based on her symptoms and dependence on oxygen, the team decided to rule out pulmonary embolism (PE) with a computerized tomography with pulmonary angiography (CTPA), which was reported back as normal.
In view of her symptoms and significant pulmonary hypertension, a decision was made to deliver her by category (Cat) 3 C-section in accordance with The Royal College of Obstetricians and Gynaecologists’ guidelines for classification of urgency of C-section (Cat 1: Immediate threat to life of woman or fetus, Cat 2: Maternal or fetal compromise, which is not immediately life-threatening, Cat 3: Needing early delivery but no maternal or fetal compromise, Cat 4: At a time to suit the woman and maternity team). Maternal steroids were administered to accelerate fetal lung maturity. After discussion with the patient of the potential risks and benefits of general anesthesia (GA) compared with neuraxial anesthesia, it was decided to perform the surgery under combined spinal-epidural (CSE) anesthesia. The decision process incorporated the patient’s preference to stay awake and witness the delivery of her baby along with partner in the operating theatre.
In theatre, a 16 gauge (G) peripheral cannula was inserted and the patient had ECG, SpO2, and invasive BP monitoring was established in theatre via a radial artery catheter. Baseline HR was 86 beats/min and BP was 100/58 mmHg. A 12-h interval between the last dose of prophylactic tinzaparin and administration of CSE anesthetic was followed in accordance with The European Society of Anesthesiology guidance [3]. CTG was monitored during and after the CSE insertion and was normal at all times.
With the patient in the sitting position, using an aseptic technique, the epidural space initially was detected with a 16 G Tuohy needle using a loss-of-resistance to saline technique at the L3–4 intervertebral space and an epidural catheter threaded into the epidural space. A test dose of 5 ml of 0.1% bupivacaine was given to rule out intrathecal catheter placement. This was followed by a subarachnoid injection at L4–5 interspace of 7.5 mg of hyperbaric bupivacaine and 300 ug diamorphine with a 25 G pencil point needle. The patient was positioned supine with left uterine displacement and 500 ml of compound sodium lactate (CSL) solution commenced along with a phenylephrine infusion 100 μg/ml at the rate of 30 ml/h. Within 12 min, a bilateral block to cold up to T8 to S5 dermatomes was established. To augment the block height, 5 ml of 0.75% ropivacaine was administered via the epidural catheter. Once the block height to T4 dermatome with cold spray was confirmed, C-section was commenced, and a female infant weighing 2.3 kg was delivered. APGAR scores of 5 at 1 min and 8 at 5 min were recorded. Oxytocin 5 IU was given as an IV infusion over 20 min to avoid tachycardia and hypotension. Pacemaker was kept on throughout the C-section. Patient was hemodynamically stable throughout, blood loss recorded during the C-section was 700 ml, and the procedure was completed uneventfully in 45 min. The phenylephrine infusion was weaned off gradually. Her epidural was removed at the end of the surgery to facilitate thromboprophylaxis following C-section. Tinzaparin 4,500 IU was administered subcutaneously 4 h after removal of epidural and continued for 10 days post-operatively. She stayed in our cardiac intensive care unit for 24 h, then stepped down to our obstetric high dependency unit over the next 48 h, and was discharged uneventfully from the hospital on the 7th post-operative day.
Discussion
To our knowledge, this is one of the first case report, highlighting the successful use of CSE in a parturient with SS. Considering that SS is a fixed cardiac output lesion, the physiological changes of pregnancy, including a 25% increase in HR, a 25% drop in systemic vascular resistance (SVR), a 40% increase in cardiac output, anemia, and a 25% increase in oxygen demand are poorly tolerated [4]. Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema are common presentations in SS when the MV stenosis is prominent, suggestive of heart failure or new onset arrhythmia. These were seen at 32 weeks in our parturient when the cardiac output peaks in pregnancy. On echocardiography, our patient had moderate MV stenosis, mild AS with a BAV, pulmonary hypertension, and a normal aorta. Appropriate medical therapy was instituted, and we ruled out PE with a CTPA in view of our patient’s persistent dyspnea.
The obstetric, cardiology, anesthetic as well as the neonatal teams were involved early in our case so as to plan the mode of delivery, analgesia, anesthesia, and post-partum care in accordance with the National Institute of Health Care and Excellence and the European Society of Cardiology guidelines [5,6]. Our team made the decision of delivering our patient with a C-section at 33 weeks in view of her persistent dyspnea, oxygen requirements, and significant pulmonary hypertension.
The optimal choice of analgesic and anesthetic technique for delivery in a patient with SS where MV stenosis as well as AS is predominant lesion should encompass the following goals:
1) Optimum analgesia
2) A slow HR to decrease oxygen demand and increase diastolic filling time
3) Maintain sinus rhythm
4) Avoiding fall in SVR and maintaining contractility
5) Avoiding any increase in pulmonary vascular resistance (PVR), (hypoxia, hypercarbia, acidosis, hypothermia, high positive end-expiratory pressure)
6) Avoidance of Valsalva maneuver and shortening the second stage of labor
7) Avoiding fluid overload, aortocaval compression, and maintaining euvolemic status and if coarctation exists, avoid swings in BP and hypertension.
Neuraxial anesthesia for C-section in fixed cardiac output lesions though may result in a drop in SVR, but when titrated appropriately with a suitable vasopressor, might be a technique of choice in these cases and has been reported in AS and MV stenosis [7,8]. We opted for a CSE technique as it allowed us to place a small intrathecal dose of local anesthetic along with an opioid to initiate the block, the final height of which could then be titrated using the epidural top up. The low dose of local anesthetic in CSE provided us with a good quality of block, avoided the sudden hypotension, and the intrathecal diamorphine added to the local anesthetic contributed to good post-operative pain relief. A CSE technique with separate needle and separate interspaces was utilized in our case as it allowed us to test the epidural catheter before placement of intrathecal drug. After intrathecal local anesthetic with opioid achieved a block of T8, we topped up our epidural catheter with ropivacaine to augment block height to T4 dermatome, which allowed the surgery to be carried out uneventfully. BP was maintained in our case by using phenylephrine infusion, which is the vasopressor of choice in obstetric anesthesia. It also avoids tachycardia and maintains SVR, which was advantageous in SS.
Other options for neuraxial anesthesia include using:
1) A de novo spinal anesthetic (SA), which could lead to a dramatic drop in SVR with an unpredictable spread
2) A continuous SA using an intrathecal catheter, which we were unfamiliar with
3) A de novo epidural technique, which is associated with incomplete sensory and motor block, and conversion to GA.
We avoided a GA as our patient was keen to stay awake during the C-section. GA has the advantage of secure airway and the ability to perform a real time transesophageal echocardiography but also has the disadvantages of sympathetic stimulation associated with laryngoscopy, positive pressure ventilation, and increasing PVR thus decreasing venous return, as well as the known obstetric risks of difficult intubation, aspiration, and awareness.
We chose IBP monitoring in our case using an arterial line to facilitate beat-to-beat BP monitoring and blood gas analysis as our patient was dependent on oxygen. Central venous access was not thought to be necessary as we were mindful of the possible risk of inducing an arrhythmia. Oxytocin was given as a slow infusion to avoid tachycardia and hypotension and fluid neutral balance was maintained replacing blood loss with CSL. Though our neonate was premature, a good neonatal outcome was reported in our case.
We present a systematic review of all the published case reports of SS over the last two decades. Using the NICE Healthcare Databases’ advanced search engine, a search of the Medline, CINAHL, and EMBASE databases from January 1, 2000 to December 31, 2019 was conducted in January 2020. The following search terms were used in the search strategy: Shone’s syndrome OR Shone’s complex OR Shone’s anomaly AND Obstetric OR Pregnant OR Labor OR Cesarean. The search was limited to humans, and to case reports written and published in English. All articles generated had their reference lists and citations hand-checked by the authors and any additional articles were scrutinized. Full text articles were included in the analysis if they confirmed the diagnosis of SS and described the mode of delivery. Information extracted from the case reports included age, parity, BMI, mode of delivery, weeks of gestation, clinical presentation, echocardiographic findings, anesthesia details, and neonatal outcomes.
Results
We found five published case reports of SS in pregnancy since the year 2000 [9–13]. Their demographics, initial presentation to the delivery unit, echocardiogram findings, maternal, and neonatal outcomes along with their anesthetic management are presented in Table 1.
Mean age of women in the literature review was 22.6 years, mean BMI was 26.3 kg/m2, and three of the five women (60%) were primiparous [10,11,13]. All the published case reports in our review had a partial or incomplete form of SS (100%) with two of the five women (40 %) having some form of surgical correction in childhood [12,13].
Clinical presentation
Dyspnea on exertion, orthopnea, palpitations, and pulmonary edema were the presenting symptoms in three case reports (60%) [10,11,13]. Beta blockers and diuretics were commonly utilized in these cases.
Women can also present with systemic hypertension where Co-A features in SS prominently. In three of the case reports (60%), the reported BP on presentation was greater than 140/90 mmHg [9,10,13]. These patients may be mistakenly diagnosed with pre-eclampsia but absence of proteinuria, a normal urinary:protein creatinine ratio, and use of biomarkers such as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an anti-angiogenic factor)/PlGF (placental growth factor; an angiogenic factor) might provide clues to the obstetric team in ruling out pre-eclampsia [14].
Echocardiography findings
In the five case reports described in our review:
1) MV: Parachute MV was seen in one woman (20%) [12]. Dysplastic MV leaflets were observed in one case (20%) and mild MV stenosis seen in one (20%) woman [9,11]. Supra-valvular mitral ring was seen in one of the women (20%) [10]. Valve area varied between 1.2 and 2.17 m2 and gradient across MV varied between 14 and 22 mmHg [10,12,13]. Overall, MV stenosis was found in three of the five case reports (60%).
2) Aortic valve: BAV with AS was seen in three of the five case reports (60%). Three women had AS with peak gradients varying from 35 to 80 mmHg with one patient having mild AS [9,11,13]. Subaortic membrane was resected (40%) in two cases [12,13] with the aortic valve being normal (40%) in two [10,12].
3) Co-A: Two of the women had Co-A at the time of C-section (40%) with gradients varying from 37 to 70 mmHg [10,13]. One woman had proximal aortic aneurysm (20%) and one had a normal (20%) aorta [9,11]. Two of the women had Co-A repaired (40%) during childhood [12,13].
The echocardiographic findings in the review highlight that MV stenosis along with BAV seems to be the most common findings in SS in pregnancy. It is important that if MV stenosis of non-rheumatic origin or a parachute MV is noted on the echocardiogram, the cardiology team should look out for other lesions to confirm the diagnosis of SS.
Multidisciplinary input
Of the five case reports two of them (40%) had multidisciplinary input in them [12,13]. Multidisciplinary input by the obstetric cardiac team is recommended for heart disease in pregnancy as per the European Society of Cardiology guidance [6].
Mode of delivery
This will be dictated by a number of factors including both obstetric as well as cardiac. In women with severe cardiac lesions, significant pulmonary hypertension, heart failure, and a dilated aortic root, a C-section might be the preferable mode in line with the European Society of Cardiology recommendations [6]. Vaginal delivery (20%) was reported in just one of the case reports with SS [10]. C-section (80%) was reported in four other cases [9,11–13].
Anesthesia and analgesia
Three of the five cases (60%) having C-section described the anesthetic management in detail [9,11,13]. Use of de novo epidural anesthesia was reported in two cases [11,13]. One proceeded uneventfully; the other case resulted in significant hypotension, fetal distress, and a conversion to an unplanned GA [11]. Thiopentone and suxamethonium were utilized in that case. Planned GA was administered using etomidate, propofol target-controlled infusion, remifentanil, and rocuronium in one case to manage a SS lady who also had an ascending aortic aneurysm, which was being repaired at the time of CS [9]. No analgesia was utilized in the case of the woman having a vaginal delivery [10]. If choosing a GA technique, a rocuronium-sugammadex combination for muscle relaxant and a reversal might avoid the tachycardia seen with glycopyrrolate and neostigmine and might be advantageous in this cohort.
Blood pressure management and monitoring
Phenylephrine was used in two (40%) of the five case reports [11,13]. Ephedrine should be avoided in this cohort. Arterial line monitoring was utilized in three (60%) of the five reports [9,10,13]. Central venous access was utilized in two (40%) of the case reports [9,13]. Though fluid was administered in one case report using the central venous pressure (CVP) monitor, we are unsure in a patient with valvular stenosis how reliable CVP monitoring would be to guide fluid replacement.
In women presenting with active Co-A, the post ductal BP is more suggestive of uterine perfusion. BP should be maintained to avoid compromising utero-placental blood flow and systemic hypertension [15].
Oxytocic
Two of the five case reports (40%) describe the use of oxytocin infusion to maintain uterine tone [9,13]. Regarding oxytocic agents, it is best to avoid ergometrine in SS as it does cause hypertension with tachycardia and prostaglandin F2 alpha in the presence of pulmonary hypertension as it can increase PVR. The cardiac output does peak again post-delivery and these patients are at risk of pulmonary edema following delivery; hence fluid should be administered cautiously aiming for a neutral fluid balance.
Neonatal outcomes
Preterm (gestational age < 37 weeks) birth was reported in two of the five case reports (60%) as was seen in our case as well [9,13]. Mean gestational age at the time of delivery was 35.75 weeks on our review. Three of the other case reports described normal APGAR scores (60%) with mostly good outcomes [10,11,13]. In one of the case reports where GA was administered, the neonate was intubated (20%) and ventilated [9].
The information detailed in the review of literature could provide useful information for the obstetric cardiac team when preconception counseling and risk-assessment are undertaken in women with SS. Based on the review of the literature, we provide a summary of recommendations, which could be utilized by the multidisciplinary cardiac, obstetric, anesthetic, and neonatal team when they encounter a parturient with SS (Table 2).
Limitations of our review include limited number of patients, some information that was missing in the case reports, and it being limited to only the last two decades. There is also a possibility that we might have missed case reports in other languages as the literature review was limited to case reports in English.
In conclusion, our case report along with the review of literature raises awareness about this condition, highlights the safe use of CSE anesthesia, and provides guidance to the multidisciplinary obstetric, cardiac, anesthetic, and neonatal team on the varied presentation and the optimum management of women with SS during the peripartum period.
Fig. 1. Shone’s syndrome and various lesions affecting the left ventricular (LV) inlet and LV outlet. Reproduced from Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? Can J Cardiol 2017; 33: 214-5. Opotowsky AR, Webb G with permission from Elsevier.
Table 1. Published Case Reports of Parturients with Shone’s Syndrome
Maternal demographics and outcomes Koelble et al. [9] 2001 Goswami et al. [10] 2003 Sachse et al. [11] 2008 Purvis and Sharma [12] 2010 Naz et al. [13] 2016
Maternal age (yr) 29 15 17 26 26
BMI (kg/m2) 29.2 Not reported 23.6 Not reported 27.1
Parity 1 0 0 Not reported 0
Gestation (weeks) 31 37 39 Not reported 36
Presentation Raised BP Orthopnea, hypertension, pulmonary edema Orthopnea, palpitations, fatigue Not reported Dyspnea
Baseline BP mmHg 145/90 152/98 103/51 Not reported 140/96
Aortic valve Bicuspid mean ΔP 35 mmHg Normal Bicuspid mild AS Normal previous resection of subaortic membrane Bicuspid peak ΔP 80 mmHg, previous resection of subaortic membrane
Mitral valve Dysplastic thickened leaflets Supra-valvular mitral ring Mild MS Parachute MV valve area 1.2 cm2 2.17 cm2 severe MR
ΔP 22 mmHg then decreased to 14 mmHg ΔP 21 mmHg
Aorta Aortic aneurysm Co-A of aorta mean ΔP 70 mmHg Normal Repaired Co-A Repaired Co-A
Proximal aorta Re-Co-A descending aorta
ΔP 37 mmHg
Other findings LA dilation 65 mm PAP – 50 mmHg LV outflow tract obstruction LV hypertrophy subaortic membrane
Mode of delivery Cesarean Vaginal Cesarean Cesarean Cesarean
Invasive monitoring Arterial and CVP Arterial None initially Not reported Arterial and CVP
Anesthesia/Analgesia General None Epidural with conversion to general Not reported Epidural
APGAR Score 1 min – 4 Normal 1 min – 9 Not reported 1 min – 9
10 min – 6 5 min – 9
ΔP: pressure gradient; AS: aortic stenosis; MV: mitral valve; MR: mitral regurgitation, LV: left ventricle, MS: mitral Stenosis, LA: left atrium, RV: right ventricle, Co-A: coarctation of aorta, PAP: pulmonary artery systolic pressure, CVP: central venous pressure, BMI: body mass index.
Table 2. Summary of Peripartum Recommendations for Women with Shone’s Syndrome (SS)
1. Pre-pregnancy counseling should be provided to all women with SS.
2. All women during the antepartum period should be looked after by a multidisciplinary obstetric, cardiac, anesthetic, and neonatal team.
3. Serial monitoring of maternal signs and symptoms include dyspnea, orthopnea, and/or hypertension that should be looked out for along with serial echocardiograms and managed with appropriate medications including beta blockers, diuretics, and anti-hypertensive agents depending on the lesion.
4. Individualized care plans regarding mode of delivery tailored to the woman depending on obstetric and cardiac history should be formulated by the multidisciplinary team.
5. When considering vaginal delivery, a shortened second stage of labor is preferable.
6. Regional analgesia and anesthesia should be considered in women during vaginal delivery and for cesarean section provided no other contraindications exist.
7. Phenylephrine should be the vasopressor of choice and invasive blood pressure monitoring should be considered in women with severe obstructive lesions.
8. Oxytocin should preferably be given as an infusion to maintain uterine tone following delivery.
9. All patients should have cardiac monitoring at least for 24–48 h in hospital as they will be at risk of pulmonary edema following delivery.
10. Following hospital discharge, all patients should be followed up by the obstetric cardiac team.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Kailash Bhatia (Conceptualization; Formal analysis; Supervision; Writing – review & editing)
Jennifer Eccles (Methodology; Writing – review & editing)
Dinesh Meessala (Writing – original draft) | MATERNAL EXPOSURE DURING PREGNANCY: UNK | DrugDosageText | CC BY-NC | 32434290 | 20,960,163 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,932,064 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal distress syndrome'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,962,298 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,962,298 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal growth restriction'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,932,064 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL\LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,941,910 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature baby'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,962,298 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature labour'. | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | HYDRALAZINE HYDROCHLORIDE, LABETALOL HYDROCHLORIDE, METHYLDOPA, NIFEDIPINE | DrugsGivenReaction | CC BY | 32501623 | 18,962,383 | 2021-01 |
What was the administration route of drug 'LABETALOL\LABETALOL HYDROCHLORIDE'? | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 32501623 | 18,941,910 | 2021-01 |
What was the administration route of drug 'METHYLDOPA'? | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | Transplacental | DrugAdministrationRoute | CC BY | 32501623 | 18,962,298 | 2021-01 |
What was the dosage of drug 'LABETALOL HYDROCHLORIDE'? | Subendocardial stress in pre-eclampsia.
A primigravida 26-year-old woman who had developed pre-eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST-segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic "basal septal bulge", and a left ventricular mid-cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre-eclampsia has been described in the literature.
1 CASE DESCRIPTION
A 26‐year‐old primigravida woman presented to obstetrics clinic at 30 weeks of gestation to establish prenatal care after moving to the United States from Ghana one week earlier. At that time, she complained of severe headaches and bilateral lower extremity edema. She had been prescribed methyldopa and nifedipine at the beginning of her pregnancy for hypertension, but denied a past personal or family history of cardiovascular disease. Physical examination was remarkable for a blood pressure of 216/133 mmHg and bilateral lower extremity pitting edema, and laboratory findings included an elevated serum creatinine level of 2.1 mg/dl (normal 0.5–1.39 mg/dl) with nephrotic‐range urinary protein/creatinine ratio at 11.4 (normal < 0.3), leading to a diagnosis of pre‐eclampsia with severe features. Given the presence of malignant hypertension, she was admitted to the intensive care unit. However, despite therapy with maximal doses of intravenous labetalol and hydralazine, and oral nifedipine, her blood pressure remained uncontrolled. Fetal ultrasound showed severe intrauterine growth restriction and fetal monitoring demonstrated fetal distress, manifest by a category II tracing with deep variable decelerations and periods of minimal variability. Given the high‐risk fetal tracing and maternal refractory malignant hypertension, delivery by Cesarean section was recommended, which was carried out without complications.
Two days postpartum, while blood pressure remained elevated at 191/105 mmHg, the patient became acutely diaphoretic and mildly dyspneic, but denied chest pain. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) by Sokolow‐Lyon criteria with ST‐segment depressions in leads II, III, aVF, V5, and V6 and ST‐segment elevation in lead aVR (Figure 1). Blood work was remarkable for an elevated troponin‐I level of 4.63 ng/ml (normal < 0.03 ng/ml), consistent with acute myocardial infarction (AMI). Physical examination revealed tachycardia with a regular rhythm and a III/VI holosystolic murmur heard best at the apex, without jugular venous distention or lower extremity edema. Computed tomography did not reveal any evidence of pulmonary embolism. Transthoracic echocardiography demonstrated severe LVH with a prominent bulge at the basal septum (Figure 2a), a mid‐cavitary gradient of 51 mmHg, but no segmental wall motion abnormalities. Cardiac catheterization revealed an elevated left ventricular end‐diastolic pressure (LVEDP) of 30 mmHg, an intracavitary gradient of 15 mmHg, but no coronary artery disease. Labetalol was discontinued in favor of carvedilol, which is indicated in AMI, and antihypertensive medications were increased with improvement of her blood pressure and troponin‐I levels.
Figure 1 12‐lead ECG demonstrates diffuse ST‐segment depression (arrows) with ST‐segment elevation in lead aVR (arrowheads)
Figure 2 Initial Transthoracic echocardiotraphy (a) demonstrates basal septal bulge (arrow), which resolved (b) after treatment of hypertension. RV = right ventricle, RA = right atrium. LA = left atrium. LV = left ventricle
Two months postdischarge, the patient had a repeat echocardiogram. Her blood pressure at this time was 139/105 mmHg. Moderate LVH was present; however, the intracavitary gradient and characteristic “basal septal bulge” seen on the previous echocardiogram were no longer present (Figure 2b).
2 DISCUSSION
This patient demonstrated the characteristic findings of pre‐eclampsia with severe features (Magee et al., 2014) and hypertensive emergency, both of which share the diagnostic criteria of elevated blood pressure associated with end‐organ dysfunction (Whelton et al., 2018). The patient also met the criteria for AMI, given clinical, ECG and cardiac biomarker profiles (Thygesen et al., 2018). Although AMI during pregnancy is rare, occurring at a rate of approximately 8.1 per 100,000 hospitalizations according to an analysis of a US national sample, it carries an approximately 40‐fold increase in mortality risk (Smilowitz et al., 2018).
The differential diagnosis for AMI during pregnancy includes acute atherothrombotic coronary artery disease (type 1 AMI), coronary vasospasm, spontaneous coronary artery dissection (SCAD), and type 2 AMI secondary to a mismatch in oxygen supply and demand. The presence of ST‐segment elevation in lead aVR with diffuse ST‐segment depressions has been shown to be a strong predictor of both left main and three‐vessel coronary artery disease (D'Ascenzo et al., 2012). Therefore, type 1 AMI and SCAD were prioritized in this case. The true incidence of type 1 AMI during pregnancy is unknown; however, 25% of AMI patients underwent coronary revascularization in an analysis of a US national sample (Smilowitz et al., 2018). In the same analysis, SCAD was identified in 15% of patients (Smilowitz et al., 2018), though in a previous case‐series, SCAD was found to be the leading etiology of AMI in pregnancy, comprising of 43% of patients (Elkayam et al., 2014). Clinching a diagnosis of SCAD requires a high index of suspicion and coronary angiography. It should be noted, however, that invasive coronary angiography may result in further extension of the coronary artery dissection (Hayes et al., 2018), and intervention should generally be deferred if possible. As such, given the absence of acute atherothrombotic disease and SCAD, type 2 AMI secondary to very high wall stress, augmented by the intracavitary gradient, was considered the most likely diagnosis in this patient, although coronary vasospasm cannot be definitively excluded, especially considering that endothelial dysfunction is a hallmark of pre‐eclampsia (Melchiorre, Sharma, & Thilaganathan, 2014).
In a case‐control study, women with pre‐eclampsia who had echocardiography performed showed cardiac remodeling, which included concentric LVH, diastolic dysfunction, and increased cardiac work indices (Melchiorre, Sutherland, Baltabaeva, Liberati, & Thilaganathan, 2011). Mid‐cavitary obstruction can be seen in a subgroup of patients with hypertrophic cardiomyopathy and may be observed with concomitant apical aneurysm, which was absent in our patient (Efthimiadis et al., 2013). Our patient's echocardiogram also showed focal, basal septal hypertrophy, described as a characteristic “basal septal bulge,” similar in appearance to the “sigmoid septum” that is often seen in the elderly, and can confound the diagnosis of hypertrophic cardiomyopathy (Canepa et al., 2016). However, this finding has also been described in patients with pre‐eclampsia (Melchiorre et al., 2011). Increased left ventricular wall thickness is an adaptive response, aiming to reduce wall stress, which can result in increased LVEDP, which in turn can reduce coronary perfusion pressure.
Coronary artery perfusion pressure (CPP) is the difference between aortic diastolic blood pressure and LVEDP. Normally, CPP is auto‐regulated between approximately 60 and 180 mmHg. However, patients with LVH have been shown to require higher blood pressures to maintain adequate CPP (Cruickshank, 1992). Left heart catheterization in our patient revealed a CPP of 52 mmHg, which may have been inadequate to perfuse the subendocardial tissue, thus resulting in subendocardial ischemia, which would not be expected to result in segmental wall motion abnormalities. Therefore, we contend that the etiology of AMI in our patient was subendocardial ischemia due to increased oxygen demand in the context of severe LVH and very high afterload from malignant hypertension, coupled with reduced coronary artery perfusion pressure secondary to left ventricular outflow tract (LVOT) obstruction and malignant hypertension, both of which increase LVEDP.
Aggressive blood pressure control is the mainstay of treatment in hypertensive crises and pre‐eclampsia. However, in rare cases of LVOT obstruction, CPP may be further diminished. Reducing chronotropy is critical in such cases as increasing the duration of diastole and reducing LVEDP can lead to improved CPP. First‐line treatment in hypertensive crises of pregnancy include labetalol, methyldopa, and nifedipine, with hydralazine used as a second‐line agent (Regitz‐Zagrosek et al., 2018). While labetalol is the preferred beta‐antagonist in pregnancy, its beta‐antagonistic activity on reducing chronotropy is minimal (MacCarthy & Bloomfield, 1983) and it has not been utilized in the setting of AMI. Beta‐antagonists carry the risk of causing intrauterine growth restriction (IUGR); however, its use in pregnancy is warranted if the benefits outweigh the risks. In such cases, beta‐1‐selective antagonists such as metoprolol and bisoprolol are preferred, while atenolol should be avoided (Regitz‐Zagrosek et al., 2018). Nonselective beta‐antagonists should generally be avoided, however, carvedilol may be an acceptable agent since a small retrospective study showed that pregnant women receiving carvedilol displayed no IUGR (Tanaka et al., 2016).
To our knowledge, this is only the second report of peripartum AMI associated with LVH and the previously reported, “basal septal bulge.” In the first published such case report, the patient was found to have a gene mutation associate with hypertrophic cardiomyopathy (Singla, Lipshultz, & Fisher, 2011). Our case highlights the maladaptive cardiac remodeling that occurs with pre‐eclampsia, which may predispose such patient to AMI via a unique, nonthrombotic mechanism. Specifically, this highlights the potential synergistic impact of LVH and LVOT obstruction, which in extreme cases, can result in subendocardial injury. In addition, presence of the characteristic “basal septal bulge” on echocardiography during the peripartum period, and its absence on follow‐up echocardiography, suggests that this may be a reversible finding in pre‐eclampsia.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTION
Reviewed and approved the report: all authors; Wrote the main manuscript: Tran, Krantz, Farasat; Directed the report: Krantz; Collected data: Tran; Gave suggestions on the report: Farasat; Statistical analysis: NA.
ETHICS
The report was conducted in accordance with the declaration of Helsinki and in accordance with the Colorado Multiple Institutional Review Board policies. | MAXIMAL DOSES | DrugDosageText | CC BY | 32501623 | 18,932,064 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Athetosis'. | Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.
OBJECTIVE
The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms.
RESULTS
Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive.
CONCLUSIONS
ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.
Case report
Seven years ago, a 57-year-old woman with a family history of Huntington's disease presented with depression, changes in personality, apathy, anxiety, poor memory and clumsiness. Her genetics confirmed Huntington's disease, with a CAG repeat number of 17/46. Over the subsequent 4 years, her condition was marked by psychiatric symptoms and mild chorea, which responded well to tetrabenazine 25 mg once daily, reaching 25 mg twice daily by 2014. Her mood was controlled with citalopram followed by sertraline. Her main complaints were bouts of introversion and tearfulness, but she remained socially engaged with friends. By early 2015, her swallowing had ostensibly become problematic. However, a speech and language assessment and a gastroscopy determined that her swallowing was normal. By spring 2016, she was starting to fall often, with worsening athetoid movements and increased somnolence. These changes led to a switch in medication to olanzapine at 15 mg per day and an increase in her dose of sertraline to 100 mg a day.
By summer of 2017, her choreoathetoid movements had worsened and were accompanied by weight loss and a deterioration in her mood. She required a short in-patient stay for fluids via a nasogastric tube. A psychiatric review diagnosed her with a depressive psychosis with retarded affect, mood-congruent delusions and auditory command hallucinations. She believed she did not deserve to eat and drink, and the command hallucinations ordered her not to do so. She had extracampine hallucinations, sensing people at the end of her garden. In light of her clinical state of emaciation and the requirement for support, a trial of bilateral electroconvulsive therapy (ECT) was suggested for her depressive psychosis. A twice-weekly regimen was started, with the aim of optimising seizure length to between 30 and 60 s. In winter of 2017, she received an initial 12 courses of biweekly bilateral ECT treatments using between 75 and 150 mC. Her initial response was favourable and she became euthymic, with remission of her psychomotor retardation, but her psychotic symptoms persisted in the form of command hallucinations despite developing insight. Her delusion of guilt also resolved and, by the tenth dose of ECT, she started to eat and drink again. The initial course of treatment was complete by early February 2018 and, with the exception of her hallucinations, her psychiatric symptoms ceased and insight was retained.
However, the persistence of psychotic symptoms in the absence of a significant mood component led to an additional 12 sessions of bilateral ECT (administered biweekly with 150–225 mC; maintenance treatment consisting of bilateral 150–300 mC treatment biweekly continued into late 2019) with the aim of eradicating the hallucinations. She then developed a respiratory tract infection, which led to a relapse in her psychiatric symptoms with agitation, hallucinations, and marked choreoathetosis and dyskinesia that led to the reintroduction of tetrabenazine. Despite this setback, she did improve following the last 12 doses of ECT. This course was completed in late spring 2019. She was kept on maintenance ECT once per week, with partial remission of the auditory hallucinations, which had reduced in frequency and no longer distressed her. There was a subsequent increase in the frequency of the hallucinations, with preservation of insight, and a corresponding reduction in ECT to fortnightly. She has remained stable on this regimen to date. Her involuntary movements have also improved over that time, although she remains on tetrabenazine, haloperidol and sertraline.
Method
A literature search of PubMed for ‘Electroconvulsive therapy and Huntington's’ and ‘ECT and Huntington's’ led to the discovery of 20 papers, 18 of which were in English. Six publications were based on in vitro studies and animal studies, leaving 12 publications for review. A further three papers that were not listed in the PubMed search were sourced from references in papers from earlier years. All publications were either single-case reports or retrospective case series; there were no randomised controlled trials or prospective studies.
Consent for publication
Signed informed consent was obtained from the patient described in our case report.
Results
Table 1 shows a breakdown by demographic and disease characteristics of the 37 patients described in 15 studies. Tables 2–5 summarise the predominant psychiatric complaints, the effects of ECT on the number of medications used during ECT treatment, the CAG copy number, ECT treatment and seizure duration. Supplementary Table 1 (available online at https://doi.org/10.1192/bjb.2020.51) summarises individual patient details from the literature, including our aforementioned case. Table 1 Summary of patient characteristics and ECT treatment
Characteristic Median
Sex 43% female (7 N/A)
Age at presentation 20–65 47
Length of psychiatric symptoms (years) 0–22 2.5
Time from diagnosis to ECT (years) 0–17 3
Number of courses of ECT 3–41 8
Seizure duration (s) 5–120 40
Dose delivered (mC) 25–504 –
Lead position (out of 22 documented) 54% right unilateral
N/A, not available.
Table 2 Breakdown of main presenting symptoms
Major presenting complaint N
Depressiona 26 (18)
Choreaa 14 (1)
Suicidal ideation 13
Psychosisa 12 (6)
Dysphagia/dysarthria 10
Hallucinations 7
Aggression 6
Catatonia 4
Psychomotor retardation 4
Inappropriate sexual behaviour 2
Pain/dystonia 1
a. In total (sole reason); see text for details.
Table 3 Treatment before, during and after ECT
Study Before ECT Changes during ECT After ECT
Evans et al11 Chlorpromazine, diphenhydramine Haloperidol, trazodone Benztropine, desipramine
Ranen et al1
Patient 1 Nortriptyline Fluoxetine, lithium Desipramine
Patient 2 Nortriptyline Desipramine, haloperidol
Patient 3 Amitriptyline, carbamazepine Nortriptyline added (6 weeks) Droperidol, Chlorpromazine
Patient 4 Nortriptyline, haloperidol, carbamazepine, lorazepam (catatonia) Lithium
Lewis et al14 Haloperidol Amoxapine
Beale et al3 Haloperidol, pimozide, benztropine, diphenhydramine, Reserpine, propranolol, Diazepam (all for chorea) haloperidol, carbamazepine
Merida-Puga et al4 Risperidone, lorazepam Clozapine, olanzapine Amantadine, lorazepam, levodopa, carbidopa (catatonia)
Nakano et al5 Risperidone, olanzapine N/A
Cusin et al2
Patient 1 Clonazepam, haloperidol, levetiracetam, lorazepam, quetiapine, risperidone, tizanidine, trazodone Duloxetine
Patient 2 Chlorpromazine, citalopram, phenytoin Chlorpromazine, citalopram, lorazepam, olanzapine, phenytoin
Patient 3 Fluoxetine Aripiprazole, fluoxetine
Patient 4 Clonazepam, duloxetine, risperidone, trazodone Clonazepam, duloxetine, olanzapine, trazodone, valproic acid
Patient 5 Clonazepam, duloxetine, olanzapine, trazodone, valproic acid Clonazepam, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 6 Clozapine, duloxetine, fluoxetine, haloperidol, lamotrigine, lorazepam, methadone, milnacipran, trazodone, zolpidem Chlorpromazine, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 7 Duloxetine, olanzapine Amantadine, clonazepam, paroxetine, risperidone, sertraline, trazodone, valproic acid
Magid et al8 Olanzapine, chlorpromazine, aripiprazole, risperidone, haloperidol, fluphenazine Citalopram, mirtazapine, sertraline, trazodone Lorazepam, clonazepam, buspirone
Petit et al9 Not mentioned but patient refractory to neuroleptics, antidepressants, atypical antipsychotics and mood stabilisers Clozapine Mirtazapine
Shah et al15 Buspirone, divalproex, lorazepam, paliperidone, quetiapine, venlafaxine Quetiapine, olanzapine
Adrissi et al10
Patient 1 Nortriptyline, quetiapine, tetrabenazine Amantadine, sertraline, quetiapine
Patient 2 Haloperidol, lorazepam Lorazepam, venlafaxine
Patient 3 Amantadine, baclofen, chlorpromazine, clozapine, gabapentin, lithium Chlorpromazine, clozapine, diazepam, gabapentin
Patient 4 Bupropion, clonazepam, escitalopram, levothyroxine, lithium Bupropion, clonazepam, escitalopram, levothyroxine, trazadone
Our case Citalopram, sertraline, tetrabenazine Olanzapine Tetrabenazine, haloperidol, sertraline
N/A, not available.
Table 4 Number of trinucleotide repeats, age of diagnosis, ECT treatments and length of psychiatric symptoms prior to ECT
Cases CAG repeat copy number Age at diagnosis of Huntington's disease (years) Cumulative number of ECT treatments Psychiatric symptoms (years)
Adrissi et al10 patient 4 39 45 7 2
Petit et al9 41 59 18 20
Adrissi et al10 patient 2 42 51 27 0.5
Magid et al8 43 57 3 7
Adrissi et al10 patient 1 44 45 29 3
Nakano et al5 44 59 4 0
Lewis et al14 44 65 8 1
Merida-Puga et al4 45 26 42 5
Beale et al3 46 56 11 19
Adrissi et al10 patient 3 46 31 41 6
Our case 46 50 40 7
Table 5 ECT seizure length in seconds and treatment characteristics
Cases Seizure duration (s) Mean ECT characteristics Dose (mC)
Ranen et ala,1
Patient 1 40–120 60
Patient 2 20–50 37
Patient 3 5–35 21 70 Hz pulse width 1 s, duration 2 ms 112
Patient 4 20–55 39
Patient 5 25–45 30 (MECTA SR1)
Patient 6 40–55 46
Lewis et al14 24–140 – 90 Hz pulse width 1–1.6 ms, 33.3–57.5 J (MECTA SR1) –
Beale et al3 57–19 – (MECTA SR2) 72–233
Merida-Puga et al4 42–80 – 25% (Thymatron DGx)b 126
Cusin et al2 90 Hz pulse width 1 ms, 2–4 sc 180–360
Adrissi et al10
Patient 1 25–48 –
Patient 2 30–75 – 10–140 Hz, pulse width 0.25–1 ms, 5–50% (Thymatron IV)d 25.2–504
Patient 3 21–84 –
Patient 4 21–42 –
Evans et al11 239/6 treatments – (MECTA apparatus) –
Our case 30–60 – (Thymatron IV) 75–300
a. Double stimulus was administered in Ranen et al’s patients, but no further details were provided.
b. Assumed to be the USA version with 0.9 A and charge of 504 mC. The lowest percentage given to Merida-Puga et al’s patient was calculated according to the half-life method. While no figure was given for the lowest percentage, 25% was the maximum stated.
c. Text does not state machine used or charge or current characteristics but states 'stimulus intensities comparable to patients without HD'. 0.8 A is presumed for the purpose of calculation.
d. As per specification sheet from the manufacturer, the maximum output is 504 mC with the range calculated based on quoted percentage delivered. This machine is capable of double stimulus, but this was not mentioned in Adrissi et al's paper.
