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The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols. The use of inhaled antibiotics in the treatment of cystic fibrosis has become widespread despite controversy in the literature as to the appropriate dosing regimen and its effectiveness. This study compared two tobramycin (T) preparations (one with and one without the addition of albuterol) using two different jet nebulizers in order to determine if drug output would be affected. Using calibrated flows from a dry compressed gas source of 6 and 8 L/min as well as a specific compressor (Pulmo-Aide), the Hudson 1720 nebulizer was compared with the newer disposable Hudson 1730. The albuterol preparation used in this study was the Ventolin (albuterol) Respirator Solution (VRS). The nebulizers were charged with (1) 2 mL T (80 mg/2 mL) with 0.5 mL VRS (5 mg/mL) and normal saline solution to make the total nebulizer charge of 3 or 4 mL, or (2) 2 mL T and either 1 or 2 mL normal saline solution. A laser diffraction analyzer (Malvern 2600) was used to determine the aerosol particle size distribution. From the distribution, the respirable fraction, which is the fraction of aerosol that could enter and remain in the lungs, was calculated. For all solutions and each particular flow, the Hudson 1730 had a larger respirable fraction of T. The addition of VRS lowered the surface tension of the solution in the nebulizer and resulted in a greater output of T. This effect was most apparent for the 3-mL volume fills of the Hudson 1720. The greatest differences were between the 3-mL nebulizer charges of T using the Hudson 1720 driven by a flow of 6 L/min, which produced 8 mg of T in the respirable fraction, compared with 35 mg produced by the Hudson 1730 driven by a flow of 8 L/min. These results suggest that different nebulizers, different nebulizer solutions, and different techniques of nebulization may result in very different amounts of T aerosol output in the respirable fraction.
The usefulness of diagnostic tests on pericardial fluid. STUDY OBJECTIVES To determine the physical, chemical, and cellular characteristics of pericardial fluid in various disease states and to assess their diagnostic accuracies. SETTING A metropolitan university hospital. DESIGN Consecutive case series. PATIENTS One hundred seventy-five hospital patients, aged 1 month to 87 years, who had undergone pericardiocentesis (n = 165) or control subjects who had undergone open heart surgery (n = 10) between 1984 and 1996. MEASUREMENTS The appearance of pericardial fluid and results of chemistry tests, cell counts, cytologic studies, Gram's stain, and microbial cultures were obtained by chart review. The etiology of each pericardial fluid sample was determined using prospective diagnostic criteria. RESULTS Exudates differed from transudates by higher leukocyte counts and ratios of fluid to serum lactate dehydrogenase levels. Fluid glucose levels were significantly less in exudates. Sensitivity for detecting exudates was high for specific gravity > 1.015 (90%), fluid total protein > 3.0 g/dL (97%), fluid to serum protein ratio > 0.5 (96%), fluid lactate dehydrogenase ratio > 0.6 (94%), and fluid to serum glucose ratio < 1.0 (85%). None of these indicators were specific. Fluid total protein and specific gravity were moderately correlated (r = 0.56). Fluid cytologic study had a sensitivity of 92% and specificity of 100% for malignant effusion. No other test was diagnostic for a specific etiology. Among infection-associated effusions, culture-positive fluid had more neutrophils, higher lactate dehydrogenase levels, and lower ratios of fluid to serum glucose than culture-negative (parainfective) fluid. CONCLUSIONS Evaluation of pericardial fluid might be limited to cell count, glucose, protein, and lactate dehydrogenase determinations plus bacterial culture and cytology. While not used routinely, other tests that may be highly specific for particular diseases should be ordered only to confirm a high clinical suspicion.
Noninvasive assessment of right ventricular diastolic function by electrical impedance tomography. STUDY OBJECTIVES Electrical impedance tomography (EIT) offers the possibility to study blood volume changes within the right atrium during the cardiac cycle. The aim of this study was to determine the applicability of EIT in the assessment of right ventricular diastolic function in COPD. DESIGN By means of region of interest analysis, impedance changes within the right atrium during the cardiac cycle were plotted as a function of time. As a diastolic index of the right ventricle, the right atrium emptying volume (RAEV), defined as the ratio between the volume change during the rapid filling phase relative to the total ventricular filling volume, was calculated. In a first study, the validity of the EIT method was assessed by comparison of the RAEV measured by EIT and MRI in a group of eight patients with severe COPD and seven control subjects. A second study was undertaken to assess the relation between RAEV and pulmonary artery pressure in a group of 27 patients measured by right-sided heart catheterization. RESULTS The correlation coefficient between RAEV measured with MRI and EIT was 0.78. The difference between RAEV measured by MRI and EIT was 8.3 +/- 15.7% (mean +/- SD) for the control subjects and 3.5 +/- 10.9% for the COPD patients. RAEV values measured by EIT and MRI were larger in the control group (47.1 +/- 7.6%) compared with the patient group (38.1 +/- 10.4%). There was a clear nonlinear relationship between RAEV and the pulmonary artery pressure (y = 315 x-0.64, r = 0.83, p < 0.001). CONCLUSION Our results indicate that RAEV measured by EIT is a useful noninvasive and inexpensive method for assessing right ventricular diastolic function in COPD patients.
Intraoperative transesophageal echocardiographic assessment of vascular anastomoses in lung transplantation. A report on 18 cases. BACKGROUND In patients after lung transplantation, dysfunction of pulmonary venous and artery anastomoses leading to reoperation is described. METHODS AND RESULTS Pulmonary artery and vein anastomoses were evaluated intraoperatively by monoplane transesophageal echocardiography (TEE) in 18 patients undergoing lung transplantation (nine right, five left single lung transplantations, and four bilateral transplantations). All 13 right pulmonary artery anastomoses and all 22 pulmonary vein anastomoses could be visualized by TEE. None of the nine left pulmonary anastomoses could be visualized. Of the 13 right pulmonary anastomoses, 12 were considered normal, their diameter ranging from 1 to 1.7 cm (mean, 1.26 +/- 0.24 cm). A moderate stenosis of one pulmonary artery anastomosis was identified but did not require reoperation. Of the 22 pulmonary vein anastomoses, 16 were considered normal, their diameter being > 0.5 cm and the peak systolic flow velocity < or = 1 m/s at the location of the anastomoses. In five cases, the anastomoses were not considered normal, but reoperation was not indicated. In one case, a severe stenosis of pulmonary vein associated with graft dysfunction led to an early reoperation. CONCLUSION Intraoperative TEE during lung transplantation contributes to the immediate evaluation of pulmonary vein and right pulmonary artery anastomoses and allows immediate surgical correction. Further investigations are necessary to establish threshold values requiring reoperation.
Comparison of transesophageal and transthoracic contrast echocardiography for detection of an intrapulmonary shunt in liver disease. STUDY OBJECTIVES Contrast transthoracic echocardiography (TTE) is currently used to identify intrapulmonary shunt (IPS) in patients with end-stage liver disease. The aim of this study was to compare the use of contrast TTE and transesophageal echocardiography (TEE) in detecting IPS. DESIGN Thirty-seven consecutive outpatients with severe liver disease awaiting liver transplantation underwent contrast TEE and TTE. The IPS was assessed semiquantitatively in four grades with TEE and as positive or negative with TTE. SETTING ICU. INTERVENTIONS Patients underwent contrast TEE after pharyngeal anesthesia alone followed by contrast TTE. Contrast echocardiography was performed with a modified fluid gelatin solution. RESULTS Overall detection rate of an IPS was 51% with TEE and 32% with TTE (p < 0.001). Four patients had an IPS detected with TEE but not with TTE. Quality of imaging was poor in 22% with TTE and 0% with TEE (p < 0.001). A PaO2 < 80 mm Hg or a dyspnea was associated with an IPS in 56% and 50% of patients with TEE and in 33% and 25% with TTE, respectively. CONCLUSION Contrast-enhanced TEE is superior to TTE for detecting an IPS in patients with severe liver disease awaiting liver transplantation. The use of gelatin contrast solution allows an early detection of IPS. Because of the high sensitivity of TEE, all patients suspected of hepatopulmonary syndrome should undergo TEE in search of an IPS if TTE is normal.
Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. STUDY OBJECTIVES To determine the risk factors and frequency of intracranial hemorrhage among patients undergoing thrombolysis for pulmonary embolism. DESIGN A retrospective descriptive and controlled analysis. SETTING Hospitalized patients at centers in the United States, Canada, and Italy. PATIENTS All had evidence of pulmonary embolism on perfusion scans or angiography. INTERVENTIONS None. MEASUREMENTS AND RESULTS Data were analyzed on 312 patients from five previously reported studies of pulmonary embolism thrombolysis. The frequency of intracranial hemorrhage up to 14 days after pulmonary embolism thrombolysis was 6 of 312 or 1.9% (95% confidence interval, 0.7 to 4.1%). Two of six intracranial hemorrhages were fatal. Two of the six patients received thrombolysis in violation of the protocol because they had pre-existing, known intracranial disease. Average diastolic BP at the time of hospital admission was significantly elevated in patients who developed an intracranial hemorrhage (90.3 +/- 15.1 mm Hg) compared with those who did not (77.6 +/- 10.9 mm Hg; p = 0.04). Other baseline characteristics and laboratory data were similar in both groups. Decreased level of consciousness, hemiparesis, and visual field deficits were the most common clinical signs of intracranial hemorrhage. CONCLUSIONS Intracranial hemorrhage after pulmonary embolism thrombolysis is an infrequent but often grave complication. Meticulous patient screening before administering thrombolysis is imperative. Diastolic hypertension at the time of hospital admission is a risk factor for intracranial hemorrhage after pulmonary embolism thrombolysis.
Prevalence of acute pulmonary embolism in central and subsegmental pulmonary arteries and relation to probability interpretation of ventilation/perfusion lung scans. PURPOSE The purpose of this investigation is to determine the prevalence of acute pulmonary embolism (PE) limited to subsegmental pulmonary arteries. BACKGROUND Contrast-enhanced helical (spiral) and electron-beam CT, in the hands of experienced radiologists who are skillful with this modality, are sensitive for the detection of acute PE in central pulmonary arteries, but have a low sensitivity for the detection of PE limited to subsegmental pulmonary arteries. The potential for CT to diagnose PE, therefore, is partially dependent on the prevalence of PE limited to subsegmental pulmonary arteries. METHODS Data are from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). The largest pulmonary arteries that showed PE, as interpreted by the PIOPED angiographic readers, were identified in 375 patients in PIOPED with angiographically diagnosed PE. RESULTS Among all patients with PE, 6% (95% confidence interval [CI], 4 to 9%) had PE limited to subsegmental branches of the pulmonary artery. Patients with high-probability ventilation/ perfusion (V/Q) scans had PE limited to subsegmental branches in only 1% (95% CI, 0 to 4%). Among patients with low-probability V/Q lung scans, 17% (95% CI, 8 to 29%) had PE limited to the subsegmental branches. Patients with low-probability V/Q scans and no prior cardiopulmonary disease had PE limited to the subsegmental pulmonary arteries in 30% (95% CI, 13 to 53%), whereas patients with low-probability V/Q scans who had prior cardiopulmonary disease had PE limited to subsegmental pulmonary arteries in 8% (95% CI, 2 to 22%) (p < 0.05). CONCLUSION Based on data from all patients with PE in PIOPED, the prevalence of PE limited to subsegmental pulmonary arteries is low, 6%. PE limited to subsegmental pulmonary arteries was most prevalent among patients with low-probability V/Q scans, particularly if they had no prior cardiopulmonary disease.
The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma. STUDY OBJECTIVE To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms. DESIGN Double-blind, randomized, placebo-controlled crossover study. SETTING Tertiary care hospital specializing in respiratory diseases. PARTICIPANTS Ten patients with nocturnal asthma. INTERVENTIONS Subjects were randomized to salmeterol, 100 micrograms twice daily, or placebo for 6 weeks with a 1-week washout between treatment periods. Symptoms, nocturnal awakenings, and beta 2-agonist use were recorded daily. Spirometry was performed at weeks 1 and 6 of each period at bedtime and at 4 AM, and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL. BAL fluid analysis included cell count and differential count, eosinophil cationic protein, Charcot-Leyden crystal protein, leukotriene B4, and thromboxane B2. RESULTS The percentage of nights with awakenings decreased significantly with salmeterol (69.8 +/- 8.7% vs 30.6 +/- 10.8% for placebo and salmeterol, respectively; p = 0.02). The percentage of 24-h days with supplemental inhaled beta 2-agonist use significantly decreased with salmeterol (85.9 +/- 9.4% vs 70.4 +/- 10.1% for placebo and salmeterol, respectively; p = 0.04). There were no significant differences in bronchial reactivity, 4 AM FEV1, overnight percentage change in FEV1, or indexes of airway inflammation. CONCLUSIONS Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h beta 2-agonist use in nocturnal asthma without significantly altering lung function and airway inflammation.
Lung epithelial permeability and bronchial responsiveness in subjects with stable asthma. Lung epithelial permeability of asthmatic patients has been reported to be similar or lower than that of healthy subjects and to be correlated or not to bronchial hyperresponsiveness. To clarify these discrepancies, we evaluated 99mTc-DTPA pulmonary clearance in a group of carefully selected asthmatic patients with mild, stable asthma (n = 13; seven women; mean age +/- SD = 27.69 +/- 6.63 years), and compared them with a group of healthy, nonsmoking subjects (n = 8; six women; mean age +/- SD = 24.38 +/- 5.15 years). Selection criteria for asthmatics were as follows: baseline FEV1 > or = 80% of predicted values, no bronchial infections, and/or no asthma attacks during 4 weeks prior to study and peak expiratory flow rate variability lower than 20%, over a period of 3 weeks. Patients controlled symptoms with beta 2-adrenergic drugs only, regularly or on demand. Mean baseline FEV1 (+/-SD) as percent of predicted was 102.38 +/- 13.97 and 112.88 +/- 18.36, respectively (p < 0.05). In the asthmatic group, bronchial responsiveness to methacholine (PC20 M FEV1) ranged between 0.55 and 28.5 mg/mL. Mean value (+/-SD) of DTPA clearance from lungs to blood (evaluated on the first 10 min out of 30 min of the curves) in the asthmatic group was not different from that of control group (68.31 +/- 21.46 and 69.5 +/- 15.73). In the asthmatic patients, there was no correlation between PC20 M values and DTPA T1/2 min of the whole lung, nor between PC20 M and inner and outer lung clearance zones. Moreover, both in asthmatics and healthy subjects, DTPA clearance of outer (alveolar) zones was significantly faster than that of inner (bronchial) zones (57.69 +/- 19.94 vs 102.08 +/- 38.19, p < 0.001, and 59.75 +/- 12.49 vs 103.5 +/- 31.86, p < 0.003, respectively). Our data show that DTPA clearance in patients with stable asthma is similar to that found in healthy subjects; it is not correlated to degree of bronchial responsiveness and occurs more rapidly in the outer zones than in the inner zones, both in asthmatic patients and in healthy subjects. Thus, to date, DTPA clearance index is not a valid tool for identifying and/or monitoring asthmatic patients.
Bed partners' assessment of nasal continuous positive airway pressure therapy in obstructive sleep apnea. STUDY OBJECTIVE This study aimed to evaluate the effects of nasal continuous positive airway pressure (nCPAP) therapy on sleep and daytime symptoms of bed partners and patients with obstructive sleep apnea (OSA). DESIGN A cross-sectional questionnaire survey. SETTING The sleep laboratory of a university teaching hospital. PATIENTS Ninety-one consecutive OSA patients within 2 to 12 months of being prescribed nCPAP. RESULTS Eighty-five replies (93% of sample population) were received. Twelve patients (14% of replies) had discontinued nCPAP therapy; two patients had not yet been supplied with an nCPAP device. Seventy-one patients continued nightly nCPAP therapy. Bed partners of these patients (n = 55) answered a separate questionnaire assessing improvements in their own sleep quality, daytime alertness, mood and quality of life (questions 1 to 4), and evaluated the same parameters for the patients (questions 5 to 8). Possible scores ranged from -1 (worse) to +3 (marked improvement). Questions 1 to 4 yielded median scores of 2, 1, 1, and 2, respectively, and scores of 3, 3, 2, and 3 for questions 5 to 8. A ninth question addressing perceived changes in the quality of their relationship resulted in a median score of 2. Mean (SD) Epworth sleepiness scores improved from 14.3 (5.8) to 5.2 (4.3) in patients receiving therapy (p < 0.005). CONCLUSIONS These data indicate that bed partners of OSA patients treated with nCPAP experience important improvements in symptoms and personal relationships. The findings are of practical clinical use when counseling patients with OSA and their partners on the likely impact of nCPAP therapy on their quality of life.