The time to ECT treatment after the diagnosis of Huntington's disease was between 0 and 17 years, with a median of 3 years and mean of 4.42 years. However, the sixth patient of Ranen et al. had previously had ECT for depression before she was diagnosed.1 The age of psychiatric symptoms at presentation for ECT varied from 0 to 22 years prior, with a median of 2.5 years and a mean of 5.73 years.
It should be noted that the diagnostic confirmation of Huntington's was solely clinical prior to 1993; however, despite the availability of genetic testing after 1993 (Huntington disease Collaborative Research Group), diagnosis only preceded presentation in this group of patients after 2013 (Cusin et al's first patient2). Prior to 2013, patients first presented on average 7.4 years before the diagnosis of Huntington's was made. After 2013, all patients with psychiatric complaints who went on to have ECT presented an average of 6.6 years after the diagnosis of Huntington's had been established. Six patients in total were diagnosed at the time of presentation, although five of them were diagnosed prior to 2013. For example, Beale et al's patient had choreiform movements (and no psychiatric manifestations) from the age of 35, but was not diagnosed until the age of 56 in 1995.3 However, this apparent lag after the introduction of genetic testing is likely to reflect the 16-year gap between Beale et al's paper in 1995 and those of Merida-Puga et al and Nakano et al in 2011 and 2013, respectively.3–5 Merida-Puga et al's patient was diagnosed following postpartum psychosis and a family history suggestive of Huntington's in her father; she went on to have ECT for catatonia. Nakano et al's patient was diagnosed owing to his brother's recent diagnosis with Huntington's at another hospital, having already received ECT for treatment-refractory psychosis.
Reason for referral for ECT
Table 2 shows a breakdown of the main characteristics of the clinical presentations; 48.6% of patients were referred for depression alone without psychotic features, and psychosis was the main cause of referral in 16%. Many of the referrals for depression alone were from some of the earliest reports, which lacked a clear description of the referral characteristics.6,7 The remainder of patients had numerous coexisting factors such as paranoia, delusions and other manifestations of psychosis, including hallucinations1,2,4,5,8–11.
Coexistent motor symptoms were present in 20 patients1–3,5,9,10,12–15 (including our case), with chorea being the most commonly used term. Involuntary movement and impaired gait were also terms used without further clarification (e.g. Cusin et al uses both terms for different patients within the same series2). Psychomotor retardation was reported in four patients1,2,10 (including our case), with one patient being described as having neurovegetative symptoms (Cusin et al,2 patient 3), and coexistent dysarthria/dysphagia in two patients. Catatonia was mentioned in four patients1,2,4 (fourth and fifth patient of series,1 postpartum4 and the second patient of series2) but was the primary focus of treatment only in Merida-Puga et al4; see Supplementary Table 1.
Effects on psychiatric symptoms
The primary reason for prescribing ECT in all but seven patients (six for psychosis and one for chorea) was depression (Table 2 and Supplementary Table 1). There were universally favourable outcomes in the use of ECT for this purpose. It was reported to be successful in most cases, and the patients who were reported to relapse did so on shorter courses of ECT.12,13 However, these were early reports, and there have been numerous subsequent reports of relatively short courses with no relapse. For example, Ranen et al's third patient, who had depression, psychosis and catatonia, only needed five ECT treatments to achieve symptom resolution.
Psychosis responded to ECT in all six patients2,4,8,11 who were reported to have it as the primary presentation, which included our case. When coexistent disease such as depression was considered, 12 patients in total had prominent psychosis, and all responded to varying degrees, including our case.1,5,9,10 Merida-Puga et al reported refractory psychosis thought to be due to use of depot dopamine antagonists, although the focus of their treatment was the refractory catatonia.4
Hallucinations, either auditory (three cases including our case),1,11,13 visual (two cases)2,10 or both visual and auditory (two cases),4,8 also responded well to treatment. The exception was Ranen et al's fourth patient, where this was unclear, although the hallucinations probably improved with the patient's other symptoms.
There were four cases of reported psychomotor retardation, including our patient1,10,12 (in addition, speech retardation was reported in Nakano et al); all were described as improved following ECT without further clarification. Benson and Blumer's first patient had a ‘temporary recovery’.
Catatonia (second and fourth patients of Ranen et al; second patient of Cusin et al1,2,4) was described in four patients and improved in all. This improvement often paralleled the response to ECT of depression, suicidality and psychosis. Two of these cases were resolved by relatively short courses of ECT (five treatments for Ranen et al's fourth patient – though their condition was, surprisingly, described as refractory – and seven treatments for Cusin et al's second patient). However, the presence of catatonia was refractory in the remaining two patients. Both Ranen et al's second patient (who relapsed repeatedly) and Merida-Puga et al's patient4 (who required withdrawal from long-acting antipsychotics) needed extended ECT courses (4 years for Ranen et al's patient but just over 3 months of an in-patient stay for the latter) to resolve the catatonia, with 35 and 42 ECT treatments, respectively. Merida-Puga et al's patient had a Busch–Francis catatonia score of 26 (total severity) on first admission, falling to 4 after a second hospital admission and discharge.
Our patient required repeated doses of ECT following a relapse of psychosis over 2 years. Eventually, she showed a partial response, with improvements in her mobility and psychomotor retardation. She started to gain weight, although her delusions persisted. Improved gait was reported in six cases, including Lewis et al and the first, fourth, fifth and sixth patients of Cusin et al, who had bilateral frontotemporal and right unilateral (RUL) placement, respectively.2,14
Disorders of eating and/or speech were mentioned for a total of ten patients. Dysphagia was mentioned in two cases (Cusin et al's2 second patient and ours) and dysarthria in another two (Cusin et al's third and sixth patients). Both dysarthria and dysphagia were reported for two patients (Cusin et al's fourth and fifth patients). For all six of these patients, their symptoms were described as resolving or dramatically improved. Refusal to eat was described in two patients (Ranen et al's second patient and Magid et al's patient1,8), while poor appetite was described in another two (Ranen et al's sixth patient and Adrissi et al's second10). Both of Ranen et al's patients were described as improved, but there was no further clarification regarding outcome for the remaining two.
Aggression,1,2,10–12,15 inappropriate sexual behaviour2,15 and agitation15 were also mentioned and described as improved.
Only two reports documented improvement using psychiatric rating scales, with the BPRS-E (Brief Psychiatric Rating Scale, Expanded) score dropping from 88 to 38 after 12 ECT sessions in Petit el al's patient, and BPRS dropping from 139 to 68 in Nakano et al's patient (the PANS (Positive and Negative Syndrome Scale) score fell from 139 to 68 in the latter).5,9 Both Beale et al and Lewis et al documented improvement in the Hamilton rating scale for depression from 36 pre-treatment to 13 post-treatment in Beale et al and 36 to 10 post-treatment in Lewis et al.3,14
Effects on motor symptoms
Chorea was mentioned in 14 cases,1–3,5,9–11,13–15 including our case (three patients of Cusin et al and two of Adrissi et al2,10). Improvement was documented in three cases (Beale et al, Petit et al and Shah et al), although five were described as showing no change (Ranen et al, Lewis et al, Nakano et al, Cusin et al's fifth patient and Adrissi et al's first patient). In two cases, chorea was described as worse (Adrissi et al's second patient and Evans et al). In the remaining four patients, no details were given, despite this symptom initially having been described as present.
Only one patient was treated with ECT specifically for chorea. This patient demonstrated improvement initially and, despite worsening, their chorea never returned to the original level and was sustained at the improved level for a year.3
Our patient showed some response with respect to the choreoathetoid movements, which had become unresponsive to tetrabenazine. The medication had been withdrawn given her depression and fears of worsening those symptoms. Olanzapine, however, did not lead to any improvement in her chorea or psychiatric symptoms. Following a favourable response of the chorea to ECT, a low dose of tetrabenazine was reintroduced with good effect and had no further influence on her mood. Her gait and mobility also improved.
The use of rating scales for motor function was mentioned in only three cases. The Unified Huntington's Disease Rating Scale (UHDRS) motor score was recorded before and after only for Adrissi et al's second patient (27/31 out of a total of 124; their first case had an initial score of 49 with no follow-up score), while Petit et al's patient's UHDRS score decreased from 47 to 37 after 12 treatments and then rose to 57 after 1 year.9,10 For most cases, there was no mention of any response, which is not surprising because this was the focus of the treatment in only one of the studies. Surprisingly, despite admitting their patient specifically for the treatment of chorea (there were no psychiatric manifestations), Beale et al used no rating scales to document improvement.3
Effects on cognition
Many of the case reports mentioned problems with cognition, but few documented it with formal scores either before or after treatment. Scores were recorded before and after treatment by Nakano et al (Mini-Mental State Examination (MMSE) 27/26), Lewis et al (MMSE 23/24) and Ranen et al (second and fourth patients; MMSE 20/30 rose to 26 by discharge in the former and was 20/30 rising to 24–26/30 (administered twice) in the latter1,5,14). Cusin et al used the Montreal Cognitive Assessment (MoCA) scale for their patients and described the scores as improved, although they did not publish the values.2
Ranen et al's third patient showed a drop in MMSE from 26/30 to 18/28, with an episode of delirium after his eighth ECT treatment. No further scores were recorded, but the patient was described as ‘not completely recovered cognitively’.1 Adrissi et al's second patient had an initial MoCA of 17/20, but no further score was documented.10
Effect on medication used
Table 3 documents the treatment at admission; changes, if any, that occurred during the course of treatment for the psychiatric manifestations of disease; and discharge medication for those patients where it was recorded.
In those patients who required a number of drugs to treat the psychiatric manifestations of Huntington's disease, implying difficulty in management, there was not necessarily a requirement for more ECT doses or prolonged ECT treatment. However, in patients with pharmacological treatment resistance and the requirement for many drugs to manage symptoms, there does appear to be scope for significant rationalisation of pharmacological therapy when ECT is used adjunctively. Beale et al's patient and Cusin et al's first and sixth patients all presented between 10.5 and 19 years after diagnosis but responded well to limited ECT treatments and were discharged on much less medication.2,3 Only Adrissi et al's third patient, Ranen et al's second patient and ours required extended ECT. It is not clear why there was resistance to conventional treatment in these cases.1,10
However, this was not a consistent outcome; for example, Cusin et al's seventh patient was discharged on more medication after ECT than prior, and Adrissi et al's third and fourth patients were discharged on a comparable number of drugs to those given on admission.2,10
Effect of CAG copy number on disease or treatment
The earliest reference to CAG copy number, and therefore genetic confirmation of the diagnosis, comes from Lewis et al in 1994 – in keeping with testing, which became available after the discovery of the trinucleotide repeat a year earlier by the Huntington Disease Collaborative Research Group. Copy numbers of trinucleotide repeats have no effect on the severity of the disease, but the age of presentation is inversely correlated with increasing copy number.16
Table 4 shows copy number, number of ECT treatments and length of psychiatric symptoms for cases where this information was documented. Although those requiring more cumulative ECT treatments may appear to be clustered with those with higher repeat copy numbers, Petit et al's and Adrissi et al's second and first patients represent evidence to the contrary.9,10 Given that there was only a difference of seven CAG repeats among the 11 patients, there appears to be no significance to this. In keeping with this, the youngest patient in the review, who at 20 years old was likely to have had genetic testing, although the results of this were not documented, responded well to ECT, with his symptoms described as resolved after only seven treatments (Cusin et al's second patient2).
ECT treatment course
Treatment courses varied between three and 42 treatments in total, with a median of eight. Relapse was mentioned in seven cases (Cusin et al's fifth and sixth patients).2,4,12,13,15 For Heathfield's patient (who had three treatments) and Benson and Blumer's patients, relapse was described in general terms, with no description of the treatment course in the latter's series.12,13 In the remaining patients, it is not clear why they relapsed, except for having received relatively short courses of between five and nine ECT treatments. Merida-Puga et al's patient had treatment-resistant catatonia exacerbated by dopamine antagonists prescribed for her psychosis; this led to relapses and an extended in-patient stay.
Most patients had treatment for up to 1 year (22 patients), although our patient has been undergoing continuing maintenance treatment at increasing intervals for more than 2 years to date. Ranen et al's second patient required treatment for 4 years and Petit et al's patient for more than 1 year.1,9 Those requiring extended treatment presumably did so because of continued symptoms1,10 (see below).
Patients who had an extended course, arbitrarily taken to be more than 20 treatments (seven patients including ours1,4,9,10), did not have different characteristics from patients with similar symptoms but much less cumulative ECT treatment. Characteristics such as the nature of symptoms, length of time from diagnosis, length of time of psychiatric symptoms, age and sex did not appear to affect the number of ECT treatments. However, refractory catatonia complicating psychosis may have been a factor in extended treatment, with Ranen et al's second patient and Merida-Puga et al's patient4 requiring 35 and 42 treatments, respectively.
The four patients who had ECT more than 10 years after diagnosis1,2 (Ranen et al's sixth, Cusin et al's first, fifth and seventh patients) also showed excellent responses to ECT with between 8 and 13 treatments.
Length of seizure in seconds
Table 5 shows the seizure duration in the cases where it was recorded.1,3,4,10,11,14 Only Beale et al mentioned a reduction in seizure time from 57 s at the beginning of treatment to 19 s by the end. This was for the sole case in which ECT was administered for chorea.3 Our patient required ongoing treatment with increasing doses of ECT, although control of delusions was eventually achieved with seizure lengths between 30 and 60 s.
Dose of ECT treatment
It was not always possible to discern the dose of treatment given, as doses were rarely documented and were not necessarily consistent with other reports.1–4,10,11,14 For example, Beale et al's patient was stated as needing 72 mC initially, rising to 233 mC, with a corresponding drop in seizure duration from 57 s initially to 19 s at the end.3 When recorded, the frequency and pulse width varied. Alternatively, descriptions of percentage of maximum charge, where stated, together with the machine used (and its specifications), allowed for calculation of this figure where it was not explicitly stated (Table 5).
There did not appear to be any factors to explain why five patients, including our patient, required higher cumulative ECT treatments (Ranen et al's second patient, Adrissi et al's first, second and third patients).1,10 More generally, most patients were started on relatively low doses of ECT and titrated as treatment progressed, though this was not always documented. Only Adrissi et al's third patient was started on maximum charge dose of 100% (504 mC) due to refractory psychosis. This was later cut down to 50% (252 mC) owing to a bout of delerium that was subsequently felt to be due to medication. The presence of catatonia in Merida-Puga et al and Ranen et al's second patient may be considered a proxy for severity, but this was not the case for the other two catatonic patients (see above). Likewise, short treatment courses were reported in the earlier studies to be more likely to lead to relapse, but this was not borne out by later studies (see above). Getting the dose and the induced seizure length right appears to take more time in the out-patient setting, as may be expected. The three intense in-patient stays for our patient, Merida-Puga et al's patient and Adrissi et al's third patient (3 months in the latter two cases) allowed this to be achieved more rapidly, but the cumulative doses were all high.4,10 Overall, there appear to be no overt factors that predict who is likely to respond quickly or otherwise, although most patients will not require extended treatment based on this review.
Lead positioning
The predominant positions were RUL in 12 patients, one RUL unilateral and bilateral (unspecified), four bilateral (one bilateral frontotemporal, three bilateral) and two bitemporal (Supplementary Table 1).
Conclusion
The diagnosis of Huntington's disease is usually preceded by psychiatric symptoms in cases where family history is absent, sometimes by years.17 However, as we found in this review, patients are now likely to have an established diagnosis of Huntington's by the time they are considered for ECT. Although a CAG repeat number greater than 36 in the Huntington gene confirms the disease, an increased number of repeats is negatively correlated with age at presentation rather than severity of disease.16
Psychiatric manifestations of Huntington's disease vary according to the stage of the disease; apathy, for example, is found in 50% of patients by stage four on the UHDRS. Also present are obsessive–compulsive behaviour, irritability and aggression. Depression also increases over time, with only psychosis remaining consistent throughout at 11%.18
The prevalence of depression is about 50%, compared with anxiety at 17–61%, irritability at 35–73%, obsessive–compulsive disorders at 7–50% and psychosis at 3–11%. The prevalence of hypersexuality is between 2.1 and 30% and is slightly lower in women, whereas the prevalence of hyposexuality is higher at 63% in men and 75% in women.19 The use of ECT, however, is recommended only for depression on the basis of two of the above series.1,14,20
There appeared to be little in the way of any effect on cognition with the use of ECT, although this was not a primary concern in this patient group. In the few reports where cognition was mentioned, the patients responded well and appeared to retain comparable pre-treatment scores over time, although the numbers were too small for us to draw any firm conclusions. However, Nakano et al's patient, despite comparable pre- and post-treatment MMSE scores (and significantly improved PANSS and BPRS scores), had greatly decreased 99 mTc uptake in the basal ganglia, cingulate gyrus and thalamus on SPECT after 21 ECT treatments compared to pre-treatment SPECT.5
There is little consistent evidence regarding the use of ECT for the motor manifestations of the disease. Chorea, a hyperkinetic movement disorder, shows variable response. In the studies considered in this review, chorea often responded to ECT (including for our patient), but this finding was not always documented and thus it cannot be extrapolated to a recommendation given the small number of patients. However, psychomotor retardation and catatonia, which are manifestations of psychiatric disease, all responded favourably, although the presence of catatonia may require more protracted ECT treatment. The reported swallowing issues and weight loss in our patient and others responded well. A situation that appeared terminal in our case has been managed effectively for the patient and her family with good control, for over 2 years following the first dose of ECT.
All the studies considered in the current review were either single-case reports or retrospective case series. There were no comparison or prospective studies. The most striking aspect of this literature was how the choice of ECT as a treatment came to be prescribed. In nearly all cases, ECT was a last resort when all else had failed, with the exception of one case in which it was used for the specific management of chorea.3 Consequently, strict psychiatric criteria were lacking prior to the decision to start ECT. The main concern in using ECT was related to controlling the manifestations of psychosis or depression/suicidality, with concerns regarding other manifestations, such as outward aggression, in only a few cases. Clinical success was documented by a general clinical sense of improvement, serving as an indication of efficacy, with no clearly defined end points. Similarly, the cognitive and motor scoring of patients was haphazard and inconsistent, with only limited numbers of patients having clear objective scoring on any scales – motor, cognitive or psychiatric performance – either before or after ECT was administered in order to monitor patient responses.
It is clear that the preliminary though limited evidence from this review supports the use of ECT for relieving depressive symptoms. However, this is often considered as a last resort when all other interventions have failed. The current review suggests that additional consideration be given to the use of ECT as an adjunct in conventional treatment-resistant cases of depression, as well as for wider psychiatric manifestations of the disease, especially where depressive and psychotic symptoms coexist. These wider psychiatric manifestations and complications, which include psychomotor retardation and hallucinations, appear to respond well to the use of ECT. Where there are wider psychiatric manifestations of Huntington's disease, ECT may not only control these more effectively but could also lead to rationalisation of polypharmacy. Chorea may be less likely to respond to ECT, and so its use for this cannot be recommended based on the current review. Further investigative work with clear criteria and monitoring may lead to ECT being considered earlier and more often for patients with difficult-to-manage psychiatric manifestations of Huntington's disease.
About the authors
Walied Mowafi is a Consultant Neurologist at the Department of Neurology, Calderdale Royal Hospital, West Yorkshire, UK. Jon Millard is a Consultant Psychiatrist at South West Yorkshire Partnership NHS Foundation Trust, Wakefield, UK.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1192/bjb.2020.51.
click here to view supplementary material
Declaration of interest
None.
ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjb.2020.51. | CITALOPRAM HYDROBROMIDE, OLANZAPINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32513333 | 19,281,931 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.
OBJECTIVE
The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms.
RESULTS
Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive.
CONCLUSIONS
ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.
Case report
Seven years ago, a 57-year-old woman with a family history of Huntington's disease presented with depression, changes in personality, apathy, anxiety, poor memory and clumsiness. Her genetics confirmed Huntington's disease, with a CAG repeat number of 17/46. Over the subsequent 4 years, her condition was marked by psychiatric symptoms and mild chorea, which responded well to tetrabenazine 25 mg once daily, reaching 25 mg twice daily by 2014. Her mood was controlled with citalopram followed by sertraline. Her main complaints were bouts of introversion and tearfulness, but she remained socially engaged with friends. By early 2015, her swallowing had ostensibly become problematic. However, a speech and language assessment and a gastroscopy determined that her swallowing was normal. By spring 2016, she was starting to fall often, with worsening athetoid movements and increased somnolence. These changes led to a switch in medication to olanzapine at 15 mg per day and an increase in her dose of sertraline to 100 mg a day.
By summer of 2017, her choreoathetoid movements had worsened and were accompanied by weight loss and a deterioration in her mood. She required a short in-patient stay for fluids via a nasogastric tube. A psychiatric review diagnosed her with a depressive psychosis with retarded affect, mood-congruent delusions and auditory command hallucinations. She believed she did not deserve to eat and drink, and the command hallucinations ordered her not to do so. She had extracampine hallucinations, sensing people at the end of her garden. In light of her clinical state of emaciation and the requirement for support, a trial of bilateral electroconvulsive therapy (ECT) was suggested for her depressive psychosis. A twice-weekly regimen was started, with the aim of optimising seizure length to between 30 and 60 s. In winter of 2017, she received an initial 12 courses of biweekly bilateral ECT treatments using between 75 and 150 mC. Her initial response was favourable and she became euthymic, with remission of her psychomotor retardation, but her psychotic symptoms persisted in the form of command hallucinations despite developing insight. Her delusion of guilt also resolved and, by the tenth dose of ECT, she started to eat and drink again. The initial course of treatment was complete by early February 2018 and, with the exception of her hallucinations, her psychiatric symptoms ceased and insight was retained.
However, the persistence of psychotic symptoms in the absence of a significant mood component led to an additional 12 sessions of bilateral ECT (administered biweekly with 150–225 mC; maintenance treatment consisting of bilateral 150–300 mC treatment biweekly continued into late 2019) with the aim of eradicating the hallucinations. She then developed a respiratory tract infection, which led to a relapse in her psychiatric symptoms with agitation, hallucinations, and marked choreoathetosis and dyskinesia that led to the reintroduction of tetrabenazine. Despite this setback, she did improve following the last 12 doses of ECT. This course was completed in late spring 2019. She was kept on maintenance ECT once per week, with partial remission of the auditory hallucinations, which had reduced in frequency and no longer distressed her. There was a subsequent increase in the frequency of the hallucinations, with preservation of insight, and a corresponding reduction in ECT to fortnightly. She has remained stable on this regimen to date. Her involuntary movements have also improved over that time, although she remains on tetrabenazine, haloperidol and sertraline.
Method
A literature search of PubMed for ‘Electroconvulsive therapy and Huntington's’ and ‘ECT and Huntington's’ led to the discovery of 20 papers, 18 of which were in English. Six publications were based on in vitro studies and animal studies, leaving 12 publications for review. A further three papers that were not listed in the PubMed search were sourced from references in papers from earlier years. All publications were either single-case reports or retrospective case series; there were no randomised controlled trials or prospective studies.
Consent for publication
Signed informed consent was obtained from the patient described in our case report.
Results
Table 1 shows a breakdown by demographic and disease characteristics of the 37 patients described in 15 studies. Tables 2–5 summarise the predominant psychiatric complaints, the effects of ECT on the number of medications used during ECT treatment, the CAG copy number, ECT treatment and seizure duration. Supplementary Table 1 (available online at https://doi.org/10.1192/bjb.2020.51) summarises individual patient details from the literature, including our aforementioned case. Table 1 Summary of patient characteristics and ECT treatment
Characteristic Median
Sex 43% female (7 N/A)
Age at presentation 20–65 47
Length of psychiatric symptoms (years) 0–22 2.5
Time from diagnosis to ECT (years) 0–17 3
Number of courses of ECT 3–41 8
Seizure duration (s) 5–120 40
Dose delivered (mC) 25–504 –
Lead position (out of 22 documented) 54% right unilateral
N/A, not available.
Table 2 Breakdown of main presenting symptoms
Major presenting complaint N
Depressiona 26 (18)
Choreaa 14 (1)
Suicidal ideation 13
Psychosisa 12 (6)
Dysphagia/dysarthria 10
Hallucinations 7
Aggression 6
Catatonia 4
Psychomotor retardation 4
Inappropriate sexual behaviour 2
Pain/dystonia 1
a. In total (sole reason); see text for details.
Table 3 Treatment before, during and after ECT
Study Before ECT Changes during ECT After ECT
Evans et al11 Chlorpromazine, diphenhydramine Haloperidol, trazodone Benztropine, desipramine
Ranen et al1
Patient 1 Nortriptyline Fluoxetine, lithium Desipramine
Patient 2 Nortriptyline Desipramine, haloperidol
Patient 3 Amitriptyline, carbamazepine Nortriptyline added (6 weeks) Droperidol, Chlorpromazine
Patient 4 Nortriptyline, haloperidol, carbamazepine, lorazepam (catatonia) Lithium
Lewis et al14 Haloperidol Amoxapine
Beale et al3 Haloperidol, pimozide, benztropine, diphenhydramine, Reserpine, propranolol, Diazepam (all for chorea) haloperidol, carbamazepine
Merida-Puga et al4 Risperidone, lorazepam Clozapine, olanzapine Amantadine, lorazepam, levodopa, carbidopa (catatonia)
Nakano et al5 Risperidone, olanzapine N/A
Cusin et al2
Patient 1 Clonazepam, haloperidol, levetiracetam, lorazepam, quetiapine, risperidone, tizanidine, trazodone Duloxetine
Patient 2 Chlorpromazine, citalopram, phenytoin Chlorpromazine, citalopram, lorazepam, olanzapine, phenytoin
Patient 3 Fluoxetine Aripiprazole, fluoxetine
Patient 4 Clonazepam, duloxetine, risperidone, trazodone Clonazepam, duloxetine, olanzapine, trazodone, valproic acid
Patient 5 Clonazepam, duloxetine, olanzapine, trazodone, valproic acid Clonazepam, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 6 Clozapine, duloxetine, fluoxetine, haloperidol, lamotrigine, lorazepam, methadone, milnacipran, trazodone, zolpidem Chlorpromazine, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 7 Duloxetine, olanzapine Amantadine, clonazepam, paroxetine, risperidone, sertraline, trazodone, valproic acid
Magid et al8 Olanzapine, chlorpromazine, aripiprazole, risperidone, haloperidol, fluphenazine Citalopram, mirtazapine, sertraline, trazodone Lorazepam, clonazepam, buspirone
Petit et al9 Not mentioned but patient refractory to neuroleptics, antidepressants, atypical antipsychotics and mood stabilisers Clozapine Mirtazapine
Shah et al15 Buspirone, divalproex, lorazepam, paliperidone, quetiapine, venlafaxine Quetiapine, olanzapine
Adrissi et al10
Patient 1 Nortriptyline, quetiapine, tetrabenazine Amantadine, sertraline, quetiapine
Patient 2 Haloperidol, lorazepam Lorazepam, venlafaxine
Patient 3 Amantadine, baclofen, chlorpromazine, clozapine, gabapentin, lithium Chlorpromazine, clozapine, diazepam, gabapentin
Patient 4 Bupropion, clonazepam, escitalopram, levothyroxine, lithium Bupropion, clonazepam, escitalopram, levothyroxine, trazadone
Our case Citalopram, sertraline, tetrabenazine Olanzapine Tetrabenazine, haloperidol, sertraline
N/A, not available.
Table 4 Number of trinucleotide repeats, age of diagnosis, ECT treatments and length of psychiatric symptoms prior to ECT
Cases CAG repeat copy number Age at diagnosis of Huntington's disease (years) Cumulative number of ECT treatments Psychiatric symptoms (years)
Adrissi et al10 patient 4 39 45 7 2
Petit et al9 41 59 18 20
Adrissi et al10 patient 2 42 51 27 0.5
Magid et al8 43 57 3 7
Adrissi et al10 patient 1 44 45 29 3
Nakano et al5 44 59 4 0
Lewis et al14 44 65 8 1
Merida-Puga et al4 45 26 42 5
Beale et al3 46 56 11 19
Adrissi et al10 patient 3 46 31 41 6
Our case 46 50 40 7
Table 5 ECT seizure length in seconds and treatment characteristics
Cases Seizure duration (s) Mean ECT characteristics Dose (mC)
Ranen et ala,1
Patient 1 40–120 60
Patient 2 20–50 37
Patient 3 5–35 21 70 Hz pulse width 1 s, duration 2 ms 112
Patient 4 20–55 39
Patient 5 25–45 30 (MECTA SR1)
Patient 6 40–55 46
Lewis et al14 24–140 – 90 Hz pulse width 1–1.6 ms, 33.3–57.5 J (MECTA SR1) –
Beale et al3 57–19 – (MECTA SR2) 72–233
Merida-Puga et al4 42–80 – 25% (Thymatron DGx)b 126
Cusin et al2 90 Hz pulse width 1 ms, 2–4 sc 180–360
Adrissi et al10
Patient 1 25–48 –
Patient 2 30–75 – 10–140 Hz, pulse width 0.25–1 ms, 5–50% (Thymatron IV)d 25.2–504
Patient 3 21–84 –
Patient 4 21–42 –
Evans et al11 239/6 treatments – (MECTA apparatus) –
Our case 30–60 – (Thymatron IV) 75–300
a. Double stimulus was administered in Ranen et al’s patients, but no further details were provided.
b. Assumed to be the USA version with 0.9 A and charge of 504 mC. The lowest percentage given to Merida-Puga et al’s patient was calculated according to the half-life method. While no figure was given for the lowest percentage, 25% was the maximum stated.
c. Text does not state machine used or charge or current characteristics but states 'stimulus intensities comparable to patients without HD'. 0.8 A is presumed for the purpose of calculation.
d. As per specification sheet from the manufacturer, the maximum output is 504 mC with the range calculated based on quoted percentage delivered. This machine is capable of double stimulus, but this was not mentioned in Adrissi et al's paper.
The time to ECT treatment after the diagnosis of Huntington's disease was between 0 and 17 years, with a median of 3 years and mean of 4.42 years. However, the sixth patient of Ranen et al. had previously had ECT for depression before she was diagnosed.1 The age of psychiatric symptoms at presentation for ECT varied from 0 to 22 years prior, with a median of 2.5 years and a mean of 5.73 years.
It should be noted that the diagnostic confirmation of Huntington's was solely clinical prior to 1993; however, despite the availability of genetic testing after 1993 (Huntington disease Collaborative Research Group), diagnosis only preceded presentation in this group of patients after 2013 (Cusin et al's first patient2). Prior to 2013, patients first presented on average 7.4 years before the diagnosis of Huntington's was made. After 2013, all patients with psychiatric complaints who went on to have ECT presented an average of 6.6 years after the diagnosis of Huntington's had been established. Six patients in total were diagnosed at the time of presentation, although five of them were diagnosed prior to 2013. For example, Beale et al's patient had choreiform movements (and no psychiatric manifestations) from the age of 35, but was not diagnosed until the age of 56 in 1995.3 However, this apparent lag after the introduction of genetic testing is likely to reflect the 16-year gap between Beale et al's paper in 1995 and those of Merida-Puga et al and Nakano et al in 2011 and 2013, respectively.3–5 Merida-Puga et al's patient was diagnosed following postpartum psychosis and a family history suggestive of Huntington's in her father; she went on to have ECT for catatonia. Nakano et al's patient was diagnosed owing to his brother's recent diagnosis with Huntington's at another hospital, having already received ECT for treatment-refractory psychosis.
Reason for referral for ECT
Table 2 shows a breakdown of the main characteristics of the clinical presentations; 48.6% of patients were referred for depression alone without psychotic features, and psychosis was the main cause of referral in 16%. Many of the referrals for depression alone were from some of the earliest reports, which lacked a clear description of the referral characteristics.6,7 The remainder of patients had numerous coexisting factors such as paranoia, delusions and other manifestations of psychosis, including hallucinations1,2,4,5,8–11.
Coexistent motor symptoms were present in 20 patients1–3,5,9,10,12–15 (including our case), with chorea being the most commonly used term. Involuntary movement and impaired gait were also terms used without further clarification (e.g. Cusin et al uses both terms for different patients within the same series2). Psychomotor retardation was reported in four patients1,2,10 (including our case), with one patient being described as having neurovegetative symptoms (Cusin et al,2 patient 3), and coexistent dysarthria/dysphagia in two patients. Catatonia was mentioned in four patients1,2,4 (fourth and fifth patient of series,1 postpartum4 and the second patient of series2) but was the primary focus of treatment only in Merida-Puga et al4; see Supplementary Table 1.
Effects on psychiatric symptoms
The primary reason for prescribing ECT in all but seven patients (six for psychosis and one for chorea) was depression (Table 2 and Supplementary Table 1). There were universally favourable outcomes in the use of ECT for this purpose. It was reported to be successful in most cases, and the patients who were reported to relapse did so on shorter courses of ECT.12,13 However, these were early reports, and there have been numerous subsequent reports of relatively short courses with no relapse. For example, Ranen et al's third patient, who had depression, psychosis and catatonia, only needed five ECT treatments to achieve symptom resolution.
Psychosis responded to ECT in all six patients2,4,8,11 who were reported to have it as the primary presentation, which included our case. When coexistent disease such as depression was considered, 12 patients in total had prominent psychosis, and all responded to varying degrees, including our case.1,5,9,10 Merida-Puga et al reported refractory psychosis thought to be due to use of depot dopamine antagonists, although the focus of their treatment was the refractory catatonia.4
Hallucinations, either auditory (three cases including our case),1,11,13 visual (two cases)2,10 or both visual and auditory (two cases),4,8 also responded well to treatment. The exception was Ranen et al's fourth patient, where this was unclear, although the hallucinations probably improved with the patient's other symptoms.
There were four cases of reported psychomotor retardation, including our patient1,10,12 (in addition, speech retardation was reported in Nakano et al); all were described as improved following ECT without further clarification. Benson and Blumer's first patient had a ‘temporary recovery’.
Catatonia (second and fourth patients of Ranen et al; second patient of Cusin et al1,2,4) was described in four patients and improved in all. This improvement often paralleled the response to ECT of depression, suicidality and psychosis. Two of these cases were resolved by relatively short courses of ECT (five treatments for Ranen et al's fourth patient – though their condition was, surprisingly, described as refractory – and seven treatments for Cusin et al's second patient). However, the presence of catatonia was refractory in the remaining two patients. Both Ranen et al's second patient (who relapsed repeatedly) and Merida-Puga et al's patient4 (who required withdrawal from long-acting antipsychotics) needed extended ECT courses (4 years for Ranen et al's patient but just over 3 months of an in-patient stay for the latter) to resolve the catatonia, with 35 and 42 ECT treatments, respectively. Merida-Puga et al's patient had a Busch–Francis catatonia score of 26 (total severity) on first admission, falling to 4 after a second hospital admission and discharge.
Our patient required repeated doses of ECT following a relapse of psychosis over 2 years. Eventually, she showed a partial response, with improvements in her mobility and psychomotor retardation. She started to gain weight, although her delusions persisted. Improved gait was reported in six cases, including Lewis et al and the first, fourth, fifth and sixth patients of Cusin et al, who had bilateral frontotemporal and right unilateral (RUL) placement, respectively.2,14
Disorders of eating and/or speech were mentioned for a total of ten patients. Dysphagia was mentioned in two cases (Cusin et al's2 second patient and ours) and dysarthria in another two (Cusin et al's third and sixth patients). Both dysarthria and dysphagia were reported for two patients (Cusin et al's fourth and fifth patients). For all six of these patients, their symptoms were described as resolving or dramatically improved. Refusal to eat was described in two patients (Ranen et al's second patient and Magid et al's patient1,8), while poor appetite was described in another two (Ranen et al's sixth patient and Adrissi et al's second10). Both of Ranen et al's patients were described as improved, but there was no further clarification regarding outcome for the remaining two.
Aggression,1,2,10–12,15 inappropriate sexual behaviour2,15 and agitation15 were also mentioned and described as improved.
Only two reports documented improvement using psychiatric rating scales, with the BPRS-E (Brief Psychiatric Rating Scale, Expanded) score dropping from 88 to 38 after 12 ECT sessions in Petit el al's patient, and BPRS dropping from 139 to 68 in Nakano et al's patient (the PANS (Positive and Negative Syndrome Scale) score fell from 139 to 68 in the latter).5,9 Both Beale et al and Lewis et al documented improvement in the Hamilton rating scale for depression from 36 pre-treatment to 13 post-treatment in Beale et al and 36 to 10 post-treatment in Lewis et al.3,14
Effects on motor symptoms
Chorea was mentioned in 14 cases,1–3,5,9–11,13–15 including our case (three patients of Cusin et al and two of Adrissi et al2,10). Improvement was documented in three cases (Beale et al, Petit et al and Shah et al), although five were described as showing no change (Ranen et al, Lewis et al, Nakano et al, Cusin et al's fifth patient and Adrissi et al's first patient). In two cases, chorea was described as worse (Adrissi et al's second patient and Evans et al). In the remaining four patients, no details were given, despite this symptom initially having been described as present.
Only one patient was treated with ECT specifically for chorea. This patient demonstrated improvement initially and, despite worsening, their chorea never returned to the original level and was sustained at the improved level for a year.3
Our patient showed some response with respect to the choreoathetoid movements, which had become unresponsive to tetrabenazine. The medication had been withdrawn given her depression and fears of worsening those symptoms. Olanzapine, however, did not lead to any improvement in her chorea or psychiatric symptoms. Following a favourable response of the chorea to ECT, a low dose of tetrabenazine was reintroduced with good effect and had no further influence on her mood. Her gait and mobility also improved.
The use of rating scales for motor function was mentioned in only three cases. The Unified Huntington's Disease Rating Scale (UHDRS) motor score was recorded before and after only for Adrissi et al's second patient (27/31 out of a total of 124; their first case had an initial score of 49 with no follow-up score), while Petit et al's patient's UHDRS score decreased from 47 to 37 after 12 treatments and then rose to 57 after 1 year.9,10 For most cases, there was no mention of any response, which is not surprising because this was the focus of the treatment in only one of the studies. Surprisingly, despite admitting their patient specifically for the treatment of chorea (there were no psychiatric manifestations), Beale et al used no rating scales to document improvement.3
Effects on cognition
Many of the case reports mentioned problems with cognition, but few documented it with formal scores either before or after treatment. Scores were recorded before and after treatment by Nakano et al (Mini-Mental State Examination (MMSE) 27/26), Lewis et al (MMSE 23/24) and Ranen et al (second and fourth patients; MMSE 20/30 rose to 26 by discharge in the former and was 20/30 rising to 24–26/30 (administered twice) in the latter1,5,14). Cusin et al used the Montreal Cognitive Assessment (MoCA) scale for their patients and described the scores as improved, although they did not publish the values.2
Ranen et al's third patient showed a drop in MMSE from 26/30 to 18/28, with an episode of delirium after his eighth ECT treatment. No further scores were recorded, but the patient was described as ‘not completely recovered cognitively’.1 Adrissi et al's second patient had an initial MoCA of 17/20, but no further score was documented.10
Effect on medication used
Table 3 documents the treatment at admission; changes, if any, that occurred during the course of treatment for the psychiatric manifestations of disease; and discharge medication for those patients where it was recorded.
In those patients who required a number of drugs to treat the psychiatric manifestations of Huntington's disease, implying difficulty in management, there was not necessarily a requirement for more ECT doses or prolonged ECT treatment. However, in patients with pharmacological treatment resistance and the requirement for many drugs to manage symptoms, there does appear to be scope for significant rationalisation of pharmacological therapy when ECT is used adjunctively. Beale et al's patient and Cusin et al's first and sixth patients all presented between 10.5 and 19 years after diagnosis but responded well to limited ECT treatments and were discharged on much less medication.2,3 Only Adrissi et al's third patient, Ranen et al's second patient and ours required extended ECT. It is not clear why there was resistance to conventional treatment in these cases.1,10
However, this was not a consistent outcome; for example, Cusin et al's seventh patient was discharged on more medication after ECT than prior, and Adrissi et al's third and fourth patients were discharged on a comparable number of drugs to those given on admission.2,10
Effect of CAG copy number on disease or treatment
The earliest reference to CAG copy number, and therefore genetic confirmation of the diagnosis, comes from Lewis et al in 1994 – in keeping with testing, which became available after the discovery of the trinucleotide repeat a year earlier by the Huntington Disease Collaborative Research Group. Copy numbers of trinucleotide repeats have no effect on the severity of the disease, but the age of presentation is inversely correlated with increasing copy number.16
Table 4 shows copy number, number of ECT treatments and length of psychiatric symptoms for cases where this information was documented. Although those requiring more cumulative ECT treatments may appear to be clustered with those with higher repeat copy numbers, Petit et al's and Adrissi et al's second and first patients represent evidence to the contrary.9,10 Given that there was only a difference of seven CAG repeats among the 11 patients, there appears to be no significance to this. In keeping with this, the youngest patient in the review, who at 20 years old was likely to have had genetic testing, although the results of this were not documented, responded well to ECT, with his symptoms described as resolved after only seven treatments (Cusin et al's second patient2).
ECT treatment course
Treatment courses varied between three and 42 treatments in total, with a median of eight. Relapse was mentioned in seven cases (Cusin et al's fifth and sixth patients).2,4,12,13,15 For Heathfield's patient (who had three treatments) and Benson and Blumer's patients, relapse was described in general terms, with no description of the treatment course in the latter's series.12,13 In the remaining patients, it is not clear why they relapsed, except for having received relatively short courses of between five and nine ECT treatments. Merida-Puga et al's patient had treatment-resistant catatonia exacerbated by dopamine antagonists prescribed for her psychosis; this led to relapses and an extended in-patient stay.
Most patients had treatment for up to 1 year (22 patients), although our patient has been undergoing continuing maintenance treatment at increasing intervals for more than 2 years to date. Ranen et al's second patient required treatment for 4 years and Petit et al's patient for more than 1 year.1,9 Those requiring extended treatment presumably did so because of continued symptoms1,10 (see below).
Patients who had an extended course, arbitrarily taken to be more than 20 treatments (seven patients including ours1,4,9,10), did not have different characteristics from patients with similar symptoms but much less cumulative ECT treatment. Characteristics such as the nature of symptoms, length of time from diagnosis, length of time of psychiatric symptoms, age and sex did not appear to affect the number of ECT treatments. However, refractory catatonia complicating psychosis may have been a factor in extended treatment, with Ranen et al's second patient and Merida-Puga et al's patient4 requiring 35 and 42 treatments, respectively.
The four patients who had ECT more than 10 years after diagnosis1,2 (Ranen et al's sixth, Cusin et al's first, fifth and seventh patients) also showed excellent responses to ECT with between 8 and 13 treatments.
Length of seizure in seconds
Table 5 shows the seizure duration in the cases where it was recorded.1,3,4,10,11,14 Only Beale et al mentioned a reduction in seizure time from 57 s at the beginning of treatment to 19 s by the end. This was for the sole case in which ECT was administered for chorea.3 Our patient required ongoing treatment with increasing doses of ECT, although control of delusions was eventually achieved with seizure lengths between 30 and 60 s.
Dose of ECT treatment
It was not always possible to discern the dose of treatment given, as doses were rarely documented and were not necessarily consistent with other reports.1–4,10,11,14 For example, Beale et al's patient was stated as needing 72 mC initially, rising to 233 mC, with a corresponding drop in seizure duration from 57 s initially to 19 s at the end.3 When recorded, the frequency and pulse width varied. Alternatively, descriptions of percentage of maximum charge, where stated, together with the machine used (and its specifications), allowed for calculation of this figure where it was not explicitly stated (Table 5).
There did not appear to be any factors to explain why five patients, including our patient, required higher cumulative ECT treatments (Ranen et al's second patient, Adrissi et al's first, second and third patients).1,10 More generally, most patients were started on relatively low doses of ECT and titrated as treatment progressed, though this was not always documented. Only Adrissi et al's third patient was started on maximum charge dose of 100% (504 mC) due to refractory psychosis. This was later cut down to 50% (252 mC) owing to a bout of delerium that was subsequently felt to be due to medication. The presence of catatonia in Merida-Puga et al and Ranen et al's second patient may be considered a proxy for severity, but this was not the case for the other two catatonic patients (see above). Likewise, short treatment courses were reported in the earlier studies to be more likely to lead to relapse, but this was not borne out by later studies (see above). Getting the dose and the induced seizure length right appears to take more time in the out-patient setting, as may be expected. The three intense in-patient stays for our patient, Merida-Puga et al's patient and Adrissi et al's third patient (3 months in the latter two cases) allowed this to be achieved more rapidly, but the cumulative doses were all high.4,10 Overall, there appear to be no overt factors that predict who is likely to respond quickly or otherwise, although most patients will not require extended treatment based on this review.
Lead positioning
The predominant positions were RUL in 12 patients, one RUL unilateral and bilateral (unspecified), four bilateral (one bilateral frontotemporal, three bilateral) and two bitemporal (Supplementary Table 1).
Conclusion
The diagnosis of Huntington's disease is usually preceded by psychiatric symptoms in cases where family history is absent, sometimes by years.17 However, as we found in this review, patients are now likely to have an established diagnosis of Huntington's by the time they are considered for ECT. Although a CAG repeat number greater than 36 in the Huntington gene confirms the disease, an increased number of repeats is negatively correlated with age at presentation rather than severity of disease.16
Psychiatric manifestations of Huntington's disease vary according to the stage of the disease; apathy, for example, is found in 50% of patients by stage four on the UHDRS. Also present are obsessive–compulsive behaviour, irritability and aggression. Depression also increases over time, with only psychosis remaining consistent throughout at 11%.18
The prevalence of depression is about 50%, compared with anxiety at 17–61%, irritability at 35–73%, obsessive–compulsive disorders at 7–50% and psychosis at 3–11%. The prevalence of hypersexuality is between 2.1 and 30% and is slightly lower in women, whereas the prevalence of hyposexuality is higher at 63% in men and 75% in women.19 The use of ECT, however, is recommended only for depression on the basis of two of the above series.1,14,20
There appeared to be little in the way of any effect on cognition with the use of ECT, although this was not a primary concern in this patient group. In the few reports where cognition was mentioned, the patients responded well and appeared to retain comparable pre-treatment scores over time, although the numbers were too small for us to draw any firm conclusions. However, Nakano et al's patient, despite comparable pre- and post-treatment MMSE scores (and significantly improved PANSS and BPRS scores), had greatly decreased 99 mTc uptake in the basal ganglia, cingulate gyrus and thalamus on SPECT after 21 ECT treatments compared to pre-treatment SPECT.5
There is little consistent evidence regarding the use of ECT for the motor manifestations of the disease. Chorea, a hyperkinetic movement disorder, shows variable response. In the studies considered in this review, chorea often responded to ECT (including for our patient), but this finding was not always documented and thus it cannot be extrapolated to a recommendation given the small number of patients. However, psychomotor retardation and catatonia, which are manifestations of psychiatric disease, all responded favourably, although the presence of catatonia may require more protracted ECT treatment. The reported swallowing issues and weight loss in our patient and others responded well. A situation that appeared terminal in our case has been managed effectively for the patient and her family with good control, for over 2 years following the first dose of ECT.
All the studies considered in the current review were either single-case reports or retrospective case series. There were no comparison or prospective studies. The most striking aspect of this literature was how the choice of ECT as a treatment came to be prescribed. In nearly all cases, ECT was a last resort when all else had failed, with the exception of one case in which it was used for the specific management of chorea.3 Consequently, strict psychiatric criteria were lacking prior to the decision to start ECT. The main concern in using ECT was related to controlling the manifestations of psychosis or depression/suicidality, with concerns regarding other manifestations, such as outward aggression, in only a few cases. Clinical success was documented by a general clinical sense of improvement, serving as an indication of efficacy, with no clearly defined end points. Similarly, the cognitive and motor scoring of patients was haphazard and inconsistent, with only limited numbers of patients having clear objective scoring on any scales – motor, cognitive or psychiatric performance – either before or after ECT was administered in order to monitor patient responses.
It is clear that the preliminary though limited evidence from this review supports the use of ECT for relieving depressive symptoms. However, this is often considered as a last resort when all other interventions have failed. The current review suggests that additional consideration be given to the use of ECT as an adjunct in conventional treatment-resistant cases of depression, as well as for wider psychiatric manifestations of the disease, especially where depressive and psychotic symptoms coexist. These wider psychiatric manifestations and complications, which include psychomotor retardation and hallucinations, appear to respond well to the use of ECT. Where there are wider psychiatric manifestations of Huntington's disease, ECT may not only control these more effectively but could also lead to rationalisation of polypharmacy. Chorea may be less likely to respond to ECT, and so its use for this cannot be recommended based on the current review. Further investigative work with clear criteria and monitoring may lead to ECT being considered earlier and more often for patients with difficult-to-manage psychiatric manifestations of Huntington's disease.
About the authors
Walied Mowafi is a Consultant Neurologist at the Department of Neurology, Calderdale Royal Hospital, West Yorkshire, UK. Jon Millard is a Consultant Psychiatrist at South West Yorkshire Partnership NHS Foundation Trust, Wakefield, UK.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1192/bjb.2020.51.
click here to view supplementary material
Declaration of interest
None.
ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjb.2020.51. | CITALOPRAM HYDROBROMIDE, OLANZAPINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32513333 | 19,281,931 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.
OBJECTIVE
The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms.
RESULTS
Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive.
CONCLUSIONS
ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.
Case report
Seven years ago, a 57-year-old woman with a family history of Huntington's disease presented with depression, changes in personality, apathy, anxiety, poor memory and clumsiness. Her genetics confirmed Huntington's disease, with a CAG repeat number of 17/46. Over the subsequent 4 years, her condition was marked by psychiatric symptoms and mild chorea, which responded well to tetrabenazine 25 mg once daily, reaching 25 mg twice daily by 2014. Her mood was controlled with citalopram followed by sertraline. Her main complaints were bouts of introversion and tearfulness, but she remained socially engaged with friends. By early 2015, her swallowing had ostensibly become problematic. However, a speech and language assessment and a gastroscopy determined that her swallowing was normal. By spring 2016, she was starting to fall often, with worsening athetoid movements and increased somnolence. These changes led to a switch in medication to olanzapine at 15 mg per day and an increase in her dose of sertraline to 100 mg a day.
By summer of 2017, her choreoathetoid movements had worsened and were accompanied by weight loss and a deterioration in her mood. She required a short in-patient stay for fluids via a nasogastric tube. A psychiatric review diagnosed her with a depressive psychosis with retarded affect, mood-congruent delusions and auditory command hallucinations. She believed she did not deserve to eat and drink, and the command hallucinations ordered her not to do so. She had extracampine hallucinations, sensing people at the end of her garden. In light of her clinical state of emaciation and the requirement for support, a trial of bilateral electroconvulsive therapy (ECT) was suggested for her depressive psychosis. A twice-weekly regimen was started, with the aim of optimising seizure length to between 30 and 60 s. In winter of 2017, she received an initial 12 courses of biweekly bilateral ECT treatments using between 75 and 150 mC. Her initial response was favourable and she became euthymic, with remission of her psychomotor retardation, but her psychotic symptoms persisted in the form of command hallucinations despite developing insight. Her delusion of guilt also resolved and, by the tenth dose of ECT, she started to eat and drink again. The initial course of treatment was complete by early February 2018 and, with the exception of her hallucinations, her psychiatric symptoms ceased and insight was retained.
However, the persistence of psychotic symptoms in the absence of a significant mood component led to an additional 12 sessions of bilateral ECT (administered biweekly with 150–225 mC; maintenance treatment consisting of bilateral 150–300 mC treatment biweekly continued into late 2019) with the aim of eradicating the hallucinations. She then developed a respiratory tract infection, which led to a relapse in her psychiatric symptoms with agitation, hallucinations, and marked choreoathetosis and dyskinesia that led to the reintroduction of tetrabenazine. Despite this setback, she did improve following the last 12 doses of ECT. This course was completed in late spring 2019. She was kept on maintenance ECT once per week, with partial remission of the auditory hallucinations, which had reduced in frequency and no longer distressed her. There was a subsequent increase in the frequency of the hallucinations, with preservation of insight, and a corresponding reduction in ECT to fortnightly. She has remained stable on this regimen to date. Her involuntary movements have also improved over that time, although she remains on tetrabenazine, haloperidol and sertraline.
Method
A literature search of PubMed for ‘Electroconvulsive therapy and Huntington's’ and ‘ECT and Huntington's’ led to the discovery of 20 papers, 18 of which were in English. Six publications were based on in vitro studies and animal studies, leaving 12 publications for review. A further three papers that were not listed in the PubMed search were sourced from references in papers from earlier years. All publications were either single-case reports or retrospective case series; there were no randomised controlled trials or prospective studies.
Consent for publication
Signed informed consent was obtained from the patient described in our case report.
Results
Table 1 shows a breakdown by demographic and disease characteristics of the 37 patients described in 15 studies. Tables 2–5 summarise the predominant psychiatric complaints, the effects of ECT on the number of medications used during ECT treatment, the CAG copy number, ECT treatment and seizure duration. Supplementary Table 1 (available online at https://doi.org/10.1192/bjb.2020.51) summarises individual patient details from the literature, including our aforementioned case. Table 1 Summary of patient characteristics and ECT treatment
Characteristic Median
Sex 43% female (7 N/A)
Age at presentation 20–65 47
Length of psychiatric symptoms (years) 0–22 2.5
Time from diagnosis to ECT (years) 0–17 3
Number of courses of ECT 3–41 8
Seizure duration (s) 5–120 40
Dose delivered (mC) 25–504 –
Lead position (out of 22 documented) 54% right unilateral
N/A, not available.
Table 2 Breakdown of main presenting symptoms
Major presenting complaint N
Depressiona 26 (18)
Choreaa 14 (1)
Suicidal ideation 13
Psychosisa 12 (6)
Dysphagia/dysarthria 10
Hallucinations 7
Aggression 6
Catatonia 4
Psychomotor retardation 4
Inappropriate sexual behaviour 2
Pain/dystonia 1
a. In total (sole reason); see text for details.
Table 3 Treatment before, during and after ECT
Study Before ECT Changes during ECT After ECT
Evans et al11 Chlorpromazine, diphenhydramine Haloperidol, trazodone Benztropine, desipramine
Ranen et al1
Patient 1 Nortriptyline Fluoxetine, lithium Desipramine
Patient 2 Nortriptyline Desipramine, haloperidol
Patient 3 Amitriptyline, carbamazepine Nortriptyline added (6 weeks) Droperidol, Chlorpromazine
Patient 4 Nortriptyline, haloperidol, carbamazepine, lorazepam (catatonia) Lithium
Lewis et al14 Haloperidol Amoxapine
Beale et al3 Haloperidol, pimozide, benztropine, diphenhydramine, Reserpine, propranolol, Diazepam (all for chorea) haloperidol, carbamazepine
Merida-Puga et al4 Risperidone, lorazepam Clozapine, olanzapine Amantadine, lorazepam, levodopa, carbidopa (catatonia)
Nakano et al5 Risperidone, olanzapine N/A
Cusin et al2
Patient 1 Clonazepam, haloperidol, levetiracetam, lorazepam, quetiapine, risperidone, tizanidine, trazodone Duloxetine
Patient 2 Chlorpromazine, citalopram, phenytoin Chlorpromazine, citalopram, lorazepam, olanzapine, phenytoin
Patient 3 Fluoxetine Aripiprazole, fluoxetine
Patient 4 Clonazepam, duloxetine, risperidone, trazodone Clonazepam, duloxetine, olanzapine, trazodone, valproic acid
Patient 5 Clonazepam, duloxetine, olanzapine, trazodone, valproic acid Clonazepam, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 6 Clozapine, duloxetine, fluoxetine, haloperidol, lamotrigine, lorazepam, methadone, milnacipran, trazodone, zolpidem Chlorpromazine, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 7 Duloxetine, olanzapine Amantadine, clonazepam, paroxetine, risperidone, sertraline, trazodone, valproic acid
Magid et al8 Olanzapine, chlorpromazine, aripiprazole, risperidone, haloperidol, fluphenazine Citalopram, mirtazapine, sertraline, trazodone Lorazepam, clonazepam, buspirone
Petit et al9 Not mentioned but patient refractory to neuroleptics, antidepressants, atypical antipsychotics and mood stabilisers Clozapine Mirtazapine
Shah et al15 Buspirone, divalproex, lorazepam, paliperidone, quetiapine, venlafaxine Quetiapine, olanzapine
Adrissi et al10
Patient 1 Nortriptyline, quetiapine, tetrabenazine Amantadine, sertraline, quetiapine
Patient 2 Haloperidol, lorazepam Lorazepam, venlafaxine
Patient 3 Amantadine, baclofen, chlorpromazine, clozapine, gabapentin, lithium Chlorpromazine, clozapine, diazepam, gabapentin
Patient 4 Bupropion, clonazepam, escitalopram, levothyroxine, lithium Bupropion, clonazepam, escitalopram, levothyroxine, trazadone
Our case Citalopram, sertraline, tetrabenazine Olanzapine Tetrabenazine, haloperidol, sertraline
N/A, not available.
Table 4 Number of trinucleotide repeats, age of diagnosis, ECT treatments and length of psychiatric symptoms prior to ECT
Cases CAG repeat copy number Age at diagnosis of Huntington's disease (years) Cumulative number of ECT treatments Psychiatric symptoms (years)
Adrissi et al10 patient 4 39 45 7 2
Petit et al9 41 59 18 20
Adrissi et al10 patient 2 42 51 27 0.5
Magid et al8 43 57 3 7
Adrissi et al10 patient 1 44 45 29 3
Nakano et al5 44 59 4 0
Lewis et al14 44 65 8 1
Merida-Puga et al4 45 26 42 5
Beale et al3 46 56 11 19
Adrissi et al10 patient 3 46 31 41 6
Our case 46 50 40 7
Table 5 ECT seizure length in seconds and treatment characteristics
Cases Seizure duration (s) Mean ECT characteristics Dose (mC)
Ranen et ala,1
Patient 1 40–120 60
Patient 2 20–50 37
Patient 3 5–35 21 70 Hz pulse width 1 s, duration 2 ms 112
Patient 4 20–55 39
Patient 5 25–45 30 (MECTA SR1)
Patient 6 40–55 46
Lewis et al14 24–140 – 90 Hz pulse width 1–1.6 ms, 33.3–57.5 J (MECTA SR1) –
Beale et al3 57–19 – (MECTA SR2) 72–233
Merida-Puga et al4 42–80 – 25% (Thymatron DGx)b 126
Cusin et al2 90 Hz pulse width 1 ms, 2–4 sc 180–360
Adrissi et al10
Patient 1 25–48 –
Patient 2 30–75 – 10–140 Hz, pulse width 0.25–1 ms, 5–50% (Thymatron IV)d 25.2–504
Patient 3 21–84 –
Patient 4 21–42 –
Evans et al11 239/6 treatments – (MECTA apparatus) –
Our case 30–60 – (Thymatron IV) 75–300
a. Double stimulus was administered in Ranen et al’s patients, but no further details were provided.
b. Assumed to be the USA version with 0.9 A and charge of 504 mC. The lowest percentage given to Merida-Puga et al’s patient was calculated according to the half-life method. While no figure was given for the lowest percentage, 25% was the maximum stated.
c. Text does not state machine used or charge or current characteristics but states 'stimulus intensities comparable to patients without HD'. 0.8 A is presumed for the purpose of calculation.
d. As per specification sheet from the manufacturer, the maximum output is 504 mC with the range calculated based on quoted percentage delivered. This machine is capable of double stimulus, but this was not mentioned in Adrissi et al's paper.
The time to ECT treatment after the diagnosis of Huntington's disease was between 0 and 17 years, with a median of 3 years and mean of 4.42 years. However, the sixth patient of Ranen et al. had previously had ECT for depression before she was diagnosed.1 The age of psychiatric symptoms at presentation for ECT varied from 0 to 22 years prior, with a median of 2.5 years and a mean of 5.73 years.
It should be noted that the diagnostic confirmation of Huntington's was solely clinical prior to 1993; however, despite the availability of genetic testing after 1993 (Huntington disease Collaborative Research Group), diagnosis only preceded presentation in this group of patients after 2013 (Cusin et al's first patient2). Prior to 2013, patients first presented on average 7.4 years before the diagnosis of Huntington's was made. After 2013, all patients with psychiatric complaints who went on to have ECT presented an average of 6.6 years after the diagnosis of Huntington's had been established. Six patients in total were diagnosed at the time of presentation, although five of them were diagnosed prior to 2013. For example, Beale et al's patient had choreiform movements (and no psychiatric manifestations) from the age of 35, but was not diagnosed until the age of 56 in 1995.3 However, this apparent lag after the introduction of genetic testing is likely to reflect the 16-year gap between Beale et al's paper in 1995 and those of Merida-Puga et al and Nakano et al in 2011 and 2013, respectively.3–5 Merida-Puga et al's patient was diagnosed following postpartum psychosis and a family history suggestive of Huntington's in her father; she went on to have ECT for catatonia. Nakano et al's patient was diagnosed owing to his brother's recent diagnosis with Huntington's at another hospital, having already received ECT for treatment-refractory psychosis.
Reason for referral for ECT
Table 2 shows a breakdown of the main characteristics of the clinical presentations; 48.6% of patients were referred for depression alone without psychotic features, and psychosis was the main cause of referral in 16%. Many of the referrals for depression alone were from some of the earliest reports, which lacked a clear description of the referral characteristics.6,7 The remainder of patients had numerous coexisting factors such as paranoia, delusions and other manifestations of psychosis, including hallucinations1,2,4,5,8–11.
Coexistent motor symptoms were present in 20 patients1–3,5,9,10,12–15 (including our case), with chorea being the most commonly used term. Involuntary movement and impaired gait were also terms used without further clarification (e.g. Cusin et al uses both terms for different patients within the same series2). Psychomotor retardation was reported in four patients1,2,10 (including our case), with one patient being described as having neurovegetative symptoms (Cusin et al,2 patient 3), and coexistent dysarthria/dysphagia in two patients. Catatonia was mentioned in four patients1,2,4 (fourth and fifth patient of series,1 postpartum4 and the second patient of series2) but was the primary focus of treatment only in Merida-Puga et al4; see Supplementary Table 1.
Effects on psychiatric symptoms
The primary reason for prescribing ECT in all but seven patients (six for psychosis and one for chorea) was depression (Table 2 and Supplementary Table 1). There were universally favourable outcomes in the use of ECT for this purpose. It was reported to be successful in most cases, and the patients who were reported to relapse did so on shorter courses of ECT.12,13 However, these were early reports, and there have been numerous subsequent reports of relatively short courses with no relapse. For example, Ranen et al's third patient, who had depression, psychosis and catatonia, only needed five ECT treatments to achieve symptom resolution.
Psychosis responded to ECT in all six patients2,4,8,11 who were reported to have it as the primary presentation, which included our case. When coexistent disease such as depression was considered, 12 patients in total had prominent psychosis, and all responded to varying degrees, including our case.1,5,9,10 Merida-Puga et al reported refractory psychosis thought to be due to use of depot dopamine antagonists, although the focus of their treatment was the refractory catatonia.4
Hallucinations, either auditory (three cases including our case),1,11,13 visual (two cases)2,10 or both visual and auditory (two cases),4,8 also responded well to treatment. The exception was Ranen et al's fourth patient, where this was unclear, although the hallucinations probably improved with the patient's other symptoms.
There were four cases of reported psychomotor retardation, including our patient1,10,12 (in addition, speech retardation was reported in Nakano et al); all were described as improved following ECT without further clarification. Benson and Blumer's first patient had a ‘temporary recovery’.
Catatonia (second and fourth patients of Ranen et al; second patient of Cusin et al1,2,4) was described in four patients and improved in all. This improvement often paralleled the response to ECT of depression, suicidality and psychosis. Two of these cases were resolved by relatively short courses of ECT (five treatments for Ranen et al's fourth patient – though their condition was, surprisingly, described as refractory – and seven treatments for Cusin et al's second patient). However, the presence of catatonia was refractory in the remaining two patients. Both Ranen et al's second patient (who relapsed repeatedly) and Merida-Puga et al's patient4 (who required withdrawal from long-acting antipsychotics) needed extended ECT courses (4 years for Ranen et al's patient but just over 3 months of an in-patient stay for the latter) to resolve the catatonia, with 35 and 42 ECT treatments, respectively. Merida-Puga et al's patient had a Busch–Francis catatonia score of 26 (total severity) on first admission, falling to 4 after a second hospital admission and discharge.
Our patient required repeated doses of ECT following a relapse of psychosis over 2 years. Eventually, she showed a partial response, with improvements in her mobility and psychomotor retardation. She started to gain weight, although her delusions persisted. Improved gait was reported in six cases, including Lewis et al and the first, fourth, fifth and sixth patients of Cusin et al, who had bilateral frontotemporal and right unilateral (RUL) placement, respectively.2,14
Disorders of eating and/or speech were mentioned for a total of ten patients. Dysphagia was mentioned in two cases (Cusin et al's2 second patient and ours) and dysarthria in another two (Cusin et al's third and sixth patients). Both dysarthria and dysphagia were reported for two patients (Cusin et al's fourth and fifth patients). For all six of these patients, their symptoms were described as resolving or dramatically improved. Refusal to eat was described in two patients (Ranen et al's second patient and Magid et al's patient1,8), while poor appetite was described in another two (Ranen et al's sixth patient and Adrissi et al's second10). Both of Ranen et al's patients were described as improved, but there was no further clarification regarding outcome for the remaining two.
Aggression,1,2,10–12,15 inappropriate sexual behaviour2,15 and agitation15 were also mentioned and described as improved.
Only two reports documented improvement using psychiatric rating scales, with the BPRS-E (Brief Psychiatric Rating Scale, Expanded) score dropping from 88 to 38 after 12 ECT sessions in Petit el al's patient, and BPRS dropping from 139 to 68 in Nakano et al's patient (the PANS (Positive and Negative Syndrome Scale) score fell from 139 to 68 in the latter).5,9 Both Beale et al and Lewis et al documented improvement in the Hamilton rating scale for depression from 36 pre-treatment to 13 post-treatment in Beale et al and 36 to 10 post-treatment in Lewis et al.3,14
Effects on motor symptoms
Chorea was mentioned in 14 cases,1–3,5,9–11,13–15 including our case (three patients of Cusin et al and two of Adrissi et al2,10). Improvement was documented in three cases (Beale et al, Petit et al and Shah et al), although five were described as showing no change (Ranen et al, Lewis et al, Nakano et al, Cusin et al's fifth patient and Adrissi et al's first patient). In two cases, chorea was described as worse (Adrissi et al's second patient and Evans et al). In the remaining four patients, no details were given, despite this symptom initially having been described as present.
Only one patient was treated with ECT specifically for chorea. This patient demonstrated improvement initially and, despite worsening, their chorea never returned to the original level and was sustained at the improved level for a year.3
Our patient showed some response with respect to the choreoathetoid movements, which had become unresponsive to tetrabenazine. The medication had been withdrawn given her depression and fears of worsening those symptoms. Olanzapine, however, did not lead to any improvement in her chorea or psychiatric symptoms. Following a favourable response of the chorea to ECT, a low dose of tetrabenazine was reintroduced with good effect and had no further influence on her mood. Her gait and mobility also improved.
The use of rating scales for motor function was mentioned in only three cases. The Unified Huntington's Disease Rating Scale (UHDRS) motor score was recorded before and after only for Adrissi et al's second patient (27/31 out of a total of 124; their first case had an initial score of 49 with no follow-up score), while Petit et al's patient's UHDRS score decreased from 47 to 37 after 12 treatments and then rose to 57 after 1 year.9,10 For most cases, there was no mention of any response, which is not surprising because this was the focus of the treatment in only one of the studies. Surprisingly, despite admitting their patient specifically for the treatment of chorea (there were no psychiatric manifestations), Beale et al used no rating scales to document improvement.3
Effects on cognition
Many of the case reports mentioned problems with cognition, but few documented it with formal scores either before or after treatment. Scores were recorded before and after treatment by Nakano et al (Mini-Mental State Examination (MMSE) 27/26), Lewis et al (MMSE 23/24) and Ranen et al (second and fourth patients; MMSE 20/30 rose to 26 by discharge in the former and was 20/30 rising to 24–26/30 (administered twice) in the latter1,5,14). Cusin et al used the Montreal Cognitive Assessment (MoCA) scale for their patients and described the scores as improved, although they did not publish the values.2
Ranen et al's third patient showed a drop in MMSE from 26/30 to 18/28, with an episode of delirium after his eighth ECT treatment. No further scores were recorded, but the patient was described as ‘not completely recovered cognitively’.1 Adrissi et al's second patient had an initial MoCA of 17/20, but no further score was documented.10
Effect on medication used
Table 3 documents the treatment at admission; changes, if any, that occurred during the course of treatment for the psychiatric manifestations of disease; and discharge medication for those patients where it was recorded.
In those patients who required a number of drugs to treat the psychiatric manifestations of Huntington's disease, implying difficulty in management, there was not necessarily a requirement for more ECT doses or prolonged ECT treatment. However, in patients with pharmacological treatment resistance and the requirement for many drugs to manage symptoms, there does appear to be scope for significant rationalisation of pharmacological therapy when ECT is used adjunctively. Beale et al's patient and Cusin et al's first and sixth patients all presented between 10.5 and 19 years after diagnosis but responded well to limited ECT treatments and were discharged on much less medication.2,3 Only Adrissi et al's third patient, Ranen et al's second patient and ours required extended ECT. It is not clear why there was resistance to conventional treatment in these cases.1,10
However, this was not a consistent outcome; for example, Cusin et al's seventh patient was discharged on more medication after ECT than prior, and Adrissi et al's third and fourth patients were discharged on a comparable number of drugs to those given on admission.2,10
Effect of CAG copy number on disease or treatment
The earliest reference to CAG copy number, and therefore genetic confirmation of the diagnosis, comes from Lewis et al in 1994 – in keeping with testing, which became available after the discovery of the trinucleotide repeat a year earlier by the Huntington Disease Collaborative Research Group. Copy numbers of trinucleotide repeats have no effect on the severity of the disease, but the age of presentation is inversely correlated with increasing copy number.16
Table 4 shows copy number, number of ECT treatments and length of psychiatric symptoms for cases where this information was documented. Although those requiring more cumulative ECT treatments may appear to be clustered with those with higher repeat copy numbers, Petit et al's and Adrissi et al's second and first patients represent evidence to the contrary.9,10 Given that there was only a difference of seven CAG repeats among the 11 patients, there appears to be no significance to this. In keeping with this, the youngest patient in the review, who at 20 years old was likely to have had genetic testing, although the results of this were not documented, responded well to ECT, with his symptoms described as resolved after only seven treatments (Cusin et al's second patient2).
ECT treatment course
Treatment courses varied between three and 42 treatments in total, with a median of eight. Relapse was mentioned in seven cases (Cusin et al's fifth and sixth patients).2,4,12,13,15 For Heathfield's patient (who had three treatments) and Benson and Blumer's patients, relapse was described in general terms, with no description of the treatment course in the latter's series.12,13 In the remaining patients, it is not clear why they relapsed, except for having received relatively short courses of between five and nine ECT treatments. Merida-Puga et al's patient had treatment-resistant catatonia exacerbated by dopamine antagonists prescribed for her psychosis; this led to relapses and an extended in-patient stay.
Most patients had treatment for up to 1 year (22 patients), although our patient has been undergoing continuing maintenance treatment at increasing intervals for more than 2 years to date. Ranen et al's second patient required treatment for 4 years and Petit et al's patient for more than 1 year.1,9 Those requiring extended treatment presumably did so because of continued symptoms1,10 (see below).
Patients who had an extended course, arbitrarily taken to be more than 20 treatments (seven patients including ours1,4,9,10), did not have different characteristics from patients with similar symptoms but much less cumulative ECT treatment. Characteristics such as the nature of symptoms, length of time from diagnosis, length of time of psychiatric symptoms, age and sex did not appear to affect the number of ECT treatments. However, refractory catatonia complicating psychosis may have been a factor in extended treatment, with Ranen et al's second patient and Merida-Puga et al's patient4 requiring 35 and 42 treatments, respectively.
The four patients who had ECT more than 10 years after diagnosis1,2 (Ranen et al's sixth, Cusin et al's first, fifth and seventh patients) also showed excellent responses to ECT with between 8 and 13 treatments.
Length of seizure in seconds
Table 5 shows the seizure duration in the cases where it was recorded.1,3,4,10,11,14 Only Beale et al mentioned a reduction in seizure time from 57 s at the beginning of treatment to 19 s by the end. This was for the sole case in which ECT was administered for chorea.3 Our patient required ongoing treatment with increasing doses of ECT, although control of delusions was eventually achieved with seizure lengths between 30 and 60 s.
Dose of ECT treatment
It was not always possible to discern the dose of treatment given, as doses were rarely documented and were not necessarily consistent with other reports.1–4,10,11,14 For example, Beale et al's patient was stated as needing 72 mC initially, rising to 233 mC, with a corresponding drop in seizure duration from 57 s initially to 19 s at the end.3 When recorded, the frequency and pulse width varied. Alternatively, descriptions of percentage of maximum charge, where stated, together with the machine used (and its specifications), allowed for calculation of this figure where it was not explicitly stated (Table 5).
There did not appear to be any factors to explain why five patients, including our patient, required higher cumulative ECT treatments (Ranen et al's second patient, Adrissi et al's first, second and third patients).1,10 More generally, most patients were started on relatively low doses of ECT and titrated as treatment progressed, though this was not always documented. Only Adrissi et al's third patient was started on maximum charge dose of 100% (504 mC) due to refractory psychosis. This was later cut down to 50% (252 mC) owing to a bout of delerium that was subsequently felt to be due to medication. The presence of catatonia in Merida-Puga et al and Ranen et al's second patient may be considered a proxy for severity, but this was not the case for the other two catatonic patients (see above). Likewise, short treatment courses were reported in the earlier studies to be more likely to lead to relapse, but this was not borne out by later studies (see above). Getting the dose and the induced seizure length right appears to take more time in the out-patient setting, as may be expected. The three intense in-patient stays for our patient, Merida-Puga et al's patient and Adrissi et al's third patient (3 months in the latter two cases) allowed this to be achieved more rapidly, but the cumulative doses were all high.4,10 Overall, there appear to be no overt factors that predict who is likely to respond quickly or otherwise, although most patients will not require extended treatment based on this review.
Lead positioning
The predominant positions were RUL in 12 patients, one RUL unilateral and bilateral (unspecified), four bilateral (one bilateral frontotemporal, three bilateral) and two bitemporal (Supplementary Table 1).