Quantitative aspiration during sleep in normal subjects. STUDY OBJECTIVE To determine the within-subject variability and to estimate the quantity of occult aspiration of nasopharyngeal secretions during sleep in normal humans. DESIGN Prospective duplicate full-night sleep studies. SETTING Pulmonary sleep laboratory, university hospital. PARTICIPANTS Ten normal male volunteers aged 22 to 55 years. INTERVENTIONS Two full-night polysomnographic recordings with infusion of 2 mL/h radioactive 99mTc tracer into the nasopharynx through a small catheter during EEG-documented sleep. Standard lung scans were conducted immediately following final awakening. Aspiration was defined as the presence of radioactivity in the pulmonary parenchyma on two separate views. RESULTS A mean sleep efficiency of 85.7 +/- 2.6% was found with no difference between the two study nights. A total of 5 of the 10 subjects studied had tracer evident in the pulmonary parenchyma following final awakening. Three had the tracer apparent following the first-night study and four had tracer apparent following the second-night study. Thus, two subjects aspirated on both nights. Comparing the subjects who aspirated with those who did not, no significant difference could be found for age, time spent in bed, sleep efficiency, apnea-hypopnea index, arousal plus awakening index, or percent of sleep time spent in a supine position. The quantities of tracer aspirated were on the order of magnitude of 0.01 to 0.2 mL. CONCLUSIONS Aspiration measured by this technique occurs commonly in healthy young men during sleep, is unrelated to sleep quality, and is variable within subjects studied on more than one occasion. The quantity aspirated is of an order of magnitude likely to contain bacterial organisms in physiologically significant quantities.
Group education sessions and compliance with nasal CPAP therapy. STUDY OBJECTIVES To determine an effective means of improving compliance with nasal continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). DESIGN Retrospective chart review. SETTING An outpatient clinic at a Veterans Affairs Medical Center. PATIENTS Seventy-three patients with OSA. INTERVENTIONS Hour meters on CPAP machines provided documentation of nightly machine use. A 2-h group CPAP clinic, scheduled every 6 months, provided education, support, symptom treatment, and equipment monitoring for all CPAP patients. RESULTS Twenty-five patients had hour meter readings taken at their first CPAP clinic. In these patients, nightly CPAP use increased from 5.2 +/- 0.6 to 6.3 +/- 0.6 h per night after attendance at one CPAP clinic (p < 0.05). CPAP use increased from 5.2 +/- 0.5 before CPAP clinic to 6.3 +/- 0.6 h per night after attendance at all subsequent CPAP clinics for 34 patients (p < 0.05), an improvement that was sustained over 605 +/- 34 days. Twenty-nine percent of patients increased nightly CPAP use by at least 2 h, while only 6% decreased by > or = 2 h (p < 0.025). Patients receiving supplemental oxygen had higher CPAP use prior to CPAP clinic compared to patients not receiving oxygen (p < 0.05). CONCLUSIONS Attendance in a group clinic designed to encourage patient compliance with CPAP therapy provided a simple and effective means of improving treatment of OSA.
Postpneumonectomy pulmonary edema. A retrospective analysis of incidence and possible risk factors. OBJECTIVE To analyze the incidence of postpneumonectomy pulmonary edema (PPE) and to determine potential risk factors for PPE. MATERIAL AND METHODS A group of 197 patients was studied retrospectively, and the incidence of PPE was recorded over a 5-year period. Preoperative, perioperative, and postoperative clinical data were collected, and preoperative and postoperative chest radiographs were reviewed. A scoring system was used to distinguish between premanifest and manifest PPE. Postpneumonectomy patients with pulmonary edema, with no clinically evident cause, were considered to have PPE. RESULTS The incidence of premanifest PPE was 12.2% (n = 24), and that of manifest PPE was 2.5% (n = 5). Mortality in the group of patients who developed manifest PPE was 100%. Two significant perioperative associations were found in the PPE group. One was the administration of fresh frozen plasma (FFP) transfusions (relative risk, 4.3; 95% confidence interval, 1.3 to 14.4 corrected for age and sex), while the other was higher mechanical ventilation pressures during surgery (relative risk, 3.0; 95% confidence interval, 1.2 to 7.3). CONCLUSION Our data suggest that FFP transfusions form an important risk factor for PPE. The mechanism may be an increased permeability of the pulmonary vessels due to an immunologic reaction after multiple FFP transfusions. The significantly higher mechanical ventilation pressures we found in the PPE group may be explained as an early sign of the development of PPE.
Complete lobar collapse following pulmonary lobectomy. Its incidence, predisposing factors, and clinical ramifications. STUDY OBJECTIVE To define the most severe form of postlobectomy atelectasis and determine its incidence, predisposing factors, and clinical ramifications. DESIGN Retrospective case control. SETTING The thoracic surgery unit at a 900-bed tertiary care hospital. PATIENTS OR PARTICIPANTS Two hundred eighteen patients undergoing pulmonary lobectomy or bilobectomy over a 7-year time period. MEASUREMENTS AND RESULTS Severe postlobectomy atelectasis (SPLA) was defined as complete ipsilateral lobar or bilobar collapse with whiteout of the involved lobe(s) and mediastinal shift on the chest radiograph. Data were collected consisting of patient age, lobe(s) resected, type of postoperative pain control, length of hospital and ICU stay, preoperative pulmonary function, and single- vs double-lumen tube intubation during surgery. The incidence of SPLA was 7.8%, comprising 24.6% of all postoperative complications seen. There was no statistically significant difference in patient age, preoperative room air PO2, and preoperative FEV1/FVC ratio for the SPLA group vs the group without this complication. Patients with SPLA had significantly longer ICU stays (112.7 h vs 28.4 h; p < 0.001) and hospital stays (14.7 days vs 9.3 days; p < 0.001) than the patients without complications. Patients undergoing right upper lobectomy, both alone or in combination with the right middle lobe, had a significantly higher incidence of SPLA when compared with all other types of resections (15.5% vs 3.0%; p < 0.005). There was no influence on the incidence of SPLA when the types of postoperative pain control regimen and endotracheal tubes used were examined. CONCLUSIONS We conclude that SPLA as defined in this study is an important postoperative complication with a significant incidence. Although patients undergoing right upper lobectomy are markedly predisposed to this problem, the exact pathophysiology remains unclear. Factors shown to be causes of less severe forms of postoperative atelectasis do not seem to contribute to the formation of SPLA, indicating that these two complications may be two unrelated entities.
Is atelectasis following aortocoronary bypass related to temperature? OBJECTIVE To determine the frequency of acute postoperative atelectasis in patients undergoing aortocoronary bypass with either normothermic (warm) or hypothermic (cold) technique. DESIGN Prospective, randomized study comparing two groups. SETTING University-affiliated hospital. PATIENTS Three hundred thirty-one patients (166 cold and 165 warm) undergoing isolated aortocoronary bypass. MEASUREMENTS Chest radiographs were obtained preoperatively, on the day of surgery, and subsequently as clinically indicated until discharge from the hospital. Radiologist (blinded to the patient allocation into warm or cold group) scored the atelectasis from 0 to 3 based on its severity. Regression analysis was used to determine if there was any difference in the atelectasis scores between the two groups. RESULTS Mean daily postoperative atelectasis scores were not different between the cold and warm groups. The number of patients requiring chest radiographs was similar in both groups. The percent of patients with abnormal chest radiographs was similar in both groups. CONCLUSION The temperature of cardioplegia has no effect on the development of atelectasis following aortocoronary bypass, and therefore temperature-related cold injury is not a major cause of atelectasis following this type of surgery.
Noninvasive measurement of cardiac output by an acetylene uptake technique and simultaneous comparison with thermodilution in ICU patients. A simple, accurate, and noninvasive method of cardiac output measurement can be an extremely useful tool for the clinician and researcher. This study used the acetylene gas uptake technique to measure the absorption of acetylene into the pulmonary circulation during a constant exhalation, which is proportional to the pulmonary capillary blood flow and to the cardiac output, assuming no anatomic shunts. We compared cardiac output measured simultaneously by this and by the standard thermodilution (TD) technique in 21 patients in the ICU with a variety of medical and surgical conditions and a wide range of cardiac outputs. We also compared the two techniques in 19 ambulatory patients with a 2-h interval between the invasive and noninvasive test to assess variability over time. The two tests had an excellent correlation when done simultaneously with a correlation coefficient of 0.89 (p < 0.001). With a 2-h interval between the two tests, the correlation coefficient was 0.66 (p = 0.0018). Nine patients in the simultaneous group had cardiomyopathy. When they were excluded, the correlation coefficient increased to 0.96. Most of these patients had documented tricuspid regurgitation (TR), which may underlie the greater difference between acetylene uptake and TD values, with consistently higher TD values in these patients. This study confirms the correlation between the acetylene uptake and the standard invasive TD techniques in sick patients with various medical and surgical conditions and a wide range of cardiac outputs. Furthermore, we believe this would be a more accurate method for measuring cardiac output in patients with cardiomyopathy and TR because it is based only on pulmonary capillary blood flow.
Release of lactate by the lung in acute lung injury. UNLABELLED The pathogenesis of hyperlactatemia during sepsis is poorly understood. We have previously described an increase in lactate concentration across the lung in the dog during early endotoxemia. Accordingly, we sought to determine if the lung releases lactate in humans and what relation this has with lung injury. METHODS We measured lactate concentrations across the lung and lung injury scores (LIS) in two groups of patients. Group 1 consisted of nine patients with acute lung injury (LIS > or = 2.0) and elevated lactate concentrations (> 2.0 mmol/L). Group 2 contained 12 patients with no acute lung injury (LIS scores < or = 1.5), with or without increased lactate concentrations. Simultaneous measurements of plasma lactate and blood gases were obtained from indwelling arterial and pulmonary artery catheters. Measurements of cardiac output were also obtained. Lactate measurements were done using a lactate analyzer (YSI; Yellow Springs, Ohio). RESULTS For each patient with acute lung injury and hyperlactatemia, an arterial-venous lactate gradient existed demonstrating release of lactate by the lung. This gradient persisted after correction for changes in hemoconcentration across the lung. The lactate gradient across the lung was 0.4 +/- 0.2 mmol/L for group 1 vs 0.05 +/- 0.1 mmol/L for group 2 (p = 0.001). This corresponded to a mean pulmonary lactate flux of 231.3 +/- 211.3 vs 5.0 +/- 37.2 mmol/h (p = 0.001). The lactate flux and the arterial-venous lactate difference correlated with LIS both for the entire sample and for the subgroup with hyperlactatemia (r = 0.69, p < 0.01). Pulmonary lactate flux was not related to arterial lactate levels (r = 0.25). CONCLUSION In patients with acute lung injury and hyperlactatemia, the lung is a major source of lactate and lactate flux correlates with LIS. This lactate flux could explain some of the hyperlactatemia seen in sepsis.
Infections and the inflammatory response in acute respiratory distress syndrome. STUDY OBJECTIVE Systemic inflammatory response syndrome (SIRS) and infections are frequently associated with the development and progression of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). We investigated, at onset and during the progression of ARDS, the relationships among (1) clinical variables and biological markers of SIRS, (2) infections defined by strict criteria, and (3) patient outcome. Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8-in plasma and BAL fluid. METHODS We prospectively studied two groups of ARDS patients: 34 patients treated conventionally (group 1) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS (group 2). Individual SIRS criteria and SIRS composite score were recorded daily for all patients. Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients received mechanical ventilation. Unless contraindicated, bilateral BAL was performed on day 1, weekly, and when ventilator-associated pneumonia was suspected. Patients were closely monitored for the development of nosocomial infections (NIs). RESULTS ICU mortality was similar among patients with and without sepsis on admission (54% vs 40%; p < 0.45). Among patients with sepsis-induced ARDS, mortality was higher in those who subsequently developed NIs (71% vs 18%; p < 0.05). At the onset of ARDS, plasma TNF-alpha, IL-1 beta, IL-6, and IL-8 levels were significantly higher (p < 0.0001) in nonsurvivors (NS) and in those with sepsis (p < 0.0001). The NS group, contrary to survivors (S), had persistently elevated plasma IC levels over time. In 17 patients, 36 definitive NIs (17 in group 1 and 19 in group 2) were diagnosed by strict criteria. No definitive or presumed NIs caused an increase in plasma IC levels above patients' preinfection baseline. Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS, were unaffected by the development of NI, and did not correlate with plasma IC levels. CONCLUSIONS Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels. However, NIs were not associated with an increase in SIRS composite scores, individual SIRS criteria, or plasma IC levels above patients' preinfection baseline. SIRS composite scores over time were similar in S and NS. SIRS criteria, including fever, were found to be nonspecific for NI. Irrespective of etiology of ARDS, plasma IC levels, but not clinical criteria, correlated with patient outcome. These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs.
Comparison of pressure support ventilation and assist-control ventilation in the treatment of respiratory failure. STUDY OBJECTIVE To assess whether pressure support ventilation (PSV) could be used as an alternative ventilatory mode to assist-control (A/C) ventilation in the treatment of respiratory failure. DESIGN A short-term (4-h) prospective study in which the beneficial effect of PSV on respiratory mechanics, gas exchange, arterial oxygenation, cardiovascular hemodynamics, and oxygen consumption was compared with A/C ventilation. SETTING ICU of a community hospital. PATIENTS Forty-five patients (mean age, 62.8 [11.8] years) with respiratory failure secondary to COPD, restrictive disorders, or neuromuscular disease requiring mechanical ventilatory support in the ICU were selected for study. INTERVENTIONS The mean duration of mechanical ventilation before the study was 7.16 (8.64) days. Patients were switched to the PSV mode of the mechanical ventilator for a period of 4 h after which conventional A/C ventilation was resumed. RESULTS Patients supported with PSV compared with A/C ventilation showed significantly higher tidal volume, minute ventilation, and inspiratory time in association with significantly lower pressure in the airway and I:E ratio. With regard to gas exchange data, an increase in dead space/tidal volume ratio (VD/VT), decrease in PaO2, and statistically but not clinically significant alteration of arterial oxygenation indexes were noted. However, when patients with COPD, restrictive disorders, and neuromuscular disease were compared, significant changes in arterial oxygenation parameters were found only in patients with restrictive disorders. There were significant decreases in heart rate, systolic pulmonary artery pressure, and pulmonary capillary wedge pressure when PSV was applied. Oxygen transport and oxygen consumption were unchanged. CONCLUSIONS PSV could be a possible alternative to A/C ventilation in patients with respiratory failure. PSV caused an increase in VD/VT in association with a significantly lower pressure in the airway and I:E ratio. Randomized studies are needed to define the long-term benefits of both respiratory modes and the conditions in which PSV may be a valuable alternative to A/C ventilation.
Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. STUDY OBJECTIVES To identify the relative contribution of hydrostatic and permeability mechanisms to the development of human neurogenic pulmonary edema. DESIGN Retrospective review of patients with neurogenic pulmonary edema who had pulmonary edema fluid analysis. SETTING University hospital ICU. PATIENTS Twelve patients with neurogenic pulmonary edema in whom the associated neurologic condition was subarachnoid hemorrhage (n = 8, 67%), postcraniotomy (n = 2), and stroke (n = 2). MEASUREMENTS Protein concentration was measured from pulmonary edema fluid and plasma samples obtained shortly after the onset of clinical pulmonary edema. RESULTS The mechanism of pulmonary edema was classified according to the initial alveolar edema fluid to plasma protein concentration ratio. A hydrostatic mechanism (ratio < or = 0.65) was observed in seven patients, none of whom had cardiac failure or intravascular volume overload. Five patients had evidence for increased permeability (ratio > 0.70). Patients with a hydrostatic mechanism had better initial oxygenation (mean +/- SD PaO2/FIO2 [fraction of inspired oxygen] = 233 +/- 132) compared with patients with increased permeability (PaO2/FIo2 = 80 +/- 42), and oxygenation improved more rapidly in the hydrostatic patients. Overall mortality (58%) was high, but it was related to unresolved neurologic deficits, not to respiratory failure. CONCLUSION Many of our patients had a hydrostatic mechanism for neurogenic pulmonary edema. This is a novel observation in humans since prior clinical case reports have emphasized increased permeability as the usual mechanism for neurogenic pulmonary edema. These findings are consistent with pulmonary venoconstriction or transient elevation in left-sided cardiovascular pressures as contributing causes to the development of human neurogenic pulmonary edema.
Increased mortality of older patients with acute respiratory distress syndrome. OBJECTIVE To examine the relationship between age and mortality in ARDS patients and evaluate the importance of factors that increase the mortality of older ARDS patients. DESIGN Prospective inception cohort study. SETTING Community-based referral hospital. PATIENTS Two hundred fifty-six ARDS patients identified from May 1987 to December 1990. ARDS was defined by the following: (1) PaO2/PAO2 < or = 0.2; (2) pulmonary capillary wedge pressure < or = 15 mm Hg; (3) total static thoracic compliance < or = 50 mL/cm H2O; (4) bilateral infiltrates on chest radiograph; and (5) an appropriate clinical setting for ARDS. MAIN OUTCOME MEASURES Comparison of organ failure, incidence of sepsis, patient demographics, arterial oxygenation, and level of support in those 55 years and younger and those older than 55 years of age. Withdrawal of support in patients who died. RESULTS Seventy-two of 112 patients older than 55 years (64%) died vs 65 of 144 patients 55 years and younger (45%) (p = 0.002). Examination of patient groups using age identified older than 55 years as a "cutpoint" above which mortality was greater (p = 0.002). Older nonsurvivors did not differ from nonsurvivors 55 years or younger with respect to gender, smoking history, ARDS risk factors, ARDS identifying characteristics, APACHE II (acute physiology and chronic health evaluation), number of organ failures, or the incidence of sepsis. In the 48 h prior to death, nonsurvivors 55 years and younger had more organ failure (3.4 +/- 0.2 vs 2.8 +/- 0.2; p = 0.03), higher fraction of inspired oxygen (0.82 +/- 0.03 vs 0.68 +/- 0.03; p = 0.008), and higher positive end-expiratory pressure levels (13 +/- 1 vs 8 +/- 1; p = 0.001) than older nonsurvivors. Despite more severe expression of disease, only 32 (50%) nonsurvivors 55 years and younger had support withdrawn. Significantly more nonsurvivors older than 55 years (73%) had support withdrawn (p = 0.009). Even in the absence of chronic disease states, withdrawal was more likely for patients older than 55 years (21/51) than in those 55 years and younger (3/32; p < 0.001). CONCLUSIONS Mortality is significantly higher for patients with ARDS older than 55 years. Decisions to withdraw support are made more often in ARDS patients older than 55 years. These data suggest that age bias may influence decisions to withdraw support.
Clinically recognized cardiac dysfunction: an independent determinant of mortality among critically ill patients. Is there a role for serial measurement of cardiac troponin I? OBJECTIVE To determine the relative importance of clinically recognized cardiac dysfunction and unrecognized cardiac injury to hospital mortality. DESIGN Prospective, blinded, single-center study. SETTING Medical ICU of Barnes-Jewish Hospital, St. Louis, a university-affiliated teaching hospital. PATIENTS Two hundred sixty adult patients requiring admission to the medical ICU. INTERVENTIONS Daily blood collection. MAIN OUTCOME MEASURES The presence of cardiac dysfunction (myocardial infarction, unstable angina, cardiac arrest, or congestive heart failure) as determined by the physicians responsible for the care of the patient. Daily measurement of levels of cardiac troponin I, a sensitive, highly specific, and long-lived marker of myocardial injury. RESULTS Fifty-five (21.2%) patients had clinical evidence of cardiac dysfunction, among whom 22 (40%) had an elevated level of cardiac troponin I. A total of 41 (15.8%) patients had evidence of acute myocardial injury based on elevated levels of cardiac troponin I. Patients with clinically recognized cardiac dysfunction had a significantly greater hospital mortality rate compared to patients without clinically recognized cardiac dysfunction (45.5% vs 10.2%; p < 0.001). Similarly, patients with elevated blood levels of cardiac troponin I had a greater hospital mortality rate compared to patients without elevated blood levels of cardiac troponin I (26.8% vs 16.0%; p = 0.095). Multiple logistic-regression analysis controlling for potential confounding variables demonstrated that the presence of clinically recognized cardiac dysfunction was independently associated with hospital mortality (adjusted odds ratio = 3.0; 95% confidence interval = 1.9 to 4.8; p = 0.016). However, having an elevated blood level of cardiac troponin I was not found to be an independent determinant of hospital mortality. CONCLUSION Among critically ill medical patients, clinically recognized cardiac dysfunction is an independent determinant of hospital mortality. The identification of unrecognized cardiac injury, using serial measurements of cardiac troponin I, did not independently contribute to the prediction of hospital mortality.
Radiofrequency volumetric reduction of the tongue. A porcine pilot study for the treatment of obstructive sleep apnea syndrome. STUDY OBJECTIVE To investigate, in an animal model, the feasibility of radiofrequency (RF) volumetric tongue reduction for the future purpose of determining its clinical applications in obstructive sleep apnea syndrome (OSAS). DESIGN The study was performed in three stages, one in vitro bovine stage and two in vivo porcine stages. The last stage was a prospective investigation with histologic and volumetric analyses to establish outcomes. SETTING Laboratory and operating room of veterinary research center. PARTICIPANTS A homogeneous population of porcine animal models, including seven in stage 2 and 12 in stage 3. INTERVENTION RF energy was delivered by a custom-fabricated needle electrode and RF generator to the tongue tissue of both the in vitro and in vivo models. MEASUREMENTS AND RESULTS Microultransonic crystals were used to measure three-dimensional changes (volumetric reduction). Lesion size correlated well with increasing RF energy delivery (Sperman correlation coefficient of 0.986; p = 0.0003). Histologic assessments done serially over time (1 h through 3 weeks) showed a well-circumscribed lesion with a normal healing progression and no peripheral damage to nerves. Volumetric analysis documented a very mild initial edematous response that promptly tapered at 24 h. At 10 days after RF, a 26.3% volume reduction was documented at the treatment site (circumscribed by the microultrasonic crystals). CONCLUSION RF, in a porcine animal model, can safely reduce tongue volume in a precise and controlled manner. Further studies will validate the use of RF in the treatment of OSAS.
Dexamethasone treatment does not ameliorate subglottic ischemic injury in rabbits. BACKGROUND Following tracheal intubation, a small proportion of patients develop laryngeal inflammation or tissue necrosis severe enough to result in clinical symptoms. Although corticosteroids are frequently advocated to prevent such injury, human studies have been inconclusive because of the low incidence of the problem. This study developed a rabbit model of endotracheal tube-induced laryngeal injury to test the hypothesis that a corticosteroid, dexamethasone, could ameliorate the inflammation and necrosis. METHODS Subglottic injury was induced in 21 anesthetized rabbits by inflating the cuff of an endotracheal tube to 100 mm Hg with the cuff just below the vocal cords. Every 30 min for 2 h, the cuff was deflated, the tube turned 90 degrees, and the cuff then reinflated. After 2 h, the rabbits' tracheas were extubated. Rabbits were divided into two groups: the treatment group received dexamethasone (1 mg/kg) i.v. 1 h prior to extubation with the dose repeated 6 h following extubation; the untreated group received a saline solution placebo. Four additional rabbits were anesthetized for the same period but did not have a tracheal tube inserted. All rabbits were killed 24 h later and the larynxes were harvested. Sections through the larynx at the level of the cricoid cartilage were randomized and submitted blindly to a veterinary pathologist. Larynxes were scored and ranked according to the severity of mucosal inflammation and necrosis, and submucosal hemorrhage, edema, inflammation, and necrosis. Specimens were also evaluated for focal vs diffuse disease. RESULTS Injured rabbits demonstrated focal to diffuse mucosal and submucosal inflammation and necrosis. Inflammatory exudates were present in sections from most of the injured rabbits and large sections of the larynxes were denuded of epithelium. There were no differences in injury scores between the treated and untreated rabbits. The four uninjured control rabbits had normal larynxes. CONCLUSIONS Two hours of endotracheal tube cuff inflation to 100 mm Hg causes an inflammatory laryngeal injury. The histologic features of the injury are unaltered by treatment with 2 mg/kg dexamethasone.
Measuring nebulizer output. Aerosol production vs gravimetric analysis. STUDY OBJECTIVES The function of jet nebulizers has been measured traditionally by gravimetric methods, i.e., by weighing nebulizers before and after nebulization. Newer techniques measure aerosol output directly by analyzing aerosolized drug or tracer, i.e., radioactive 99mTc. Because of evaporation, the equivalence of these methods is uncertain. The aim of this study was to determine if the gravimetric method is an accurate measure of aerosol production under different conditions of aerosol generation (i.e., nebulizer type, flow rate, pressure, volume fill, and concentration of solution used to nebulize a drug). METHODS In the first phase of the study, we measured the aerosol output of nine commercially available jet nebulizers (AvaNeb; Up-Draft-Hudson RCI; Cirrus-Intersurgical Inc; DeVilbiss 646-DeVilbiss; Powermist-Hospitak, Inc; Respirgard II-Marquest Medical Products; Seamless-Seamless/Dart Respiratory; Salter; Salter Labs; Airlife-Baxter Health Care) run under commonly used conditions (2.5 mL volume fill, 2.0 mL normal saline solvent, 0.5 mL albuterol, flow of 6 L/min, and pressures averaging 15.0 +/- 2.3 [mean +/- SD] pounds per square inch [on the] gauge [psig] provided by a DeVilbiss PulmoAide compressor) with simultaneously measured gravimetrics and filtered radioactivity. Each nebulizer was run to dryness with data acquired every 2 min. The change in the weight of the nebulizer and radioactivity captured on the filter were expressed as percentages of the total in the nebulizer solution. In the second phase of the study, the experiments were repeated using the same nebulizers with a volume fill of 5 mL (diluted to half normal saline solution plus albuterol), flow of 10 L/min, and pressures of 35.6 +/- 8.8 psig. RESULTS The cumulative (sum of all 2-min runs) weight loss for each individual nebulizer ranged from 25.00 to 64.55% and cumulative aerosol captured varied from 12.63 to 38.76%. While different, the weight loss and aerosol captured were closely correlated (y = -0.62 + 0.62x; r = 0.961, p < 0.0001). Changing volume fill and concentration of solvent did not affect this correlation (p = 0.921 and 0.373, respectively). However, changing flow from 6 L/min to 10 L/min significantly (p = 0.02) affected the relationship (y = -3.80 + 0.83x; r = 0.969, p < 0.001). CONCLUSIONS When compared with direct methods such as filtering generated particles, the gravimetric method of assessing nebulizer function overestimates aerosol output by 1.8 +/- 0.18 times, presumably because of the loss of solvent during nebulization. However, the relationship between methods is predictable and appears unaffected by changing the type of nebulizer, volume fill, and concentration of solvent. Changes in nebulizer flow and pressure significantly affected the correlation. Gravimetric methods can be used as simple and convenient screening techniques for comparing jet nebulizers under a wide range of experimental conditions.
Combination of tracheal gas insufflation and airway pressure release ventilation. STUDY OBJECTIVE We hypothesized that the continuous gas flow administration delivered through an insufflation catheter positioned above the carina during airway pressure release ventilation (APRV) would facilitate carbon dioxide (CO2) elimination, resulting in normocarbia with a substantially reduced peak airway pressure (Paw). To test this hypothesis, we compared intermittent positive pressure ventilation (IPPV), tracheal gas insufflation (TGI), APRV, and combined TGI and APRV (TGI + APRV). DESIGN Animal study with random application of four ventilatory modes in a canine restrictive-thorax model with and without pulmonary edema. SETTING Research laboratory at Kumamoto (Japan) University School of Medicine. SUBJECTS Six mongrel dogs. INTERVENTIONS Application of four ventilatory modes (IPPV, TGI, APRV, and TGI + APRV). MEASUREMENTS AND RESULTS TGI + APRV facilitated CO2 elimination. The peak Paw was significantly lower during TGI + APRV than during IPPV (nonpulmonary edema model; 15 +/- 4 vs 28 +/- 9 cm H2O; p < 0.05; pulmonary edema model: 20 +/- 4 vs 34 +/- 10 cm H2O; p < 0.05). Normocarbia was observed in both models. Neither TGI nor APRV alone maintained normocarbia. CONCLUSION The combined use of TGI and APRV is a more effective method of maintaining normocarbia with reduced peak Paw than either IPPV or APRV alone.
Effect of erionite on the pleural mesothelium of the Fischer 344 rat. OBJECTIVE This study sought to assess the fibrogenic and carcinogenic potential of erionite (a fibrous zeolite) on the pleural mesothelium of the Fischer 344 rat (n = 24). DESIGN The study was designed to examine rat pleural mesothelial changes by three independent observers at timed intervals, ranging from 1 to 480 days postinoculation using erionite from the Pine Valley, Nevada (USA) area. The mean length and width of the erionite fibers were 2.29 and 0.48 microns, respectively. Only microscopic observations made by majority (2/3) or unanimity (3/3) were accepted for final diagnosis. RESULTS Pleural and lung tissue were available for examination in 21 of the 24 rats. Fibrosis, chronic inflammation, and foreign body reaction occurred in 6 of 21 rats. Mesothelial hyperplasia and dysplasia occurred in 9 and 3 of the 21 rats, respectively. A single mesothelioma was identified at 434 days in a rat that had gross nodular pleural lesions. CONCLUSIONS The findings reported herein confirm the strong fibrogenic potential of erionite but are at variance with previous studies reporting much higher yields of mesothelioma. The reasons for the low yield of mesothelioma in this study are not known, but may be related to the study design, the strict criteria used for histopathologic diagnosis, and/or possible differences in erionite physicochemical properties, associated with its geographic distribution, most previous animal studies having used erionite from the Rome, Oregon (USA) area.
Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats. The capacity of the alveolar epithelial barrier to remove excess alveolar fluid from the airspaces of the lung was studied in an experimental model of moderate hyperoxic lung injury. Rats were exposed to 100% oxygen for 40 h in an exposure chamber and compared with control animals exposed to room air. Extravascular lung water was calculated gravimetrically. Alveolar and lung liquid clearance were studied over 1 h by instillation of a 5% albumin solution with 1.5 microCi of 125I-labeled albumin (6 mL/kg into both lungs). The concentration of both the unlabeled and labeled albumin was used to calculate alveolar liquid clearance. Hyperoxic rats developed pulmonary edema, with a 33% increase in extravascular lung water to 5.3 +/- 0.1 g of water per gram of dry lung, compared with 4.0 +/- 0.2 g of water per gram of dry lung in control rats (p < 0.05). This degree of edema was associated with a significant increase in the alveolar-arterial oxygen difference (241 +/- 61 vs 124 +/- 14 mm Hg in control animals exposed to room air, p < 0.05). Despite this moderate degree of lung injury, alveolar fluid clearance was normal (30 +/- 3%) compared with control rats (33 +/- 6%). Furthermore, the hyperoxic injured rats responded normally to an exogenous beta-adrenergic agonist (terbutaline, 10(-4) mol/L) with a 67% increase in the rate of alveolar liquid clearance (50 +/- 5%). Thus, in the setting of moderate hyperoxic lung injury, the alveolar epithelial barrier is still capable of removing fluid at a normal rate and responding to beta-adrenergic agonist treatment. These experimental results have potential clinical implications for patients with acute lung injury.