Conclusion
The diagnosis of Huntington's disease is usually preceded by psychiatric symptoms in cases where family history is absent, sometimes by years.17 However, as we found in this review, patients are now likely to have an established diagnosis of Huntington's by the time they are considered for ECT. Although a CAG repeat number greater than 36 in the Huntington gene confirms the disease, an increased number of repeats is negatively correlated with age at presentation rather than severity of disease.16
Psychiatric manifestations of Huntington's disease vary according to the stage of the disease; apathy, for example, is found in 50% of patients by stage four on the UHDRS. Also present are obsessive–compulsive behaviour, irritability and aggression. Depression also increases over time, with only psychosis remaining consistent throughout at 11%.18
The prevalence of depression is about 50%, compared with anxiety at 17–61%, irritability at 35–73%, obsessive–compulsive disorders at 7–50% and psychosis at 3–11%. The prevalence of hypersexuality is between 2.1 and 30% and is slightly lower in women, whereas the prevalence of hyposexuality is higher at 63% in men and 75% in women.19 The use of ECT, however, is recommended only for depression on the basis of two of the above series.1,14,20
There appeared to be little in the way of any effect on cognition with the use of ECT, although this was not a primary concern in this patient group. In the few reports where cognition was mentioned, the patients responded well and appeared to retain comparable pre-treatment scores over time, although the numbers were too small for us to draw any firm conclusions. However, Nakano et al's patient, despite comparable pre- and post-treatment MMSE scores (and significantly improved PANSS and BPRS scores), had greatly decreased 99 mTc uptake in the basal ganglia, cingulate gyrus and thalamus on SPECT after 21 ECT treatments compared to pre-treatment SPECT.5
There is little consistent evidence regarding the use of ECT for the motor manifestations of the disease. Chorea, a hyperkinetic movement disorder, shows variable response. In the studies considered in this review, chorea often responded to ECT (including for our patient), but this finding was not always documented and thus it cannot be extrapolated to a recommendation given the small number of patients. However, psychomotor retardation and catatonia, which are manifestations of psychiatric disease, all responded favourably, although the presence of catatonia may require more protracted ECT treatment. The reported swallowing issues and weight loss in our patient and others responded well. A situation that appeared terminal in our case has been managed effectively for the patient and her family with good control, for over 2 years following the first dose of ECT.
All the studies considered in the current review were either single-case reports or retrospective case series. There were no comparison or prospective studies. The most striking aspect of this literature was how the choice of ECT as a treatment came to be prescribed. In nearly all cases, ECT was a last resort when all else had failed, with the exception of one case in which it was used for the specific management of chorea.3 Consequently, strict psychiatric criteria were lacking prior to the decision to start ECT. The main concern in using ECT was related to controlling the manifestations of psychosis or depression/suicidality, with concerns regarding other manifestations, such as outward aggression, in only a few cases. Clinical success was documented by a general clinical sense of improvement, serving as an indication of efficacy, with no clearly defined end points. Similarly, the cognitive and motor scoring of patients was haphazard and inconsistent, with only limited numbers of patients having clear objective scoring on any scales – motor, cognitive or psychiatric performance – either before or after ECT was administered in order to monitor patient responses.
It is clear that the preliminary though limited evidence from this review supports the use of ECT for relieving depressive symptoms. However, this is often considered as a last resort when all other interventions have failed. The current review suggests that additional consideration be given to the use of ECT as an adjunct in conventional treatment-resistant cases of depression, as well as for wider psychiatric manifestations of the disease, especially where depressive and psychotic symptoms coexist. These wider psychiatric manifestations and complications, which include psychomotor retardation and hallucinations, appear to respond well to the use of ECT. Where there are wider psychiatric manifestations of Huntington's disease, ECT may not only control these more effectively but could also lead to rationalisation of polypharmacy. Chorea may be less likely to respond to ECT, and so its use for this cannot be recommended based on the current review. Further investigative work with clear criteria and monitoring may lead to ECT being considered earlier and more often for patients with difficult-to-manage psychiatric manifestations of Huntington's disease.
About the authors
Walied Mowafi is a Consultant Neurologist at the Department of Neurology, Calderdale Royal Hospital, West Yorkshire, UK. Jon Millard is a Consultant Psychiatrist at South West Yorkshire Partnership NHS Foundation Trust, Wakefield, UK.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1192/bjb.2020.51.
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Declaration of interest
None.
ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjb.2020.51. | OLANZAPINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32513333 | 19,278,589 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fall'. | Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.
OBJECTIVE
The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms.
RESULTS
Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive.
CONCLUSIONS
ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.
Case report
Seven years ago, a 57-year-old woman with a family history of Huntington's disease presented with depression, changes in personality, apathy, anxiety, poor memory and clumsiness. Her genetics confirmed Huntington's disease, with a CAG repeat number of 17/46. Over the subsequent 4 years, her condition was marked by psychiatric symptoms and mild chorea, which responded well to tetrabenazine 25 mg once daily, reaching 25 mg twice daily by 2014. Her mood was controlled with citalopram followed by sertraline. Her main complaints were bouts of introversion and tearfulness, but she remained socially engaged with friends. By early 2015, her swallowing had ostensibly become problematic. However, a speech and language assessment and a gastroscopy determined that her swallowing was normal. By spring 2016, she was starting to fall often, with worsening athetoid movements and increased somnolence. These changes led to a switch in medication to olanzapine at 15 mg per day and an increase in her dose of sertraline to 100 mg a day.
By summer of 2017, her choreoathetoid movements had worsened and were accompanied by weight loss and a deterioration in her mood. She required a short in-patient stay for fluids via a nasogastric tube. A psychiatric review diagnosed her with a depressive psychosis with retarded affect, mood-congruent delusions and auditory command hallucinations. She believed she did not deserve to eat and drink, and the command hallucinations ordered her not to do so. She had extracampine hallucinations, sensing people at the end of her garden. In light of her clinical state of emaciation and the requirement for support, a trial of bilateral electroconvulsive therapy (ECT) was suggested for her depressive psychosis. A twice-weekly regimen was started, with the aim of optimising seizure length to between 30 and 60 s. In winter of 2017, she received an initial 12 courses of biweekly bilateral ECT treatments using between 75 and 150 mC. Her initial response was favourable and she became euthymic, with remission of her psychomotor retardation, but her psychotic symptoms persisted in the form of command hallucinations despite developing insight. Her delusion of guilt also resolved and, by the tenth dose of ECT, she started to eat and drink again. The initial course of treatment was complete by early February 2018 and, with the exception of her hallucinations, her psychiatric symptoms ceased and insight was retained.
However, the persistence of psychotic symptoms in the absence of a significant mood component led to an additional 12 sessions of bilateral ECT (administered biweekly with 150–225 mC; maintenance treatment consisting of bilateral 150–300 mC treatment biweekly continued into late 2019) with the aim of eradicating the hallucinations. She then developed a respiratory tract infection, which led to a relapse in her psychiatric symptoms with agitation, hallucinations, and marked choreoathetosis and dyskinesia that led to the reintroduction of tetrabenazine. Despite this setback, she did improve following the last 12 doses of ECT. This course was completed in late spring 2019. She was kept on maintenance ECT once per week, with partial remission of the auditory hallucinations, which had reduced in frequency and no longer distressed her. There was a subsequent increase in the frequency of the hallucinations, with preservation of insight, and a corresponding reduction in ECT to fortnightly. She has remained stable on this regimen to date. Her involuntary movements have also improved over that time, although she remains on tetrabenazine, haloperidol and sertraline.
Method
A literature search of PubMed for ‘Electroconvulsive therapy and Huntington's’ and ‘ECT and Huntington's’ led to the discovery of 20 papers, 18 of which were in English. Six publications were based on in vitro studies and animal studies, leaving 12 publications for review. A further three papers that were not listed in the PubMed search were sourced from references in papers from earlier years. All publications were either single-case reports or retrospective case series; there were no randomised controlled trials or prospective studies.
Consent for publication
Signed informed consent was obtained from the patient described in our case report.
Results
Table 1 shows a breakdown by demographic and disease characteristics of the 37 patients described in 15 studies. Tables 2–5 summarise the predominant psychiatric complaints, the effects of ECT on the number of medications used during ECT treatment, the CAG copy number, ECT treatment and seizure duration. Supplementary Table 1 (available online at https://doi.org/10.1192/bjb.2020.51) summarises individual patient details from the literature, including our aforementioned case. Table 1 Summary of patient characteristics and ECT treatment
Characteristic Median
Sex 43% female (7 N/A)
Age at presentation 20–65 47
Length of psychiatric symptoms (years) 0–22 2.5
Time from diagnosis to ECT (years) 0–17 3
Number of courses of ECT 3–41 8
Seizure duration (s) 5–120 40
Dose delivered (mC) 25–504 –
Lead position (out of 22 documented) 54% right unilateral
N/A, not available.
Table 2 Breakdown of main presenting symptoms
Major presenting complaint N
Depressiona 26 (18)
Choreaa 14 (1)
Suicidal ideation 13
Psychosisa 12 (6)
Dysphagia/dysarthria 10
Hallucinations 7
Aggression 6
Catatonia 4
Psychomotor retardation 4
Inappropriate sexual behaviour 2
Pain/dystonia 1
a. In total (sole reason); see text for details.
Table 3 Treatment before, during and after ECT
Study Before ECT Changes during ECT After ECT
Evans et al11 Chlorpromazine, diphenhydramine Haloperidol, trazodone Benztropine, desipramine
Ranen et al1
Patient 1 Nortriptyline Fluoxetine, lithium Desipramine
Patient 2 Nortriptyline Desipramine, haloperidol
Patient 3 Amitriptyline, carbamazepine Nortriptyline added (6 weeks) Droperidol, Chlorpromazine
Patient 4 Nortriptyline, haloperidol, carbamazepine, lorazepam (catatonia) Lithium
Lewis et al14 Haloperidol Amoxapine
Beale et al3 Haloperidol, pimozide, benztropine, diphenhydramine, Reserpine, propranolol, Diazepam (all for chorea) haloperidol, carbamazepine
Merida-Puga et al4 Risperidone, lorazepam Clozapine, olanzapine Amantadine, lorazepam, levodopa, carbidopa (catatonia)
Nakano et al5 Risperidone, olanzapine N/A
Cusin et al2
Patient 1 Clonazepam, haloperidol, levetiracetam, lorazepam, quetiapine, risperidone, tizanidine, trazodone Duloxetine
Patient 2 Chlorpromazine, citalopram, phenytoin Chlorpromazine, citalopram, lorazepam, olanzapine, phenytoin
Patient 3 Fluoxetine Aripiprazole, fluoxetine
Patient 4 Clonazepam, duloxetine, risperidone, trazodone Clonazepam, duloxetine, olanzapine, trazodone, valproic acid
Patient 5 Clonazepam, duloxetine, olanzapine, trazodone, valproic acid Clonazepam, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 6 Clozapine, duloxetine, fluoxetine, haloperidol, lamotrigine, lorazepam, methadone, milnacipran, trazodone, zolpidem Chlorpromazine, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 7 Duloxetine, olanzapine Amantadine, clonazepam, paroxetine, risperidone, sertraline, trazodone, valproic acid
Magid et al8 Olanzapine, chlorpromazine, aripiprazole, risperidone, haloperidol, fluphenazine Citalopram, mirtazapine, sertraline, trazodone Lorazepam, clonazepam, buspirone
Petit et al9 Not mentioned but patient refractory to neuroleptics, antidepressants, atypical antipsychotics and mood stabilisers Clozapine Mirtazapine
Shah et al15 Buspirone, divalproex, lorazepam, paliperidone, quetiapine, venlafaxine Quetiapine, olanzapine
Adrissi et al10
Patient 1 Nortriptyline, quetiapine, tetrabenazine Amantadine, sertraline, quetiapine
Patient 2 Haloperidol, lorazepam Lorazepam, venlafaxine
Patient 3 Amantadine, baclofen, chlorpromazine, clozapine, gabapentin, lithium Chlorpromazine, clozapine, diazepam, gabapentin
Patient 4 Bupropion, clonazepam, escitalopram, levothyroxine, lithium Bupropion, clonazepam, escitalopram, levothyroxine, trazadone
Our case Citalopram, sertraline, tetrabenazine Olanzapine Tetrabenazine, haloperidol, sertraline
N/A, not available.
Table 4 Number of trinucleotide repeats, age of diagnosis, ECT treatments and length of psychiatric symptoms prior to ECT
Cases CAG repeat copy number Age at diagnosis of Huntington's disease (years) Cumulative number of ECT treatments Psychiatric symptoms (years)
Adrissi et al10 patient 4 39 45 7 2
Petit et al9 41 59 18 20
Adrissi et al10 patient 2 42 51 27 0.5
Magid et al8 43 57 3 7
Adrissi et al10 patient 1 44 45 29 3
Nakano et al5 44 59 4 0
Lewis et al14 44 65 8 1
Merida-Puga et al4 45 26 42 5
Beale et al3 46 56 11 19
Adrissi et al10 patient 3 46 31 41 6
Our case 46 50 40 7
Table 5 ECT seizure length in seconds and treatment characteristics
Cases Seizure duration (s) Mean ECT characteristics Dose (mC)
Ranen et ala,1
Patient 1 40–120 60
Patient 2 20–50 37
Patient 3 5–35 21 70 Hz pulse width 1 s, duration 2 ms 112
Patient 4 20–55 39
Patient 5 25–45 30 (MECTA SR1)
Patient 6 40–55 46
Lewis et al14 24–140 – 90 Hz pulse width 1–1.6 ms, 33.3–57.5 J (MECTA SR1) –
Beale et al3 57–19 – (MECTA SR2) 72–233
Merida-Puga et al4 42–80 – 25% (Thymatron DGx)b 126
Cusin et al2 90 Hz pulse width 1 ms, 2–4 sc 180–360
Adrissi et al10
Patient 1 25–48 –
Patient 2 30–75 – 10–140 Hz, pulse width 0.25–1 ms, 5–50% (Thymatron IV)d 25.2–504
Patient 3 21–84 –
Patient 4 21–42 –
Evans et al11 239/6 treatments – (MECTA apparatus) –
Our case 30–60 – (Thymatron IV) 75–300
a. Double stimulus was administered in Ranen et al’s patients, but no further details were provided.
b. Assumed to be the USA version with 0.9 A and charge of 504 mC. The lowest percentage given to Merida-Puga et al’s patient was calculated according to the half-life method. While no figure was given for the lowest percentage, 25% was the maximum stated.
c. Text does not state machine used or charge or current characteristics but states 'stimulus intensities comparable to patients without HD'. 0.8 A is presumed for the purpose of calculation.
d. As per specification sheet from the manufacturer, the maximum output is 504 mC with the range calculated based on quoted percentage delivered. This machine is capable of double stimulus, but this was not mentioned in Adrissi et al's paper.
The time to ECT treatment after the diagnosis of Huntington's disease was between 0 and 17 years, with a median of 3 years and mean of 4.42 years. However, the sixth patient of Ranen et al. had previously had ECT for depression before she was diagnosed.1 The age of psychiatric symptoms at presentation for ECT varied from 0 to 22 years prior, with a median of 2.5 years and a mean of 5.73 years.
It should be noted that the diagnostic confirmation of Huntington's was solely clinical prior to 1993; however, despite the availability of genetic testing after 1993 (Huntington disease Collaborative Research Group), diagnosis only preceded presentation in this group of patients after 2013 (Cusin et al's first patient2). Prior to 2013, patients first presented on average 7.4 years before the diagnosis of Huntington's was made. After 2013, all patients with psychiatric complaints who went on to have ECT presented an average of 6.6 years after the diagnosis of Huntington's had been established. Six patients in total were diagnosed at the time of presentation, although five of them were diagnosed prior to 2013. For example, Beale et al's patient had choreiform movements (and no psychiatric manifestations) from the age of 35, but was not diagnosed until the age of 56 in 1995.3 However, this apparent lag after the introduction of genetic testing is likely to reflect the 16-year gap between Beale et al's paper in 1995 and those of Merida-Puga et al and Nakano et al in 2011 and 2013, respectively.3–5 Merida-Puga et al's patient was diagnosed following postpartum psychosis and a family history suggestive of Huntington's in her father; she went on to have ECT for catatonia. Nakano et al's patient was diagnosed owing to his brother's recent diagnosis with Huntington's at another hospital, having already received ECT for treatment-refractory psychosis.
Reason for referral for ECT
Table 2 shows a breakdown of the main characteristics of the clinical presentations; 48.6% of patients were referred for depression alone without psychotic features, and psychosis was the main cause of referral in 16%. Many of the referrals for depression alone were from some of the earliest reports, which lacked a clear description of the referral characteristics.6,7 The remainder of patients had numerous coexisting factors such as paranoia, delusions and other manifestations of psychosis, including hallucinations1,2,4,5,8–11.
Coexistent motor symptoms were present in 20 patients1–3,5,9,10,12–15 (including our case), with chorea being the most commonly used term. Involuntary movement and impaired gait were also terms used without further clarification (e.g. Cusin et al uses both terms for different patients within the same series2). Psychomotor retardation was reported in four patients1,2,10 (including our case), with one patient being described as having neurovegetative symptoms (Cusin et al,2 patient 3), and coexistent dysarthria/dysphagia in two patients. Catatonia was mentioned in four patients1,2,4 (fourth and fifth patient of series,1 postpartum4 and the second patient of series2) but was the primary focus of treatment only in Merida-Puga et al4; see Supplementary Table 1.
Effects on psychiatric symptoms
The primary reason for prescribing ECT in all but seven patients (six for psychosis and one for chorea) was depression (Table 2 and Supplementary Table 1). There were universally favourable outcomes in the use of ECT for this purpose. It was reported to be successful in most cases, and the patients who were reported to relapse did so on shorter courses of ECT.12,13 However, these were early reports, and there have been numerous subsequent reports of relatively short courses with no relapse. For example, Ranen et al's third patient, who had depression, psychosis and catatonia, only needed five ECT treatments to achieve symptom resolution.
Psychosis responded to ECT in all six patients2,4,8,11 who were reported to have it as the primary presentation, which included our case. When coexistent disease such as depression was considered, 12 patients in total had prominent psychosis, and all responded to varying degrees, including our case.1,5,9,10 Merida-Puga et al reported refractory psychosis thought to be due to use of depot dopamine antagonists, although the focus of their treatment was the refractory catatonia.4
Hallucinations, either auditory (three cases including our case),1,11,13 visual (two cases)2,10 or both visual and auditory (two cases),4,8 also responded well to treatment. The exception was Ranen et al's fourth patient, where this was unclear, although the hallucinations probably improved with the patient's other symptoms.
There were four cases of reported psychomotor retardation, including our patient1,10,12 (in addition, speech retardation was reported in Nakano et al); all were described as improved following ECT without further clarification. Benson and Blumer's first patient had a ‘temporary recovery’.
Catatonia (second and fourth patients of Ranen et al; second patient of Cusin et al1,2,4) was described in four patients and improved in all. This improvement often paralleled the response to ECT of depression, suicidality and psychosis. Two of these cases were resolved by relatively short courses of ECT (five treatments for Ranen et al's fourth patient – though their condition was, surprisingly, described as refractory – and seven treatments for Cusin et al's second patient). However, the presence of catatonia was refractory in the remaining two patients. Both Ranen et al's second patient (who relapsed repeatedly) and Merida-Puga et al's patient4 (who required withdrawal from long-acting antipsychotics) needed extended ECT courses (4 years for Ranen et al's patient but just over 3 months of an in-patient stay for the latter) to resolve the catatonia, with 35 and 42 ECT treatments, respectively. Merida-Puga et al's patient had a Busch–Francis catatonia score of 26 (total severity) on first admission, falling to 4 after a second hospital admission and discharge.
Our patient required repeated doses of ECT following a relapse of psychosis over 2 years. Eventually, she showed a partial response, with improvements in her mobility and psychomotor retardation. She started to gain weight, although her delusions persisted. Improved gait was reported in six cases, including Lewis et al and the first, fourth, fifth and sixth patients of Cusin et al, who had bilateral frontotemporal and right unilateral (RUL) placement, respectively.2,14
Disorders of eating and/or speech were mentioned for a total of ten patients. Dysphagia was mentioned in two cases (Cusin et al's2 second patient and ours) and dysarthria in another two (Cusin et al's third and sixth patients). Both dysarthria and dysphagia were reported for two patients (Cusin et al's fourth and fifth patients). For all six of these patients, their symptoms were described as resolving or dramatically improved. Refusal to eat was described in two patients (Ranen et al's second patient and Magid et al's patient1,8), while poor appetite was described in another two (Ranen et al's sixth patient and Adrissi et al's second10). Both of Ranen et al's patients were described as improved, but there was no further clarification regarding outcome for the remaining two.
Aggression,1,2,10–12,15 inappropriate sexual behaviour2,15 and agitation15 were also mentioned and described as improved.
Only two reports documented improvement using psychiatric rating scales, with the BPRS-E (Brief Psychiatric Rating Scale, Expanded) score dropping from 88 to 38 after 12 ECT sessions in Petit el al's patient, and BPRS dropping from 139 to 68 in Nakano et al's patient (the PANS (Positive and Negative Syndrome Scale) score fell from 139 to 68 in the latter).5,9 Both Beale et al and Lewis et al documented improvement in the Hamilton rating scale for depression from 36 pre-treatment to 13 post-treatment in Beale et al and 36 to 10 post-treatment in Lewis et al.3,14
Effects on motor symptoms
Chorea was mentioned in 14 cases,1–3,5,9–11,13–15 including our case (three patients of Cusin et al and two of Adrissi et al2,10). Improvement was documented in three cases (Beale et al, Petit et al and Shah et al), although five were described as showing no change (Ranen et al, Lewis et al, Nakano et al, Cusin et al's fifth patient and Adrissi et al's first patient). In two cases, chorea was described as worse (Adrissi et al's second patient and Evans et al). In the remaining four patients, no details were given, despite this symptom initially having been described as present.
Only one patient was treated with ECT specifically for chorea. This patient demonstrated improvement initially and, despite worsening, their chorea never returned to the original level and was sustained at the improved level for a year.3
Our patient showed some response with respect to the choreoathetoid movements, which had become unresponsive to tetrabenazine. The medication had been withdrawn given her depression and fears of worsening those symptoms. Olanzapine, however, did not lead to any improvement in her chorea or psychiatric symptoms. Following a favourable response of the chorea to ECT, a low dose of tetrabenazine was reintroduced with good effect and had no further influence on her mood. Her gait and mobility also improved.
The use of rating scales for motor function was mentioned in only three cases. The Unified Huntington's Disease Rating Scale (UHDRS) motor score was recorded before and after only for Adrissi et al's second patient (27/31 out of a total of 124; their first case had an initial score of 49 with no follow-up score), while Petit et al's patient's UHDRS score decreased from 47 to 37 after 12 treatments and then rose to 57 after 1 year.9,10 For most cases, there was no mention of any response, which is not surprising because this was the focus of the treatment in only one of the studies. Surprisingly, despite admitting their patient specifically for the treatment of chorea (there were no psychiatric manifestations), Beale et al used no rating scales to document improvement.3
Effects on cognition
Many of the case reports mentioned problems with cognition, but few documented it with formal scores either before or after treatment. Scores were recorded before and after treatment by Nakano et al (Mini-Mental State Examination (MMSE) 27/26), Lewis et al (MMSE 23/24) and Ranen et al (second and fourth patients; MMSE 20/30 rose to 26 by discharge in the former and was 20/30 rising to 24–26/30 (administered twice) in the latter1,5,14). Cusin et al used the Montreal Cognitive Assessment (MoCA) scale for their patients and described the scores as improved, although they did not publish the values.2
Ranen et al's third patient showed a drop in MMSE from 26/30 to 18/28, with an episode of delirium after his eighth ECT treatment. No further scores were recorded, but the patient was described as ‘not completely recovered cognitively’.1 Adrissi et al's second patient had an initial MoCA of 17/20, but no further score was documented.10
Effect on medication used
Table 3 documents the treatment at admission; changes, if any, that occurred during the course of treatment for the psychiatric manifestations of disease; and discharge medication for those patients where it was recorded.
In those patients who required a number of drugs to treat the psychiatric manifestations of Huntington's disease, implying difficulty in management, there was not necessarily a requirement for more ECT doses or prolonged ECT treatment. However, in patients with pharmacological treatment resistance and the requirement for many drugs to manage symptoms, there does appear to be scope for significant rationalisation of pharmacological therapy when ECT is used adjunctively. Beale et al's patient and Cusin et al's first and sixth patients all presented between 10.5 and 19 years after diagnosis but responded well to limited ECT treatments and were discharged on much less medication.2,3 Only Adrissi et al's third patient, Ranen et al's second patient and ours required extended ECT. It is not clear why there was resistance to conventional treatment in these cases.1,10
However, this was not a consistent outcome; for example, Cusin et al's seventh patient was discharged on more medication after ECT than prior, and Adrissi et al's third and fourth patients were discharged on a comparable number of drugs to those given on admission.2,10
Effect of CAG copy number on disease or treatment
The earliest reference to CAG copy number, and therefore genetic confirmation of the diagnosis, comes from Lewis et al in 1994 – in keeping with testing, which became available after the discovery of the trinucleotide repeat a year earlier by the Huntington Disease Collaborative Research Group. Copy numbers of trinucleotide repeats have no effect on the severity of the disease, but the age of presentation is inversely correlated with increasing copy number.16
Table 4 shows copy number, number of ECT treatments and length of psychiatric symptoms for cases where this information was documented. Although those requiring more cumulative ECT treatments may appear to be clustered with those with higher repeat copy numbers, Petit et al's and Adrissi et al's second and first patients represent evidence to the contrary.9,10 Given that there was only a difference of seven CAG repeats among the 11 patients, there appears to be no significance to this. In keeping with this, the youngest patient in the review, who at 20 years old was likely to have had genetic testing, although the results of this were not documented, responded well to ECT, with his symptoms described as resolved after only seven treatments (Cusin et al's second patient2).
ECT treatment course
Treatment courses varied between three and 42 treatments in total, with a median of eight. Relapse was mentioned in seven cases (Cusin et al's fifth and sixth patients).2,4,12,13,15 For Heathfield's patient (who had three treatments) and Benson and Blumer's patients, relapse was described in general terms, with no description of the treatment course in the latter's series.12,13 In the remaining patients, it is not clear why they relapsed, except for having received relatively short courses of between five and nine ECT treatments. Merida-Puga et al's patient had treatment-resistant catatonia exacerbated by dopamine antagonists prescribed for her psychosis; this led to relapses and an extended in-patient stay.
Most patients had treatment for up to 1 year (22 patients), although our patient has been undergoing continuing maintenance treatment at increasing intervals for more than 2 years to date. Ranen et al's second patient required treatment for 4 years and Petit et al's patient for more than 1 year.1,9 Those requiring extended treatment presumably did so because of continued symptoms1,10 (see below).
Patients who had an extended course, arbitrarily taken to be more than 20 treatments (seven patients including ours1,4,9,10), did not have different characteristics from patients with similar symptoms but much less cumulative ECT treatment. Characteristics such as the nature of symptoms, length of time from diagnosis, length of time of psychiatric symptoms, age and sex did not appear to affect the number of ECT treatments. However, refractory catatonia complicating psychosis may have been a factor in extended treatment, with Ranen et al's second patient and Merida-Puga et al's patient4 requiring 35 and 42 treatments, respectively.
The four patients who had ECT more than 10 years after diagnosis1,2 (Ranen et al's sixth, Cusin et al's first, fifth and seventh patients) also showed excellent responses to ECT with between 8 and 13 treatments.
Length of seizure in seconds
Table 5 shows the seizure duration in the cases where it was recorded.1,3,4,10,11,14 Only Beale et al mentioned a reduction in seizure time from 57 s at the beginning of treatment to 19 s by the end. This was for the sole case in which ECT was administered for chorea.3 Our patient required ongoing treatment with increasing doses of ECT, although control of delusions was eventually achieved with seizure lengths between 30 and 60 s.
Dose of ECT treatment
It was not always possible to discern the dose of treatment given, as doses were rarely documented and were not necessarily consistent with other reports.1–4,10,11,14 For example, Beale et al's patient was stated as needing 72 mC initially, rising to 233 mC, with a corresponding drop in seizure duration from 57 s initially to 19 s at the end.3 When recorded, the frequency and pulse width varied. Alternatively, descriptions of percentage of maximum charge, where stated, together with the machine used (and its specifications), allowed for calculation of this figure where it was not explicitly stated (Table 5).
There did not appear to be any factors to explain why five patients, including our patient, required higher cumulative ECT treatments (Ranen et al's second patient, Adrissi et al's first, second and third patients).1,10 More generally, most patients were started on relatively low doses of ECT and titrated as treatment progressed, though this was not always documented. Only Adrissi et al's third patient was started on maximum charge dose of 100% (504 mC) due to refractory psychosis. This was later cut down to 50% (252 mC) owing to a bout of delerium that was subsequently felt to be due to medication. The presence of catatonia in Merida-Puga et al and Ranen et al's second patient may be considered a proxy for severity, but this was not the case for the other two catatonic patients (see above). Likewise, short treatment courses were reported in the earlier studies to be more likely to lead to relapse, but this was not borne out by later studies (see above). Getting the dose and the induced seizure length right appears to take more time in the out-patient setting, as may be expected. The three intense in-patient stays for our patient, Merida-Puga et al's patient and Adrissi et al's third patient (3 months in the latter two cases) allowed this to be achieved more rapidly, but the cumulative doses were all high.4,10 Overall, there appear to be no overt factors that predict who is likely to respond quickly or otherwise, although most patients will not require extended treatment based on this review.
Lead positioning
The predominant positions were RUL in 12 patients, one RUL unilateral and bilateral (unspecified), four bilateral (one bilateral frontotemporal, three bilateral) and two bitemporal (Supplementary Table 1).
Conclusion
The diagnosis of Huntington's disease is usually preceded by psychiatric symptoms in cases where family history is absent, sometimes by years.17 However, as we found in this review, patients are now likely to have an established diagnosis of Huntington's by the time they are considered for ECT. Although a CAG repeat number greater than 36 in the Huntington gene confirms the disease, an increased number of repeats is negatively correlated with age at presentation rather than severity of disease.16
Psychiatric manifestations of Huntington's disease vary according to the stage of the disease; apathy, for example, is found in 50% of patients by stage four on the UHDRS. Also present are obsessive–compulsive behaviour, irritability and aggression. Depression also increases over time, with only psychosis remaining consistent throughout at 11%.18
The prevalence of depression is about 50%, compared with anxiety at 17–61%, irritability at 35–73%, obsessive–compulsive disorders at 7–50% and psychosis at 3–11%. The prevalence of hypersexuality is between 2.1 and 30% and is slightly lower in women, whereas the prevalence of hyposexuality is higher at 63% in men and 75% in women.19 The use of ECT, however, is recommended only for depression on the basis of two of the above series.1,14,20
There appeared to be little in the way of any effect on cognition with the use of ECT, although this was not a primary concern in this patient group. In the few reports where cognition was mentioned, the patients responded well and appeared to retain comparable pre-treatment scores over time, although the numbers were too small for us to draw any firm conclusions. However, Nakano et al's patient, despite comparable pre- and post-treatment MMSE scores (and significantly improved PANSS and BPRS scores), had greatly decreased 99 mTc uptake in the basal ganglia, cingulate gyrus and thalamus on SPECT after 21 ECT treatments compared to pre-treatment SPECT.5
There is little consistent evidence regarding the use of ECT for the motor manifestations of the disease. Chorea, a hyperkinetic movement disorder, shows variable response. In the studies considered in this review, chorea often responded to ECT (including for our patient), but this finding was not always documented and thus it cannot be extrapolated to a recommendation given the small number of patients. However, psychomotor retardation and catatonia, which are manifestations of psychiatric disease, all responded favourably, although the presence of catatonia may require more protracted ECT treatment. The reported swallowing issues and weight loss in our patient and others responded well. A situation that appeared terminal in our case has been managed effectively for the patient and her family with good control, for over 2 years following the first dose of ECT.
All the studies considered in the current review were either single-case reports or retrospective case series. There were no comparison or prospective studies. The most striking aspect of this literature was how the choice of ECT as a treatment came to be prescribed. In nearly all cases, ECT was a last resort when all else had failed, with the exception of one case in which it was used for the specific management of chorea.3 Consequently, strict psychiatric criteria were lacking prior to the decision to start ECT. The main concern in using ECT was related to controlling the manifestations of psychosis or depression/suicidality, with concerns regarding other manifestations, such as outward aggression, in only a few cases. Clinical success was documented by a general clinical sense of improvement, serving as an indication of efficacy, with no clearly defined end points. Similarly, the cognitive and motor scoring of patients was haphazard and inconsistent, with only limited numbers of patients having clear objective scoring on any scales – motor, cognitive or psychiatric performance – either before or after ECT was administered in order to monitor patient responses.
It is clear that the preliminary though limited evidence from this review supports the use of ECT for relieving depressive symptoms. However, this is often considered as a last resort when all other interventions have failed. The current review suggests that additional consideration be given to the use of ECT as an adjunct in conventional treatment-resistant cases of depression, as well as for wider psychiatric manifestations of the disease, especially where depressive and psychotic symptoms coexist. These wider psychiatric manifestations and complications, which include psychomotor retardation and hallucinations, appear to respond well to the use of ECT. Where there are wider psychiatric manifestations of Huntington's disease, ECT may not only control these more effectively but could also lead to rationalisation of polypharmacy. Chorea may be less likely to respond to ECT, and so its use for this cannot be recommended based on the current review. Further investigative work with clear criteria and monitoring may lead to ECT being considered earlier and more often for patients with difficult-to-manage psychiatric manifestations of Huntington's disease.
About the authors
Walied Mowafi is a Consultant Neurologist at the Department of Neurology, Calderdale Royal Hospital, West Yorkshire, UK. Jon Millard is a Consultant Psychiatrist at South West Yorkshire Partnership NHS Foundation Trust, Wakefield, UK.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1192/bjb.2020.51.
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Declaration of interest
None.
ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjb.2020.51. | CITALOPRAM HYDROBROMIDE, OLANZAPINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32513333 | 19,281,931 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.
OBJECTIVE
The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms.
RESULTS
Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive.
CONCLUSIONS
ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.
Case report
Seven years ago, a 57-year-old woman with a family history of Huntington's disease presented with depression, changes in personality, apathy, anxiety, poor memory and clumsiness. Her genetics confirmed Huntington's disease, with a CAG repeat number of 17/46. Over the subsequent 4 years, her condition was marked by psychiatric symptoms and mild chorea, which responded well to tetrabenazine 25 mg once daily, reaching 25 mg twice daily by 2014. Her mood was controlled with citalopram followed by sertraline. Her main complaints were bouts of introversion and tearfulness, but she remained socially engaged with friends. By early 2015, her swallowing had ostensibly become problematic. However, a speech and language assessment and a gastroscopy determined that her swallowing was normal. By spring 2016, she was starting to fall often, with worsening athetoid movements and increased somnolence. These changes led to a switch in medication to olanzapine at 15 mg per day and an increase in her dose of sertraline to 100 mg a day.
By summer of 2017, her choreoathetoid movements had worsened and were accompanied by weight loss and a deterioration in her mood. She required a short in-patient stay for fluids via a nasogastric tube. A psychiatric review diagnosed her with a depressive psychosis with retarded affect, mood-congruent delusions and auditory command hallucinations. She believed she did not deserve to eat and drink, and the command hallucinations ordered her not to do so. She had extracampine hallucinations, sensing people at the end of her garden. In light of her clinical state of emaciation and the requirement for support, a trial of bilateral electroconvulsive therapy (ECT) was suggested for her depressive psychosis. A twice-weekly regimen was started, with the aim of optimising seizure length to between 30 and 60 s. In winter of 2017, she received an initial 12 courses of biweekly bilateral ECT treatments using between 75 and 150 mC. Her initial response was favourable and she became euthymic, with remission of her psychomotor retardation, but her psychotic symptoms persisted in the form of command hallucinations despite developing insight. Her delusion of guilt also resolved and, by the tenth dose of ECT, she started to eat and drink again. The initial course of treatment was complete by early February 2018 and, with the exception of her hallucinations, her psychiatric symptoms ceased and insight was retained.
However, the persistence of psychotic symptoms in the absence of a significant mood component led to an additional 12 sessions of bilateral ECT (administered biweekly with 150–225 mC; maintenance treatment consisting of bilateral 150–300 mC treatment biweekly continued into late 2019) with the aim of eradicating the hallucinations. She then developed a respiratory tract infection, which led to a relapse in her psychiatric symptoms with agitation, hallucinations, and marked choreoathetosis and dyskinesia that led to the reintroduction of tetrabenazine. Despite this setback, she did improve following the last 12 doses of ECT. This course was completed in late spring 2019. She was kept on maintenance ECT once per week, with partial remission of the auditory hallucinations, which had reduced in frequency and no longer distressed her. There was a subsequent increase in the frequency of the hallucinations, with preservation of insight, and a corresponding reduction in ECT to fortnightly. She has remained stable on this regimen to date. Her involuntary movements have also improved over that time, although she remains on tetrabenazine, haloperidol and sertraline.
Method
A literature search of PubMed for ‘Electroconvulsive therapy and Huntington's’ and ‘ECT and Huntington's’ led to the discovery of 20 papers, 18 of which were in English. Six publications were based on in vitro studies and animal studies, leaving 12 publications for review. A further three papers that were not listed in the PubMed search were sourced from references in papers from earlier years. All publications were either single-case reports or retrospective case series; there were no randomised controlled trials or prospective studies.
Consent for publication
Signed informed consent was obtained from the patient described in our case report.
Results
Table 1 shows a breakdown by demographic and disease characteristics of the 37 patients described in 15 studies. Tables 2–5 summarise the predominant psychiatric complaints, the effects of ECT on the number of medications used during ECT treatment, the CAG copy number, ECT treatment and seizure duration. Supplementary Table 1 (available online at https://doi.org/10.1192/bjb.2020.51) summarises individual patient details from the literature, including our aforementioned case. Table 1 Summary of patient characteristics and ECT treatment
Characteristic Median
Sex 43% female (7 N/A)
Age at presentation 20–65 47
Length of psychiatric symptoms (years) 0–22 2.5
Time from diagnosis to ECT (years) 0–17 3
Number of courses of ECT 3–41 8
Seizure duration (s) 5–120 40
Dose delivered (mC) 25–504 –
Lead position (out of 22 documented) 54% right unilateral
N/A, not available.
Table 2 Breakdown of main presenting symptoms
Major presenting complaint N
Depressiona 26 (18)
Choreaa 14 (1)
Suicidal ideation 13
Psychosisa 12 (6)
Dysphagia/dysarthria 10
Hallucinations 7
Aggression 6
Catatonia 4
Psychomotor retardation 4
Inappropriate sexual behaviour 2
Pain/dystonia 1
a. In total (sole reason); see text for details.