Distinguishing left ventricular aneurysm from pseudoaneurysm. A review of the literature. A postmyocardial infarction left ventricular pseudoaneurysm occurs when a rupture of the ventricular free wall is contained by overlying, adherent pericardium. A postinfarction aneurysm, in contrast, is caused by scar formation resulting in thinning of the myocardium. Although the usual treatment for patients with pseudoaneurysm is urgent surgical repair, the imaging characteristics of pseudoaneurysm and aneurysm, for which treatment is more conservative, are quite similar. The literature on the natural history and imaging characteristics of the two entities is reviewed, and an approach to distinguishing between the two entities is proposed.
Cigarette smoking and lung cancer trends. A light at the end of the tunnel? OBJECTIVE To update the epidemic curves for lung cancer in the United States by gender in relation to the temporal trends in adult current cigarette smoking prevalence. METHODS The design of the study was ecologic, based on population figures. Available data on the prevalence of current cigarette smoking from 1920 to 1990 were plotted in conjunction with age-adjusted lung cancer mortality rates from 1930 to 1992 for each sex. RESULTS There was a strong temporal relationship between the curves for cigarette smoking prevalence and lung cancer mortality rate with approximately a 30-year population latency period in both men and women. The curves occurred later in women than in men. The lung cancer rate in men peaked in 1990 and then began to decline while the rate in women continued to rise. CONCLUSIONS The temporal association between cigarette smoking prevalence and lung cancer mortality provides additional support for the causal relationship between smoking and lung cancer.
Curative irradiation of limited endobronchial carcinomas with high-dose rate brachytherapy. Results of a pilot study. OBJECTIVES OF THE STUDY Pilot study to assess high-dose rate (HDR) brachytherapy as sole treatment for limited endobronchial non-small cell lung carcinomas. INCLUSION CRITERIA Proximal non-small cell lung cancer in a not previously irradiated area, with a maximal diameter of 1 cm, no visible tumor on CT scan, lack of other treatment options in patients with severe, chronic respiratory failure, surgery, or external radiotherapy for a previous lung cancer. TREATMENT PROTOCOL Treatment was based on an escalating dose protocol. Patients received three to five fractions of 7 Gy prescribed at 10 mm from the center of the applicator, once a week. RESULTS Nineteen patients were included in this trial. The first two patients received three fractions of 7 Gy, the four next patients received four fractions, and the 13 remaining patients were treated with five fractions of 7 Gy. Two months after the end of the procedure, tumors in 15 of 18 evaluable patients (83%) were locally controlled with negative results of biopsies. At 1 year, local control was still obtained in 12 of 16 evaluable patients (75%). With a mean follow-up of 28-months, 1-year and 2-year actuarial survival rates were 78% and 58%, respectively, with a 28-month median survival. One patient with local control died from hemoptysis 12 months after treatment. Two patients suffered from severe necrosis of the bronchial wall; one of them died from hemoptysis. CONCLUSIONS HDR brachytherapy is an effective treatment for small endobronchial tumors. Late toxicity on the bronchial wall is still too high and was attributed mainly to contact between the catheter and the bronchial mucosa. Exclusive HDR brachytherapy should be restricted to carefully selected patients for whom there is no alternative curative treatment. New bronchial applicators and a lower dose per fraction may reduce the incidence and attenuate the severity of late complications.
Pentoxifylline does not alter the response to inhaled grain dust. Pentoxifylline (PTX) has been shown to reduce sepsis-induced neutrophil sequestration in the lung and inhibit endotoxin-mediated release of tumor necrosis factor-alpha (TNF-alpha). Previously, we have shown that endotoxin appears to be the principal agent in grain dust causing airway inflammation and airflow obstruction following grain dust inhalation. To determine whether PTX affects the physiologic and inflammatory events following acute grain dust inhalation, 10 healthy, nonsmoking subjects with normal airway reactivity were treated with PTX or placebo (PL) followed by corn dust extract (CDE) inhalation (0.08 mL/kg), using a single-blinded, crossover design. Subjects received PTX (1,200 mg/d) or PL for 4 days prior to CDE inhalation and 400 mg PTX or PL on the exposure day. Both respiratory symptoms and declines in FEV1 and FVC occurred following CDE exposure in both groups, but there were no significant differences in the frequency of symptoms or percent declines from baseline in the FEV1 and FVC at any of the time points measured in the study. Elevations in peripheral blood leukocyte and neutrophil concentrations and BAL total cell, neutrophil, TNF-alpha, and interleukin-8 concentrations were measured 4 h following exposure to CDE in both the PTX- and PL-treated subjects, but no significant differences were found between treatment groups. These results suggest that pretreatment with PTX prior to inhalation of CDE, in the doses used in this study, does not alter the acute physiologic or inflammatory events following exposure to inhaled CDE.
Aortic root abscess with fistula formation. Aortic root abscess is a common complication of aortic valve endocarditis. However, aortic root abscess and formation of a fistula from the aortic root to the right ventricular outflow tract in the setting of a native aortic valve and previous repair of an aortic dissection with a Dacron graft is an uncommon event. Transesophageal echocardiography is superior to transthoracic echocardiography for the diagnosis of aortic root abscess. To our knowledge, no studies have compared the diagnostic value of cardiac MRI with transesophageal echocardiography for this condition.
Very early onset of acute amiodarone pulmonary toxicity presenting with hemoptysis. A case of amiodarone pulmonary toxicity (APT) occurring within days of the start of therapy and presenting with hemoptysis is reported. Both the very early onset and the presenting symptom are highly unusual in this entity. Implications in the diagnosis of APT are discussed.
Catamenial hemoptysis. Diagnosis with MRI. Thoracic endometriosis is a rare disorder. We report a case of a 26-year-old woman with a 4-year history of catamenial hemoptysis due to thoracic endometriosis which was diagnosed by MRI and treated successfully by means of video-assisted thoracoscopic wedge-resection of the solitary pulmonary lesion. Medical therapy with hormones was not necessary. There is no evidence of recurrence 10 months after the operation. This case demonstrates that MRI of the chest may be considered for the diagnostic work-up of patients with catamenial hemoptysis. It also shows that wedge-resection of pulmonary endometriosis foci by means of video-assisted thoracoscopy-an approach that has not been described in the literature thus far-is an effective therapy in localized peripheral pulmonary parenchymal endometriosis.
Immediate transcatheter embolization of Swan-Ganz catheter-induced pulmonary artery pseudoaneurysm. Digital subtraction angiography is an indispensable complement to cut film studies for the detection of pulmonary artery injury. Immediate transcatheter embolization of catheter-induced pulmonary artery pseudoaneurysm is a safe, minimally invasive, fast, and cost-effective alternative to surgical treatment.
Management of bronchopleural fistula with a variable-resistance valve and a single ventilator. Independent lung ventilation with two ventilators is sometimes used in the management of bronchopleural fistula (BPF). We describe a patient in whom gas flow through a large BPF was initially reduced, and subsequently eliminated, during differential lung ventilation using a single ventilator and a variable-resistance valve attached to one lumen of a bifurcated endotracheal tube.
Nonsustained polymorphous ventricular tachycardia during amiodarone therapy for atrial fibrillation complicating cardiomyopathy. Management with intravenous magnesium sulfate. A case is presented in which amiodarone was administered to suppress paroxysmal atrial fibrillation in a patient with an idiopathic cardiomyopathy. Eleven days after initiation of therapy with amiodarone, the patient experienced syncope and was noted to have recurrent episodes of polymorphous ventricular tachycardia. The patient was hospitalized and treated with a bolus as well as continuous infusion of intravenous magnesium sulfate. When the infusion was transiently discontinued, recurrences of polymorphous ventricular tachycardia were noted. The probable proarrhythmic action of amiodarone, although rare, is reviewed along with a discussion of the novel use of intravenous magnesium sulfate therapy.
Recurrent alveolar proteinosis following double lung transplantation. We present a case of recurrent alveolar proteinosis following double lung transplantation.
Pulmonary tuberculosis after lung transplantation. During a 5-year study period, we diagnosed pulmonary tuberculosis in two (2%) of 94 lung and heart-lung transplant recipients. Each infection occurred 3 months after bilateral lung transplantation in the presence of evidence implicating donor-to-recipient transmission of the pathogen. The radiographic patterns of pulmonary tuberculosis were subtle: narrowing of the middle lobe bronchus of the right lung caused by an endobronchial granulomatous mass (n = 1) and a focal cluster of small nodules in the upper lobe of the left lung and small bilateral pleural effusions (n = 1). Each patient achieved complete clinical and radiographic response after antituberculous therapy. We conclude that Mycobacterium tuberculosis may be transmitted directly by a donor lung and may involve bronchial mucosa, pulmonary parenchyma, and pleura.
Idiopathic myocardial vasculitis presenting as restrictive cardiomyopathy. A previously unreported case of small-vessel myocardial vasculitis presenting as restrictive cardiomyopathy and congestive heart failure is described. The hemodynamic study, showing severely increased and equalized diastolic pressures in atrial and ventricular chambers, and cardiac MRI, showing normal pericardium and ventricular endomyocardial biopsy, not including myocardial vascular component, were insufficient to make a diagnosis. This made a thoracotomy and surgical cardiac biopsy necessary. Steroids and cyclophosphamide, introduced after histologic evidence of necrotizing vasculitis, unassociated with a systemic disease, became available and improved the clinical profile and the diastolic dysfunction at two-dimensional echocardiographic Doppler analysis.
Nails and nail disorders in children and adults. Abnormalities of the nails can provide both subtle and obvious clues to common medical problems or severe systemic diseases. Heredity, minor injuries and a variety of infections account for many changes in the appearance of nails. Several dermatologic disorders, such as psoriasis and alopecia areata, and other multisystem disorders may present with nail changes; abnormalities of the nails may be the single most prominent feature. Common habits and the use of various cosmetics also may result in nail changes. Awareness of normal nail variants and well-defined abnormalities and their disease associations will be beneficial to most clinicians. Specific management and therapy for most nail problems are usually simple and appropriate for primary care physicians.
Evaluation and management of diabetes insipidus. Diabetes insipidus is an uncommon condition characterized by polyuria and polydipsia. The symptoms and biochemical changes of this condition result from either a lack of antidiuretic hormone or renal insensitivity to its effect. Failure to produce or release antidiuretic hormone may result from cranial pathology, including trauma and surgery. The renal insensitivity to antidiuretic hormone that occurs in patients with nephrogenic diabetes insipidus may be caused by genetic factors, drugs (especially lithium) or specific disease processes. Patients may compensate for polyuria and nocturia by excessive water intake but show marked decreases in urine specific gravity and osmolality. Patients with severe and uncompensated symptoms develop marked dehydration, neurologic symptoms and encephalopathy. The water deprivation test is useful in diagnosing diabetes insipidus and in differentiating neurogenic from nephrogenic cases. Neurogenic diabetes insipidus may respond to nasal administration of desmopressin. Nephrogenic diabetes insipidus requires good hydration and monitoring of body chemistry. Thiazides and amiloride may relieve symptoms.
Getting the most from review articles: a guide for readers and writers. A good medical review article is easily readable and pares down the seemingly overwhelming amount of information available in the literature. The research experience and clinical expertise of the writer do not guarantee valid and relevant recommendations. Uncritical acceptance of information by readers further potentiates the dissemination of misinformation. Only through teamwork, with each partner--both writer and reader--taking responsibility for a role, can review articles result in improved patient care. This article offers guidance to both consumers and producers--readers and writers-of review articles.
Standardized forms to use in the management of HIV infection. Family physicians should be prepared to care for the increasing number of patients infected with human immunodeficiency virus (HIV) and those who have acquired immunodeficiency syndrome. Strategies are needed to help practicing physicians become more competent in the medical care of patients with HIV infection and AIDS. This article introduces three forms that can serve as templates for the physician to use in evaluating and managing patients with HIV infection. These forms incorporate current recommendations for monitoring patients and cue the physician to consider specific prevention strategies.
Exercise prescription for chronically ill patients. Although patients with chronic illnesses typically refrain from exercise, many of them could benefit significantly from mild, long-term exercise therapy. While factors such as pain or weakness often discourage the chronically ill person from being physically active, lack of motivation and lack of knowledge are the primary obstacles. An effective way of overcoming these obstacles is to provide an individualized exercise regimen that both motivates and instructs. Patients who receive an exercise prescription enjoy this individualized approach, tend to exercise safely and quickly become aware of the benefits of exercise therapy as an adjuvant to their medical treatment.
Vacuum-assisted vaginal delivery. Vacuum extraction is an effective method of operative vaginal delivery. The procedure is widely used in Europe and many developing countries as the instrument of choice for assisted vaginal deliveries and has recently gained greater acceptance in the United States. The vacuum procedure is relatively easy to learn and offers a safer, less traumatic alternative to the use of forceps or cesarean section for indicated deliveries. Advances in extractor cup design have resulted in fewer cases of neonatal and maternal trauma and improved efficacy. As with any procedure, strict attention to technique and sound clinical judgment are essential for success.
The painful foot, Part II: Common rearfoot deformities. As with deformities of the forefoot, deformities of the rearfoot often respond well to conservative therapy. Rest and nonsteroidal anti-inflammatory medications are often used. Patients with plantar fasciitis may benefit from corticosteroid injections. Surgery may be helpful in refractory cases. Haglund's deformity is associated with pain in the area of the osseous ridge on the posterosuperior aspect of the calcaneus. The retrocalcaneal bursa may be inflamed. This disorder is diagnosed by palpation of the painful area. Conservative treatment consists of minimizing pressure over the osseous ridge. Corticosteroid injection is not advised since it may weaken the Achilles tendon. Surgical intervention consists of resection or reduction of the osseous ridge. Posterior calcaneal spur is another cause of heel pain. The spur can be visualized radiographically in the tendon insertion. Treatment is conservative, with footgear modification and nonsteroidal anti-inflammatory drug therapy. Surgery to remove the spur may be indicated if conservative measures fall to relieve the pain. Tarsal tunnel syndrome is characterized by pain and numbness from the medial malleolus to the sole of the foot. Conservative treatment includes reducing abnormal pronation with an orthosis.
Management of radial head fracture. A fracture involves not only bone, but also surrounding soft tissues. Attention to soft tissue injury may help prevent long-term complications such as contractures, weakness, instability and loss of proprioception. Appropriate treatment is directed at three phases of healing: inflammation, repair and remodeling. The two- to seven-day inflammatory phase is controlled with rest, ice, elevation, immobilization and medications to reduce the pain and swelling. Immobilization during the two- to eight-week repair phase promotes bone healing but may lead to contractures and loss of strength if continued for too long. Physical therapy during the several-month remodeling phase helps restore strength, range of motion and proprioception. Although six to eight weeks is a usual estimate for fracture healing, the actual time can be affected by the type of fracture and the person's age, nutritional and health status, and medication use. This review of the diagnosis and treatment of radial head fractures illustrates the importance of directing the treatment toward the three phases of healing.
Endoscopic ultrasonography: a new diagnostic imaging modality. Endoscopic ultrasonography uses high-frequency ultrasound to visualize the gut wall and the surrounding structures of the mediastinum, the abdomen and the pelvis. Echoendoscopes are available in two different designs. A radial scanning echoendoscope produces a 360 degree real-time view perpendicular to the shaft of the echoendoscope. A linear-array instrument produces a 100 degrees real-time view parallel to the shaft of the echoendoscope, permitting direct ultrasonographic guidance of fine needles exiting the biopsy channel. Endoscopic ultrasonography has been established as the preferred diagnostic tool for the evaluation of submucosal masses of the upper gastrointestinal tract and the rectosigmoid, for differentiating benign from pathologic thickened gastric folds and for locating pancreatic endocrine tumors. The widest application of endoscopic ultrasonography is in the diagnosis and staging of esophageal, gastric, rectal and pancreaticobiliary neoplasms. Endosonography is the most accurate modality available for determining the T and N stages of these tumors. The recent development of endoscopic ultrasound-guided fine-needle aspiration provides physicians with the ability to cytologically diagnose lesions visualized endosonographically and to confirm cancer staging with tissue.