Table 3 Treatment before, during and after ECT
Study Before ECT Changes during ECT After ECT
Evans et al11 Chlorpromazine, diphenhydramine Haloperidol, trazodone Benztropine, desipramine
Ranen et al1
Patient 1 Nortriptyline Fluoxetine, lithium Desipramine
Patient 2 Nortriptyline Desipramine, haloperidol
Patient 3 Amitriptyline, carbamazepine Nortriptyline added (6 weeks) Droperidol, Chlorpromazine
Patient 4 Nortriptyline, haloperidol, carbamazepine, lorazepam (catatonia) Lithium
Lewis et al14 Haloperidol Amoxapine
Beale et al3 Haloperidol, pimozide, benztropine, diphenhydramine, Reserpine, propranolol, Diazepam (all for chorea) haloperidol, carbamazepine
Merida-Puga et al4 Risperidone, lorazepam Clozapine, olanzapine Amantadine, lorazepam, levodopa, carbidopa (catatonia)
Nakano et al5 Risperidone, olanzapine N/A
Cusin et al2
Patient 1 Clonazepam, haloperidol, levetiracetam, lorazepam, quetiapine, risperidone, tizanidine, trazodone Duloxetine
Patient 2 Chlorpromazine, citalopram, phenytoin Chlorpromazine, citalopram, lorazepam, olanzapine, phenytoin
Patient 3 Fluoxetine Aripiprazole, fluoxetine
Patient 4 Clonazepam, duloxetine, risperidone, trazodone Clonazepam, duloxetine, olanzapine, trazodone, valproic acid
Patient 5 Clonazepam, duloxetine, olanzapine, trazodone, valproic acid Clonazepam, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 6 Clozapine, duloxetine, fluoxetine, haloperidol, lamotrigine, lorazepam, methadone, milnacipran, trazodone, zolpidem Chlorpromazine, duloxetine, fluoxetine, haloperidol, lorazepam
Patient 7 Duloxetine, olanzapine Amantadine, clonazepam, paroxetine, risperidone, sertraline, trazodone, valproic acid
Magid et al8 Olanzapine, chlorpromazine, aripiprazole, risperidone, haloperidol, fluphenazine Citalopram, mirtazapine, sertraline, trazodone Lorazepam, clonazepam, buspirone
Petit et al9 Not mentioned but patient refractory to neuroleptics, antidepressants, atypical antipsychotics and mood stabilisers Clozapine Mirtazapine
Shah et al15 Buspirone, divalproex, lorazepam, paliperidone, quetiapine, venlafaxine Quetiapine, olanzapine
Adrissi et al10
Patient 1 Nortriptyline, quetiapine, tetrabenazine Amantadine, sertraline, quetiapine
Patient 2 Haloperidol, lorazepam Lorazepam, venlafaxine
Patient 3 Amantadine, baclofen, chlorpromazine, clozapine, gabapentin, lithium Chlorpromazine, clozapine, diazepam, gabapentin
Patient 4 Bupropion, clonazepam, escitalopram, levothyroxine, lithium Bupropion, clonazepam, escitalopram, levothyroxine, trazadone
Our case Citalopram, sertraline, tetrabenazine Olanzapine Tetrabenazine, haloperidol, sertraline
N/A, not available.
Table 4 Number of trinucleotide repeats, age of diagnosis, ECT treatments and length of psychiatric symptoms prior to ECT
Cases CAG repeat copy number Age at diagnosis of Huntington's disease (years) Cumulative number of ECT treatments Psychiatric symptoms (years)
Adrissi et al10 patient 4 39 45 7 2
Petit et al9 41 59 18 20
Adrissi et al10 patient 2 42 51 27 0.5
Magid et al8 43 57 3 7
Adrissi et al10 patient 1 44 45 29 3
Nakano et al5 44 59 4 0
Lewis et al14 44 65 8 1
Merida-Puga et al4 45 26 42 5
Beale et al3 46 56 11 19
Adrissi et al10 patient 3 46 31 41 6
Our case 46 50 40 7
Table 5 ECT seizure length in seconds and treatment characteristics
Cases Seizure duration (s) Mean ECT characteristics Dose (mC)
Ranen et ala,1
Patient 1 40–120 60
Patient 2 20–50 37
Patient 3 5–35 21 70 Hz pulse width 1 s, duration 2 ms 112
Patient 4 20–55 39
Patient 5 25–45 30 (MECTA SR1)
Patient 6 40–55 46
Lewis et al14 24–140 – 90 Hz pulse width 1–1.6 ms, 33.3–57.5 J (MECTA SR1) –
Beale et al3 57–19 – (MECTA SR2) 72–233
Merida-Puga et al4 42–80 – 25% (Thymatron DGx)b 126
Cusin et al2 90 Hz pulse width 1 ms, 2–4 sc 180–360
Adrissi et al10
Patient 1 25–48 –
Patient 2 30–75 – 10–140 Hz, pulse width 0.25–1 ms, 5–50% (Thymatron IV)d 25.2–504
Patient 3 21–84 –
Patient 4 21–42 –
Evans et al11 239/6 treatments – (MECTA apparatus) –
Our case 30–60 – (Thymatron IV) 75–300
a. Double stimulus was administered in Ranen et al’s patients, but no further details were provided.
b. Assumed to be the USA version with 0.9 A and charge of 504 mC. The lowest percentage given to Merida-Puga et al’s patient was calculated according to the half-life method. While no figure was given for the lowest percentage, 25% was the maximum stated.
c. Text does not state machine used or charge or current characteristics but states 'stimulus intensities comparable to patients without HD'. 0.8 A is presumed for the purpose of calculation.
d. As per specification sheet from the manufacturer, the maximum output is 504 mC with the range calculated based on quoted percentage delivered. This machine is capable of double stimulus, but this was not mentioned in Adrissi et al's paper.
The time to ECT treatment after the diagnosis of Huntington's disease was between 0 and 17 years, with a median of 3 years and mean of 4.42 years. However, the sixth patient of Ranen et al. had previously had ECT for depression before she was diagnosed.1 The age of psychiatric symptoms at presentation for ECT varied from 0 to 22 years prior, with a median of 2.5 years and a mean of 5.73 years.
It should be noted that the diagnostic confirmation of Huntington's was solely clinical prior to 1993; however, despite the availability of genetic testing after 1993 (Huntington disease Collaborative Research Group), diagnosis only preceded presentation in this group of patients after 2013 (Cusin et al's first patient2). Prior to 2013, patients first presented on average 7.4 years before the diagnosis of Huntington's was made. After 2013, all patients with psychiatric complaints who went on to have ECT presented an average of 6.6 years after the diagnosis of Huntington's had been established. Six patients in total were diagnosed at the time of presentation, although five of them were diagnosed prior to 2013. For example, Beale et al's patient had choreiform movements (and no psychiatric manifestations) from the age of 35, but was not diagnosed until the age of 56 in 1995.3 However, this apparent lag after the introduction of genetic testing is likely to reflect the 16-year gap between Beale et al's paper in 1995 and those of Merida-Puga et al and Nakano et al in 2011 and 2013, respectively.3–5 Merida-Puga et al's patient was diagnosed following postpartum psychosis and a family history suggestive of Huntington's in her father; she went on to have ECT for catatonia. Nakano et al's patient was diagnosed owing to his brother's recent diagnosis with Huntington's at another hospital, having already received ECT for treatment-refractory psychosis.
Reason for referral for ECT
Table 2 shows a breakdown of the main characteristics of the clinical presentations; 48.6% of patients were referred for depression alone without psychotic features, and psychosis was the main cause of referral in 16%. Many of the referrals for depression alone were from some of the earliest reports, which lacked a clear description of the referral characteristics.6,7 The remainder of patients had numerous coexisting factors such as paranoia, delusions and other manifestations of psychosis, including hallucinations1,2,4,5,8–11.
Coexistent motor symptoms were present in 20 patients1–3,5,9,10,12–15 (including our case), with chorea being the most commonly used term. Involuntary movement and impaired gait were also terms used without further clarification (e.g. Cusin et al uses both terms for different patients within the same series2). Psychomotor retardation was reported in four patients1,2,10 (including our case), with one patient being described as having neurovegetative symptoms (Cusin et al,2 patient 3), and coexistent dysarthria/dysphagia in two patients. Catatonia was mentioned in four patients1,2,4 (fourth and fifth patient of series,1 postpartum4 and the second patient of series2) but was the primary focus of treatment only in Merida-Puga et al4; see Supplementary Table 1.
Effects on psychiatric symptoms
The primary reason for prescribing ECT in all but seven patients (six for psychosis and one for chorea) was depression (Table 2 and Supplementary Table 1). There were universally favourable outcomes in the use of ECT for this purpose. It was reported to be successful in most cases, and the patients who were reported to relapse did so on shorter courses of ECT.12,13 However, these were early reports, and there have been numerous subsequent reports of relatively short courses with no relapse. For example, Ranen et al's third patient, who had depression, psychosis and catatonia, only needed five ECT treatments to achieve symptom resolution.
Psychosis responded to ECT in all six patients2,4,8,11 who were reported to have it as the primary presentation, which included our case. When coexistent disease such as depression was considered, 12 patients in total had prominent psychosis, and all responded to varying degrees, including our case.1,5,9,10 Merida-Puga et al reported refractory psychosis thought to be due to use of depot dopamine antagonists, although the focus of their treatment was the refractory catatonia.4
Hallucinations, either auditory (three cases including our case),1,11,13 visual (two cases)2,10 or both visual and auditory (two cases),4,8 also responded well to treatment. The exception was Ranen et al's fourth patient, where this was unclear, although the hallucinations probably improved with the patient's other symptoms.
There were four cases of reported psychomotor retardation, including our patient1,10,12 (in addition, speech retardation was reported in Nakano et al); all were described as improved following ECT without further clarification. Benson and Blumer's first patient had a ‘temporary recovery’.
Catatonia (second and fourth patients of Ranen et al; second patient of Cusin et al1,2,4) was described in four patients and improved in all. This improvement often paralleled the response to ECT of depression, suicidality and psychosis. Two of these cases were resolved by relatively short courses of ECT (five treatments for Ranen et al's fourth patient – though their condition was, surprisingly, described as refractory – and seven treatments for Cusin et al's second patient). However, the presence of catatonia was refractory in the remaining two patients. Both Ranen et al's second patient (who relapsed repeatedly) and Merida-Puga et al's patient4 (who required withdrawal from long-acting antipsychotics) needed extended ECT courses (4 years for Ranen et al's patient but just over 3 months of an in-patient stay for the latter) to resolve the catatonia, with 35 and 42 ECT treatments, respectively. Merida-Puga et al's patient had a Busch–Francis catatonia score of 26 (total severity) on first admission, falling to 4 after a second hospital admission and discharge.
Our patient required repeated doses of ECT following a relapse of psychosis over 2 years. Eventually, she showed a partial response, with improvements in her mobility and psychomotor retardation. She started to gain weight, although her delusions persisted. Improved gait was reported in six cases, including Lewis et al and the first, fourth, fifth and sixth patients of Cusin et al, who had bilateral frontotemporal and right unilateral (RUL) placement, respectively.2,14
Disorders of eating and/or speech were mentioned for a total of ten patients. Dysphagia was mentioned in two cases (Cusin et al's2 second patient and ours) and dysarthria in another two (Cusin et al's third and sixth patients). Both dysarthria and dysphagia were reported for two patients (Cusin et al's fourth and fifth patients). For all six of these patients, their symptoms were described as resolving or dramatically improved. Refusal to eat was described in two patients (Ranen et al's second patient and Magid et al's patient1,8), while poor appetite was described in another two (Ranen et al's sixth patient and Adrissi et al's second10). Both of Ranen et al's patients were described as improved, but there was no further clarification regarding outcome for the remaining two.
Aggression,1,2,10–12,15 inappropriate sexual behaviour2,15 and agitation15 were also mentioned and described as improved.
Only two reports documented improvement using psychiatric rating scales, with the BPRS-E (Brief Psychiatric Rating Scale, Expanded) score dropping from 88 to 38 after 12 ECT sessions in Petit el al's patient, and BPRS dropping from 139 to 68 in Nakano et al's patient (the PANS (Positive and Negative Syndrome Scale) score fell from 139 to 68 in the latter).5,9 Both Beale et al and Lewis et al documented improvement in the Hamilton rating scale for depression from 36 pre-treatment to 13 post-treatment in Beale et al and 36 to 10 post-treatment in Lewis et al.3,14
Effects on motor symptoms
Chorea was mentioned in 14 cases,1–3,5,9–11,13–15 including our case (three patients of Cusin et al and two of Adrissi et al2,10). Improvement was documented in three cases (Beale et al, Petit et al and Shah et al), although five were described as showing no change (Ranen et al, Lewis et al, Nakano et al, Cusin et al's fifth patient and Adrissi et al's first patient). In two cases, chorea was described as worse (Adrissi et al's second patient and Evans et al). In the remaining four patients, no details were given, despite this symptom initially having been described as present.
Only one patient was treated with ECT specifically for chorea. This patient demonstrated improvement initially and, despite worsening, their chorea never returned to the original level and was sustained at the improved level for a year.3
Our patient showed some response with respect to the choreoathetoid movements, which had become unresponsive to tetrabenazine. The medication had been withdrawn given her depression and fears of worsening those symptoms. Olanzapine, however, did not lead to any improvement in her chorea or psychiatric symptoms. Following a favourable response of the chorea to ECT, a low dose of tetrabenazine was reintroduced with good effect and had no further influence on her mood. Her gait and mobility also improved.
The use of rating scales for motor function was mentioned in only three cases. The Unified Huntington's Disease Rating Scale (UHDRS) motor score was recorded before and after only for Adrissi et al's second patient (27/31 out of a total of 124; their first case had an initial score of 49 with no follow-up score), while Petit et al's patient's UHDRS score decreased from 47 to 37 after 12 treatments and then rose to 57 after 1 year.9,10 For most cases, there was no mention of any response, which is not surprising because this was the focus of the treatment in only one of the studies. Surprisingly, despite admitting their patient specifically for the treatment of chorea (there were no psychiatric manifestations), Beale et al used no rating scales to document improvement.3
Effects on cognition
Many of the case reports mentioned problems with cognition, but few documented it with formal scores either before or after treatment. Scores were recorded before and after treatment by Nakano et al (Mini-Mental State Examination (MMSE) 27/26), Lewis et al (MMSE 23/24) and Ranen et al (second and fourth patients; MMSE 20/30 rose to 26 by discharge in the former and was 20/30 rising to 24–26/30 (administered twice) in the latter1,5,14). Cusin et al used the Montreal Cognitive Assessment (MoCA) scale for their patients and described the scores as improved, although they did not publish the values.2
Ranen et al's third patient showed a drop in MMSE from 26/30 to 18/28, with an episode of delirium after his eighth ECT treatment. No further scores were recorded, but the patient was described as ‘not completely recovered cognitively’.1 Adrissi et al's second patient had an initial MoCA of 17/20, but no further score was documented.10
Effect on medication used
Table 3 documents the treatment at admission; changes, if any, that occurred during the course of treatment for the psychiatric manifestations of disease; and discharge medication for those patients where it was recorded.
In those patients who required a number of drugs to treat the psychiatric manifestations of Huntington's disease, implying difficulty in management, there was not necessarily a requirement for more ECT doses or prolonged ECT treatment. However, in patients with pharmacological treatment resistance and the requirement for many drugs to manage symptoms, there does appear to be scope for significant rationalisation of pharmacological therapy when ECT is used adjunctively. Beale et al's patient and Cusin et al's first and sixth patients all presented between 10.5 and 19 years after diagnosis but responded well to limited ECT treatments and were discharged on much less medication.2,3 Only Adrissi et al's third patient, Ranen et al's second patient and ours required extended ECT. It is not clear why there was resistance to conventional treatment in these cases.1,10
However, this was not a consistent outcome; for example, Cusin et al's seventh patient was discharged on more medication after ECT than prior, and Adrissi et al's third and fourth patients were discharged on a comparable number of drugs to those given on admission.2,10
Effect of CAG copy number on disease or treatment
The earliest reference to CAG copy number, and therefore genetic confirmation of the diagnosis, comes from Lewis et al in 1994 – in keeping with testing, which became available after the discovery of the trinucleotide repeat a year earlier by the Huntington Disease Collaborative Research Group. Copy numbers of trinucleotide repeats have no effect on the severity of the disease, but the age of presentation is inversely correlated with increasing copy number.16
Table 4 shows copy number, number of ECT treatments and length of psychiatric symptoms for cases where this information was documented. Although those requiring more cumulative ECT treatments may appear to be clustered with those with higher repeat copy numbers, Petit et al's and Adrissi et al's second and first patients represent evidence to the contrary.9,10 Given that there was only a difference of seven CAG repeats among the 11 patients, there appears to be no significance to this. In keeping with this, the youngest patient in the review, who at 20 years old was likely to have had genetic testing, although the results of this were not documented, responded well to ECT, with his symptoms described as resolved after only seven treatments (Cusin et al's second patient2).
ECT treatment course
Treatment courses varied between three and 42 treatments in total, with a median of eight. Relapse was mentioned in seven cases (Cusin et al's fifth and sixth patients).2,4,12,13,15 For Heathfield's patient (who had three treatments) and Benson and Blumer's patients, relapse was described in general terms, with no description of the treatment course in the latter's series.12,13 In the remaining patients, it is not clear why they relapsed, except for having received relatively short courses of between five and nine ECT treatments. Merida-Puga et al's patient had treatment-resistant catatonia exacerbated by dopamine antagonists prescribed for her psychosis; this led to relapses and an extended in-patient stay.
Most patients had treatment for up to 1 year (22 patients), although our patient has been undergoing continuing maintenance treatment at increasing intervals for more than 2 years to date. Ranen et al's second patient required treatment for 4 years and Petit et al's patient for more than 1 year.1,9 Those requiring extended treatment presumably did so because of continued symptoms1,10 (see below).
Patients who had an extended course, arbitrarily taken to be more than 20 treatments (seven patients including ours1,4,9,10), did not have different characteristics from patients with similar symptoms but much less cumulative ECT treatment. Characteristics such as the nature of symptoms, length of time from diagnosis, length of time of psychiatric symptoms, age and sex did not appear to affect the number of ECT treatments. However, refractory catatonia complicating psychosis may have been a factor in extended treatment, with Ranen et al's second patient and Merida-Puga et al's patient4 requiring 35 and 42 treatments, respectively.
The four patients who had ECT more than 10 years after diagnosis1,2 (Ranen et al's sixth, Cusin et al's first, fifth and seventh patients) also showed excellent responses to ECT with between 8 and 13 treatments.
Length of seizure in seconds
Table 5 shows the seizure duration in the cases where it was recorded.1,3,4,10,11,14 Only Beale et al mentioned a reduction in seizure time from 57 s at the beginning of treatment to 19 s by the end. This was for the sole case in which ECT was administered for chorea.3 Our patient required ongoing treatment with increasing doses of ECT, although control of delusions was eventually achieved with seizure lengths between 30 and 60 s.
Dose of ECT treatment
It was not always possible to discern the dose of treatment given, as doses were rarely documented and were not necessarily consistent with other reports.1–4,10,11,14 For example, Beale et al's patient was stated as needing 72 mC initially, rising to 233 mC, with a corresponding drop in seizure duration from 57 s initially to 19 s at the end.3 When recorded, the frequency and pulse width varied. Alternatively, descriptions of percentage of maximum charge, where stated, together with the machine used (and its specifications), allowed for calculation of this figure where it was not explicitly stated (Table 5).
There did not appear to be any factors to explain why five patients, including our patient, required higher cumulative ECT treatments (Ranen et al's second patient, Adrissi et al's first, second and third patients).1,10 More generally, most patients were started on relatively low doses of ECT and titrated as treatment progressed, though this was not always documented. Only Adrissi et al's third patient was started on maximum charge dose of 100% (504 mC) due to refractory psychosis. This was later cut down to 50% (252 mC) owing to a bout of delerium that was subsequently felt to be due to medication. The presence of catatonia in Merida-Puga et al and Ranen et al's second patient may be considered a proxy for severity, but this was not the case for the other two catatonic patients (see above). Likewise, short treatment courses were reported in the earlier studies to be more likely to lead to relapse, but this was not borne out by later studies (see above). Getting the dose and the induced seizure length right appears to take more time in the out-patient setting, as may be expected. The three intense in-patient stays for our patient, Merida-Puga et al's patient and Adrissi et al's third patient (3 months in the latter two cases) allowed this to be achieved more rapidly, but the cumulative doses were all high.4,10 Overall, there appear to be no overt factors that predict who is likely to respond quickly or otherwise, although most patients will not require extended treatment based on this review.
Lead positioning
The predominant positions were RUL in 12 patients, one RUL unilateral and bilateral (unspecified), four bilateral (one bilateral frontotemporal, three bilateral) and two bitemporal (Supplementary Table 1).
Conclusion
The diagnosis of Huntington's disease is usually preceded by psychiatric symptoms in cases where family history is absent, sometimes by years.17 However, as we found in this review, patients are now likely to have an established diagnosis of Huntington's by the time they are considered for ECT. Although a CAG repeat number greater than 36 in the Huntington gene confirms the disease, an increased number of repeats is negatively correlated with age at presentation rather than severity of disease.16
Psychiatric manifestations of Huntington's disease vary according to the stage of the disease; apathy, for example, is found in 50% of patients by stage four on the UHDRS. Also present are obsessive–compulsive behaviour, irritability and aggression. Depression also increases over time, with only psychosis remaining consistent throughout at 11%.18
The prevalence of depression is about 50%, compared with anxiety at 17–61%, irritability at 35–73%, obsessive–compulsive disorders at 7–50% and psychosis at 3–11%. The prevalence of hypersexuality is between 2.1 and 30% and is slightly lower in women, whereas the prevalence of hyposexuality is higher at 63% in men and 75% in women.19 The use of ECT, however, is recommended only for depression on the basis of two of the above series.1,14,20
There appeared to be little in the way of any effect on cognition with the use of ECT, although this was not a primary concern in this patient group. In the few reports where cognition was mentioned, the patients responded well and appeared to retain comparable pre-treatment scores over time, although the numbers were too small for us to draw any firm conclusions. However, Nakano et al's patient, despite comparable pre- and post-treatment MMSE scores (and significantly improved PANSS and BPRS scores), had greatly decreased 99 mTc uptake in the basal ganglia, cingulate gyrus and thalamus on SPECT after 21 ECT treatments compared to pre-treatment SPECT.5
There is little consistent evidence regarding the use of ECT for the motor manifestations of the disease. Chorea, a hyperkinetic movement disorder, shows variable response. In the studies considered in this review, chorea often responded to ECT (including for our patient), but this finding was not always documented and thus it cannot be extrapolated to a recommendation given the small number of patients. However, psychomotor retardation and catatonia, which are manifestations of psychiatric disease, all responded favourably, although the presence of catatonia may require more protracted ECT treatment. The reported swallowing issues and weight loss in our patient and others responded well. A situation that appeared terminal in our case has been managed effectively for the patient and her family with good control, for over 2 years following the first dose of ECT.
All the studies considered in the current review were either single-case reports or retrospective case series. There were no comparison or prospective studies. The most striking aspect of this literature was how the choice of ECT as a treatment came to be prescribed. In nearly all cases, ECT was a last resort when all else had failed, with the exception of one case in which it was used for the specific management of chorea.3 Consequently, strict psychiatric criteria were lacking prior to the decision to start ECT. The main concern in using ECT was related to controlling the manifestations of psychosis or depression/suicidality, with concerns regarding other manifestations, such as outward aggression, in only a few cases. Clinical success was documented by a general clinical sense of improvement, serving as an indication of efficacy, with no clearly defined end points. Similarly, the cognitive and motor scoring of patients was haphazard and inconsistent, with only limited numbers of patients having clear objective scoring on any scales – motor, cognitive or psychiatric performance – either before or after ECT was administered in order to monitor patient responses.
It is clear that the preliminary though limited evidence from this review supports the use of ECT for relieving depressive symptoms. However, this is often considered as a last resort when all other interventions have failed. The current review suggests that additional consideration be given to the use of ECT as an adjunct in conventional treatment-resistant cases of depression, as well as for wider psychiatric manifestations of the disease, especially where depressive and psychotic symptoms coexist. These wider psychiatric manifestations and complications, which include psychomotor retardation and hallucinations, appear to respond well to the use of ECT. Where there are wider psychiatric manifestations of Huntington's disease, ECT may not only control these more effectively but could also lead to rationalisation of polypharmacy. Chorea may be less likely to respond to ECT, and so its use for this cannot be recommended based on the current review. Further investigative work with clear criteria and monitoring may lead to ECT being considered earlier and more often for patients with difficult-to-manage psychiatric manifestations of Huntington's disease.
About the authors
Walied Mowafi is a Consultant Neurologist at the Department of Neurology, Calderdale Royal Hospital, West Yorkshire, UK. Jon Millard is a Consultant Psychiatrist at South West Yorkshire Partnership NHS Foundation Trust, Wakefield, UK.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1192/bjb.2020.51.
click here to view supplementary material
Declaration of interest
None.
ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjb.2020.51. | CITALOPRAM HYDROBROMIDE, OLANZAPINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 32513333 | 19,281,931 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Back pain'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiovascular disorder'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Headache'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myalgia'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oropharyngeal pain'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pruritus'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rhinitis'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vertigo'. | PCSK9 Inhibitors in a German Single-Center Clinical Practice: Real-World Treatment of Patients at High Cardiovascular Risk Over 68 Weeks.
OBJECTIVE
Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs).
OBJECTIVE
We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks.
METHODS
In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68.
RESULTS
At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68.
CONCLUSIONS
Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.
Key points
In a clinical single-center practice, the PCSK9 inhibitors alirocumab and evolocumab demonstrated long-term reductions of low-density lipoprotein cholesterol (LDL-C) similar to previously reported clinical trial data.
In addition, a greater LDL-C reduction was observed in patients receiving both PCSK9 inhibitor and statin therapies compared with those who received PCSK9 inhibitor treatment but were intolerant to statins.
PCSK9 inhibitor therapy was generally well tolerated and 8.5% of study participants discontinued treatment due to adverse events.
Introduction
Reductions in low-density lipoprotein cholesterol (LDL-C) are associated with reduced cardiovascular risk [1]. Several lipid guidelines and consensus statements recommend that it may be reasonable to consider protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk, including those with cardiovascular disease (CVD) or heterozygous familial hypercholesterolaemia (HeFH) who have persisting high LDL-C levels despite receiving maximally tolerated statin treatment with or without other non-PCSK9i lipid-lowering therapies (LLTs) [1, 2], also including patients who are statin intolerant [1]. In 2019, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C target recommendations for patients at very high and high cardiovascular risk were lowered from < 1.81 mmol/L (< 70 mg/dL, very high risk) or < 2.59 mmol/L (< 100 mg/dL, high risk) to < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L (< 70 mg/dL), respectively [1–3].
In 2015, two PCSK9i—alirocumab and evolocumab—became available to treat therapy-refractory hypercholesterolemia [4–7]. An ongoing patent infringement lawsuit means that alirocumab is not currently available in Germany [8], but it remains on the market and approved for use in other European countries. Treatment with alirocumab 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W), alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W resulted in significant percentage reductions in LDL-C in clinical phase III trials including patients with or without prior cardiovascular events or HeFH [9–12]. Both PCSK9i therapies have been shown to improve cardiovascular outcomes [11, 12].
In contrast to clinical studies that enrolled patients using more tightly controlled inclusion criteria, PCSK9i are prescribed to patients with a variety of comorbidities in real-world routine care; however, limited real-world data are available [13–19].
The aim of this study was to assess the short-term (2–4 weeks) and long-term (68 weeks) effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W in a large patient cohort (n = 635) in a real-world setting in a single-center practice in Germany.
Methods
This noninterventional, prospective, observational, single-center study was performed at the lipid clinic of the Charité Universitätsmedizin Berlin in Germany (noninterventional study number 342) [20]. The decision to prescribe either alirocumab or evolocumab was independent from study participation, and all treatment decisions remained at the discretion of the treating physician. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and all applicable amendments laid down by the World Medical Assemblies and the International Conference Harmonization guidelines for good clinical practice. The protocol was approved by the institute’s ethics committee on human research (EA4/178/15). All patients provided written informed consent prior to documentation.
Study Design
Patients recruited from the outpatient lipid clinic of the Charité Universitätsmedizin Berlin (Berlin, Germany) between 2015 and 2018 were eligible for participation if their LDL-C levels were (1) ≥ 1.81 mmol/L (≥ 70 mg/dL) with established CVD or (2) ≥ 2.59 mmol/L (≥ 100 mg/dL) with HeFH and without CVD. Enrolled patients were treated with either alirocumab or evolocumab according to the summary of product characteristics [5, 6].
All patients had hypercholesterolemia, with either very high cardiovascular risk according to ESC/EAS guidelines [1], HeFH and family history of early CVD despite maximally tolerated LLT, or homozygous FH. Cardiovascular risk was defined according to ESC guidelines [1]. HeFH diagnosis was defined by clinical criteria (World Health Organization/Dutch Lipid Clinic Network score > 8 points).
PCSK9i were prescribed Q2W on top of statin therapy and other LLTs. Patients were allocated to receive either alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W according to investigator’s judgement, with both study drugs being equally prescribed. Throughout the study, physicians were able to adjust the treatment dose (75 mg Q2W, 150 mg Q2W, or 140 mg Q2W) of the PCSK9i (alirocumab or evolocumab) and other non-PCSK9i LLTs according to their own clinical judgment and the summaries of product characteristics [5, 6].
Statin intolerance was defined as the inability to tolerate three or more statins according to patient’s adverse events (AE) and/or objective parameters (i.e., increased levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase) [21, 22]. For statin-treated patients, the intensity of statin therapy was categorized as low intensity (simvastatin 10 mg, pravastatin 10–20 mg, or fluvastatin 20–40 mg), moderate intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–80 mg, pravastatin 40 mg, or fluvastatin 80 mg), and high intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) [23].
Prior to treatment start, patients completed a standard questionnaire regarding medical history and underwent a routine clinical examination. Diabetes mellitus, hypertension, and CVD (defined as coronary artery disease and/or cerebral artery disease and/or peripheral artery disease) were identified from medical records.
All patients received usage instructions from a physician. The study inclusion criteria were PCSK9i prescription, informed consent in the form of written authorization, and patient age ≥ 18 years.
Study Endpoints
The primary effectiveness endpoint of this study was percentage change in LDL-C from baseline to week 68.
Secondary effectiveness endpoints included (1) percentage change from baseline to week 4 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) B, lipoprotein (a) [Lp(a)], total cholesterol, and Apo A1 and (2) percentage change from baseline to week 68 in HDL-C, non-HDL-C, and triglycerides.
Patient blood samples were taken and lipid data were recorded before the start of PCSK9i therapy (baseline; week 0) and after 4 weeks and approximately 68 weeks of treatment. Laboratory tests using fasting blood samples were performed at a local laboratory (Labor Berlin, Berlin, Germany) before and after 1 month of treatment during routine visits to the outpatient clinic. At weeks 4 and 68, laboratory data were obtained from the most recent available blood sample. Apo A1, Apo B, and Lp(a) were only measured at baseline (week 0) and week 4.
LDL-C was measured via beta-quantification. Pre-LLT LDL-C levels (LDL-C value without any concomitant LLT) were calculated based on conversion factors as previously described [24].
Safety was assessed regardless of treatment allocation by monitoring AEs during an in-clinic interview after 2 weeks and during either a telephone interview or routine in-clinic visit after approximately 68 weeks. No severity of AEs was recorded.
Statistical Analysis
All quantitative data of continuous and categorical variables were summarized using means and standard deviations or medians and interquartile ranges (IQRs) (Q3: 75% percentile minus Q1: 25% percentile) where appropriate. Changes in lipid levels are shown as absolute changes (defined as arithmetic mean/median of week 4 or week 68 minus baseline) and percentage changes (defined as ratio of mean/median). The paired and unpaired sample t-test was used to compare normally distributed values; skewed data were log transformed before analyses. The Wilcoxon rank-sum test was used for skewed variables (triglycerides and Lp(a)) to compare absolute changes; the t-test was used to compare percent changes. The chi-quadrat test was used to compare categorical data. Pearson correlation coefficients were used to examine associations between variables. Comparisons among the groups were made with analysis of variance. To account for missing follow-up data, linear mixed-model analyses were performed as post hoc sensitivity analyses including all percentage LDL changes from baseline to weeks 4 and 68 (both calculated from baseline LDL) while accounting for missing follow-data and repeated measures using a first-order autoregressive covariance structure and adjusting for follow-up time and prescribed PCSK9i. All statistical analyses were carried out using SAS Enterprise Guide V7.15 (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics
Of 704 eligible patients, 635 were included in this study at baseline and 69 were excluded because of incomplete clinical or laboratory data (electronic supplementary material [ESM] Fig. S1). Overall, 310 patients with complete follow-up data who received PCSK9i therapy for at least 1 year were included in the follow-up analysis. The remaining 325 patients were not included in the follow-up analysis because follow-up data were missing as these patients received PCSK9i therapy for less than 1 year.
At baseline (prior to study drug treatment), the study cohort consisted of 635 patients. Across all PCSK9i treatment groups, 19.4–26.4% of patients had diabetes mellitus, 56.9–66.7% reported hypertension, and 86.3–92.0% had a history of CVD, with coronary heart disease (CHD) being most common (49.5–57.9%; ESM Table S1). In total, 50.4–60.3% of patients were statin intolerant. The mean LDL-C levels prior to receiving any LLT (including statins) were 5.3–6.2 mmol/L (203.5–238.0 mg/dL). Before receiving PCSK9i treatment, patients enrolled in the alirocumab 75 mg group had lower mean LDL-C levels (3.5 mmol/L [135.6 mg/dL]) than those in the remaining groups (4.3–4.4 mmol/L [167.7–170.2 mg/dL]). The median follow-up period was 68 weeks (IQR 20) after enrolment, with data being available for 310 patients. In total, 2.4% (14/635) of patients discontinued the study after 4 weeks and an additional 6.8% (21/310) discontinued after 68 weeks (reasons: AEs, n = 33; pregnancy, n = 1; no improvement in LDL-C levels with both PCSK9i, n = 1; ESM Fig. S1).
Effectiveness Analysis—Overall Patient Population
The initial study drug dose was alirocumab 75 mg Q2W in 19.7% of patients (n = 125), alirocumab 150 mg Q2W in 30.7% (n = 195), and evolocumab 140 mg Q2W in 49.6% (n = 315). In total, 81.0% (n = 51) of patients in the alirocumab 75 mg Q2W, 75.0% (n = 81) in the alirocumab 150 mg Q2W, and 84.9% (n = 118) in the evolocumab 140 mg Q2W groups remained on their initially prescribed PCSK9i dose throughout the study (ESM Table S2). At week 68, in total, 15.9% and 3.2% of patients in the alirocumab 75 mg Q2W group were initially prescribed alirocumab 150 mg Q2W and evolocumab 140 mg Q2W, respectively.
In patients who remained on their initially prescribed PCSK9i dose, mean percentage change from baseline to week 68 in LDL-C was − 41.7% in the alirocumab 75 mg Q2W group, − 53.7% in the alirocumab 150 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group), and − 54.1% in the evolocumab 140 mg Q2W group (P < 0.05 vs. alirocumab 75 mg Q2W group; ESM Table S3). Similar results were obtained with linear mixed-model analyses, which account for missing follow-up data. LDL-C reductions remained largely similar from weeks 4 to 68 in each treatment group (Fig. 1 and ESM Table S3). At week 4, alirocumab 150 mg Q2W and evolocumab 140 mg Q2W reduced LDL-C from baseline by 59.0% and 57.5%, respectively. In the alirocumab 75 mg group, the LDL-C reduction of 48.1% from baseline to week 4 was significantly lower than in the other treatment groups (all P < 0.05). Waterfall plots of individual patient data at weeks 4 and 68 showed a similar distribution of percentage LDL-C reduction in all PCSK9i groups (Fig. 2). No nonresponders with LDL-C reduction < 10% from baseline were observed.Fig. 1 LDL-C levels over time in patients continuously treated with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W. The area highlighted in grey shows LDL-C ≤ 1.81 mmol/L (≤ 70 mg/dL). Data values show mean percentage LDL-C reduction from baseline at weeks 4 and 68 (95% CI). aP < 0.05 vs. alirocumab 75 mg. CI confidence interval, LDL-C low-density lipoprotein cholesterol, Q2W every 2 weeks, SE standard error
Fig. 2 Waterfall plots of percentage low-density lipoprotein cholesterol (LDL-C) reduction from baseline to (a) week 4 and (b) week 68 according to treatment received at week 68
Regardless of treatment allocation, 59.5% of patients at week 4 and 57.3% at week 68 achieved LDL-C < 1.81 mmol/L (70 mg/dL) or < 2.59 mmol/L (100 mg/dL), depending on cardiovascular risk. Overall, 57.5% and 54.8% of patients achieved LDL-C < 1.81 mmol/L (70 mg/dL) at weeks 4 and 68, respectively.
Regardless of PCSK9i treatment, improvements in lipid levels from baseline to weeks 4 and 68 were observed (Fig. 1 and ESM Table S3). At week 4, percentage reductions from baseline in non-HDL-C, total cholesterol, Lp(a), and Apo B were significantly lower in the alirocumab 75 mg Q2W versus alirocumab 150 mg Q2W and evolocumab 140 mg Q2W groups (all P < 0.05; ESM Table S3). Similar results were observed at week 68, except for nonsignificant differences in LDL-C percentage reduction between the alirocumab 75 mg Q2W and alirocumab 150 Q2W groups. No week 68 data were available for Lp(a), Apo B, and Apo A1.
In exploratory analyses, we assessed the associations between changes in Lp(a) due to PCSK9i therapy and concomitant changes in LDL-C and baseline Lp(a) (Fig. 3). At week 4, increased percentage Lp(a) reduction was associated with a greater concomitant percentage LDL-C reduction (r = 0.31, P < 0.0001; Fig. 3a), and a higher Lp(a) concentration at baseline was associated with reduced percentage reduction in Lp(a) (r = 0.21, P < 0.0001; Fig. 3b). In patients with baseline Lp(a) levels < 72 mmol/L, a higher baseline Lp(a) was associated with a greater percentage reduction in Lp(a) with PCSK9i therapy (r = –0.26, P = 0.0003; Fig. 3c). In contrast, no association was observed in patients with baseline Lp(a) levels > 72 mmol/L (P = 0.21; Fig. 3d).Fig. 3 Association between percentage Lp(a) reduction and (a) percentage LDL-C reduction from baseline to week 4, baseline Lp(a) (b) for the overall population and according to (c) Lp(a) < 72 mmol/L and (d) Lp(a) > 72 mmol/L. LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a)
In total, 12.6% of patients reported cardiovascular events over the course of the study, with revascularization being the most common (8.1%; ESM Table S4).