Fecal incontinence in children. Functional constipation is the cause of fecal incontinence in 95 percent of affected children, and anatomic or neurologic causes account for up to 5 percent of cases. The history and the physical examination (with emphasis on abdominal, rectal and neurologic examinations) are most helpful in identifying organic disease. In some children, anorectal manometry, a barium enema radiographic examination and a rectal biopsy are necessary to determine the etiology. Most children with fecal incontinence benefit from a strict treatment plan that includes defecation trials, a fiber-rich diet and laxative medications. Surgery followed by medical treatment is required in patients with Hirschsprung's disease and in some patients with anal stenosis or a history of surgical repair of an anorectal malformation.
Captopril renal scintigraphy in renovascular hypertension. Renovascular disease is a common cause of secondary hypertension. Renal artery stenosis is present in up to one third of patients with clinical markers suggestive of renovascular hypertension, such as hypertension refractory to medical management, severe hypertension in a young patient and worsening of renal function after the use of an angiotensin-converting enzyme inhibitor. Early discovery of renal artery stenosis may allow amelioration or cure of the hypertension and halt progressive loss of renal function. Although renal arteriography remains the gold-standard aid to diagnosis and to planning surgical intervention, it is an invasive procedure that may cause deterioration of renal function. In the presence of renal artery stenosis, glomerular filtration is maintained by angiotensin. Administration of captopril in renal scintigraphy removes this compensatory mechanism and causes a temporary impairment of renal function in the affected kidney. Nuclear tracers can visualize this impairment, thus allowing assessment of the physiologic significance of a renal artery stenosis. The test can be done as a outpatient procedure.
Prevention of coronary heart disease through cholesterol reduction. Growing evidence suggests that lowering serum cholesterol levels, particularly low-density lipoprotein levels, will reduce the risk for coronary heart disease. The benefit of cholesterol-lowering therapy has been documented by many clinical trials. Two secondary prevention trials, the Scandinavian Simvastatin Survival Study and the Cholesterol and Recurrent Events trial, demonstrated a striking reduction in recurrent coronary heart disease without an increase in noncardiovascular mortality; treatment with simvastatin reduced total mortality by 30 percent. A primary prevention trial, the West of Scotland Coronary Prevention Study, demonstrated similar results in high-risk patients without established coronary heart disease. More recent angiographic trials revealed that cholesterol-lowering therapy will reduce progression of atherosclerosis and, in some cases, will reverse existing lesions. Use of HMG-CoA reductase inhibitors also appears to be beneficial and safe. Evidence supports cholesterol-lowering therapy in high-risk patients, both with and without established atherosclerotic disease.
Cervical angina. Cervical angina is defined as chest pain that resembles true cardiac angina but originates from a cervical discopathy with nerve root compression. This condition, which is also referred to as pseudoangina, most commonly results from compression of the C7 nerve root. Several simple findings from the history and the physical examination help make the diagnosis, which can then be confirmed with magnetic resonance imaging and/or discography. Coexisting coronary artery disease must always be ruled out. Treatment includes intermittent cervical traction, physical therapy, nonsteroidal anti-inflammatory drugs and muscle relaxants. If these measures fall to alleviate the patient's pain, referral to a spine surgeon may be indicated.
Chemotherapy in the treatment of non-small cell lung cancer. Non-small cell cancers of the lung include squamous cell carcinoma, adenocarcinoma and large cell carcinoma. These tumors have traditionally been considered to be quite resistant to both chemotherapy and radiation therapy. Although surgery has offered the best chance for cure, the tumor has usually spread too far for effective surgery by the time it is discovered. Several newer chemotherapeutic agents show improved survival rates in the treatment of these tumors. These agents include paclitaxel, carboplatin and vinorelbine. These drugs may be used as single agents or in combination and have also been used in combination with radiation. Although further study will be required before the optimal regimen is determined, it appears that use of these agents can improve the survival of patients with inoperable non-small cell cancer of the lung.
NHLBI issues update on task force report on high blood pressure in children and adolescents. Health-related behaviors that reduce the risk of cardiovascular disease should be encouraged for all children and their families. Physicians should monitor blood pressure, counsel patients about appropriate nutrition and exercise, and emphasize the importance of not smoking. Because black adults in the United States have an increased prevalence, morbidity and mortality of essential hypertension, the working group advises physicians to be particularly vigilant in monitoring blood pressure in black children, especially those with a family history of hypertension. Other groups with a higher prevalence of hypertension and any person with a family history of hypertension should be monitored closely.
Distribution and association of chronic disease and mobility difficulty across four body mass index categories of African-American women. A majority of African-American women over the age of 50 are obese, have at least one chronic disease, and experience mobility difficulty. Using self-reported data from the 1992 Health and Retirement Study of 1,150 African-American women aged 30-70 years, this report first compares chronic disease prevalence and severity, pain, sensory deficits, and mobility difficulty across four categories of body mass index and, second, investigates whether body mass index affects the association of chronic disease with mobility difficulty. Body mass index was categorized as low, medium, high, and severe, being equal to 19-24 (20%), 25-29 (38%), 30-34 (24%), and 35 or over (18%), respectively. There were few differences when comparing the medium category with either the low or high category. Those in the severe body mass index category, however, reported significantly more frequent and severe hypertension, diabetes, cancer, heart disease, arthritis, pain, sensory deficits, and mobility difficulty than did those in the medium body mass index category. Obesity did not appear to affect the association between chronic disease and mobility difficulty. The relatively high rates of mobility difficulty observed among the severe body mass index group appear to be more likely a result of relatively high chronic disease prevalence and severity than to a disproportionate impact of these on mobility.
Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The relation of intakes of specific fatty acids and the risk of coronary heart disease was examined in a cohort of 21,930 smoking men aged 50-69 years who were initially free of diagnosed cardiovascular disease. All men participated in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and completed a detailed and validated dietary questionnaire at baseline. After 6.1 years of follow-up from 1985-1988, the authors documented 1,399 major coronary events and 635 coronary deaths. After controlling for age, supplement group, several coronary risk factors, total energy, and fiber intake, the authors observed a significant positive association between the intake of trans-fatty acids and the risk of coronary death. For men in the top quintile of trans-fatty acid intake (median = 6.2 g/day), the multivariate relative risk of coronary death was 1.39 (95% confidence interval (CI) 1.09-1.78) (p for trend = 0.004) as compared with men in the lowest quintile of intake (median = 1.3 g/day). The intake of omega-3 fatty acids from fish was also directly related to the risk of coronary death in the multivariate model adjusting also for trans-saturated and cis-monounsaturated fatty acids (relative risk (RR) = 1.30, 95% CI 1.01-1.67) (p for trend = 0.06 for men in the highest quintile of intake compared with the lowest). There was no association between intakes of saturated or cis-monounsaturated fatty acids, linoleic or linolenic acid, or dietary cholesterol and the risk of coronary deaths. All the associations were similar but somewhat weaker for all major coronary events.
Tracking of risk factors for coronary heart disease over a 14-year period: a comparison between lifestyle and biologic risk factors with data from the Amsterdam Growth and Health Study. Because the magnitude of tracking coefficients (i.e., stability coefficients and tracking for subjects at risk) greatly depends on the initial age of subjects, the number and spacing of longitudinal measurements, and the length of the total time period, it is difficult to compare tracking coefficients from different studies with each other. Because in the Amsterdam Growth and Health Study both biologic (i.e., lipoproteins, blood pressure, body fatness, and cardiopulmonary fitness) and lifestyle (i.e., dietary intake, daily physical activity, smoking, and alcohol consumption) risk factors for coronary heart disease were measured, this study gives the unique possibility of comparing tracking coefficients of biologic and lifestyle risk factors within one data set. In the Amsterdam Growth and Health Study, six repeated measurements were carried out on 181 subjects over a period from 13 to 27 years of age, beginning in 1977. The results indicated that, over a period of 14 years covering adolescence and young adulthood, both stability coefficients and tracking for subjects at risk for lifestyle risk factors were low (except for smoking), indicating low predictability of early measurements for values later in life. For the biologic risk factors cardiopulmonary fitness and blood pressure, tracking was also low, while for the lipoproteins and body fatness, tracking was much better, indicating good predictability.
Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Low heart rate variability is associated with high risk of sudden death in myocardial infarction patients. This has been attributed to unfavorable autonomic cardiac control. In the present study, the predictive value of heart rate variability for sudden death, mortality from coronary heart disease, and from all causes was investigated in the general population, using brief electrocardiographic recordings. From 1960 to 1985, 878 middle-aged Dutch men, aged 40-60 years, were followed and repeatedly examined as part of the Zutphen Study. In 1985 the remaining cohort was extended to 885 elderly men, aged 65-85 years, and followed until 1990. Heart rate variability (standard deviation of duration of normal RR intervals) was determined from the resting 12-lead electrocardiogram. The 5-year age-adjusted relative rate of total mortality of men with heart rate variability of < 20 milliseconds (msec) compared with men with heart rate variability of 20-39 msec was 2.1 (95 percent confidence interval 1.4-3.0) in middle-aged men and 1.4 (95% confidence interval 0.9-2.2) in elderly men. Death from noncoronary causes, especially cancer, contributed significantly to this elevated risk. The association of low heart rate variability with sudden death or coronary heart disease mortality was less consistent. In conclusion, in middle-aged men and probably in elderly men, low heart rate variability is predictive of mortality from all causes. This suggests that low heart rate variability is an indicator of compromised health in the general population.
Alcohol intake and insulin levels. The Normative Aging Study. Much remains to be clarified in the apparently protective effect of moderate alcohol use against coronary heart disease risk. Insulin levels are positively associated with coronary heart disease risk, so recent reports of decreased insulin sensitivity among nondrinkers and lower fasting insulin levels with increasing alcohol intake suggest the possibility that insulin may play a role. Between 1987 and 1991, the authors examined fasting insulin concentrations and the empiric fasting insulin resistance index in relation to reported alcohol intake (mean, 15.3 g/day; standard deviation, 19.6; range, 0-120.6) and potential confounders. The latter included age, obesity, fat distribution, smoking, energy, saturated fat intake, antihypertensive medication, and physical activity. Participants in this cross-sectional analysis were 938 nondiabetic men from the Boston, Massachusetts, area who were part of the Normative Aging Study. Unadjusted fasting insulin levels were significantly different (p = 0.008) between categories of alcohol intake, as were fasting insulin resistance index values (p = 0.01). After adjustment for potential confounders, analysis revealed that subjects consuming moderate amounts of alcohol had the lowest fasting insulin and fasting insulin resistance index values. Compared with values from moderate drinkers, fasting insulin resistance index values were higher in those subjects reporting no alcohol intake (p = 0.011), low intake (p = 0.004), and high intake (p = 0.04). A similar pattern was observed for fasting insulin values. Among this sample of nondiabetic men, moderate drinkers had the lowest levels of fasting insulin resistance index and fasting insulin, consistent with lower levels of insulin resistance and thus lower risk for coronary heart disease. These findings suggest the possibility that the coronary heart disease-protective effects of moderate alcohol use are at least partially mediated by insulin.
Comparison of effect estimates from a meta-analysis of summary data from published studies and from a meta-analysis using individual patient data for ovarian cancer studies. To determine the relative merits of two quantitative methods used to estimate the summary effects of observational studies, the authors compared two methods of meta-analysis. Each quantified the relation between oral contraceptive use and the risk for ovarian cancer. One analysis consisted of a meta-analysis using summary data from 11 published studies from the literature (MAL) in which the study was the unit of analysis, and the second consisted of a meta-analysis using individual patient data (MAP) in which the patient was the unit of analysis. The authors found excellent quantitative agreement between the summary effect estimates from the MAL and the MAP. The MAP permits analysis 1) among outcomes, exposures, and confounders not investigated in the original studies, 2) when the original effect measures differ among studies and cannot be converted to a common measure (e.g., slopes vs. correlation coefficients), and 3) when there is a paucity of studies. The MAL permits analysis 1) when resources are limited, 2) when time is limited, and 3) when original study data are not available or are available only from a biased sample of studies. In public health epidemiology, data from original studies are often accessible only to limited numbers of research groups and for only a few types of studies that have high public health priority. Consequently, few opportunities for pooled analysis exist. However, from a policy view, MAL will provide answers to many questions and will help in identifying questions for future investigation.
Calcium intake and fracture risk: results from the study of osteoporotic fractures. The relation between dietary calcium, calcium, and vitamin D supplements and the risk of fractures of the hip (n = 332), ankle (n = 210), proximal humerus (n = 241), wrist (n = 467), and vertebrae (n = 389) was investigated in a cohort study involving 9,704 US white women aged 65 years or older. Baseline assessments took place in 1986-1988 in four US metropolitan areas. Dietary calcium intake was assessed at baseline with a validated food frequency questionnaire. Data on new nonvertebral fractures were collected every 4 months during a mean of 6.6 years of follow-up; identification of new vertebral fractures was based on comparison of baseline and follow-up radiographs of the spine done a mean of 3.7 years apart. Results were adjusted for numerous potential confounders, including weight, physical activity, estrogen use, protein intake, and history of falls, osteoporosis, and fractures. There were no important associations between dietary calcium intake and the risk of any of the fractures studied. Current use of calcium supplements was associated with increased risk of hip (relative risk = 1.5, 95% confidence interval 1.1-2.0) and vertebral (relative risk = 1.4, 95% confidence interval 1.1-1.9) fractures; current use of Tums antacid tablets was associated with increased risk of fractures of the proximal humerus (relative risk = 1.7, 95% confidence interval 1.3-2.4). There was no evidence of a protective effect of vitamin D supplements. Although a true adverse effect of calcium supplements on fracture risk cannot be ruled out, it is more likely that our findings are due to inadequately controlled confounding by indications for use of supplements. In conclusion, this study did not find a substantial beneficial effect of calcium on fracture risk.
Incidence of functional decline and improvement in a community-dwelling, very elderly population. With the aging of the population, functional decline is one of the major challenges to health care systems. The objective of this study was to estimate the incidence of functional decline and improvement in a community-dwelling population of people aged 75 years and above. A representative sample of elderly people living at home in the city of Sherbrooke (Québec, Canada) was assessed yearly on three occasions (1991-1993) by a nurse. Disabilities were measured by the Functional Autonomy Measurement System, a 29-item rating scale developed according to the World Health Organization classification of disabilities. From the 655 subjects who agreed to participate, a total of 572 subjects completed the study, including 68 who subsequently died. The probability of declining was 20.1% for the first year and 12.4% for the second year. The incidence of functional decline among previously stable subjects was 11.9% (95% confidence interval (CI) 8.9-15.9). Age was strongly related to decline (relative risk (RR) = 1.15/year, 95% CI 1.09-1.21), but there was no significant sex effect (RRmale = 0.88, 95% CI 0.55-1.39). The incidence of improvement among previously disabled subjects was estimated at 7.5% (95% CI 5.1-10.9) for the first year and 17.9% (95% CI 14.0-23.0) for the second year. Neither age (RR = 1.07, 95% CI 0.99-1.15) nor sex (RRmale = 1.70, 95% CI 0.90-3.18) was significantly associated with the probability of improving. This study stresses the importance of precise measurement of disabilities and the complex and dynamic process of functional transitions.
Dose- and time-dependent relations between infective Anopheles inoculation and outcomes of Plasmodium falciparum parasitemia among children in western Kenya. Blood-stage level Plasmodium falciparum infection (parasitemia density) is generally elevated prior to, or at the time of, clinical presentation of severe pediatric malaria episodes. Intensity of exposure to infective Anopheles mosquito bites is a suspected determinant of higher density parasitemia. Analyses of entomologic and parasitologic data collected in 1986-1987 were conducted to investigate whether the dose of infective bites predicted the incidence or degree of P. falciparum parasitemia in Kenyan children < 6 years old. At 21 consecutive 30-day intervals, a new cohort (n approximately 50 each) was enrolled, cured of malaria parasites, and monitored over 84 days for recurrent parasitemia. Outcomes included time to parasitemia, time to parasitemia > or = 5,000/microliter, and parasitemia density. Ecologic and individual-level analyses were conducted. The mean infective bite exposure experienced by each cohort was significantly associated with the incidence of parasitemia (age-adjusted r2 = 0.38, p = 0.022) and more strongly associated with the incidence of parasitemia > or = 5,000/microliter (age-adjusted r2 = 0.72, p < 0.001). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia > or = 5,000/microliter among children exposed to > or = 1 infective bite per day as compared with the referent (rate ratio (RR) = 2.82, 95% confidence interval (CI) 2.24-3.56). Cumulative infective bite exposure, exposure duration, and age were significant predictors of recurrent parasitemia density in multiple linear regression analyses. The results support the contention that reductions in P. falciparum transmission intensity, in the absence of complete elimination, will reduce higher level parasitemia among African children.