Effectiveness Analysis According to Statin Therapy Status
Greater percentage reductions from baseline to week 4 in LDL-C, total cholesterol, and triglycerides were observed in patients receiving statin therapy than in those with statin intolerance (P < 0.05; Fig. 4a). In patients with statin intolerance, a higher baseline Dutch Lipid Clinic Network Score was associated with a reduced percentage LDL-C reduction from baseline at week 4 (r = 0.22, P < 0.0001; Fig. 4b). In contrast, no association was observed in patients receiving statins (Fig. 4c).Fig. 4 Influence of statin therapy on PCSK9i effectiveness regardless of treatment allocation: (a) mean percentage change from baseline to week 4 for lipids, and correlation of percentage change of LDL-C from baseline to week 4 according to Dutch Lipid Clinic Network Score in (b) patients not receiving statins and (c) those receiving statins. *P < 0.05 and ***P < 0.0001 (both assessed by unpaired t-test). FH familial hypercholesterolaemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lp(a) lipoprotein (a), PCSK9i protein convertase subtilisin/kexin type 9 inhibitor
Safety Analysis
Overall, a total of 47.7% of patients had reported AEs by week 2 (after the first treatment dose), with rhinitis (17.4%), fatigue (15.7%), and myalgia (9.1%) being among the most common (ESM Table S5). In total, 47.1% of patients reported AEs throughout the study, with myalgia (12.6%), rhinitis (11.6%), and fatigue (10.3%) being the most common. A total of 2.4% of patients discontinued the study due to AEs at week 2 and a further 6.1% discontinued by week 68. By week 68, a total of 8.7% of patients had changed PCSK9i treatment because of AEs.
In a safety analysis by sex, 41.1% of male patients and 57.1% of female patients had reported AEs by week 2 (ESM Table S6). Significant differences were observed between both groups for fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus (all P ≤ 0.05). These sex-specific differences were not observed at week 68 (ESM Table S6).
Discussion
In this study presenting real-world data from patients receiving maximally tolerated statin and other non-PCSK9i LLTs, LDL-C levels were reduced from baseline to week 68 by 43.2% in the alirocumab 75 mg Q2W group, 53.8% in the alirocumab 150 mg Q2W group, and 53.3% in the evolocumab 140 mg Q2W group.
The observed alirocumab effectiveness data were consistent with results from a pooled analysis from eight ODYSSEY phase III studies (n = 4629), in particular the study pool with the dosing regimen 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) showing 48.6–48.9% reduction in LDL-C levels from baseline to week 24 in alirocumab-treated patients (placebo, 4.2% increase; ezetimibe, 19.3% reduction) [9]. Clinical study results for evolocumab 140 mg Q2W were generally similar to effectiveness results from this study, showing reductions in LDL-C levels from baseline to week 12 of an average of 57.0% in 614 patients with LDL-C ≥ 2.59 mmol/L (100 mg/dL) and < 4.91 mmol/L (190 mg/dL; placebo, 0.1% reduction) [25]. These data are also consistent with an audit study in the UK showing a reduction in LDL-C levels of 49% in patients (n = 105) on maximally tolerated statin who received PCSK9i therapy [18] and an alirocumab expanded use program demonstrating that alirocumab 150 mg Q2W reduced LDL-C levels by 55.1% at week 24 in patients with HeFH and/or CHD in the USA [26]. In an outpatient clinic in the Netherlands, approximately 17 months of treatment with either alirocumab or evolocumab resulted in a mean LDL-C reduction of 55% from baseline (4.4 mmol/L [170.1 mg/dL]) in a cohort of 238 patients, with similar reductions being observed across alirocumab (75 mg Q2W or 150 mg Q2W) and evolocumab dose regimens (140 mg Q2W or 420 mg monthly) [13]. In a retrospective study (n = 122) in Italy, a mean LDL-C reduction of 52% from baseline (4.5 mmol/L [174 mg/dL]) was observed after approximately 13 months of treatment with either alirocumab or evolocumab, with no difference between drug regimens [27].
In comparison, this present study enrolled more patients (n = 635) and assessed the effectiveness according to evolocumab and alirocumab dose regimens at weeks 4 and 68, demonstrating significantly (P < 0.05) lower LDL-C reductions in the alirocumab 75 mg Q2W group than in either the alirocumab 150 mg Q2W group or the evolocumab 140 mg Q2W group. In contrast to a previously published systematic review and network meta-analysis of LLTs (69 trials) demonstrating approximately 10% greater reduction with evolocumab than with alirocumab 150 mg Q2W, the reductions in LDL-C with alirocumab 150 mg Q2W and evolocumab 140 mg Q2W were similar in this study [28].
ESC/EAS lipid guidelines recommend treatment goals of < 1.42 mmol/L (< 55 mg/dL) or < 1.81 mmol/L ( 70 mg/dL) in patients at very high and high cardiovascular risk, respectively [3]. In this study, LDL-C target levels were < 1.81 mmol/L (< 70 mg/dL) or < 2.59 mmol/L (< 100 mg/dL), depending on cardiovascular risk and based on 2016 ESC/EAS guidelines, which were relevant during patient enrolment in this study [1]. LDL-C target levels were achieved by 59.5% of patients at week 4 and by 57.3% at week 68 regardless of PCSK9i treatment. Similar results were observed at week 24 in the ODYSSEY ALTERNATIVE study (41.9%) and at week 96 in the ODYSSEY OLE study (55.3%) [29, 30].
In many countries, such as the USA, PCSK9i accessibility is limited because they are more expensive than other LLTs [31, 32]. However, in Germany, there is no possible barrier to access PCSK9i as they can be prescribed according to directives from the Federal Joint Committee (“Gemeinsamer Bundesausschuss”), which are based on ESC guidelines [33, 34]. Compulsory health insurance accepts full responsibility for these costs.
For this study, the dose interval remained at Q2W throughout the study period and was not adjusted to every 4 weeks; however, possible benefits from extending the dosing interval to every 3 weeks to further individualize treatment were shown [35].
It has been shown that statin treatment increases PCSK9 expression in hepatocytes [36], which might reduce the effectiveness of statins by increasing LDL-receptor degradation [37]. In this study, at least 50% of patients had statin intolerance (50.4–60.3%, depending on treatment allocation). This relatively high number of statin-intolerant patients is due to enrolled patients were being treated at a lipid clinic that specializes in the treatment of statin-intolerant patients. A similar ratio of statin-intolerant patients was observed in the German PEARL real-world study [38]. Patients without statin therapy demonstrated significantly lower reductions in LDL-C from baseline to week 4 than did patients on background statins (53.1% and 60.2%, respectively; P < 0.0001). These data concur with clinical study data that might indicate greater efficacy of PCSK9i in patients receiving background statins [9, 10] versus those with statin intolerance [39, 40].
Alirocumab and evolocumab were generally well-tolerated, with 47.7% and 47.1% of patients reporting AEs at weeks 2 and 68, respectively, and with 2.4% and 6.1% of enrolled patients discontinuing the study due to AEs after week 2 and after week 68, respectively (most common were myalgias and gastrointestinal side effects). In a pooled analysis of 14 clinical studies with alirocumab (8–104 weeks study duration), 76.0–78.4% of alirocumab-treated patients (n = 3340) reported treatment-emergent AEs (placebo, 78.7% [n = 1276]; ezetimibe, 73.9% [n = 618]) [41]. In a pooled analysis of four evolocumab studies (12-week study), 56.1% of patients treated with evolocumab 140 mg Q2W (n = 123) reported treatment-emergent AEs [10].
In this study, more women than men reported fatigue, joint pain, back pain, headache, sore throat, nausea, vertigo, and pruritus at week 2. Sex differences in AEs were previously reported [42]; however, to our knowledge, no data have been previously published for PCSK9i therapy.
Cardiovascular events were reported for 12.6% of patients, which is a higher frequency than in ODYSSEY OUTCOMES (9.5% of patients in the alirocumab group) and FOURIER (9.8% in the evolocumab group) [11, 12]. However, this study was neither designed nor powered for analysis of the effects of alirocumab or evolocumab on cardiovascular events; this was assessed in the ODYSSEY OUTCOMES [11] and FOURIER [12] studies. Furthermore, the patient population included in this real-world study was more heterogenous because patients with severe CVD, renal impairment, and other comorbidities would be excluded from participating in clinical trials.
Limitations of this study include the restriction of assessments to routine clinical visits and lack of comparison to a control group not receiving PCSK9i therapy. Patients knew they were receiving PCSK9i treatment, which may have influenced their adherence to background LLTs and diet, thereby creating a bias. Furthermore, in patients who remained on stable PCSK9i therapy throughout the study, adjustment in concomitant LLTs might have altered the effectiveness results at week 68. This study also enrolled patients at only one study center, which further limits the generalizability of the study results. In addition, alirocumab is currently withdrawn from the market in Germany.
To our knowledge, this is the largest real-world study in Germany observing the effectiveness and safety of alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, and evolocumab 140 mg Q2W, analyzing data from 635 patients with a diverse range of comorbidities treated for up to 68 weeks with PCSK9i therapy.
Conclusions
The results of this single-center real-world study in Germany demonstrate that individualized therapy with alirocumab 75 mg Q2W, alirocumab 150 mg Q2W, or evolocumab 140 mg Q2W improved LDL-C levels and other lipoproteins and was generally well-tolerated; the overall discontinuation rate due to AEs was 8.5%.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1599 kb)
Tim Hollstein and Ursula Kassner Shared first author.
Open Access funding provided by Projekt DEAL.
Funding
No external funding was used to conduct this study or prepare this manuscript.
Compliance with Ethical Standards
Conflicts of Interest
Tim Hollstein received non-financial support from Sanofi during the conduct of the study and has received non-financial support from Sanofi and Amgen unrelated to the submitted work. Ursula Kassner has received speaker honoraria from Amgen, Sanofi, Alexion, Amrhyt, Berlin Chemie, Fresenius Medical Care, and Synlab Academy. Thomas Grenkowitz has received personal fees from Sanofi and Fresenius Medical Care unrelated to the submitted work. Friederike Schumann has received grants from Amgen unrelated to the submitted work. Thomas Bobbert has no potential conflicts of interest that might be relevant to this work. Elisabeth Steinhagen-Thiessen has received speakers’ honoraria from Sanofi, Amgen, Pfizer, Berlin Chemie, and Akcea. | EVOLOCUMAB | DrugsGivenReaction | CC BY-NC | 32514867 | 17,938,316 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood disorder'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiovascular insufficiency'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal distress syndrome'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic disorder'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neonatal gastrointestinal disorder'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neonatal infection'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nervous system disorder'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory disorder neonatal'. | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | LITHIUM CARBONATE | DrugsGivenReaction | CC BY | 32526071 | 18,040,404 | 2021-02 |
What was the administration route of drug 'LITHIUM CARBONATE'? | Management of lithium dosing around delivery: An observational study.
Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.
In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.
There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.
Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.
1 INTRODUCTION
Women with bipolar disorder are at high risk of relapse in the postpartum period.
1
,
2
Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.
1
Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.
3
Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.
4
Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.
5
,
6
An increased risk could not be found for lithium use during the second and third trimester.
Dosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.
7
Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.
8
,
9
As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).
4
,
8
,
10
,
11
Several reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,
9
,
12
,
13
,
14
,
15
and others recommend to stop lithium prior to delivery.
16
,
17
,
18
The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.
19
In the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).
2 PATIENTS AND METHODS
This retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.
8
Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).
The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).
2.1 Statistical analysis
For aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).
For our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.
3 RESULTS
3.1 Lithium blood level changes following delivery (Aim 1)
We identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).
There were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.
FIGURE 1 Course of lithium blood level/dose ration around delivery
3.2 Lithium blood levels and neonatal complications (Aim 2)
We included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.
TABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)
Maternal characteristics All (N = 29)
Lithium dosage in mg/day, mean (SD)
a
1142.82 (350.74)
Lithium blood level in mmol/L, mean (SD) 0.67 (0.23)
Complications during delivery, n (%)
b
16 (55.2)
Neonatal characteristics
Lithium blood level in mmol/L, mean (SD) 0.61 (0.31)
Preterm (<37 weeks), n (%) 3 (10.3)
Birth weight in grams, mean (SD) 3589.14 (457.16)
Apgar score 1 minute, median (IQR) 8 (2)
Apgar score 5 minutes, median (IQR) 9 (2)
pH‐value cord blood, mean (SD) 7.24 (0.10)
Base Excess value cord blood, mean (SD) −4.50 (5.12)
Admission medium/high care, n (%) 13 (44.8)
Duration admission medium/high care in days, median (IQR) 3 (4)
Any complication (including mild/transient), n (%)
c
14 (48.3)
Neurological complications, n (%) 5 (17.2)
Respiratory complications, n (%) 5 (17.2)
Circulatory complications, n (%) 1 (3.4)
Gastro‐intestinal complications, n (%) 1 (3.4)
Infectious complications, n (%) 4 (13.8)
Hematological complications, n (%) 1 (3.4)
Metabolic complications, n (%) 7 (24.1)
a Lithium dosage closest to delivery.
b Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).
c Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).
John Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).
FIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)
Univariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).
4 DISCUSSION
In this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.
Several guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.
13
,
14
,
15
,
16
,
17
,
18
Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.
A second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,
19
in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.
19
The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,
20
and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.
The high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.
This study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.
Lithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.
21
Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.
22
In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.
23
Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.
5 DECLARATIONS
Ethics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGEMENTS
VB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy. | Transplacental | DrugAdministrationRoute | CC BY | 32526071 | 18,040,404 | 2021-02 |
What was the administration route of drug 'PAMIDRONATE DISODIUM'? | Bone mineral density improves during 2 years of treatment with bisphosphonates in patients with ankylosing spondylitis.
To evaluate whether 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements has an effect on lumbar spine and hip bone mineral density (BMD) in ankylosing spondylitis (AS) patients starting tumour necrosis factor-α inhibitors or receiving conventional treatment. Secondly, to explore the development of radiographic vertebral fractures.
Patients from the Groningen Leeuwarden AS cohort receiving bisphosphonates based on clinical indication and available 2-year follow-up BMD measurements were included. BMD of lumbar spine (L1-L4) and hip (total proximal femur) were measured using dual-energy X-ray absorptiometry. Spinal radiographs (Th4-L4) were scored for vertebral fractures according to the Genant method.
In the 20 included patients (median 52 years, 14 males), lumbar spine and hip BMD Z-scores increased significantly; median from -1.5 (interquartile range [IQR] -2.2 to 0.4) to 0.1 (IQR -1.5 to 1.0); P < .001 and median from -1.0 (IQR -1.6 to -0.7) to -0.8 (IQR -1.2 to 0.0); P = .006 over 2 years, respectively. In patients also treated with tumour necrosis factor-α inhibitors (n = 11), lumbar spine and hip BMD increased significantly (median 2-year change +8.6% [IQR 2.4 to 19.6; P = .009] and +3.6% [IQR 0.7-9.0; P = .007]). In patients on conventional treatment (n = 9), lumbar spine BMD increased significantly (median 2-year change +3.6%; IQR 0.7 to 9.0; P = .011) and no improvement was seen in hip BMD (median -0.6%; IQR -3.1 to 5.1; P = .61). Overall, younger AS males with limited spinal radiographic damage showed most improvement in lumbar spine BMD. Four mild radiographic vertebral fractures developed in 3 patients and 1 fracture increased from mild to moderate over 2 years in postmenopausal women and middle-aged men.
This explorative observational cohort study in AS showed that 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements significantly improves lumbar spine BMD. Mild radiographic vertebral fractures still occurred.
pmcWhat is already known about this subject
Osteoporosis and vertebral fractures occur in hip ankylosing spondylitis (AS) patients at relatively young age.
In daily clinical practice, treatment with bisphosphonates is often applied in AS, but scientific studies with >6 months follow‐up regarding the effect on bone mineral density (BMD) and vertebral fractures are lacking.
What this study adds
Lumbar spine BMD improved significantly during 2 years of bisphosphonates, which was most pronounced in younger AS males with limited spinal radiographic damage.
Hip BMD only improved significantly in patients also treated with tumour necrosis factor‐α inhibitors.
Mild radiographic vertebral fractures still occurred in postmenopausal women and middle‐aged men. Most fractures were observed in patients who already had vertebral fractures and who were also treated with tumour necrosis factor‐α inhibitors because of persistent active disease.
1 INTRODUCTION
Ankylosing spondylitis (AS) is a chronic rheumatic inflammatory disease, which mainly affects the axial skeleton. Besides spinal osteoproliferation, excessive bone loss is a major complication of AS. Low bone mineral density (BMD), especially at the lumbar spine, can already be observed at a relatively young age. 1 , 2 Acute inflammatory lesions on sacroiliac joint magnetic resonance imaging were found to be associated with low BMD. 3 Vertebral fractures are the most important outcome of excessive bone loss and are frequently present in AS patients. 1 , 4
The main cause of primary osteoporosis is age‐related bone loss in postmenopausal women. Secondary osteoporosis results from the presence of other diseases or conditions that predisposes to bone loss and occurs in both males and females. Currently, there are no clear guidelines for the evaluation of bone loss and the treatment of secondary osteoporosis in patients with AS. In daily clinical practice, secondary osteoporosis is often treated according to the same guidelines as primary osteoporosis, although AS mainly affects males at relatively young age. This antiosteoporotic treatment consists of bisphosphonates in combination with calcium/vitamin D supplements.
Several studies in AS investigated the anti‐inflammatory effect of bisphosphonates. 5 , 6 , 7 , 8 , 9 , 10 However, follow‐up data regarding the effect of bisphosphonates on BMD are scarce and data about the effect on vertebral fractures are lacking. There is 1 open‐label study in AS patients with active disease that showed a significant improvement in absolute BMD scores at the lumbar spine after 6 months of treatment with neridronate, which was not observed at the hip. 8 Another retrospective study in AS patients with spinal pain intensity score >4 (on a scale of 0–10) did not show beneficial effect on lumbar spine or hip BMD after 6 months treatment with alendronate. 11
Nowadays, tumour necrosis factor‐α (TNF‐α) inhibitors are prescribed to control disease activity, with good long‐term adherence in daily clinical practice. 12 These agents also have proven to have an effect on BMD. A large randomized controlled trial found a significant increase in BMD at the lumbar spine and hip after 6 months of infliximab compared with placebo. Open‐label extension showed further improvement in BMD after 2 years of infliximab. 13 Multiple observational studies reported a continuous improvement in BMD at the lumbar spine and, to a lesser extent, at the hip after long‐term treatment with TNF‐α inhibitors. 1 , 14
The aim of the present study was to evaluate whether 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements has an effect on lumbar spine and hip BMD in AS patients starting TNF‐α inhibitors or receiving conventional treatment in daily clinical practice. Secondly, to explore the development of radiographic vertebral fractures in these patients.
2 METHODS
The Groningen Leeuwarden AS (GLAS) cohort is an ongoing prospective observational cohort study which started at the end of 2004 in the north of the Netherlands (principal investigator: Dr A. Spoorenberg). For the present analysis, patients fulfilling the modified New York criteria for AS, who were treated with bisphosphonates in combination with calcium and/or vitamin D supplements and had available 2‐year follow‐up BMD measurements were included. The antiosteoporotic treatment was started based on clinical indication according to the treating physician.
The GLAS cohort was approved by the local ethics committees of the Medical Center Leeuwarden (MCL) and University Medical Center Groningen (UMCG). All patients provided written informed consent according to the Declaration of Helsinki.
2.1 Assessments of bone loss
2.1.1 BMD
At first visit and after 2 years of follow‐up, BMD at the lumbar spine (anterior–posterior projection at L1–L4) and hip (total proximal femur) were measured using the same dual‐energy X‐ray absorptiometry machine within patients (Hologic QDR Discovery for UMCG patients and Hologic QDR Delphi for MCL patients, Waltman, MA, USA). Coefficient of variation (CV) and least significant change were evaluated automatically using Hologic software. CV for total BMD was reported to be 1.0%, least significant change was reported to be 0.022 g/cm2 for lumbar spine BMD and 0.027 g/cm2 for hip BMD. Lumbar vertebrae showing fractures were excluded from the BMD measurement. Z‐scores, the number of standard deviations from the normal mean corrected for age and sex, were calculated using the NHANES reference database. The International Society for Clinical Densitometry recommends using BMD Z‐scores instead of BMD T‐scores in premenopausal women and men younger than 50 years. 15
2.1.2 Vertebral fractures
Lateral radiographs of the thoracic and lumbar spine were scored for radiographic vertebral fractures by 2 independent readers blinded for patient characteristics. 4 According to the method of Genant et al., anterior, middle and posterior heights of the vertebra Th4–L4 were assessed. Fractures were categorized as mild (≥20–<25% height reduction), moderate (≥25–<40% height reduction) or severe (≥40% height reduction).
2.2 Other assessments
At the same time points, serum levels of 25‐hydroxyvitamin D (25OHvitD) were measured by radioimmunoassay (DiaSorin, Stillwater, MN, USA; inter assay coefficient of variation IE‐CV) 14–15%; UMCG until June 2010 and MCL until July 2008), ECLIA (Modular Analytics E170, Roche Mannheim, Germany; IE‐CV 12–13%; MCL July 2008 until 2011), or automated liquid chromatography–mass spectrometry method (IE‐CV 4–5%; UMCG since 2010 and MCL since 2011). Disease activity was assessed using AS disease activity score, Bath AS disease activity index and C‐reactive protein (measured during routine diagnostic patient care; IE‐CV < 5%). Lateral radiographs of the cervical and lumbar spine were scored for spinal radiographic damage by 2 independent readers using the modified Spine AS score (mSASSS). 4
2.3 Statistical analysis
Results were expressed as number of patients (%) or median (interquartile range [IQR]) for categorical and continuous data, respectively. Fisher's Exact and Mann–Whitney U tests were used to compare patient characteristics between groups. Wilcoxon‐signed rank test was used to compare assessments at first visit and after 2 years of follow‐up. Analyses were stratified for starting treatment with TNF‐α inhibitors or receiving conventional treatment (nonsteroidal anti‐inflammatory drugs). P‐values ≤0.05 were considered as statistically significant. Statistical analysis was performed with IBM SPSS Statistics 23 (SPSS, Chicago, IL, USA).
3 RESULTS
Of the 20 included AS patients, 11 were treated with risedronate (35 mg/wk), 7 with alendronate (70 mg/wk), 1 with intravenous pamidronate (60 mg) and 1 with etidronic acid–calcium carbonate. In the majority of patients, antiosteoporotic treatment was started because of osteoporosis. Other reasons were systemic steroid use or the presence of osteopenia and vertebral fractures. Eleven (55%) patients started TNF‐α inhibitors because of active disease (10 continued this treatment for 2 y) and the other 9 (45%) received conventional treatment for AS symptoms. Patient characteristics at first visit and type of bisphosphonate used in both treatment groups are presented in Table 1.
TABLE 1 Characteristics of the AS study population treated with bisphosphonates in combination with calcium/vitamin D supplements, stratified for the use of TNF‐α inhibitors
All patients (n = 20) Patients starting TNF‐α inhibitors (n = 11) Patients on conventional treatment (n = 9)
Male sex 14 (70) 7 (64) 7 (78)
Age (y) 52 (46 to 64) 57 (45 to 65) 50 (46 to 61)
Duration of symptoms (y) 27 (8 to 40) 20 (8 to 44) 29 (15 to 39)
Time since diagnosis (y) 7 (4 to 28) 8 (5 to 28) 6 (1 to 31)
HLA‐B27+ 15 (75) 6 (55) 9 (100) *
NSAID use 13 (65) 5 (46) 8 (89)
Systemic steroid use 3 (15) 1 (9)' 2 (22) ″
ASDASCRP 3.6 (2.2 to 4.4) 4.2 (3.5 to 4.6) 2.1 (1.8 to 3.5) *
BASDAI (range 0–10) 5.3 (2.8 to 7.3) 5.8 (5.0 to 8.0) 3.8 (1.9 to 5.5) *
CRP (mg/l) 15 (4 to 23) 19 (10 to 24) 5 (2 to 15) *
BASFI (range 0–10) 7.2 (3.8 to 7.9) 7.6 (7.1 to 8.5) 3.9 (1.3 to 7.3) *
LS BMD Z‐score −1.5 (−2.2 to 0.4) −0.8 (−2.3 to 0.6) −1.6 (−2.8 to 0.0)
LS BMD Z‐score ≤−1 10 (53) 5 (50) 5 (56)
LS BMD Z‐score ≤−2 6 (32) 3 (30) 3 (33)
Hip BMD Z‐score −1.0 (−1.6 to −0.7) −1.0 (−1.8 to −0.8) −1.0 (−1.5 to 0.1)
Hip BMD Z‐score ≤−1 11 (58) 7 (64) 4 (50)
Hip BMD Z‐score ≤−2 1 (5) 1 (9) 0 (0)
25OHvitD (nmol/L) 66 (36 to 89) 38 (29 to 70) 89 (55 to 96) *
Radiographic VFa 7 (41) 6 (60) † 1 (14) ‡
mSASSS (range 0–72)b 6.0 (2.9 to 42.3) 14.2 (3.4 to 33.7) 5.2 (1.6 to 63.2)
Type of bisphosphonate treatment
Risedronate 11 (55) 6 (55) 5 (56)
Alendronate 7 (35) 3 (27) 4 (44)
Intravenous pamidronate 1 (5) 1 (9) 0 (0)
Etidronic acid‐calcium carbonate 1 (5) 1 (9) 0 (0)
Values are number (%) of patients or median (interquartile range).
a Radiographs of the thoracic and lumbar spine could be scored in 17 patients. b Radiographs of the cervical and lumbar spine could be scored in 14 patients.
* P < .05 compared to patients starting TNF‐α inhibitors.
' prednison (5 mg/d);
″ budenofalk (3 and 6 mg/d).
† 16 vertebral fractures (9 mild, 5 moderate, 2 severe) in 6 patients;
‡ 1 vertebral fracture (mild) in 1 patientAS: ankylosing spondylitis; TNF‐α: tumour necrosis factor‐α; HLA‐B27+: human leukocyte antigen B27 positive; ASDAS: AS disease activity score; BASDAI: Bath AS disease activity index; CRP: C‐reactive protein; BASFI: Bath AS functional index; LS: lumbar spine; BMD: bone mineral density; 25OHvitD: 25‐hydroxyvitamin D; VF: vertebral fracture; mSASSS: modified stoke AS spinal score; NSAID, nonsteroidal anti‐inflammatory drug.
Seventeen (85%) patients used bisphosphonates during the entire 2‐year follow‐up within the GLAS cohort (TNF‐α inhibitor group: n = 9, conventional treatment group: n = 8). Thirteen (65%) patients started treatment with bisphosphonates median 3.1 years before inclusion in the GLAS cohort (TNF‐α inhibitor group: n = 9, median 3.1 y, conventional treatment group: n = 4, median 3.8 y).
As expected, all disease activity assessments were significantly higher in patients starting TNF‐α inhibitors. Furthermore, physical function was worse and serum levels of 25‐hydroxyvitamin D were lower. Disease severity expressed by spinal radiographic damage (mSASSS) was similar in both treatment groups. Also lumbar spine and hip BMD were comparable between both groups, although radiographic vertebral fractures were more often found in patients starting TNF‐α inhibitors.
3.1 Change in BMD over 2 years
In the total group, treatment with bisphosphonates in combination with calcium/vitamin D supplements significantly improved lumbar spine and hip BMD; median lumbar spine BMD Z‐score increased from −1.5 at first visit to 0.1 after 2 years (P < .001) and median hip BMD Z‐score from −1.0 at first visit to −0.8 after 2 years (P = .006). Similar results were found for BMD T‐scores (data not shown).
In the 11 patients starting TNF‐α inhibitors, lumbar spine BMD increased significantly (Figure 1A); median change in Z‐score was 0.7 (IQR 0.3 to 1.4) and in absolute BMD 8.6% (IQR 2.4 to 19.6). Also hip BMD increased significantly (Figure 1B); median change in Z‐score was 0.3 (IQR 0.2 to 0.6) and in absolute BMD 3.6% (IQR 1.5 to 7.8).
FIGURE 1 Lumbar spine and hip bone mineral density (BMD) Z‐scores during 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements in 20 ankylosing spondylitis patients, stratified for the use of tumour necrosis factor‐α inhibitors. GLAS, Groningen Leeuwarden ankylosing spondylitis
In the 9 patients on conventional treatment, lumbar spine BMD increased significantly (Figure 1C); median change in Z‐score was 0.4 (IQR 0.2 to 0.7) and in absolute BMD 3.6% (IQR 0.7 to 9.0). No significant improvement in hip BMD was found (Figure 1D); median change in Z‐score was 0.1 (IQR −0.2 to 0.3) and in absolute BMD −0.6% (IQR −3.1 to 5.1).
Overall, improvement in lumbar spine BMD of ≥0.5 Z‐score was found in males (82%) of relatively young age (median 45 years) and limited spinal radiographic damage (median 4.3 mSASSS units).
3.2 Development of vertebral fractures
During 2‐year follow‐up, 4 new radiographic vertebral fractures were found in 3 of the 17 (18%) patients. In patients with TNF‐α inhibitors, 3 mild fractures occurred in 2 postmenopausal females (67 and 68 years). In addition, 1 existing fracture increased in severity from mild to moderate in 1 male (48 years). In patients on conventional treatment, 1 new mild fracture was observed in 1 male (51 years). None of these fractures received clinical attention. More details about the characteristics and treatment of these patients are presented in Table 2.
3.3 Other assessments over 2 years
There was no significant change in serum levels of 25‐hydroxyvitamin D over 2 years (Table 3). Disease activity decreased significantly in both groups; median improvement in AS disease activity score was 2.1 for patients starting TNF‐α inhibitors and 0.4 for patients on conventional treatment. Overall, spinal radiographic progression was relatively low. Median progression in mSASSS was 1.4 (IQR 0.5 to 1.6) and 0.0 (IQR 0.0 to 0.4) in these 2 treatment groups, respectively. Two patients developed 1 new syndesmophyte in the TNF‐α inhibitor group compared to none in the conventional treatment group.
TABLE 2 Characteristics and treatment of AS patients with new vertebral fractures (n = 3) or increase in severity (n = 1) during 2 years of follow‐up
Patient 1 Patient 2 Patient 3 Patient 4
Development of VF + site New: Th12 and L3 grade 1, biconcave New: Th12 grade 1, biconcave Increase in severity: Th11 grade 2, wedge New: Th8 grade 1, biconcave
Sex, age Female, 67 y Female, 67 y Male, 48 y Male, 51 y
Bisphosphonate treatment, % of time used Pamidronate 60 mg/12 wk, 100% Alendronate 70 mg/wk, 100% Risedronate 35 mg/wk, 100% Alendronate 70 mg/wk, 100%
Anti‐TNF treatment, % of time used Adalimumab 40 mg/2 wk, 84% (stopped) Etanercept 50 mg/wk, 100% Infliximab, 300 mg/8 wk, 100% No
Presence of VF at baseline + site Th9, Th10 grade 2, Th11 grade 3, biconcave Th7 grade 1, wedge, Th9 grade 2, Th11 grade 3, biconcave Th9, Th10, Th11, Th12 grade 1, wedge No
BMD LS Z‐score baseline vs 2 y N/A −2.2 vs 0.1 −2.5 vs ‐1.5 −1.8 vs ‐1.1
BMD hip Z‐score baseline vs 2 y −0.9 vs 0.0 −1.9 vs ‐1.6 −1.8 vs ‐1.6 −1.2 vs ‐1.1
ASDAS baseline vs 2 y 4.41 vs 3.82 3.52 vs 2.72 4.60 vs 2.26 1.87 vs 1.42
See Table 1 for abbreviations
TABLE 3 Clinical assessments at first visit and after 2 years of follow‐up in AS patients treated with bisphosphonates in combination with calcium/vitamin D supplements, stratified for the use of TNF‐α inhibitors
First visit 2 years P‐value
Patients starting TNF‐α inhibitors (n = 11)
LS BMD Z‐score −0.8 (−2.3 to 0.6) 0.5 (−1.3 to 1.0) .009
Hip BMD Z‐score −1.0 (−1.8 to −0.8) ‐0.8 (−1.6 to 0.0) .007
25OHvitD (nmol/L) 38 (29 to 70) 58 (46 to 66) .726
ASDASCRP 4.2 (3.5 to 4.6) 2.3 (1.1 to 3.8) .008
BASDAI (range 0–10) 5.8 (5.0 to 8.0) 2.2 (1.0 to 6.2) .014
CRP (mg/l) 19 (10 to 24) 3 (2 to 12) .026
mSASSS (range 0–72) 14.2 (3.4 to 33.7) 15.8 (4.5 to 34.8) .042
Patients on conventional treatment (n = 9)
LS BMD Z‐score −1.6 (−2.8 to 0.0) −1.1 (−2.3 to 0.9) .011
Hip BMD Z‐score −1.0 (−1.5 to 0.1) −0.9 (−1.2 to 0.0) .609
25OHvitD (nmol/L) 89 (55 to 96) 69 (52 to 88) .686
ASDASCRP 2.1 (1.8 to 3.5) 1.6 (1.4 to 2.9) .021
BASDAI (range 0–10) 3.8 (1.9 to 5.5) 2.8 (1.8 to 4.7) .141
CRP (mg/l) 5 (2 to 15) 3 (2 to 8) .026
mSASSS (range 0–72) 5.2 (1.6 to 63.2) 6.4 (2.0 to 63.2) .180
See Table 1 for abbreviations.
4 DISCUSSION
The present study evaluated whether 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements has an effect on lumbar spine and hip BMD in established AS patients from daily clinical practice. BMD improved significantly during treatment with bisphosphonates, as was shown in other small studies. 8 , 16 The median change in absolute BMD scores after 2 years of bisphosphonates was +8.6 and +3.6% at the lumbar spine and +3.6 and −0.6% at the hip, respectively, in patients starting treatment with TNF‐α inhibitors or receiving conventional treatment. Interestingly, in both groups, most improvement in lumbar spine BMD was found in younger males with limited spinal radiographic damage. Previously, a retrospective cohort study compared BMD change over approximately 1‐year in 4 groups of AS patients on conventional treatment (n = 40), bisphosphonates plus conventional treatment (n = 20), TNF‐α inhibitors (n = 19) and bisphosphonates plus TNF‐α inhibitors (n = 11). They reported that BMD improvement at the greater trochanter of the hip was most pronounced in patients receiving bisphosphonates in combination with TNF‐α inhibitors. 16 An open‐label study including AS patients with active disease (Bath AS disease activity index ≥4) investigated BMD as secondary outcome during 6 months of treatment with high intravenous doses of the amino‐bisphosphonate neridronate (n = 30) or infliximab (n = 30). In line with our findings, they showed that bisphosphonates resulted in a significant increase in absolute BMD scores at the lumbar spine (mean improvement 4.3%), but not at the hip (mean improvement 0.1–2.2%). 8 In contrast to our and other studies with TNF‐α inhibitors, 12 , 16 , 17 , 18 they reported that infliximab had no significant effect on BMD. Unfortunately, no further analysis or discussion was provided. Supporting our data and those of other studies, a meta‐analysis including 568 AS patients from 1 randomized controlled trial and 7 observational studies consistently demonstrated that lumbar spine and total hip BMD increased significantly with 8.6 and 2.5%, respectively, after 2 years of treatment with TNF‐α inhibitors. 14
Bisphosphonates and TNF‐α inhibitors influence the bone metabolism differently. Bisphosphonates have an inhibitory effect on bone resorption by chemical adsorption to hydroxyapatite and/or a direct effect on osteoclast activity. 19 , 20 The underlying pathophysiological mechanism of TNF‐α inhibitors on the bone metabolism is not yet completely understood, but most likely involves the Wnt signaling pathway, which affects both osteoclasts and osteoblasts activity. 21 A recent cross‐sectional study including 71 AS patients showed that higher serum levels of Dickkopf‐1, a natural inhibitor of the Wnt pathway, were associated with lower lumbar spine BMD and prevalent radiographic vertebral fractures. This indicates that high levels of Dickkopf‐1 are related to the severity of bone loss in AS. 22
Besides the effect of bisphosphonates on BMD, we also explored the development of radiographic vertebral fractures, the most important clinical outcome reflecting bone loss of the spine. At first visit, 17 mild to severe vertebral fractures were found in 7 (41%) patients. During 2 years, 4 mild vertebral fractures developed in 3 (18%) patients and 1 existing fracture increased from mild to moderate. The majority of prevalent and incident vertebral fractures were found in patients with active disease, starting treatment with TNF‐α inhibitors. This can probably be explained by persistently high disease activity (before the start of TNF‐α inhibitors), lower serum levels of vitamin D and worse physical function in these AS patients. New radiographic vertebral fractures occurred in postmenopausal women and middle‐aged men. Three out of these 4 patients already had multiple vertebral fractures.
The present study is the first to explore the development of vertebral fractures in AS patients with a clinical indication for antiosteoporotic treatment. In our larger observational study on vertebral fractures, 39 (21%) of the 184 AS patients starting TNF‐α inhibitors already had radiographic vertebral fractures at baseline, 9 (5%) developed new vertebral fractures and 7 (4%) showed an increase in severity of existing factures after 2 years of follow‐up. 4 Another observational study in 49 AS patients starting etanercept reported that the number of patients with radiographic vertebral fractures increased from 6 (12%) at baseline to 15 (31%) after 2 years. 23
For the present analysis, we selected patients who were treated with bisphosphonates and had available 2‐year follow‐up BMD measurements. As expected, this subgroup of patients was older (median 52 vs 43 y), had longer duration of AS symptoms (median 27 vs 16 y), lower BMD (median lumbar spine Z‐score −1.5 vs −0.4, hip Z‐score −1.0 vs −0.2) and more often radiographic vertebral fractures (41 vs 20%) in comparison with the total study population from the GLAS cohort. 4
The present study is based on real life data. The antiosteoporotic treatment was started based on clinical indication according to the treating physician, mainly the presence of osteoporosis. Unfortunately, the Fracture Risk Assessment Tool score was not yet available in these patients. A limitation of our study is that the effect of bisphosphonates on BMD may be underestimated since 65% of the patients started treatment with bisphosphonates before inclusion in the GLAS cohort (median 3.1 y). An open‐label extension study in postmenopausal women showed that continuous alendronate treatment for 7 years increased BMD, but the largest increase was observed during the first 3 years of treatment. 24
It is known that the anterior–posterior view of the lumbar spine DXA can be overestimated by the presence of syndesmophytes. 25 , 26 Since mSASSS progression was relatively low and the large majority of patients did not develop new syndesmophytes over 2 years, it can be assumed that there was no influence of spinal osteoproliferation on the 2‐year improvement in lumbar spine BMD. Moreover, young AS males with limited spinal radiographic damage showed most improvement in lumbar spine BMD. We do realize that a larger number of patients, long‐term follow‐up, and a control group are needed to investigate and detect a potential extra increase in spinal radiographic damage due to the treatment effect of bisphosphonates on bone formation in AS.