Reflections on telomeres, growth, aging, and essential hypertension. Here we review the "telomere hypothesis of cellular aging." We propose that this hypothesis is relevant to our understanding of the roles of genetics as well as growth and development in the etiology of essential hypertension and its cardiovascular complications. Elements of this hypothesis and the speculations that we make can be directly tested using tissues (cells) obtained from human beings.
Angiotensinogen gene variation associated with variation in blood pressure in aboriginal Canadians. We measured blood pressure and related clinical phenotypes in 497 adult native Canadians from an isolated community in Northern Ontario. We analyzed their DNA for genotypes of angiotensinogen. We found that the frequency of the T235 variant of the angiotensinogen gene was 0.89 in this sample. This variant was associated with a significantly increased systolic pressure but not diastolic pressure. We also found that sex and body mass were each highly significantly associated with variation in both systolic and diastolic pressures. We found a significant association between age and variation in systolic pressure but not diastolic pressure. We also found a highly significant association between plasma apolipoprotein B concentration and variation in diastolic pressure but not systolic pressure. The high frequency of the angiotensinogen T235 variant suggests that subjects in this young, essentially normotensive population might be predisposed to hypertension, which may become more apparent in the presence of secondary factors.
Association of the angiotensinogen gene to serum angiotensinogen in blacks and whites. A variant of the angiotensinogen gene (AGT) that encodes for threonine at codon 235 (T235) has been associated with a higher serum angiotensinogen concentration and with hypertension in white subjects. The frequency of T235 is about two times higher in blacks than whites, suggesting that AGT may contribute to the susceptibility to hypertension in blacks more than it does in whites. However, an association of T235 with angiotensinogen level or blood pressure has not been observed in blacks, possibly because the high prevalence of T235 makes it insufficiently informative as a marker. For this reason, we undertook to further differentiate the T235 carrier state by constructing haplotypes with alleles in the 5' upstream region of AGT. One such haplotype, -1074t;T235, showed a significant association with angiotensinogen level in a cohort of black and white children and adolescents (76 blacks, mean age = 12.3 +/- 2.0 [SD] years; 139 whites, mean age = 12.4 +/- 1.8 years). With a linear regression model, the level of serum angiotensinogen was significantly related to body mass index (P = .0017) and the haplotype (P = .0001). Within specific race groups, the haplotype was significantly related to serum angiotensinogen in both the blacks (P = .0277) and whites (P = .0001). The mean level of angiotensinogen was higher in the blacks carrying a single copy of the haplotype than in those without the haplotype (1472.2 +/- 68.4 versus 1274.9 +/- 46.7 nmol angiotensin I/L), a difference that was marginally significant (P = .0609). In the whites, the level of angiotensinogen was also higher in carriers of a single copy than in those with no copy (1527.9 +/- 71.2 versus 1099.2 +/- 20.1 nmol angiotensin I/L) (P = .0003). Serum angiotensinogen level did not increase with two copies of the haplotype, but in each racial group, there were only four individuals who were homozygous. The haplotype showed a marginally significant relation (P = .0757) to the mean of longitudinally determined diastolic pressures adjusted for body mass index, race, sex, and age. In summary, using a haplotype to differentiate further the T235 carrier state, we observed an association of genotype with serum angiotensinogen level and blood pressure in blacks and whites. The findings suggest that AGT may play an important role in blood pressure regulation in both racial groups.
Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans. Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.
Cancer risk in users of calcium channel blockers. Ca2+ channel blockers may cause cancer by inhibiting apoptosis or reducing intracellular Ca2+ in certain tissues. Recent findings suggest that drug users are at increased risk for cancer in general and for colon cancer in particular. We conducted a study in one Danish county of 17911 patients who received at least one prescription of Ca2+ channel blockers between 1 January 1991 and 31 December 1993. The patients were identified from records in the National Health Insurance Program, which refunds part of the price of such drugs. Cancer occurrence and rate were determined by use of the files of the Danish Cancer Registry and compared with county-specific incidence rates for various categories of cancer. During the follow-up period of up to 3 years, 412 cancers were observed among users of Ca2+ channel blockers, compared with 414 expected, to yield an age- and sex-standardized incidence ratio (SIR) of 1.00 (95% confidence interval, 0.90 to 1.10). There was no indication of an excess risk in the subgroup of likely long-term users or users of specific drugs. The SIR of colon cancer, a site of a priori interest, was 0.8 (95% confidence interval, 0.5 to 1.1) on the basis of 34 cases. Although the results are reassuring, the lack of association could reflect the relatively short follow-up after registration in the prescription database. Continued monitoring of cancer risk is planned.
Left ventricular mass in the elderly. The Cardiovascular Health Study. Left ventricular (LV) mass, as estimated from M-mode echocardiography (echo), has previously been shown to be an independent predictor of incident cardiovascular disease morbidity and mortality. We evaluated the relationship at baseline of echo LV mass to relevant cardiovascular disease risk factors and other potential covariates in the Cardiovascular Health Study, multicenter study sponsored by the National Heart, Lung, and Blood Institute of 5201 men and women aged 65 years or older (mean, 73). Two-dimensionally directed M-mode echo LV mass measurements could be obtained in 1357 men and 2053 women (66% of this elderly cohort). Stepwise linear regression analyses of the relationship of echo LV mass to demographic and risk factor, physical activity, electrocardiographic, and prevalent disease variables resulted in a model that explained 37% of the variance for the entire cohort. In order of decreasing importance, factors positively associated with echo LV mass were body weight, male sex, systolic pressure, presence of congestive heart failure, present smoking, major and minor electrocardiographic abnormalities, treatment for hypertension, valvular heart disease, aortic regurgitation by color Doppler, and mitral regurgitation by color Doppler (in men) whereas diastolic pressure, bioresistance (a measure of adiposity), and high-density lipoprotein cholesterol were inversely related to echo LV mass. Although height and weight were both related to LV mass, height added nothing once weight was entered in multiple linear regression analyses. Furthermore, in the multiple regression models, diastolic pressure was inversely and systolic BP positively related to LV mass, with similar magnitudes for their coefficients. In consonance with these findings, pulse pressure was positively related to LV mass in bivariate analyses. Multiple linear regression analyses explained less of the variance for ventricular septal thickness (R2 = .13) and LV posterior wall thickness (R2 = .14) than for LV mass (R2 = .37) and LV diastolic dimension (R2 = .27). Intriguing findings in the elderly Cardiovascular Health Study cohort included the presence of pulse pressure as a positive correlate, and high-density lipoprotein cholesterol as an inverse correlate, of LV mass. Longitudinal studies in the Cardiovascular Health Study cohort will help to clarify the importance of demographic, risk factor, and other variables, and changes in these variables, in predicting changes in echo LV mass and its components as well as the prognostic significance of LV mass in the elderly.
Distinct mechanisms of modulation of angiotensin II type I receptor gene expression in heart and aorta. The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT1) in the thoracic aorta and heart through an Ang II-dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT1 to GAPDH mRNA in the aorta was significantly higher in RRM (1.85 +/- 0.52) compared with sham-operated (0.21 +/- 0.04) and RRM+Cap (0.55 +/- 0.20) rats. In contrast, the ratio of AT1 to GAPDH mRNA in the heart was significantly increased in both RRM (1.09 +/- 0.23) and RRM+Cap (1.00 +/- 0.09) compared with sham-operated (0.34 +/- 0.06) rats. Thus, RRM hypertension upregulates AT1 mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT1 mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT1 gene regulation exist; ie, in aorta, an Ang II-or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT1 mRNA may be pressure dependent.
Confirmation or exclusion of stage I hypertension by ambulatory blood pressure monitoring. Criteria for the diagnosis or exclusion of hypertension using ambulatory blood pressure monitoring have not been agreed upon. We designed this study to provide a statistically based guide for using results of ambulatory blood pressure monitoring to resolve this issue. To generate this information, we used a database of 228 subjects (135 men, 93 women; average age, 45 years) referred by their primary physicians over the past 7 years for evaluation of borderline or stage I hypertension (average blood pressure, 148/92 mm Hg; SD, +/-17.5/12.2 mm Hg). In this population, the pooled SDs of systolic and diastolic ambulatory blood pressures were 13.8 and 11.6 mm Hg, respectively. Using the pooled SD, we calculated the probability that a patient's blood pressure falls within the hypertensive range (> 140/90 mm Hg). The 95% confidence interval for each subject's blood pressure was also determined. For example, if 40 ambulatory blood pressure measurements are performed on a subject and the average systolic ambulatory blood pressure is 137 mm Hg, then there is a 10% probability that the patient's "true" average blood pressure is actually in the hypertensive range. By contrast, if the systolic pressure is 143 mm Hg, there is a 90% probability that the patient is hypertensive. This approach may be useful for clinical decision making and also for the design of clinical trials.
Neural circulatory responses to carbon monoxide in healthy humans. The contribution of carbon monoxide (CO) to the acute cardiovascular effects of smoking is not clear. Using a double-blind, randomized, vehicle-controlled study design, we examined the sympathetic and vascular responses to modest increases in carboxyhemoglobin in 10 healthy humans. We measured muscle sympathetic nerve activity (microneurography), forearm blood flow (plethysmography), heart rate, blood pressure, and minute ventilation at baseline and during 60 minutes of CO inhalation (1000 ppm during the first 30 minutes and 100 ppm during the last 30 minutes). The same measurements were made in a vehicle session (room air inhalation) on a separate day. During the first 30 minutes of CO inhalation, carboxyhemoglobin levels increased progressively from 0.2 +/- 0.1% to 8.3 +/- 0.5% and were maintained at about this level for a further 30 minutes. Forearm vascular resistance did not change with CO but increased slightly with vehicle; the effects of CO on muscle sympathetic nerve activity, forearm blood flow, blood pressure, heart rate, and minute ventilation were not significantly different from the effects of vehicle. Modest increases in carboxyhemoglobin levels equivalent to those resulting from cigarette smoking are unlikely to contribute to the acute sympathetic and hemodynamic effects of smoking in healthy humans.
Baroreflex sensitivity assessed by complex demodulation of cardiovascular variability. We used complex demodulation of cardiac interval and systolic arterial blood pressure oscillations in the low-frequency band (0.04 to 0.14 Hz) to investigate baroreceptor control of heart rate. Baroreflex sensitivity was defined as the instantaneous amplitude of complex-demodulated oscillations in the RR interval divided by the instantaneous amplitude of complex-demodulated oscillations in systolic blood pressure. We evaluated the method using both simulated and actual data obtained from 33 healthy nonsmokers during supine and standing postures. To test the validity and reliability of the method, we compared the mean values of baroreflex sensitivity calculated using complex demodulation with the values obtained using power spectral analysis and sequential analysis of spontaneous variations in blood pressure and RR interval. All three methods applied to the simulated data yielded the same values of baroreceptor sensitivity. Mean values of baroreflex sensitivity assessed by complex demodulation of the actual data were similar to those calculated by both power spectral analysis and sequential analysis (13.9 +/- 5.2 versus 13.7 +/- 6.7 or 14.3 +/- 6.5 ms/mm Hg for supine and 7.3 +/- 2.8 versus 7.0 +/- 3.0 or 7.2 +/- 2.8 ms/mm Hg for standing, respectively). In addition, a significant correlation existed between the values obtained by complex demodulation and power spectral analysis (r = .97, P = .0001) and sequential analysis (r = .98, P = .0001). Furthermore, complex demodulation-derived baroreflex sensitivity fluctuated across time during both the supine and standing postures, and this could not be discerned by power spectral analysis. The results indicate that complex demodulation provides a dynamic assessment of baroreflex sensitivity and may be a useful tool in exploring reflex autonomic control of the cardiovascular system.
ANP enhances bradycardic reflexes in normotensive but not spontaneously hypertensive rats. Baroreflex control of heart rate in spontaneously hypertensive rats (SHR) is defective, largely because of a poor vagal contribution to the reflex. We have demonstrated previously that atrial natriuretic peptide (ANP) enhances reflex bradycardia in normotensive rats through an action on nonarterial vagal afferent pathways. In the present study, we investigated whether ANP could reverse the baroreflex abnormality in SHR. Heart rate reflexes were activated by three different methods in conscious, instrumented SHR and Wistar-Kyoto rats (WKY) in the presence of intravenous infusions of vehicle (saline) or rat ANP (150 ng/kg per minute). Heart rate responses were measured by (1) the steady-state changes in blood pressure after alternating slow infusions (over approximately 15 to 30 seconds) of a pressor (methoxamine) and depressor (nitroprusside) drug (stimulating predominantly arterial baroreceptors), (2) the ramp method of rapid infusion of methoxamine (over < 10 seconds; stimulating arterial and cardiopulmonary baroreceptors), and (3) the von Bezold-Jarisch method of activating chemically sensitive cardiac receptors through serotonin injections. ANP enhanced the heart rate range of the arterial baroreflex (steady-state method) by 13 +/- 3% in WKY but had no significant effect on the sensitivity or any other parameter of the steady-state baroreflex. When a very rapid rise in blood pressure was elicited by the ramp method in WKY, ANP significantly enhanced baroreflex bradycardia (sensitivity increased by 29 +/- 9%, P < .05). ANP also enhanced the bradycardia of the von Bezold-Jarisch reflex (by 33 +/- 16%, P < .05) in WKY. By contrast, ANP did not influence baroreceptor or chemoreceptor heart rate reflex responses in SHR. We conclude that in normotensive rats, ANP facilitates cardiopulmonary bradycardic reflexes. The lack of effect of ANP in SHR may be related to an underlying structural or genetic alteration in their cardiac sensors, perhaps associated with cardiac hypertrophy, that prevents the ANP-induced activation of cardiac sensory afferents, resulting in cardioinhibition.
Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Pheochromocytoma is a catecholamine-secreting tumor and a rare cause of hypertension that is usually curable. However, pheochromocytoma may recur as a benign or malignant tumor, and hypertension may persist after successful surgical intervention. The frequency of and risk indicators for tumor recurrence and hypertension persistence after successful surgical intervention have not been adequately studied. We determined tumoral and blood pressure outcome in 129 patients followed-up from initial pheochromocytoma resection to death or to 1994 (796 patient-years). We assessed several candidate indicators for their predictive value for the risk of tumor recurrence or hypertension persistence. Recurrence was defined as the reappearance of disease after normalization of biochemical tests. Pheochromocytoma caused death or persistent or recurrent disease in 28 patients. Of the 114 with benign tumors at initial operation, pheochromocytoma recurred as a benign or malignant tumor 17 to 194 months after initial operation in 16 cases. Kaplan-Meier estimates of pheochromocytoma-free survival were 92% and 80% at 5 and 10 years, respectively. In the 98 living patients without recurrence, Kaplan-Meier estimates of hypertension-free survival were 74% and 45% at 5 and 10 years. In the Cox model, familial pheochromocytoma and a low ratio of plasma epinephrine to total catecholamines were independently associated with recurrence. Familial hypertension and age were similarly associated with hypertension persistence. After surgery for pheochromocytoma, patients should be followed-up indefinitely, especially those with familial tumors or a low epinephrine secretion. Pheochromocytoma should not unreservedly be considered a surgically remediable cause of hypertension.