In conclusion, the results from this observational cohort study in daily clinical practice show that treatment with bisphosphonates in combination with calcium/vitamin D supplements improves BMD over 2 years in established AS patients. Lumbar spine BMD improved significantly, which was most pronounced in younger AS males with limited spinal radiographic damage. Hip BMD only improved significantly in patients also starting TNF‐α inhibitors. Our finding that the effect of treatment was most pronounced in the lumbar spine corresponds to the disease process in AS since disease activity is predominantly observed in the axial skeleton.
This is the first study exploring the occurrence of radiographic vertebral fractures in AS patients with low BMD and/or vertebral fractures at baseline treated with bisphosphonates. Mild radiographic vertebral fractures still occurred in postmenopausal women and middle‐aged men. Most fractures were observed in patients who already had vertebral fractures and who were also treated with TNF‐α inhibitors because of persistent active disease. Due to the small number and differences in disease activity at baseline, it is difficult to put the incidence rate into perspective. Since fractures are regarded as the most important outcome of bone fragility, larger studies with long‐term follow‐up are needed to further investigate the effect of bisphosphonates and calcium/vitamin D supplements not only on BMD but also on vertebral fractures in AS.
COMPETING INTERESTS
S.A. has received research grants from Pfizer. F.W. has received consulting fees from Abbvie. A.S. has received research grants from Abbvie, Pfizer, UCB and Novartis, and consulting fees from Abbvie, Pfizer, MSD, UCB, and Novartis. The other authors declare that they have no competing interests.
CONTRIBUTORS
S.A. participated in the design of the study, performed the statistical analysis and interpretation of data, and drafted the manuscript. F.W. and R.B. performed the acquisition of clinical data and critically revised the manuscript. J.V. contributed to the to the acquisition, statistical analysis and interpretation of data, and critically revised the manuscript. E.R., E.V. and F.M. participated in the design of the study, contributed to the interpretation of data and critically revised the manuscript, AS participated in the design of the study, performed the acquisition of clinical data, contributed to the interpretation of data and critically revised the manuscript. All authors read and approved the final manuscript.
ACKNOWLEDGEMENTS
The authors wish to acknowledge Dr P.M. Houtman, Mrs W. Gerlofs, Mrs S. Katerbarg, Mrs A. Krol and Mrs R. Rumph for their contribution to the data collection. The GLAS cohort was supported by an unrestricted grant from Pfizer pharmaceuticals. Pfizer had no role in the design, conduct, interpretation, or publication of this study.
DATA AVAILABILITY STATEMENT
All data were obtained within the GLAS cohort, which was approved by the local ethics committees of the MCL and UMCG. All patients provided written informed consent according to the Declaration of Helsinki. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 32530102 | 18,066,134 | 2021-02 |
What was the administration route of drug 'HYDROXYCHLOROQUINE'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | Oral | DrugAdministrationRoute | CC BY | 32615807 | 18,753,038 | 2021-01 |
What was the administration route of drug 'LOPINAVIR\RITONAVIR'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | Oral | DrugAdministrationRoute | CC BY | 32615807 | 18,753,038 | 2021-01 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | UNKNOWN | DrugDosageText | CC BY | 32615807 | 18,786,710 | 2021-01 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | UNKNOWN | DrugDosageText | CC BY | 32615807 | 18,786,710 | 2021-01 |
What was the dosage of drug 'LOPINAVIR\RITONAVIR'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | UNKNOWN | DrugDosageText | CC BY | 32615807 | 18,786,710 | 2021-01 |
What was the dosage of drug 'OSELTAMIVIR'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | UNKNOWN | DrugDosageText | CC BY | 32615807 | 18,786,710 | 2021-01 |
What was the outcome of reaction 'Cardiac arrest'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | Fatal | ReactionOutcome | CC BY | 32615807 | 18,820,507 | 2021-01 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | Fatal | ReactionOutcome | CC BY | 32615807 | 18,820,507 | 2021-01 |
What was the outcome of reaction 'Torsade de pointes'? | Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.
Within less than six months, COVID-19 has now spread from a market in Wuhan, China, across more than 150 countries and transformed to a pandemic [1]. The infection presents with symptoms such as fever, cough, fatigue, sputum, muscle ache, dyspnea and eventually severe acute respiratory failure [1,2].
There is not much information about the mortality rate, which varies in different countries. Some studies have reported mortality rates of 1–2% [2,3]. In comparison, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), viruses of this family, had mortality rates of 10–35% [4]. In a retrospective study by Chen et al. [5] in January 2020, out of 99 patients with COVID-19, 57 (58%) were hospitalized, 31 (31%) were discharged and only 11 (11%) died of the infection. Also, in another study conducted in Iran, the mortality rate was reported to be 7.14% [6].
According to studies, the main cause of death in COVID-19 patients is severe pneumonia. However, it has been reported that mortality in the patients is significantly associated with pre-existing cardiovascular conditions [7]. In another study, Italian researchers highlighted the role of hypertension in increasing COVID-19-related mortality as high as 2.5-times in this subgroup [8]. Although clinical manifestations of COVID-19 infection are unknown in patients with cardiac conditions, evidence obtained from patients with end-stage heart failure indicates that the virus can inflict or exaggerate cardiac damage [9].
Recently, an Italian group reported that during the COVID-19 outbreak in 2020 a 58% increase in out-of-hospital cardiac arrest cases occurred when compared with the same period in 2019. Notably, the cumulative incidence of out-of-hospital cardiac arrest in 2020 strongly associated with the cumulative incidence of COVID-19. Moreover, they estimated that patients receiving a COVID-19 diagnosis accounted for most of such an increase of events, close to 80% of cases [10].
In the present study, we reported sudden cardiac death, which is not the dominant mode of death, in three patients with COVID-19 infection admitted to Shahid Mostafa Khomeini Hospital of Ilam in March and April 2020.
Case presentation
Case 1
A 50-year-old woman without known history of specific diseases or using specific drugs, complaining of fever, chills and dry cough was hospitalized in our center. On admission, her condition was as blood pressure (BP) = 130/80 mmHg, pulse rate (PR) = 80/min, body temperature (BT) = 37.2°C and O2 saturation (in room air) = 95%. She had no abnormal findings at the initial examination. Baseline ECG was within normal limits (Figure 1A). Due to pulmonary involvement evidenced in chest CT scan (Figure 2A), she was treated with levofloxacin, vancomycin, hydroxychloroquine, lopinavir/ritonavir, as well as heparin for prophylaxis of deep venous thrombosis at standard doses. There was no electrolyte abnormality during hospitalization. On the fifth day of hospitalization, the treating physician decided to discharge the patient and continue the rest of treatment at home. While being discharged; the patient developed a sudden cardiac arrest and died as resuscitation was ineffective. The patient’s laboratory information has been shown in Table 1.
Figure 1. ECG of the patients.
(A) ECG shows normal sinus rhythm, normal axis, ST segment depression and T wave inversion in II, III, aVF, QT and QTC intervals are 380 and 480 msec, respectively. (B) ECG showed normal sinus rhythm, normal axis, QT and QTC intervals are 400 and 500 msec, respectively. (C) Normal sinus rhythm, normal axis, QT and QTC intervals are 380 and 425 msec, respectively.
Table 1. Laboratory information of three patients’ with COVID-19 infection who died of sudden cardiac arrest.
Laboratory variables First case Second case Third case
WBC (*109/l) 3.4 9.1 16
RBC (*106 cells/mcl) 4.26 2.9 4.56
Hemoglobin (g/dl) 12.6 9 14.4
Hematocrit (%) 37.8 25.1 43
MCV (fl) 89 86 94
MCH (pg) 29.5 29 31.6
MCHC (g/dl) 33.3 33.5 33.5
ESR (mm/h) 31 125 82
Platelets (*109/l) 158 382 147
Neutrophil (*109/l) 75 82 90
Lymphocyte (*109/l) 20 18 10
Monocyte (*109/l) 2 N/A N/A
CRP (Qualitative) 2+ 3+ 3+
AST (U/l) N/A 28 N/A
ALT (U/l) N/A 16 N/A
Alkaline phosphatase (IU/l) N/A 187 N/A
Blood sugar (mg/dl) 75 N/A N/A
Blood urea (mg/dl) 26 77 25
Serum creatinine 1.1 1.5 1
Blood sodium (mmol/l) 138 133 142
Blood potassium (mmol/l) 4 4 4.3
Serum phosphate (mg/dl) 2.6 3.4 3.4
Serum magnesium (mg/dl) 2.7 2.6 2.06
Serum calcium (mg/dl) 10.2 9.6 8.6
Note: The symbol * denotes multiplication in the table.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; N/A: Not available; RBC: Red blood cell; WBC: White blood cell.
Case 2
The patient was a 75-year-old woman with a history of diabetes and chronic renal failure hospitalized due to dyspnea. The vital signs at the time of referral were as BP = 100/75, PR = 105/min, RR: 18/min, BT: 37 and O2 saturation (in room air) = 87%. Crackles were heard in both lungs while other examinations were normal. Due to pulmonary involvement and dyspnea, the patient was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir, meropenem, dexamethasone and enoxaparin adjusted based on serum creatinine level. The patient was consulted with a cardiologist and an endocrinologist. ECG (Figure 1B) and echocardiography revealed no abnormality and the blood glucose level was closely monitored. According to recommendations, the patients was treated with corticosteroids as well. The result of troponin I test was negative and creatinine level was reported as 1.5 mg/dl. There were no electrolyte abnormalities during hospitalization. After 7 days and with the improvement of symptoms and reaching O2 saturation >95% within the last 48 h, the patient was decided to continue quarantine in a recovery center. The next day, after being transferred while having good general condition and normal vital signs, she suddenly developed cardiac arrest and died due to lack of response to resuscitation. Table 1 shows the patient’s laboratory information and Figure 2B demonstrates the results of the patient’s chest CT scan.
Figure 2. Chest high-resolution computed tomography of the patients.
(A) Lung high-resolution computed tomography showed multifocal peripheral ground glass opacity in both lungs, highly in favor of COVID-19 pneumonia. (B) Axial thin-section noncontrast CT scan shows diffuse bilateral confluent and patchy ground-glass and consolidative pulmonary opacities with bilateral pleural effusion. (C) Chest CT scan image shows multiple patchy, peripheral, bilateral areas of ground-glass opacities.
Case 3
A 60-year-old man without any history of specific diseases was referred to our hospital due to fever and dyspnea. He was diagnosed with COVID-19 and hospitalized. On admission, the patient's vital signs were as BP = 110/70, PR = 105/min, BT = 38.7°C and O2 saturation (in room air) = 82% which increased to >94% after applying O2 masks. During a clinical examination, crackle was heard in the patient’s left lung. He was treated with oseltamivir, hydroxychloroquine, lopinavir/ritonavir and azithromycin. The patient had no specific problems and the vital signs were normal with no evidence of electrolyte disturbances. The troponin I test was negative. Baseline ECG was normal (Figure 1C). On day 2 of hospitalization, he suffered from cardiac arrest and unfortunately died as resuscitation was unsuccessful. Table 1 shows the patient’s laboratory information; and the results of the patient’s chest CT scan is shown in Figure 2C.
Discussion
During the past 18 years, coronaviruses have caused three major crises in human societies [4]. For the first time, in November 2002, SARS emerged due to SARS-CoV and spread across China. Then in September 2012, Middle East respiratory syndrome caused by the MERS-CoV spread in many parts of the world causing many deaths. And now, there has been a new pneumonia related to COVID-19 virus identified in December 2019 turning to a global pandemic since March 2020 [5]. Because of being highly contagious, as well as having high mortality rate in the elderly and people with pre-existing medical conditions [11], many concerns have been raised worldwide regarding the pandemic global outcomes.
Many studies have reported pneumonia and acute respiratory distress as the main causes of death in COVID-19 patients. Underlying diseases that increase the risk of mortality due to COVID-19 include high BP, cardiovascular and cerebral disease, diabetes, hyperlipidemia, peripheral vascular diseases and chronic renal failure [11]. Numerous studies have highlighted an association between cardiovascular conditions and risk of mortality in COVID-19 patients [7]. Cardiac troponin I is one of the laboratory parameters predicting cardiac ischemia in patients with COVID-19. In fact, this laboratory parameter indicates cardiac damage in the patients [12]. Although most studies have noted that cardiac damage as a risk factor of mortality, Inciardi et al. reported death due to cardiac failure in a patient with COVID-19 who had no history of cardiovascular problems. However, there was no indication of possible mechanisms of cardiac failure in this recent report [13].
Viral infection is an important cause of myocarditis. The most well-known viruses of this type include influenza and parvovirus B-19. Nevertheless, it is not clear whether SARS-CoV-2 also induces cardiac damage. Possible mechanisms by which COVID-19 may cause cardiac damage include inflammatory responses and cytokine storm, direct attack to cardiomyocytes and inducing severe hypoxia.
Another potential cause is the proarrhythmic effects of hydroxychloroquine. This is the standard of treatment for COVID-19 in our country, Iran. QT prolongation and torsades de pointes (TdP) are a known adverse effect of this drug. Besides hydroxychloroquine, other risky drugs include lopinavir/ritonavir (administered in all 3 cases), azithromycin (case 3) and levofloxacin (case 1) may lead to (TdP) [14]. Although we did not have the ECG of the patients prior to their death to prove this theory.
Another potentially important factor involved in QTC prolongation in COVID-19 is the high-grade systemic inflammation which characterize the diseases, frequently a real ‘cytokine storm’ in which IL-6 seems to play a pivotal role. As recently pointed out by PE et al., IL-6 could promote QTC prolongation in COVID-19 patients by different mechanisms [15].
Another very rare cause could be transient bradycardia in these patients. We have reported this complication before [16].
In compliance with our national guidelines, all patients admitted with the diagnosis of COVID-19, should be treated with hydroxychloroquine and ECG is obtained for patients >40 years old or with known cardiovascular disease. It is recommended to repeat the ECG on the third to fifth day of therapy. Prolongation of QTC intervals in the first and second case (480 and 500 msec, respectively) could be due to inflammatory activation (besides pre-existing risk factors, specifically diabetes and chronic heart failure in patient 2). Thus, it is plausible that a further QTC increase occurred after starting drug assumption, possibly reaching critical levels to favor TdP and SCD.
According to the official reports by the Shahid Mostafa Khomeini Hospital of Ilam, 353 patients have been confirmed with COVID-19 infection until 10 April 2020 in Ilam Province. Of these, 35 deaths have been reported giving a mortality rate of 9.91%. From the 35 deceased cases, sudden cardiac arrest had been observed in three patients rendering an uncommon condition (0.84%). These patients had no symptoms or recognizable predictors requiring more examinations to timely identify them.
Study limitations
ECG of the patients prior to their death are not available and in that case we could discuss more precisely about the QT and QTC.
Conclusion
Death due to sudden cardiac arrest is not common, but possible, in COVID-19 patients. It is recommended to examine and monitor COVID-19 patients’ cardiac condition to identify at risk individuals.
Summary points
COVID-19 pandemic is growing day by day.
Although the cardinal manifestations are pulmonary, cardiovascular involvements are illustrated in the literature.
Sudden cardiac arrest and death may happen in COVID-19.
Herein we reported three sudden cardiac deaths among 353 proved COVID-19 patients in our institution.
Interestingly, death occurred despite improvement of general condition and constitutional symptoms.
Sudden death could be due direct involvement of myocardium by virus and arrhythmic events, cytokine storm or adverse drug effects (hydroxychloroquine and antivirals).
Acknowledgments
The authors thank the staff of Shahid Mostafa Khomeini Hospital of Ilam for their kind cooperation.
Financial & competing interests disclosure
This research was financially supported by the Deputy of Research and Technology of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. This research was approved by ethical department of Ilam University of Medical Sciences (IR.MEDILAM.REC.1399.098). | Fatal | ReactionOutcome | CC BY | 32615807 | 18,820,507 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Human herpesvirus 6 encephalitis'. | Human herpesvirus 6B encephalitis in a liver transplant recipient: A case report and review of the literature.
Human herpesvirus 6B (HHV-6B) encephalitis in a liver transplant recipient is rarely reported. In this report, we presented a case of HHV-6B encephalitis in a liver transplant recipient and reviewed the relevant literature. A 56-year-old man was admitted to the intensive care unit (ICU) with an acute headache and intermittent convulsion 17 days after liver transplantation. Next-generation sequencing (NGS) of the cerebrospinal fluid (CSF) revealed 30691 sequence reads of HHV-6B and real-time polymerase chain reaction (real-time PCR) of the CSF detected HHV-6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV-6B encephalitis and received ganciclovir treatment promptly. The condition of the patient improved well and returned to the general ward with no neurologic deficits. This case indicated that adequate awareness, early diagnosis, and timely treatment are crucial to a good prognosis of HHV-6B encephalitis after liver transplantation.
1 INTRODUCTION
Human herpesvirus 6 (HHV‐6) is a β‐herpesvirus and consists of two genetically distinct variants: HHV‐6A and HHV‐6B. Most HHV‐6 infection is asymptomatic or manifests as diarrhea, nonspecific fever, and rash. However, HHV‐6–induced encephalitis can occur after transplantation and is associated with poor prognosis. 1 HHV‐6 encephalitis after liver transplantation has rarely been reported. Here, we present a case of human herpesvirus 6B encephalitis in a liver transplant recipient and review the relevant literature.
2 MEDICAL HISTORY
A 56‐year‐old man with liver tumor recurrence after curative surgery was admitted to the hospital and received orthotopic liver transplantation. He received the medication regimen of tacrolimus and sirolimus for immunosuppressive therapy post‐surgery. This patient developed a headache, intermittent convulsion, and the disturbance of consciousness 17 days after transplantation and then was transferred to our department.
3 PHYSICAL EXAMINATION
The temperature was 37.2°C, pulse was 147 beats/min, and blood pressure was 137/91 mm Hg, SpO2 of 88%‐92% (oxygen concentration: 5 L/min), double pupils of equal size and equal circle, the diameter of about 2.5 mm, sensitive to light reflection, and the appearance of an erythematous cutaneous rash on the trunk and back. The patient was unable to follow commands, physical examination revealed no evidence of Babinski's sign, and muscle strength and muscle tone were normal.
4 LABORATORY EXAMINATIONS
Additional laboratory values included the following: C‐reactive protein 7 mg/L, ALT 46 IU/L, AST 30 IU/L, 46 μmol/L, blood ammonia 46 μmol/L, and BNP <100 pg/mL. Imaging of the brain by CT scanning and magnetic resonance imaging (MRI) demonstrated no other abnormalities except for cerebral ischemia, and the electroencephalogram was abnormal due to the continuous electrographic seizures. Cerebrospinal fluid (CSF) pressure was 240 mH2O, and the CSF test indicated the following: nucleated cell counts 20 × 106/L, red blood cells 0, protein 0.1 g/L, glucose 4 mmol/L, and chloride 119.9 mmol/L.
5 TREATMENT AND DIAGNOSIS
On admission, the patient was diagnosed with epilepsy of unknown cause and was treated with mechanical ventilatory support and antiepileptic drugs. Then, tacrolimus and sirolimus were discontinued, and glucocorticoid was initiated. Various B vitamins were supplemented to improve neurologic symptoms. Simultaneously, a next‐generation sequencing assay was performed to identify central nervous system infection. Two days later, next‐generation sequencing (NGS) of CSF showed 30691 sequence reads of HHV‐6B with 98.59% coverage of the HHV‐6B genome (Figure 1) and real‐time polymerase chain reaction (real‐time PCR) of the CSF detected HHV‐6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV‐6B encephalitis and received intravenous ganciclovir (250 mg daily) immediately. MRI scan of the brain showed symmetric hyperintense signal distributed in the frontal lobe and temporal lobe on the fourth day of ICU admission (Figure 2). 2 weeks after starting ganciclovir, the patient's clinical manifestations markedly improved with the stable neurologic status, and real‐time PCR of HHV‐6B were all negative (blow 1000 copies/mL) for CSF and blood. The patient was weaned from the ventilator on the next day. After ganciclovir administration for four weeks, CSF pressure returned to 80 mmH2O. From this day onwards, the dosage of ganciclovir decreased to 150 mg/d. Thirty‐seven days after admission, he was discharged to the organ transplant ward for further treatment, with no obvious neurologic deficits. The clinical course was summarized in Figure 3.
Figure 1 Next‐generation sequencing (NGS) of cerebrospinal fluid (CSF) showed 30691 sequence reads of HHV‐6B with the coverage of 98.59% on its genome
Figure 2 Cranial MRI showed hyperintense signal distributed symmetrically in bilateral frontal lobe (A and B, red arrow) and temporal lobe (A and B, green arrow). Diffusion‐weighted MRI showed hyperintense signal distributed symmetrically in bilateral frontal lobe (C, red arrow) and temporal lobe (C, green arrow). Apparent diffusion coefficient MRI showed hypointense signal distributed in bilateral frontal lobe (D, red arrow), and right temporal lobe (D, green arrow)
Figure 3 Clinical course of Human herpesvirus 6B (HHV‐6B) encephalitis in a liver transplant recipient
6 DISCUSSION
Human herpesvirus 6 is a widespread virus that primarily infects most children in the first 2 years of age. 2 Seroprevalence of HHV‐6 in healthy adulthood is up to 90%, so most HHV‐6 infections in transplantation recipients are thought to be caused by virus reactivation. The prevalence of HHV‐6 reactivation among liver transplantation recipients varies widely from 4.3% to 53.7%, partly due to differences in study size and diagnostic assays for HHV‐6. 3
Most HHV‐6 reactivations in liver transplantation recipients are transient and asymptomatic with a low level of HHV‐6 DNA. 4 However, three cases of severe HHV‐6 encephalitis after liver transplantation have been reported. 5 , 6 , 7 All three patients initially present with confusion, among which one patient also developed generalized tonic‐clonic seizures. Cranial MRI of three patients was characterized by symmetric high signal intensity predominantly in the medial temporal lobes, which contained the hippocampi and amygdala. Of all three patients, PCR results of CSF were positive for HHV‐6, leading to the diagnosis of HHV‐6 encephalitis. Ganciclovir and phosphonoformic acid (foscarnet) are currently recommended first‐line treatments for HHV‐6B. 8 Among three patients, one patient received intravenous ganciclovir, and the other two patients received intravenous phosphonoformic acid, respectively, due to ganciclovir‐resistance and ganciclovir‐induced leukopenia. All three patients recovered well without detectable neurologic deficits. The patient in our report started with seizures and impaired consciousness, and cranial MRI revealed symmetric high signal intensity in the frontal lobe and medial temporal lobes. HHV‐6 was positive in CSF with a high DNA level. After four weeks of treatment of ganciclovir, the patient's mental functioning had recovered to his baseline. One‐third of HHV‐6B encephalitis in allogeneic hematopoietic transplantation recipients have been reported to be specifically diagnosed with post‐transplant limbic encephalopathy, which is characterized with temporal seizures, anterograde amnesia, syndrome of inappropriate antidiuretic hormone secretion, and the abnormal signal in the limbic system by MRI. 9 From the current four reported cases, the clinical characteristics of HHV‐6 encephalitis in liver transplantation recipients are mostly consistent with those of post‐transplant limbic encephalopathy. However, more cases are needed for further investigation.
The indirect adverse effect of HHV‐6 infection on liver transplantation has been studied. HHV‐6 positivity in blood or bile was associated with the incidence of liver allograft rejection. 10 , 11 , 12 In liver transplantation recipients, HHV‐6 infection also results in increased risks of severe opportunistic infections, including CMV, EBV, VZV, mycobacterial disease, and invasive fungal infections. 3 , 13 NGS, known as high‐throughput sequencing, can detect unexpected pathogens in a single application. NGS has been proved to be a promising method to identify abundant and transplant‐related pathogens. 14 In this case, NGS found sequence reads of HHV‐6B in the patient's CSF, which facilitated the timely diagnosis of HHV‐6B encephalitis and contributed to a favorable prognosis of the patient.
Human herpesvirus 6 has a unique ability to integrate its genome into telomeres of the human host. This phenomenon, commonly called inherited chromosomally integrated HHV‐6 (ciHHV‐6), occurs in 2% of liver transplants patients. 3 Recognition of ciHHV‐6 is vital for clinical strategy. ciHHV‐6–induced HHV‐6 infection after liver transplant has been reported to be associated with liver rejection and mortality. 15 , 16 On the other hand, misdiagnosis of ciHHV‐6 as HHV‐6 reactivation will result in unnecessary and potentially toxic antiviral therapy. 17 Thus, it has been recommended to examine donated organs and organ recipients for ciHHV‐6. If HHV‐6 load in whole blood is above 5.5 log10 copies/mL or persistently at a high level under appropriate antiviral treatment, ciHHV‐6 should be assumed and further confirmed by quantitative PCR of HHV‐6 on fingernails or hair follicles. 18 In this case, quantitative PCR of HHV‐6 revealed 12 000 copies/mL (4.08 log10 copies/mL) in CSF and negative results in whole blood, which excluded the possibility of ciHHV‐6 and indicated that the encephalitis might be caused by endogenous reactivation of HHV‐6B strain. However, we did not determine ciHHV‐6 status in the donor, which is the inadequacy of this case report.
7 CONCLUSION
In summary, HHV‐6 infection should be considered if liver transplant recipients develop confusion or epileptic seizures. The prompt early diagnosis and the timely application of antiviral therapy are of great significance for improving the patient's prognosis.
CONFLICT OF INTEREST
There are no conflicts of interest.
AUTHOR CONTRIBUTIONS
Yinfeng Wang and Di Wang wrote the manuscript, and Xiaogen Tao revised it. | SIROLIMUS, TACROLIMUS | DrugsGivenReaction | CC BY | 32638491 | 18,048,674 | 2021-02 |
What was the outcome of reaction 'Human herpesvirus 6 encephalitis'? | Human herpesvirus 6B encephalitis in a liver transplant recipient: A case report and review of the literature.
Human herpesvirus 6B (HHV-6B) encephalitis in a liver transplant recipient is rarely reported. In this report, we presented a case of HHV-6B encephalitis in a liver transplant recipient and reviewed the relevant literature. A 56-year-old man was admitted to the intensive care unit (ICU) with an acute headache and intermittent convulsion 17 days after liver transplantation. Next-generation sequencing (NGS) of the cerebrospinal fluid (CSF) revealed 30691 sequence reads of HHV-6B and real-time polymerase chain reaction (real-time PCR) of the CSF detected HHV-6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV-6B encephalitis and received ganciclovir treatment promptly. The condition of the patient improved well and returned to the general ward with no neurologic deficits. This case indicated that adequate awareness, early diagnosis, and timely treatment are crucial to a good prognosis of HHV-6B encephalitis after liver transplantation.
1 INTRODUCTION
Human herpesvirus 6 (HHV‐6) is a β‐herpesvirus and consists of two genetically distinct variants: HHV‐6A and HHV‐6B. Most HHV‐6 infection is asymptomatic or manifests as diarrhea, nonspecific fever, and rash. However, HHV‐6–induced encephalitis can occur after transplantation and is associated with poor prognosis. 1 HHV‐6 encephalitis after liver transplantation has rarely been reported. Here, we present a case of human herpesvirus 6B encephalitis in a liver transplant recipient and review the relevant literature.
2 MEDICAL HISTORY
A 56‐year‐old man with liver tumor recurrence after curative surgery was admitted to the hospital and received orthotopic liver transplantation. He received the medication regimen of tacrolimus and sirolimus for immunosuppressive therapy post‐surgery. This patient developed a headache, intermittent convulsion, and the disturbance of consciousness 17 days after transplantation and then was transferred to our department.
3 PHYSICAL EXAMINATION
The temperature was 37.2°C, pulse was 147 beats/min, and blood pressure was 137/91 mm Hg, SpO2 of 88%‐92% (oxygen concentration: 5 L/min), double pupils of equal size and equal circle, the diameter of about 2.5 mm, sensitive to light reflection, and the appearance of an erythematous cutaneous rash on the trunk and back. The patient was unable to follow commands, physical examination revealed no evidence of Babinski's sign, and muscle strength and muscle tone were normal.
4 LABORATORY EXAMINATIONS
Additional laboratory values included the following: C‐reactive protein 7 mg/L, ALT 46 IU/L, AST 30 IU/L, 46 μmol/L, blood ammonia 46 μmol/L, and BNP <100 pg/mL. Imaging of the brain by CT scanning and magnetic resonance imaging (MRI) demonstrated no other abnormalities except for cerebral ischemia, and the electroencephalogram was abnormal due to the continuous electrographic seizures. Cerebrospinal fluid (CSF) pressure was 240 mH2O, and the CSF test indicated the following: nucleated cell counts 20 × 106/L, red blood cells 0, protein 0.1 g/L, glucose 4 mmol/L, and chloride 119.9 mmol/L.
5 TREATMENT AND DIAGNOSIS
On admission, the patient was diagnosed with epilepsy of unknown cause and was treated with mechanical ventilatory support and antiepileptic drugs. Then, tacrolimus and sirolimus were discontinued, and glucocorticoid was initiated. Various B vitamins were supplemented to improve neurologic symptoms. Simultaneously, a next‐generation sequencing assay was performed to identify central nervous system infection. Two days later, next‐generation sequencing (NGS) of CSF showed 30691 sequence reads of HHV‐6B with 98.59% coverage of the HHV‐6B genome (Figure 1) and real‐time polymerase chain reaction (real‐time PCR) of the CSF detected HHV‐6B DNA at 12 000 copies/mL, so the patient was diagnosed with HHV‐6B encephalitis and received intravenous ganciclovir (250 mg daily) immediately. MRI scan of the brain showed symmetric hyperintense signal distributed in the frontal lobe and temporal lobe on the fourth day of ICU admission (Figure 2). 2 weeks after starting ganciclovir, the patient's clinical manifestations markedly improved with the stable neurologic status, and real‐time PCR of HHV‐6B were all negative (blow 1000 copies/mL) for CSF and blood. The patient was weaned from the ventilator on the next day. After ganciclovir administration for four weeks, CSF pressure returned to 80 mmH2O. From this day onwards, the dosage of ganciclovir decreased to 150 mg/d. Thirty‐seven days after admission, he was discharged to the organ transplant ward for further treatment, with no obvious neurologic deficits. The clinical course was summarized in Figure 3.
Figure 1 Next‐generation sequencing (NGS) of cerebrospinal fluid (CSF) showed 30691 sequence reads of HHV‐6B with the coverage of 98.59% on its genome
Figure 2 Cranial MRI showed hyperintense signal distributed symmetrically in bilateral frontal lobe (A and B, red arrow) and temporal lobe (A and B, green arrow). Diffusion‐weighted MRI showed hyperintense signal distributed symmetrically in bilateral frontal lobe (C, red arrow) and temporal lobe (C, green arrow). Apparent diffusion coefficient MRI showed hypointense signal distributed in bilateral frontal lobe (D, red arrow), and right temporal lobe (D, green arrow)
Figure 3 Clinical course of Human herpesvirus 6B (HHV‐6B) encephalitis in a liver transplant recipient
6 DISCUSSION
Human herpesvirus 6 is a widespread virus that primarily infects most children in the first 2 years of age. 2 Seroprevalence of HHV‐6 in healthy adulthood is up to 90%, so most HHV‐6 infections in transplantation recipients are thought to be caused by virus reactivation. The prevalence of HHV‐6 reactivation among liver transplantation recipients varies widely from 4.3% to 53.7%, partly due to differences in study size and diagnostic assays for HHV‐6. 3
Most HHV‐6 reactivations in liver transplantation recipients are transient and asymptomatic with a low level of HHV‐6 DNA. 4 However, three cases of severe HHV‐6 encephalitis after liver transplantation have been reported. 5 , 6 , 7 All three patients initially present with confusion, among which one patient also developed generalized tonic‐clonic seizures. Cranial MRI of three patients was characterized by symmetric high signal intensity predominantly in the medial temporal lobes, which contained the hippocampi and amygdala. Of all three patients, PCR results of CSF were positive for HHV‐6, leading to the diagnosis of HHV‐6 encephalitis. Ganciclovir and phosphonoformic acid (foscarnet) are currently recommended first‐line treatments for HHV‐6B. 8 Among three patients, one patient received intravenous ganciclovir, and the other two patients received intravenous phosphonoformic acid, respectively, due to ganciclovir‐resistance and ganciclovir‐induced leukopenia. All three patients recovered well without detectable neurologic deficits. The patient in our report started with seizures and impaired consciousness, and cranial MRI revealed symmetric high signal intensity in the frontal lobe and medial temporal lobes. HHV‐6 was positive in CSF with a high DNA level. After four weeks of treatment of ganciclovir, the patient's mental functioning had recovered to his baseline. One‐third of HHV‐6B encephalitis in allogeneic hematopoietic transplantation recipients have been reported to be specifically diagnosed with post‐transplant limbic encephalopathy, which is characterized with temporal seizures, anterograde amnesia, syndrome of inappropriate antidiuretic hormone secretion, and the abnormal signal in the limbic system by MRI. 9 From the current four reported cases, the clinical characteristics of HHV‐6 encephalitis in liver transplantation recipients are mostly consistent with those of post‐transplant limbic encephalopathy. However, more cases are needed for further investigation.
The indirect adverse effect of HHV‐6 infection on liver transplantation has been studied. HHV‐6 positivity in blood or bile was associated with the incidence of liver allograft rejection. 10 , 11 , 12 In liver transplantation recipients, HHV‐6 infection also results in increased risks of severe opportunistic infections, including CMV, EBV, VZV, mycobacterial disease, and invasive fungal infections. 3 , 13 NGS, known as high‐throughput sequencing, can detect unexpected pathogens in a single application. NGS has been proved to be a promising method to identify abundant and transplant‐related pathogens. 14 In this case, NGS found sequence reads of HHV‐6B in the patient's CSF, which facilitated the timely diagnosis of HHV‐6B encephalitis and contributed to a favorable prognosis of the patient.
Human herpesvirus 6 has a unique ability to integrate its genome into telomeres of the human host. This phenomenon, commonly called inherited chromosomally integrated HHV‐6 (ciHHV‐6), occurs in 2% of liver transplants patients. 3 Recognition of ciHHV‐6 is vital for clinical strategy. ciHHV‐6–induced HHV‐6 infection after liver transplant has been reported to be associated with liver rejection and mortality. 15 , 16 On the other hand, misdiagnosis of ciHHV‐6 as HHV‐6 reactivation will result in unnecessary and potentially toxic antiviral therapy. 17 Thus, it has been recommended to examine donated organs and organ recipients for ciHHV‐6. If HHV‐6 load in whole blood is above 5.5 log10 copies/mL or persistently at a high level under appropriate antiviral treatment, ciHHV‐6 should be assumed and further confirmed by quantitative PCR of HHV‐6 on fingernails or hair follicles. 18 In this case, quantitative PCR of HHV‐6 revealed 12 000 copies/mL (4.08 log10 copies/mL) in CSF and negative results in whole blood, which excluded the possibility of ciHHV‐6 and indicated that the encephalitis might be caused by endogenous reactivation of HHV‐6B strain. However, we did not determine ciHHV‐6 status in the donor, which is the inadequacy of this case report.
7 CONCLUSION
In summary, HHV‐6 infection should be considered if liver transplant recipients develop confusion or epileptic seizures. The prompt early diagnosis and the timely application of antiviral therapy are of great significance for improving the patient's prognosis.
CONFLICT OF INTEREST
There are no conflicts of interest.
AUTHOR CONTRIBUTIONS
Yinfeng Wang and Di Wang wrote the manuscript, and Xiaogen Tao revised it. | Recovered | ReactionOutcome | CC BY | 32638491 | 18,048,674 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute monocytic leukaemia'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN | DrugsGivenReaction | CC BY | 32638943 | 18,428,155 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32638943 | 18,471,753 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32638943 | 18,471,753 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus infection'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32638943 | 18,471,753 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN | DrugsGivenReaction | CC BY | 32638943 | 18,428,155 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palpitations'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN | DrugsGivenReaction | CC BY | 32638943 | 18,428,155 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN | DrugsGivenReaction | CC BY | 32638943 | 18,428,155 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Splenomegaly'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CEFEPIME HYDROCHLORIDE, CEFUROXIME, CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 32638943 | 18,509,828 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Staphylococcal infection'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32638943 | 18,471,753 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxoplasmosis'. | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | CYTARABINE, ETOPOSIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, IDARUBICIN, MERCAPTOPURINE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 32638943 | 18,471,753 | 2021 |
What was the dosage of drug 'FILGRASTIM'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | UNK UNK, CYCLIC | DrugDosageText | CC BY | 32638943 | 18,479,665 | 2021 |
What was the dosage of drug 'IDARUBICIN HYDROCHLORIDE'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | UNK UNK, CYCLIC | DrugDosageText | CC BY | 32638943 | 18,479,665 | 2021 |
What was the outcome of reaction 'Acute monocytic leukaemia'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638943 | 18,428,155 | 2021 |
What was the outcome of reaction 'Cytomegalovirus infection'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638943 | 18,471,753 | 2021 |
What was the outcome of reaction 'Death'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638943 | 18,471,753 | 2021 |
What was the outcome of reaction 'Epstein-Barr virus infection'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638943 | 18,471,753 | 2021 |
What was the outcome of reaction 'Haemophagocytic lymphohistiocytosis'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638943 | 18,509,828 | 2021 |
What was the outcome of reaction 'Staphylococcal infection'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638943 | 18,471,753 | 2021 |
What was the outcome of reaction 'Toxoplasmosis'? | HEMOPHAGOCYTOSIS BY BLASTS IN A CHILD WITH ACUTE MONOCYTIC LEUKEMIA AFTER CHEMOTHERAPY.