Differential alteration in vascular structure of resistance arteries isolated from the cerebral and mesenteric vascular beds of transgenic [(mRen-2)27], hypertensive rats. In this study we examined the structural properties of cerebral and mesenteric resistance arteries isolated from normotensive, Sprague-Dawley (SD) rats (mean arterial pressure [MAP], 110 +/- 3 mm Hg) and hypertensive, transgenic (TG) rats (MAP, 167 +/- 4 mm Hg), which express the mouse Ren-2 renin gene. Vessels were set up in a pressure myograph, and ID and vascular wall thickness were determined at increasing intraluminal pressures. Arteries were subsequently pressurized to the MAP of the animal from which they were isolated and were fixed with glutaraldehyde before being embedded in araldite, sectioned, and examined histologically. The middle cerebral artery (MCA) isolated from SD rats and TG rats had similar media cross-sectional areas. There was no difference in MCA diameter at 10 mm Hg in vessels from TG rats compared with SD rats. However, at higher distending pressures, the diameter of the MCA from TG rats was significantly smaller than that of vessels from SD rats. This reduced ID at the higher pressures was a consequence of a decreased distensibility of the MCA from TG rats (as shown by a leftward shift of the stress-strain relationship in arteries from TG rats) and was not caused by an increase in wall thickness. First- and second-order mesenteric resistance arteries isolated from TG rats displayed an increased wall thickness and media content compared with vessels from SD rats. However, this alteration in mesenteric artery structure did not impinge on the ID of arteries from TG rats; there was no difference in the IDs of mesenteric resistance arteries between the two strains at any distending pressure. These observations show that there are distinct regional alterations in vascular structure in hypertensive TG rats expressing the mouse Ren-2 renin gene. Mesenteric resistance arteries isolated from TG rats display signs of vascular growth, although this structural alteration does not produce a reduction in the ID of these arteries per se. In contrast, cerebral arteries from TG rats do not show increased growth but have a reduced vascular distensibility, which results in a smaller ID compared with vessels from SD rats.
Adrenomedullin stimulates renin release and renin mRNA in mouse juxtaglomerular granular cells. The recently discovered peptide adrenomedullin (AM) alters blood pressure through effects on the resistance vessels. Moreover, AM modifies the secretion of corticotropin and aldosterone and could thereby indirectly influence blood pressure through the renin-angiotensin-aldosterone system. Although plasma AM and renin concentration have been found to directly correlate, a causal linkage between AM and renin has not been shown. The present study tested the influence of AM on renin secretion and renin gene expression by renal juxtaglomerular granular cells. Prominent expression and release of AM by vascular structures has been reported; therefore, we investigated the local expression of AM in juxtaglomerular structures. Renin release from isolated perfused rat kidneys was dose-dependently increased by AM (1 to 30 nmol/L), whereas renal perfusate flow rate increased up to 17% at a constant perfusion pressure of 100 mm Hg. In primary cultures of mouse granular cells, AM augmented renin release, renin mRNA accumulation, and cAMP production in a dose- and time-dependent manner (threshold values in the range 10 pmol/L to 1 nmol/L). By reverse transcription-polymerase chain reaction, significant expression of the AM gene was detected in microdissected rat glomeruli with afferent arterioles and in primary cultures of mesangial and granular cells. We conclude that AM is expressed in juxtaglomerular structures and that it has a direct stimulatory effect on renin secretion and renin mRNA abundance by receptors on juxtaglomerular cells, possibly through increases in cAMP. AM could act as an autocrine/paracrine stimulatory factor in the control of renin secretion and renin gene expression.
Effect of mechanical loading on vascular alpha 1D- and alpha 1B-adrenergic receptor expression. Heterogeneous distribution and function of alpha 1-adrenergic receptor subtypes on arterial and venous vessels, together with evidence for altered alpha-adrenergic receptor expression in hypertension, led us to examine whether mechanical load influences expression of alpha 1B- and alpha 1D-adrenergic receptors in rat aortic smooth muscle cells (SMCs). We used RNase protection and radioligand binding assays to measure mRNA and alpha 1-adrenergic receptor density. In the first model, SMCs were subjected to phasic loading using flexible culture plates. As a positive control for the load stimulus, postconfluent, quiescent passage 5 cells demonstrated the expected load-dependent morphological realignment. However, no changes were detected in expression of either alpha 1D- or alpha 1B-adrenergic receptor mRNAs or receptor density after 24 to 48 hours of loading. beta-Actin and SMC-specific alpha-actin mRNA, as well as cell number and per-cell total RNA and protein, were also unaffected. In a second model, intact thoracic aortas, in either the presence or absence of endothelial cells, were cultured for 48 hours under tonic load. Like cultured cells, 48 hours of load did not affect SMC expression of alpha 1-adrenergic receptor mRNAs. We used suprarenal aortic coarctation to examine effects of increased pressure in vivo. As with the previous in vitro and in situ models, hypertension (30 days) had no effect on expression of alpha 1B- and alpha 1D-adrenergic receptor mRNAs in the suprarenal aorta compared with sham coarctation. To separate pressure per se from humoral influences, we also measured mRNAs in the subrenal, normotensive aorta, alpha 1B mRNA levels decreased to 68 +/- 14% of sham-coarcted controls in subrenal aorta exposed to normal blood pressure but also to systemic humoral changes induced by coarctation. As a positive control for a load effect, SMC-specific alpha-actin mRNA increased for loaded aorta in organ culture and in hypertensive aorta in vivo, whereas expression of beta-actin mRNA was unaffected. These results from cell culture, organ culture, and in vivo models suggest that pressure (load) alone has no effect on alpha 1B- and alpha 1D-adrenergic receptor expression. In coarctation hypertension, smooth muscle protected from the hypertension showed a decline in alpha 1B mRNA that may be due to a humoral factor or factors.
Mechanical load opposes angiotensin-mediated decrease in vascular alpha 1-adrenoceptors. alpha 1-Adrenergic receptor contraction of vascular smooth muscle is augmented by increases in angiotensin II and also in several forms of hypertension. Whether angiotensin directly modulates alpha 1-adrenoceptor subtype expression to contribute to this effect is unknown. In a previous study, we demonstrated that increased mechanical load (pressure) per se does not alter expression of alpha 1B- and alpha 1D-adrenoceptors in rat aortic smooth muscle in cell culture, in vitro or in vivo. However, findings in aortic coarctation hypertension suggested that a humoral factor, possibly angiotensin, selectively reduces alpha 1B-adrenoceptors and that increased mechanical load opposes this decrease. The present study examined this hypothesis by determining the effect of angiotensin alone and in the presence of mechanical loading on the expression of alpha 1D- and alpha 1B-adrenergic receptor mRNAs and alpha 1-receptor density in cultured aortic smooth muscle cells. alpha 1D mRNA content, per smooth muscle cell, concentration-dependently decreased after 3 hours of exposure to 0.3 nmol/L to 1 mumol/L angiotensin but by 24 hours had returned to control levels. In contrast, alpha 1B mRNA concentration-dependently declined at a later time (24 hours) and remained decreased at 48 hours to 27 +/- 6% of control with 1 mumol/L angiotensin. Angiotensin also decreased alpha 1-adrenoceptor density in a dose-dependent manner. Angiotensin had no effect on cell number in these confluent, quiescent cells but did increase cell protein and total RNA. This cellular hypertrophy and the decreases in alpha 1-adrenoceptor mRNAs were blocked by the angiotensin type 1 receptor antagonist losartan. Cyclic mechanical loading of smooth muscle cells opposed the angiotensin-mediated hypertrophy and decrease in alpha 1B mRNA expression and alpha 1-adrenergic receptor density. These data suggest that angiotensin and intravascular pressure interact to affect cell growth and expression of alpha 1B-adrenergic receptors by vascular smooth muscle.
Metformin inhibits ganglionic neurotransmission in renal nerves. Intravenous administration of the antihyperglycemic agent metformin decreases arterial pressure and sympathetic nerve activity (SNA). To test the hypothesis that metformin inhibits SNA by interrupting ganglionic neurotransmission, we compared the actions of intravenous administration of metformin and the ganglionic blocker trimethaphan on postganglionic renal and preganglionic adrenal sympathetic nerves in pentobarbital-anesthetized male Sprague-Dawley rats. Intravenous metformin elicited dose-dependent decreases in postganglionic renal SNA (1 mg/kg: 0 +/- 0%; 10 mg/kg: -20 +/- 4%; 100 mg/kg: -92 +/- 3%; n = 7). Conversely, only the maximal dose of metformin affected preganglionic adrenal SNA (100 mg/kg: delta adrenal SNA = -14 +/- 6%; n = 8). Ganglionic blockade with intravenous trimethaphan (5 mg/kg) produced a differential sympathoinhibitory response similar to the response observed after high-dose metformin (delta renal SNA = -100 +/- 3%; delta adrenal SNA = -17 +/- 7%; P < .001). Preganglionic renal neurons were electrically stimulated in the spinal cord, before and during the peak of the sympathoinhibitory response to intravenous metformin, and the magnitude of the stimulus-evoked increases in postganglionic renal SNA were compared. Metformin dose-dependently attenuated the magnitude of the increase in postganglionic renal SNA elicited by stimulation of the spinal cord (30 mg/kg: -23 +/- 8%; 90 mg/kg: -65 +/- 11%; 270 mg/kg: -91 +/- 8%; n = 6 per dose). We conclude that high-dose intravenous metformin interrupts ganglionic neurotransmission in renal nerves.
Endothelin-1 upregulation in the kidney of uninephrectomized spontaneously hypertensive rats and its modification by the angiotensin-converting enzyme inhibitor quinapril. Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription-polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
Chronic dietary L-arginine prevents endothelial dysfunction secondary to environmental tobacco smoke in normocholesterolemic rabbits. Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with L-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary L-arginine supplementation prevents this. The effects of L-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2 x 2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial L-arginine levels were measured by chromatography. Chronic L-arginine supplementation increased serum (P < .001) and endothelial (P = .003) L-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and L-arginine blocked this adverse effect (P = .04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (P = .06). Neither environmental tobacco smoke nor L-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as L-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.
Nifedipine attenuates systemic and renal vasoconstriction during nitric oxide inhibition in humans. Clinical states associated with nitric oxide deficiency are often accompanied by vasoconstriction. We studied the effects of prolonged infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on systemic and renal hemodynamics in humans and the reversibility of the established vasoconstriction by calcium channel blockade with nifedipine. Seven healthy men underwent three 7-hour clearance studies. During one study, L-NMMA (3 mg/kg priming dose plus 3 mg.kg-1.h-1) was infused during hours 2 through 5, and during another study, nifedipine (0.015 mg/kg priming dose plus 0.015 mg.kg-1.h-1) was coinfused during hours 4 and 5. A third study served as time control. L-NMMA elicited reproducible systemic and renal vasoconstriction that was stable during the 4 hours of infusion. Systemic vascular resistance index, calculated from bioimpedance-derived cardiac index, increased from 22 +/- 1 to 29 +/- 2 mm Hg.min.m2.L-1 (P < .05). Mean arterial pressure rose by 4 +/- 1 mm Hg (P < .05), and heart rate, stroke index, and cardiac index decreased. Renal blood flow, calculated from renal plasma flow, decreased from 1182 +/- 101 to 785 +/- 53 mL/min, and renal vascular resistance increased from 73 +/- 5 to 115 +/- 6 mm Hg.min.L-1 (P < .05). Glomerular filtration rate decreased from 114 +/- 6 to 104 +/- 6 mL/min (P < .05), and filtration fraction increased. Sodium excretion fell from 89 +/- 9 to 32 +/- 7 mumol/min (P < .05). Nifedipine completely reversed systemic vasoconstriction. Nifedipine caused partial restoration of renal vascular resistance and complete normalization of glomerular filtration rate and sodium excretion but left the elevated filtration fraction unaltered. We conclude that sustained nitric oxide deficiency in humans is accompanied by strong systemic and renal vasoconstriction, decreased glomerular filtration rate, and sodium retention. Nifedipine can reverse most of these effects, suggesting a role for calcium channel blockade in pathological states of impaired nitric oxide activity.
Time course changes of the mechanical properties of the carotid artery in renal hypertensive rats. Distensibility of the carotid artery is not altered 2 weeks after renal artery clipping despite adaptive vascular hypertrophy related to hypertension. The purpose of this study was to assess arterial wall behavior with hypertension persisting for a longer period. Male Wistar rats were examined 1, 5, 9, and 24 weeks after renal artery clipping (two-kidney, one clip renal hypertension; n = 40) or after sham operation (n = 39). Mean blood pressure increased significantly to 132 +/- 4, 143 +/- 4, 153 +/- 4, and 144 +/- 4 versus 98 +/- 2, 107 +/- 2, 115 +/- 3, and 108 +/- 3 mm Hg, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls. Cardiac and vascular hypertrophy increased in parallel and were correlated to mean blood pressure. Wall stress at mean blood pressure did not differ between the hypertensive and normotensive groups (3.79 +/- 0.24, 4.60 +/- 0.34, 4.49 +/- 0.27, and 4.14 +/- 0.28 versus 3.15 +/- 0.12, 4.14 +/- 0.25, 4.80 +/- 0.28, and 4.69 +/- 0.32 10(3) dyne/cm2, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls). Distensibility-pressure data from the two groups fell on a common curve for all study periods. The intrinsic properties of the wall constituents were similar in controls and hypertensive rats at 1 and 5 weeks. However, the arteries became stiffer in the 9- and 24-week hypertensive rats, as illustrated by a shift to higher levels of the incremental elastic modulus-stress curve. Wall stress remains constant at mean blood pressure as a result of the increase in wall tissue mass. With time, even though the distensibility-pressure curve is not shifted downward, the thickened wall becomes stiffer in the hypertensive rats, which may predispose them to accelerated alterations of the wall material.
Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC). The prolonged depressor but not the pressor response was reduced after alpha-adrenergic receptor blockade or cervical spinal cord transection and was inhibited by the cannabinoid type 1 (CB1) receptor antagonist SR141716A, suggesting CB1 receptor-mediated sympathoinhibition as the underlying mechanism. Here we examined the relationship between sympathetic tone and the cardiovascular effects of anandamide by testing these effects in both conscious and anesthetized, normotensive and spontaneously hypertensive rats. In urethane-anesthetized normotensive rats, SR141716A inhibited the prolonged depressor and bradycardic effects of anandamide and THC with similar potency, whereas it did not affect the pressor response to either agent. Anadamide caused similar hypotension in spontaneously breathing and in paralyzed, mechanically ventilated rats, suggesting that the hypotension is not secondary to respiratory effects. In conscious normotensive rats, anandamide elicited transient vagal activation and a brief pressor response, but the prolonged hypotensive component was absent. SR141716A potentiated and prolonged the brief pressor response to anandamide, suggesting that the depressor response may have been masked by an increased pressor response. All three phases of the anadamide response were present in both anesthetized and conscious spontaneously hypertensive rats, and the hypotensive component, inhibited by SR141716A in both, was more prolonged in the absence (> 50 minutes) than the presence (10 to 15 minutes) of anesthesia. We conclude that anandamide causes a non-CB1 receptor-mediated pressor and a CB1 receptor-mediated prolonged depressor response. The depressor response can be elicited in both conscious and anesthetized animals, but its magnitude depends on preexisting sympathetic tone.
Cold exposure and winter mortality from ischaemic heart disease, cerebrovascular disease, respiratory disease, and all causes in warm and cold regions of Europe. The Eurowinter Group. BACKGROUND Differences in baseline mortality, age structure, and influenza epidemics confound comparisons of cold-related increases in mortality between regions with different climates. The Eurowinter study aimed to assess whether increases in mortality per 1 degree C fall in temperature differ in various European regions and to relate any differences to usual winter climate and measures to protect against cold. METHODS Percentage increases in deaths per day per 1 degree C fall in temperature below 18 degrees C (indices of cold-related mortality) were estimated by generalised linear modelling. We assessed protective factors by surveys and adjusted by regression to 7 degrees C outdoor temperature. Cause-specific data gathered from 1988 to 1992 were analysed by multiple regression for men and women aged 50-59 and 65-74 in north Finland, south Finland, Baden-Württemburg, the Netherlands, London, and north Italy (24 groups). We used a similar method to analyse 1992 data in Athens and Palermo. FINDINGS The percentage increases in all-cause mortality per 1 degree C fall in temperature below 18 degrees C were greater in warmer regions than in colder regions (eg, Athens 2.15% [95% CI 1.20-3.10] vs south Finland 0.27% [0.15-0.40]). At an outdoor temperature of 7 degrees C, the mean living-room temperature was 19.2 degrees C in Athens and 21.7 degrees C in south Finland; 13% and 72% of people in these regions, respectively, wore hats when outdoors at 7 degrees C. Multiple regression analyses (with allowance for sex and age, in the six regions with full data) showed that high indices of cold-related mortality were associated with high mean winter temperatures, low living-room temperatures, limited bedroom heating, low proportions of people wearing hats, gloves, and anoraks, and inactivity and shivering when outdoors at 7 degrees C (p < 0.01 for all-cause mortality and respiratory mortality; p > 0.05 for mortality from ischaemic heart disease and cerebrovascular disease). INTERPRETATION Mortality increased to a greater extent with given fall of temperature in regions with warm winters, in populations with cooler homes, and among people who wore fewer clothes and were less active outdoors.