OBJECTIVE
To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells.
METHODS
In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse.
CONCLUSIONS
HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.
INTRODUCTION
Acute myeloid leukemia (AML) accounts for about 20% of the childhood leukemia
cases.
1
Over the last decades, the survival rate of children with AML has
significantly improved, and estimates indicate that around 60% of them have been
cured in most developed countries.
2
,
3
In children aged 0-2 years, AML has been associated with a high prevalence
of unfavorable prognosis and increased risk of treatment-related toxicity, with
acute monocytic leukemia (AMoL) being one of the most common AML subtypes in
infants.
3
Despite the advances in the treatment of children with leukemia, AMoL
continues to be responsible for high rates of morbidity and mortality.
2
AML diagnosis requires morphological, immunophenotypic, and molecular evaluation, as
well as the presence of certain cytogenetic abnormalities related to age, incidence
of unbalanced aberrations, and complex karyotypes.
4
AML with t(8;16)(p11;p13) is an example of such abnormalities, defined by a
unique gene expression signature, monocytic morphology, high frequency of leukemia
cutis, and erythrophagocytosis in childhood.
5
,
6
Reports of hemophagocytic lymphohistiocytosis (HLH) in cases of childhood AML
(especially AMoL) are very rare in the literature, corresponding mainly to
hemophagocytosis caused directly by leukemic cells. HLH is a rare and aggressive
inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and
hemophagocytosis in the bone marrow (BM), lymph nodes, spleen, and liver. HLH is
diagnosed by a combination of at least five of the following eight criteria: fever,
splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia,
hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and increased
levels of soluble CD25.
7
This disorder results from two distinct reasons: (1) Primary or familial HLH
that occurs during the first years of life, being fatal when not treated;
7
,
8
,
9
or (2) Secondary or reactive HLH associated with underlying immunological or
malignant diseases.
8
,
10
,
11
The pathogenesis of HLH was recently defined as the impaired activation of T
lymphocytes following the stimulation by immune responses, which results in large
amounts of inflammatory cytokines that promote macrophage infiltration and cytokine
network formation.
12
Malignancy-associated HLH (M-HLH) may occur concomitantly with a neoplasm or during
chemotherapy, mainly in patients who are already in remission.
13
,
14
Children and infants present M-HLH more often in lymphomas and solid
neoplasms.
10
,
14
In this paper, we described a case of HLH with blast phagocytosis in a child with
relapsed AMoL after chemotherapy.
CASE REPORT
In 2014, a previously healthy 3-year-old white Brazilian female patient was admitted
to the Hospital de Clínicas de Porto Alegre with fever and abdominal pain. Imaging
examination showed discrete amounts of pleural effusion on the left and right lungs
and enlarged spleen. Laboratory results indicated pancytopenia (leukocyte count:
1.37×109/L, lymphocytes count: 1.17×109/L, hemoglobin: 42
g/L, and platelet count: 25×109/L), high levels of C-reactive protein
(69.6 mg/dL), and lactate dehydrogenase (2,280 U/L). Screening tests for hepatitis B
surface antigen (HBsAg), toxoplasma IgG/IgM, and Venereal Disease Research
Laboratory (VDRL) were negative. BM aspirate slide review showed blast infiltration
with a monoblastic aspect. Immunophenotypic analysis identified two populations with
abnormal phenotype: (1) 28% of immature cells positive for CD64, CD4, HLADR, CD117,
CD56 bright, myeloperoxidase dim, CD11b, CD65, CD15 bright, CD38 bright, and CD45
dim, and negative for CD34, CD14, CD36, CD13, and NG2; and (2) 46% of more
differentiated cells presenting a similar immunophenotype, but positive for CD14 and
negative for CD117. Karyotype analysis showed 46XX[20] chromosomes and absence of
FMS-like tyrosine kinase 3 (FLT3) mutation. Therefore, the patient was diagnosed
with AMoL without chromosomal abnormality.
The treatment, in accordance with the 2004 Berlin-Frankfurt-Munster (BFM)
chemotherapy protocol,
15
{Creutzig, 2013, Development of a curative treatment within the AML-BFM
studies} was initiated as follows: first AIE induction
(cytarabine/idarubicin/etoposide); second HAM induction [high-dose of cytarabine (3
g/m2)/mitoxantrone] after forty-two days; and AI consolidation
[cytarabine (0.5 g/m2)/idarubicin] three months after the start of
treatment. The patient presented clinical worsening one month after febrile
neutropenia and received cefepime. A second HAM cycle (1
g/m2/mitoxantrone) was administered five months after the first
induction. A new episode of febrile neutropenia occurred after central catheter
placement, and cefepime and vancomycin therapy was restarted, with no signs of
invasive fungal infection on radiographic examinations or galactomannans. Central
culture was positive for coagulase-negative staphylococci. The
child was in complete remission one month after the second HAM. Next,
intensification HAE [high dose of cytarabine (3 g/m2)/etoposide] was
initiated, and the maintenance cycle (mercaptopurine/cytarabine) started after
forty-five days, along with radiotherapy 12Gy.
Four months after remission, the patient presented hematemesis, petechiae,
splenomegaly, and fever; she also showed pancytopenia (leukocyte count:
2.68×109/L, blast count: 0.56×109/L, hemoglobin: 73 g/L,
and platelet count: 37×109/L); high levels of lactate dehydrogenase
(5,640 U/L), ferritin (107.6 nmol/L), and C-reactive protein (31.3 mg/dL); and
normal levels of triglycerides (100 mg/dL) and fibrinogen (214 mg/dL). Screening
tests for HbsAg, VDRL, toxoplasma, cytomegalovirus, and Epstein-Barr virus IgM were
negative, whereas toxoplasma, cytomegalovirus, and Epstein-Barr virus IgG showed
positive results. A new BM aspirate slide review revealed 81% of vacuolated blasts
along with hemophagocytosis. Immunophenotypic analysis indicated 66% of neoplastic
cells presenting very high side scatter (SSC), which may be a result of the vacuoles
and phagocytic activity in these cells. Neoplastic cell populations expressed CD64
bright, CD36 bright, CD4, HLADR dim, CD56, myeloperoxidase, CD11b, CD13 dim, CD65,
CD15 bright, and CD45 dim, but they did not express CD34, CD117, CD14, CD16, or NG2
(Figure 1). The cytogenetic study revealed
a complex karyotype involving nine chromosomes into 13 cells (Figure 2). Unfortunately, cells in suspension were not available
to confirm the complex chromosome rearrangement by fluorescence in
situ hybridization (FISH) analysis.
Subsequently, the patient started a chemotherapy regimen with high-dose
cytarabine/fludarabine/idarubicin/etoposide/filgrastim. Cefuroxime, vancomycin, and
cefepime were prescribed to treat fever, neutropenia, palpitations, and shortness of
breath. Blood culture, in that period, identified a catheter-related growth of
coagulase-negative Staphylococcus. One week later, a new blood
culture was negative for microorganism growth. However, the patient had a fever of
unknown origin, and, immediately, meropenem and fluconazole were introduced, with
the maintenance of vancomycin for ten days. Nevertheless, the patient presented
progressive clinical deterioration. Blasts increased to 98% in the BM after four
weeks. Dexamethasone therapy (6 mg/m2/day) was started due to persistent
hemophagocytosis. A new blood culture showed growth of multidrug-resistant
Klebsiella pneumoniae, and the child received several
antibiotics (polymyxin B, gentamicin, vancomycin, and amphotericin). The patient
died two months after the onset of worsening.
Figure 1 Bone marrow film showing acute monocytic leukemia and phagocytosis in
leukocytes and erythrocytes (A). Immunophenotypic profile of the
leukemic population. Immature cells show high side scatter (SSC) due to
phagocytic activity and cytoplasmic vacuoles (B).
Figure 2 GTG-banded karyotype of the proband showing complex rearrangements
partly involving chromosomes 1p, 2p, 3p, 6q, 8p, 10qter, 16q, and
17q.
DISCUSSION
The association between malignancies and HLH may be related to direct immune
activation by transformed lymphocytes and/or loss of inhibitory immune function.
Many genes involved in HLH are also associated with an increased risk of several
neoplasms. Therefore, M-HLH should not preclude a complete genetic evaluation.
16
The largest multicenter study in children with M-HLH was performed in Turkey and
reported its association with acute lymphoblastic leukemia (66.6% of cases), AML
(7.4% of cases), Hodgkin lymphoma (HL), non-HL, rhabdomyosarcoma, neuroblastoma, and
Langerhans cell histiocytosis. This study showed that HLH occurred predominantly
during leukemia treatment.
10
A cohort study of 21 children revealed that mature T-cell disease was the
most frequent M-HLH. It also identified that only two children with HLH had AML (one
presenting AML with maturation and the other was not specified) during chemotherapy
and after remission.
14
Data from an Austrian study, including 508 children with several types of
malignancies, showed that six children developed HLH during antineoplastic
treatment, and two of them had AML with maturation.
8
Another study conducted in Austria reported that children with AML developed
HLH significantly more often than patients with acute lymphoblastic leukemia.
17
The description of AML cases associated with HLH in children is uncommon in the
literature and seems to be even rarer for AMoL. Lackner et al. have suggested a
predisposition of this subtype of malignancy towards the development of HLH, once
they found a 30% prevalence of HLH in children with AMoL, against a 4.6% prevalence
in other AML cases. In their study, three children with AMoL who developed HLH felt
the first symptoms after the first BFM 2004 protocol cycle.
2
HLH during chemotherapy frequently occurs in patients who have already achieved
remission and could be a result of the immune suppression caused by the treatment,
which might trigger fatal infections.
14
Moreover, in some cases of leukemia associated with HLH, blasts may perform
phagocytosis directly, instead of the mature phagocytic cells.
15
The pathogenic mechanism related to this behavior in neoplastic cells
remains unclear, although associations have been found with some chromosomal
abnormalities such as t(16;21) and t(8;16).
18
,
19
,
20
This behavior was present in blasts of the patient presented in this case report and
could be attributed to the complex cytogenetic aberrations acquired after treatment,
including chromosomes 8p and 16q.
The karyotype evolution, irrespective of diagnosis, seems secondary to the AML
treatment.
20
Even normal karyotypes can become highly unstable and turn into complex
karyotypes during the progression of the disease.
21
Regarding the immunophenotypic expression of leukemic cells, it was positive for CD56
antigen - a cell adhesion molecule present in NK/T lymphoma, multiple myeloma, and
some subtypes of AML.
18
;
22
There was overexpression of CD56 associated with AMoL in the diagnosis,
which maintained positivity after disease recurrence, although with lower intensity.
A meta-analysis by Xu et al. reported this antigen overexpression as an adverse
prognostic factor in AML.
22
Aside from the extramedullary involvement, CD56 may influence survival and
remission duration, and has also been related to HLH and vacuolation in AML cases
presenting t(16;21).
18
Decreased NK activity and high levels of soluble interleukin 2 receptor (sCD25) are
useful markers for HLH diagnosis and are typically present in infants and
children.
22
These tests were not performed due to unavailability in our laboratory
routine. Given the evaluation of the available results and following the current
diagnostic guidelines, the patient met the respective criteria for HLH. The
phagocytic activity of blasts in the BM, along with the development of karyotype
abnormalities and infections secondary to chemotherapy, might have led to the poor
prognosis of our patient.
In this study, we described a case of HLH caused directly by AMoL blasts with complex
cytogenetic aberrations after the patient underwent chemotherapy. In conclusion, HLH
in pediatric patients with malignant neoplasms remains a challenge due to its
importance and diagnostic difficulty, reflected in the high mortality rates.
Funding
This study did not receive funding. | Not recovered | ReactionOutcome | CC BY | 32638943 | 18,471,753 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Accidental overdose'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bradycardia'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Brain death'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,475,028 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depressed level of consciousness'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epistaxis'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure to toxic agent'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,475,028 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoglycaemia'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypothermia'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Shock'. | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | CLONAZEPAM, HALOPERIDOL, PROMETHAZINE HYDROCHLORIDE, VALPROIC ACID | DrugsGivenReaction | CC BY | 32638947 | 18,538,418 | 2021 |
What was the administration route of drug 'CLONAZEPAM'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Oral | DrugAdministrationRoute | CC BY | 32638947 | 18,538,418 | 2021 |
What was the administration route of drug 'HALOPERIDOL'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Oral | DrugAdministrationRoute | CC BY | 32638947 | 18,538,418 | 2021 |
What was the administration route of drug 'PROMETHAZINE HYDROCHLORIDE'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Oral | DrugAdministrationRoute | CC BY | 32638947 | 18,538,418 | 2021 |
What was the administration route of drug 'VALPROIC ACID'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Oral | DrugAdministrationRoute | CC BY | 32638947 | 18,538,418 | 2021 |
What was the outcome of reaction 'Accidental overdose'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,538,418 | 2021 |
What was the outcome of reaction 'Bradycardia'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,538,418 | 2021 |
What was the outcome of reaction 'Brain death'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,538,418 | 2021 |
What was the outcome of reaction 'Death'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,475,028 | 2021 |
What was the outcome of reaction 'Depressed level of consciousness'? | SEVERE ACUTE TOXIC EXPOSURES IN CHILDREN AND ADOLESCENTS: CASE SERIES.
OBJECTIVE
To describe a case series of severe acute toxic exposures (SATE) in individuals <20 years old followed-up by a regional Poison Control Center (PCC).
METHODS
Descriptive cross-sectional study. All patients who were <20yo and classified as score 3 (severe) and 4 (fatal) following Poisoning Severity Score were included for analysis. According to the outcome, patients were classified as PSS 3 when they developed intense clinical manifestations with risk of death or important sequelae; and as PSS 4 when death had resulted from direct cause or complication of the initial exposure. The data of patients were obtained from the Brazilian electronic database system (DATATOX).
RESULTS
During the biennium 2014-2015, Campinas PCC followed up 5,095 patients <20yo, with 30 being classified as SATE (PSS=3, n=24; PSS=4, n=6). The exposures circumstances were unintentional (15); intentional (14; suicide attempt = 11; street drugs consumption = 3); and not explained (1). The exposures were significantly more frequent in adolescents >14yo (n=17; p<0.01). The involved agents were venomous animals (8; scorpions=5); medicines (8; miscellaneous=6); chemicals (6); illegal rodenticides containing acetylcholinesterase inhibitors (chumbinho, 4); drugs of abuse (3); button battery (1). Three patients evolved with sequels (esophageal stricture post-corrosive ingestion). The median length of hospital stay was 6 days (IQR: 5-12 days); 26 patients were treated in intensive care units, and 22 of them needed mechanical ventilation; 12, inotropic/vasopressors; and 3, renal replacement therapy.
CONCLUSIONS
Scorpion stings and poisonings caused by medicines and chemicals were the main causes of SATE. The SATE were significantly more frequent in adolescents, due to deliberate self-poisoning.
INTRODUCTION
Poison Control Centers (PCC) are public reference services in clinical toxicology, of
regional or national scope, with assistance on permanent duty by telephone and/or in
person,
1
with health professionals being its main requesters in Brazil.
The services offered by PCCs involve human and animal exposures, including
information on any type of intoxication/poisoning. In general, the service aims to
assist the health professional in the clinical management of the intoxicated
patient, supported by information contained in electronic databases of international
toxicological information constantly updated and in evidence available in the
specialized literature, helping to prevent/reduce damage and lower health costs in
this activity area.
1
,
2
,
3
,
4
,
5
,
6
,
7
Among the cases registered in PCCs, the toxic exposures in pediatrics stand out due
to their frequency.
6
,
7
Despite this consideration, studies with the sole objective of evaluating
case series of cases of severe acute toxic exposures (SATE) in children and
adolescents, including epidemiological aspects and clinical management, have not
been previously described in Brazil. From the above, this work aimed to analyze a
case series SATE in children and adolescents followed by a PCC of regional reference
for a population of six million inhabitants in the Southeastern region of Brazil,
including a summary description of all fatal cases notified.
METHOD
A descriptive cross-sectional study of pediatric care (0 to 20 years old) of SATE was
carried out, followed by the Campinas PCC (exclusive and face-to-face phone calls),
from January 1st, 2014 to December 31st, 2015. The data for
analysis were obtained from the National System for Toxic-Pharmacological
Information (Datatox’s electronic base), from the Brazilian Association of
Toxicological Information and Assistance Centers (Associação Brasileira de
Centros de Informação e Assistência Toxicológica - ABRACIT). The
notification of cases in the Datatox system is not mandatory and is carried out only
by those PCCs associated to ABRACIT.
Only cases classified as severe and fatal to the outcome were included in the study
group according to the poisoning severity score (PSS) guidelines, which are similar
to the one used to close the case in the Datatox system. According to the PSS, cases
are classified according to their evolution, such as:
Asymptomatic (PSS=0).
Mild (PSS=1): discrete and transient clinical manifestations that are
quickly solved.
Moderate (PSS=2): more pronounced, more prolonged or more systemic
clinical manifestations that usually require treatment.
Severe (PSS=3): intense clinical manifestations, with risk of death or
resulting in important sequelae.
Fatal (PSS=4): as a direct cause or complication of exposure.
8
Demographic and clinical variables were analyzed, including age range,
intentionality, agents involved, treatments used and evolution. The non-parametric
statistical analysis of some variables was performed, such as position measurements
(median, quartiles and interquartile range - IQR), and, for the statistical analysis
of the difference in the distribution of values between independent and related
samples, the chi-squared test was applied, adopting p<0.05 as significant. All
toxicological analyzes mentioned in the results took place at the Campinas PCC
Analytical Toxicology Laboratory.
The present study is part of a broader project inserted in Plataforma
Brasil and approved by the Research Ethics Committee (CEP) of
Universidade Estadual de Campinas (Unicamp) - Certificate of Presentation for
Ethical Appreciation (CAAE) No. 43725215.9.0000.5404.
RESULTS
During the study period (2014-2015), the Campinas PCC served 5,095 individuals with
toxic exposures, aged <20, mainly in the age group between 1-4 years old (64.2%;
Table 1). In the rescue of cases
classified as severe and fatal in the Datatox system, 41 electronic medical records
with this classification were detected. These records were reviewed by four authors
(DBMA, ASTR, CCP and FB), in a non-blind manner, who, by consensus, concluded that
30 patients met the criteria for the outcome classification by the PSS as score 3
(n=24) and score 4 (n=6) (Table 1).
Table 1 Final classification of toxic exposure cases followed by the Campinas
Poison Control Center (PCC) (2014 and 2015), in children and
adolescents, according to the outcome and age group (years old).
Outcome (PSS)/age group (years old) <1 1-4 5-9 10-14 15-19 Total %
Asymptomatic (PSS=0) 250 2,027 346 212 273 3,108 61.0
Mild (PSS=1) 86 675 241 208 301 1,511 29.7
Moderate (PSS=2) 22 76 40 37 46 221 4.3
Severe (PSS=3) 1 4 2 2 15 24 0.5
Fatal with causal nexus (PSS=4) 0 2 2 0 2 6 0.1
Potentially toxic exposures without monitoring 3 10 1 1 1 16 0.3
Death from another cause 3 2 1 1 0 7 0.1
Ignored 14 98 26 27 37 202 4.0
Total (%) 379 (7.4) 2,894 (56.8) 659 (12.9) 488 (9.6) 675 (13.2) 5,095 (100) 100
PSS: poisoning severity score.
According to the data in Table 1, when
comparing the proportions between the groups of severe/fatal cases (PSS=3 and 4) and
non-severe (PSS=0, 1 and 2) in relation to the different age subgroups, it was
possible to find that SATE were significantly more frequent in adolescents >14
years old (<1 year old, 1/358; 14 years old, 6/2,778; 5-9 years old, 4/627; 10-14
years old, 2/457; 15-19 years old, 17/620; p<0.001). As to the demographic
characteristics of the study group (n=30), most were male (n=22), with a median age
of 15 years (IQR=7-17 years), and that most of the consultations happened through
exclusive telephone follow-up (n=26). As for the circumstance of exposure, in 15
cases it was classified as accidental, and in 14 cases, as intentional, the latter
occurring only in adolescents between 15 and 19 years old (suicide attempts, n=11;
psychoactive substance abuse, n=3) (Table 2).
In the fatal case of a 9-year-old girl, the cause of death was not clarified, with
the possibility of mistreatment/neglect or suicide considered (see synopsis of case
4). The median hospital stay was six days (IQR=5-12 days), and 26 patients were
admitted to intensive care units.
Table 2 Cases of severe acute toxic exposures in children and adolescents
according to age group (years old) in relation to the circumstance of
exposure, group of agents and evolution.
Age group (years old) <1 1-4 5-9 10-14 15-19 Total
Circumstance of exposure
Accidental 1 6 3 2 3 15
Intentional 0 0 0 0 14 14
Not clarified 0 0 1 0 0 1
Group of agents
Venomous animals 0 0 3 2 3 8
Medications 1 0 1 0 6 8
Household or industrial chemicals 0 5 0 0 1 6
Rodenticides for illegal use
(chumbinho) 0 0 0 0 4 4
Drugs of abuse 0 0 0 0 3 3
Button battery 0 1 0 0 0 1
Evolution
Cure 1 2 2 2 14 21
Anatomical sequelae (caustic esophageal
stenosis) 0 2 0 0 1 3
Fatal 0 2 2 0 2 6
Table 2 shows the groups of agents involved
according to the different age subgroups, and Table
3, the specific agents. Such data indicate that venomous animals, such as
scorpions and rattlesnakes, medicines (especially anticonvulsants and
antidepressants), household/industrial chemicals, cholinesterase-inhibiting
rodenticides (chumbinho) and recreational drugs of illegal use were
the main agents involved. The common name in Portuguese, chumbinho,
(“small lead pellets”) derives from the physical appearance of the product, which
generally consists of small, dark grey, regular-shaped granules. Table 4 shows the main clinical findings, with
emphasis on neurological depression, hypotension/shock and respiratory failure, with
73% of patients requiring mechanical ventilation and 40%,
vasopressors/inotropes.
Table 3 Cases of severe acute toxic exposures in children and adolescents
according to the agents involved and the evolution (sequelae and
deaths).
Agents involved, including associations N Sequelae Deaths
Venomous animals
Scorpions
Unidentified species (possibly Tityus
serrulatus) 4 0 0
Tityus serrulatus
1 0 1
Unidentified rattlesnake (possibly Crotalus
durissus terrificus) 3 0 0
Medications
Brimonidine 1 0 0
Carbamazepine 1 0 0
Carbamazepine and diazepam 1 0 0
Captopril and sertraline 1 0 0
Amitriptyline, diazepam and paracetamol 1 0 0
Valproic acid, haloperidol and promethazine 1 0 1
Chlordiazepoxide, lamotrigine, sertraline,
venlafaxine and desogestrel 1 0 0
Carbamazepine, lithium carbonate, chlorpromazine,
diazepam, phenytoin and phenobarbital 1 0 0
Household or industrial chemicals
Corrosive
Sodium hydroxide 2 2 0
Sodium dodecylbenzenesulfonate 1 0 1
Chlorine for swimming pool 1 1 0
Kerosene 1 0 0
Hydrocarbon solvent (derivatives of N-hexane)* 1 0 1
Rodenticides of clandestine use
(chumbinho)
Cholinesterase inhibitors ** 4 0 1
Drugs of abuse
Cocaine and tetrahydrocannabinol 1 0 1
Phenylethylamine (NBOMe) 1 0 0
Inhalants† 1 0 0
Button battery 1 0 0
Total 30 3 6
*The product accidentally ingested/inhaled was a pyrethroid
insecticide, but the death resulted from exposure to the solvent
present in the product (see case 1 synopsis); **not investigated by
laboratory analysis if the cholinesterase inhibitor was a carbamate
or an organophosphate; † presence of benzene and cyclohexane
confirmed in the blood sample and chloroform in the urine
sample.
Table 4 Main clinical findings observed during admission and evolution of the
30 cases of severe acute toxic exposures, including syndromic diagnoses
and treatments employed.
Clinical, laboratory findings and treatments
employed n
Neuromuscular changes
Neurological depression 13
Cholinergic syndrome 4
Myasthenic syndrome 3
Seizures 3
Severe rhabdomyolysis (total CK>10,000 U/L) 3
Psychomotor agitation 2
Serotonin syndrome 1
Cardiovascular changes
Hypotension/shock 12
Myocardial injury (increase in serum CKMB and
troponin) 6
Corrected QT interval widening (>440 ms) 4
Changes in the ST segment (depression and/or
elevation) 4
Myocardial dysfunction (LV ejection fraction
<56%) 3
Respiratory changes
Respiratory failure 11
Pneumonia 8
Acute pulmonary edema 4
Others
Acute kidney injury 4
Severe esophageal injury 4
Coagulopathy 2
Treatments used
Parenteral hydration 22
Mechanical ventilation 22
Vasopressors / inotropes 12
Continuous atropine infusion 4
Anti-scorpionic antivenom 4
Anticrotalic antivenom 3
Renal replacement therapy 3
Multiple doses of activated charcoal 3
Prolonged parenteral nutrition 2
Intravenous N-acetylcysteine 1
CK: creatine kinase; LV: left ventricle.
Among the three cases that evolved with sequelae (esophageal stricture after
ingestion of corrosives), two were accidental (sodium hydroxide) and one was due to
a suicide attempt (chlorine-based sanitizing for use in swimming pools). In one of
the accidental cases with sodium hydroxide (preparation of homemade soap;
one-year-old boy), the patient showed signs of acute respiratory failure and was
submitted to tracheostomy at the local service, complicated by injury to the
anterior esophageal wall, evolving, besides caustic stricture, with
tracheoesophageal fistula, being hospitalized for 28 days. In addition, a
one-year-old boy presented a circumferential lesion of the esophagus after ingesting
a button battery, evolving with transient esophageal stenosis reversed after two
endoscopic dilations.
Considering the estimated population for the administrative region of Campinas in the
years 2014 and 2015,
9
a lethality rate for toxic events of 0.24 and 0.17 cases/100 thousand
inhabitants was obtained for the age groups <5 and <20 years old,
respectively.
Here is a synopsis of the six fatal cases:
Case 1 (telephone follow-up): boy, one year old, admitted 90 minutes
after accidental ingestion / inhalation of pyrethroid insecticide,
containing hydrocarbon solvents in its formulation. He evolved with
seizures, a reversed cardiorespiratory arrest and respiratory failure
due to pulmonary edema (chemical pneumonitis), dying 24 hours after
exposure. Death was attributed to exposure to hydrocarbons present in
the product, with identification of N-hexane derivatives in blood
samples collected before death (gas chromatography-mass spectrometry -
GC-MS).
Case 2 (telephone follow-up): boy, two years old, admitted two hours
after accidental ingestion of a sip of an alkaline degreaser (sodium
dodecylbenzenesulfonate, pH=12.5-13.5), which was stored in a glass of
alcohol. The boy showed drooling and signs of respiratory difficulty. In
the service of origin, gastric lavage and administration of activated
charcoal and atropine were performed. The PCC was then contacted,
warning about the formal contraindications of the procedures that were
performed, considering the ingestion of a corrosive. The patient died
about four hours after exposure. Necropsy findings revealed signs of
chemical burn in the entire esophageal mucosa and in the stomach, with
the presence of activated charcoal inside the stomach, without signs of
esophageal or gastric perforation, in addition to hyperemia of the
tracheal mucosa, presence of activated charcoal in the trachea and lungs
with an inflammatory aspect, with the discharge of a large amount of
secretion from the tracheobronchial tree, suggesting aspiration
pneumonia as a possible cause of death.
Case 3 (face-to-face): girl, nine years old, admitted to the emergency
care unit about 40 minutes after a Tityus serrulatus
scorpion sting in her left hand, with intense local pain, psychomotor
agitation and visual blurring, treated with local anesthetic
infiltration and analgesics intravenously. Despite the improvement in
pain, she maintained agitation, progressing with hyperemesis, tachypnea,
tachycardia, arterial hypertension, diaphoresis and hypothermia, and was
treated with antiscorpionic antivenom (2 hours post-sting). She evolved
with pulmonary edema and refractory cardiogenic shock, and died on the
second day of hospitalization (D2);
Case 4 (telephone follow-up): girl, nine years old, admitted with
neurological depression, signs of shock, nasal bleeding, bradycardia,
hypothermia (33°C), hypoglycemia (28 mg/dL), acute kidney injury and QT
interval prolongation on the electrocardiogram. According to information
provided by her grandmother, the child possibly ingested, the night
before, haloperidol, clonazepam and promethazine, grandmother’s
medications, who found the empty cartons on the floor. The grandmother
reported that, since then, the child has been sleeping, and she took the
girl to the hospital only the next morning, because she would not wake
up. During evolution, she response partially to the bolus glucose
injection, maintaining signs of shock and hypothermia. Despite
supportive measures, the patient died six days after admission (signs of
brain death on the fourth day). Toxicological screening on GC-MS was
positive for haloperidol, promethazine and valproic acid and negative
for glibenclamide, metformin and benzodiazepines. It was not possible to
search for other oral hypoglycemic agents in addition to glibenclamide
in the sample sent (urine), due to the lack of standards in the
laboratory for this analysis.
Case 5 (telephone follow-up): boy, 15 years old, recent cocaine user,
found unconscious on the street. During pre-hospital care, he had a
seizure, was sedated and intubated. Upon admission, he had a mild
tachycardia, hypertension and nosebleed, and mouth bleeding. Admission
tests showed positive toxicological screening for cocaine and
tetrahydrocannabinol and a slight increase in total creatine kinase
(CK). He developed arterial hypertension, severe acute kidney injury
(hemodialysis on the fourth day), pneumonia and hemorrhagic stroke (on
the 13th day), and died on the 16th day.
Case 6 (telephone follow-up): boy, 17 years old, admitted with
neurological depression, severe sweating and bronchorrhea after
attempted suicide with chumbinho. He was treated with
mechanical ventilation and continuous infusion of atropine. In a blood
sample sent to the PCC, an absence of cholinesterase activity (0%) was
detected on both the first and third days, suggesting the possibility of
intoxication by an organophosphate insecticide. Clinical worsening was
observed on the fourth day with fever and reversed cardiorespiratory
arrest, and he died on the fifth day. Before the death was confirmed, he
showed signs that could suggest uncontrolled cholinergic intoxication
(miosis, sweating and bronchorrhea).
DISCUSSION
The data presented show, as previously reported, that, although the frequency of
toxic exposures in children under five is higher when compared to that of other age
groups, the greater severity of intoxications is related to intentional exposures,
which are more common in adolescents and adults.
7
When we analyze the Brazilian reality about care provided by the PCCs, this does not
allow a general comparison with the care reported by other countries. However, it is
possible to compare the lethality rates/100 thousand inhabitants. Whereas in the
United States, in 2016, the lethality rate/100 thousand inhabitants of SATE reported
in the annual report of the American Association of Poison Control Centers (AAPCC)
was 0.09/100 thousand inhabitants (<20 years old) and 0.1/100 thousand
inhabitants (<5 years old).
7
In the administrative region of Campinas, the rates detected in 2014/2015
were significantly higher, of 0.17/100 thousand inhabitants (<20 years old) and
0.24/100 thousand inhabitants (<5 years old). These data may suggest more
precarious care for critically ill patients (children and adolescents) in our region
of coverage.
Other variables, including iatrogenesis (see case 2), may have contributed to the
lethal outcome. In Brazil, not all chemicals with the potential risk of causing
serious local damage, such as corrosives and solvents, are packed in packaging with
safety caps and, in many cases, are stored in non-original packaging, as described
in the lethal case 2, apart from clandestine products.
6
,
10
Packaging with child-proof safety lids has proven to be effective in the
prevention of serious toxic exposures, especially in children <5 years old.
11
,
12
Another variable that should be considered reflects the local epidemiology,
such as the increasing incidence of severe and lethal cases of scorpionism in
Brazil, mainly in the Southeastern and Northeastern regions, associated to the
increase in the occurrence of poisonings caused by the yellow scorpion (T.
serrulatus), a parthenogenetic species with a high capacity to adapt to
the urban environment.
13
In Brazil, in 2017, 124,662 cases of scorpionic accidents were reported in
the Information System of Notifiable Diseases (SINAN), from the Ministry of Health,
with 87 deaths related to the condition, 46% in children <10 years old.
14
Other cases of severe poisoning were caused by rattlesnakes, possibly
Crotalus durissus terrificus, the only subspecies present in
our geographic region of care provided.
15
All had a good evolution after treatment with anticrotalic antivenom and
supportive measures, including adequate fluid replacement. Among snakebites caused
by the four genera of venomous snakes in Brazil (Bothrops,
Crotalus, Lachesis and
Micrurus), envenomation caused by rattlesnakes
(Crotalus durissus ssp.) is among the most serious, with 38
deaths among 4,160 cases reported in SINAN in 2015 and 2016 (0.9%).
14
,
15
Another form of severe intoxication was related to the ingestion of pesticides used
illegally as rodenticide, chumbinho. In Brazil, most cases of
chumbinho poisoning are associated to cholinesterase
inhibitors, such as carbamates (aldicarb and carbofuran).
16
These data indicate that, in Brazil, even with the ban on commercial
presentation of products containing aldicarb in 2012,
17
, there are still cases of serious poisoning by chumbinho,
including other cholinesterase inhibitors, such as organophosphates. A challenge in
the clinical management of these cases, in addition to life support measures, is the
correct administration of atropine (muscarinic acetylcholine antagonist), which may
require the use of high doses, for several days, until complete improvement of the
cholinergic syndrome, especially when the active ingredients are
organophosphates.
16
Nonetheless, many doctors are resistant to the administration of high doses
of atropine, a fact that can negatively interfere with the prognosis.
18
Considering exposures to new psychoactive substances of illegal use, we highlight the
case of severe intoxication by NBOMe (potent serotonergic agonist with stimulating
and hallucinogenic effects), confirmed by GC-MS, in a 15-year-old girl admitted in
another state and followed by our PCC. Most common adverse effects associated to
exposure to NBOMe include agitation, tachycardia, hypertension, seizures and
laboratory changes, including increased total CK (rhabdomyolysis). More serious
cases can progress to kidney and respiratory failure,
19
complications detected in the case we reported. As to psychoactive
substances of consecrated recreational use, it is worth mentioning the fatal case of
cocaine post-consumption resulting from hemorrhagic stroke, which is part of the set
of vascular complications that can be detected after the consumption of cocaine
hydrochloride or cocaine crack, such as acute myocardial infarction, ischemic or
hemorrhagic stroke and aortic dissection.
20
,
21
Another fatal case resulted from an accidental exposure to a pyrethroid insecticide
in a commercial presentation containing organic solvents, confirmed by GC-MS (case
1). A similar case was described in a 53-year-old man with a lethal evolution after
intentional ingestion of a product containing deltamethrin associated with a solvent
containing naphtha, whose death was attributed, based on the clinical manifestations
observed and the biological matrices analyzed post-mortem, to
aromatic hydrocarbons.
22
Medication poisoning was an important cause of SATE, mainly due to suicide attempts
in adolescents and the association of drugs, such as anticonvulsants and
antidepressants. Another serious drug intoxication involved an accidental ingestion
of a topical decongestant derived from imidazoline (brimonidine; α2-adrenergic
agonist) in a one-month-old newborn, due to administration error, which evolved with
apnea and bradycardia; the boy was intubated before the consultation at the PCC.
Similar cases evolve favorably within the first 24 hours without the need for
invasive procedures, with improvement in episodes of apnea and bradycardia after
intermittent tactile stimulation.
23
,
24
In fatal case 4, clinical manifestations and severe hypoglycemia at
admission suggest that an oral hypoglycemic intake may also have occurred.
25
Impaction of button batteries in esophageal lumen can lead to high morbidity,
including lethal outcomes.
26
,
27
Generally, the most serious exposures occur after the ingestion of batteries
≥2 cm in diameter, such as 2032 lithium batteries, often without a report by
caregivers, which can lead to delay in diagnosis and endoscopic removal, as well as
in the prognosis of local injury.
26
,
27
It should be noted that batteries lodged in the esophagus can cause serious
injuries in the first two hours of contact with the mucosa. Local damage is
basically caused by three mechanisms: direct pressure (pressure necrosis); leakage
of the battery’s chemical content; and generation of electric current by contact of
the battery poles with the esophageal mucosa (electrical burn).
26
,
27
We use the PSS for severity classification. It was prepared by the European
Association of Poison Centers and Clinical Toxicologists (EAPCCT), together with the
International Program on Chemical Safety, of the World Health Organization. The
collaborative work that validated the PSS involved 14 centers from various
countries, and an agreement index obtained was above 80%.
8
The PSS has no prognostic value and applies to acute toxic exposures, and
must be established at the end of the case.
8
Despite favorable and unfavorable criticisms,
28
,
29
the PSS is simple and widely used.
29
The present study has several limitations, which include the retrospective analysis
of medical records and possible biases in the interpretation of the recovery of the
data listed for analysis, data extracted by the authors in a non-blind manner. In
addition, most of the PCC service information was obtained from telephone
consultations, which may have been incomplete. Moreover, in the review of electronic
medical records, there were flaws in the interpretation of the PSS classification to
the outcomes, leading to the exclusion of 11 cases for final analysis.
Despite these limitations, the authors report good quality in filling out all
electronic medical records, as well as the practical interface for retrieving data
from the Datatox system. Finally, the results presented confirm the importance of
the work of a PCC of regional reference in the urgency and emergency care
network,
30
which can serve as a basis for preventing and training health teams to
manage these cases, aiming to improve care in handling these injuries.
We conclude that venomous animals’ sting/bites, poisoning by medicines and chemicals
for household/industrial use were the main causes of SATE, significantly more
frequent in adolescents, mainly due to suicide attempts.
Funding
This study did not receive funding. | Fatal | ReactionOutcome | CC BY | 32638947 | 18,538,418 | 2021 |
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