Regional patterns of disability-free life expectancy and disability-adjusted life expectancy: global Burden of Disease Study. BACKGROUND Information on non-fatal health outcomes of disease and injury has been largely neglected in health planning because of the conceptual and definitional complexity of measuring morbidity and disability in populations. One of our major objectives was to quantify disability for inclusion in health policy debates. We analysed these health outcomes in terms of disability-free life expectancy (DFLE) and disability-adjusted life expectancy (DALE). METHODS Published and unpublished data were systematically reviewed to estimate the incidence, prevalence, and duration of 483 disabling sequelae of 107 diseases and injuries. To ensure internal consistency of these estimates, a software programme (DISMOD) was applied many times until consistent parameters were identified. The severity of disability, on a scale of 0 (perfect health) to 1 (death), was measured in a deliberate manner by the person-trade-off method. Spearman's and Pearson's correlation coefficients were used to measure disability weights among groups. Prevalence of seven classes of disability was back-calculated from the distribution of each disabling sequela across disabilities. Prevalence for each class of disability for different age-sex groups was used to calculate seven forms of DFLE and DALE based on Sullivan's method. FINDINGS Prevalence of most disability classes is highest in sub-Saharan Africa and lowest in established market economies. Low-severity disabilities (class I and class II) are the most common. The expectation at birth of class I disability ranges from 6.5 years in established market economies to 14.7 years in sub-Saharan Africa, and for class II disabilities, from 8.5-18.4 years. DFLE varies significantly among regions: DFLE for class I disabilities at birth ranges from 9.9 years in sub-Saharan Africa to 47.7 years in established market economies for females and DFLE for class V disabilities ranges from 43.4 years for men in sub-Saharan Africa to 74.8 years for women in established market economies. The proportion of expected life span at birth lived with disability adjusted for severity, varies from about 8% in established market economies to 15% in sub-Saharan Africa, with little difference between men and women. In high-income regions, nearly 90% of expected disability is due to non-communicable diseases and most of the remainder to injuries. In poorer regions, almost half of expected disability is due to communicable diseases and injuries. INTERPRETATION The higher proportion of lifespan spent disabled in high-mortality populations is consistent with the compression of morbidity hypothesis. The threshold definition of disability used substantially affects the results of DFLE, DALE, which incorporates severity weights for disabilities, is a useful summary measure of the burden of disability and mortality.
Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. BACKGROUND Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an alpha-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations. METHODS Linkage analysis of three DNA markers at different distances from the alpha-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the alpha-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp alpha-adducin allele. FINDINGS Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9.1%, 6.5%, and 4.7%) and the significance level for linkage (p = 0.0006, p = 0.0119, and p = 0.0211) both decreased with increasing distance from the alpha-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p = 0.0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15.9 [SE 2.0] vs 7.4 [1.3] mm Hg; p = 0.001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14.7 [2.2] vs 6.8 [1.4] mm Hg; p = 0.002). INTERPRETATION Our findings of significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that alpha-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the alpha-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.
Microchimerism and rejection in clinical transplantation. BACKGROUND Haemopoietic microchimerism has been identified in recipients of solid-organ transplants and is thought by some to be critical for the development and maintenance of immunological tolerance. The aim of this study was to correlate prospectively the persistence of donor cells with clinical outcome in recipients of kidney, kidney and pancreas, and liver transplants. METHODS Persistence of donor cells in recipient peripheral blood was assessed at 3 days, and at 1, 3, 6, and 12 months after transplantation by a two-stage nested PCR technique to detect donor MHC HLA DR gene specifically. A pretransplant blood sample was collected from each patient to serve as an individual negative control. Seven liver, six kidney and pancreas, and 17 kidney patients were enrolled. 12 of the 17 kidney patients and all of the kidney and pancreas, and liver recipients were suitable for analysis. Exact matches for donors and recipients at the HLA DR loci (n = 1) or inability to obain primer pair specificity among similar HLA DR types (n = 4), meant that we were unable to analyse five patients. FINDINGS Donor DNA was detected in 20 (80%) of 25, ten (40%) of 25, seven (30%) of 23, five (22%) of 23, and six (32%) of 19 recipients at 3 days, and 1, 3, 6 and 12 months post-transplant, respectively. Within individuals, the detection of donor DNA varied over time; only two patients had detectable donor DNA at all times. Analysis of the whole group of transplant patients showed a similar frequency and severity of rejection episodes in patients with and without microchimerism as defined by detectable donor DR genes. INTERPRETATION These data suggest that a significant percentage of the recipients had persistent donor class II DNA in the peripheral circulation for at least 1 year after transplantation. We showed that a pretransplant blood sample is critical to avoid a false-positive result, and suggest that detectable chimerism may vary over time in individual patients. Therefore, analysis of microchimerism with a single, post-transplant analysis may not help in making clinical decisions for individual patients.
An early marker for neurological deficits after perinatal brain lesions. BACKGROUND In normal awake infants, fidgety movements are seen from the age of 6 weeks to 20 weeks. The aim of the study was to test the predictive value of absent or abnormal spontaneous movements in young infants for the later development of neurological deficits. METHODS In a collaborative study involving five hospitals we collected data on the normal and abnormal quality of fidgety movements of 130 infants and compared it with assessments of neurological development done longitudinally until the age of 2 years. On the basis of ultrasound scans infants were classified as at low-risk or at high-risk of neurological deficits. Infants were videoed for 1 h every week from birth to discharge and then for 15 min every 3 to 4 weeks; quality of general movements was assessed. Repeated neurological assessments were also done until 24 months of corrected age. FINDINGS 67 (96%) of 70 infants with normal fidgety movements had a normal neurological outcome. Abnormal quality or total absence of fidgety movements was followed by neurological abnormalities in 57 (95%) of the 60 infants (49 had cerebral palsy and eight had developmental retardation or minor neurological signs). Specificity and sensitivity of fidgety movement assessment were higher (96% and 95%, respectively) than of ultrasound imaging of the infants' brain (83% and 80%, respectively). INTERPRETATION Our technique of assessing spontaneous motor activity can identify and distinguish between those infants who require early intervention for neurological abnormalities and those who do not. Our technique is simple, non-intrusive, reliable, quick, and can be done on very young infants.
Occupational reproductive hazards. Although the causes of many reproductive disorders remain unknown, scientific evidence is accumulating to implicate occupational agents in fertility disorders and adverse pregnancy outcomes. Effective assessment and management of workers exposed to reproductive hazards often involves a team-based approach. By identifying potential reproductive hazards, making appropriate referrals, and by educating and advocating for patients, clinicians can play an important part in safeguarding the reproductive health of workers.
Neocytolysis: physiological down-regulator of red-cell mass. It is usually considered that red-cell mass is controlled by erythropoietin-driven bone marrow red-cell production, and no physiological mechanisms can shorten survival of circulating red cells. In adapting to acute plethora in microgravity, astronauts' red-cell mass falls too rapidly to be explained by diminished red-cell production. Ferrokinetics show no early decline in erythropolesis, but red cells radiolabelled 12 days before launch survive normally. Selective destruction of the youngest circulating red cells-a process we call neocytolysis-is the only plausible explanation. A fall in erythropoietin below a threshold is likely to initiate neocytolysis, probably by influencing surface-adhesion molecules. Recognition of neocytolysis will require re-examination of the pathophysiology and treatment of several blood disorders, including the anaemia of renal disease.
Biology and genetics of human neuroblastomas. PURPOSE Neuroblastomas have a variety of clinical behaviors, from spontaneous regression or differentiation to early metastasis and death. We have examined a variety of genetic variables that might explain or predict the clinical behavior. PATIENTS AND METHODS We have studied DNA or RNA from a number of children enrolled in clinical trials with the major pediatric oncology cooperative groups. RESULTS We propose that neuroblastomas may be classified into three subsets with distinct biological features and clinical behavior. The first subset consists of those tumors with hyperdiploid modal karyotypes and high TRK-A expression. Patients with these tumors are usually infants with low stages of disease and a very favorable outcome. The second group consists of tumors that have a near-diploid DNA content, usually with 1p allelic loss or other structural changes, but they lack MYCN amplification, and TRK-A expression is low. The patients are generally older, with advanced stages of disease and an intermediate outcome. The third group is characterized by tumors with MYCN amplification, 1p allelic loss, and low or absent TRK-A expression. The patients are 1-5 years of age and have advanced stages of disease, rapid tumor progression, and a very poor prognosis. Current evidence suggests the tumor types are genetically distinct, and one type seldom if ever evolves into another. CONCLUSIONS Identification of these genetic and clinical subsets permits a more accurate prediction of outcome. This, in turn, allows more appropriate selection of therapeutic intensity to minimize side effects in those with a favorable outcome but optimize the chance of cure in those requiring aggressive treatment.
One course versus two courses of antithymocyte globulin for the treatment of severe aplastic anemia in children. PURPOSE The aim of the therapeutic trials was to optimize the treatment of severe aplastic anemia (SAA) and moderate aplastic anemia in children who lack a suitable bone marrow donor, using immunosuppressive therapy in the most effective combination and dose. PATIENTS AND METHODS Two sequential therapeutic trials for the treatment of severe and moderate aplastic anemia in children were conducted by 10 institutions. The treatment protocols included antithymocyte globulin (ATG), prednisone, and cyclosporine A (CSA); patients entered on the first protocol, 0190 (ATG X 2), were given two courses of ATG, and those enrolled on the second protocol, 0190B (ATG X 1), were given only one course of ATG. Ten patients were evaluable on ATG X 2. All patients had SAA; three had hepatitis-induced severe aplastic anemia (HI-SAA). Twelve patients were evaluable on ATG X 1; all had SAA, one of whom had HI-SAA. RESULTS Seven of 10 patients on ATG X 2 responded, and eight of 12 patients treated on ATG X 1 responded. CONCLUSION Treatment with immunosuppressive therapy using ATG, CSA, and prednisone was very well tolerated. The response rates in both protocols were similar, and results compare favorably with those of previous therapeutic trials, suggesting that a second course of ATG is not necessary.
Immunosuppressive therapy: a potential alternative to bone marrow transplantation as initial therapy for acquired severe aplastic anemia in childhood? PURPOSE Currently bone marrow transplantation (BMT) with an HLA-identical sibling donor is recommended as optimal therapy for children with acquired severe aplastic anemia (SAA). Immunosuppressive therapy (IST) has become a very successful initial therapy for SAA in children lacking a related bone marrow donor. We wished to evaluate whether current IST regimens may be as efficacious as BMT. PATIENTS AND METHODS A retrospective review identified children treated for SAA over a 12-year period. Children with a related donor received a BMT. Children lacking a donor were treated with IST followed by a "rescue" BMT if IST was ineffective. IST consisted of anti-thymocyte globulin and steroid +/- cyclosporine A. Transfusion independence and survival rates were compared between the two groups. RESULTS Twenty-seven children were identified. Nine received a related BMT; seven of these survive and are transfusion independent (median follow-up 54 months). Sixteen of 18 patients who received IST are transfusion-independent survivors, including three of four patients who received a rescue BMT (median follow-up 33.5 months). Actuarial survival is 75% (95% CI = 45%, 105%) and 92% (95% CI = 78%, 107%) for the BMT and IST groups, respectively (p = 0.15). Severe toxicity was not experienced by any patient as a result of IST. CONCLUSIONS Equivalent rates of transfusion independence and survival were experienced by patients receiving BMT and IST. We propose that a prospective trial be undertaken to evaluate IST as initial therapy in all children with SAA, to be followed by BMT if there is inadequate response.
Steroid-refractory cutaneous graft-versus-host disease after transplantation of haploidentical parental CD34+ cells in children with Down's syndrome and recurrent acute leukemia. PURPOSE This study evaluated the feasibility of performing haploidentical CD34+ selected transplants for children with Down's syndrome (DS) and recurrent leukemia. PATIENTS AND METHODS Within a cohort of 15 children, two patients had DS. Transplantation of CD34+ cells from haploidentical parents was performed after the children were conditioned with fractionated total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and a short course of methotrexate. RESULTS The preparative regimen was well tolerated, and engraftment of polymorphonuclear cells and platelets took place promptly (by day 20) in both patients with DS. However, both patients with DS experienced severe grade IV GVHD that was limited to the skin and was refractory to salvage with high-dose methylprednisolone therapy. In one patient, GVHD responded to second-line salvage therapy with ATG, but the patient died on day 234 from leukemic relapse. The second patient had GVHD that did not respond to ATG and died of multisystem organ failure and refractory GVHD on day 44. Two of two DS patients had steroid refractory severe acute GVHD of the skin, while only one of 11 evaluated and identically treated non-DS patients had severe GVHD (p < 0.05). CONCLUSION These observations in patients who underwent mismatched bone marrow transplantation suggests that patients with DS have an increased risk of severe acute GVHD of the skin in this context.
Neurodevelopmental side effects of bone marrow transplantation: two case illustrations of identical twins. PURPOSE Bone marrow transplantation (BMT), particularly preparative regimens, may have a significant impact on the developing nervous system. However, the effects of various BMT regimens on children's growth and development have been poorly documented to date. Twins serve as ideal subjects to study the impact of medical treatment, since they control for nonmedical (genetic and environmental) influences upon neurodevelopmental outcome. PATIENTS AND METHODS Two cases of monozygotic twins are presented to illustrate the impact of BMT regimens. Growth data and neurocognitive testing are presented for each patient (affected twin) in relation to his/her syngeneic BMT donor and case control (control twin). RESULTS These two cases illustrate the growth retardation that has been reported after BMT. However, changes in growth trends across twins appear to have begun after diagnosis, rather than after BMT per se. Comparisons of cognitive test results within these twin pairs illustrate learning problems in the affected twins. However, there was also evidence of learning anomalies in the unaffected twins. CONCLUSIONS Results underscore the importance of longitudinal assessment in order to identify the side effects of BMT regimens for children. Differences across the two cases highlight important research questions regarding variables associated with patients, disease, and treatment (e.g., age at the time of BMT, previous neurotoxic treatments, underlying disease) and emphasize the importance of controls in this line of research.
DDAVP therapy controls bleeding in Ehlers-Danlos syndrome. PURPOSE Patients with Ehlers-Danlos syndrome (EDS), especially types IV, VI, and VIII, are at increased risk of bleeding, and most do not have specific hemostatic deficiencies that would be amenable to replacement therapy. We have investigated the ability of DDAVP (desmopressin acetate) to control bleeding in EDS. PATIENTS AND METHODS Two children with EDS, types VIII and VI, presented with hemorrhagic symptoms and scheduled surgical procedures. Ivy bleeding times (BTs) were measured before and after intravenous (i.v.) DDAVP challenge, and i.v. DDAVP was used prophylactically for their procedures. Laboratory testing was performed to rule out other hemostatic disorders. RESULTS Both patients had prolonged BTs that corrected following i.v. DDAVP therapy; all other laboratory values were normal. Both patients had excellent clinical hemostasis with surgery, and one has continued to use intranasal DDAVP to control epistaxis and gingival bleeding. CONCLUSIONS The bleeding time in both patients was corrected with DDAVP, and the patients did not have any postoperative bleeding. DDAVP should be considered in other patients who have EDS with bleeding tendencies.