xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06028789</url>
    </required_header>
    <id_info>
      <org_study_id>202202 P02</org_study_id>
      <nct_id>NCT06028789</nct_id>
    </id_info>
    <brief_title>AOrtic Surgery: Systemic Inflammatory Response Versus Sepsis</brief_title>
    <acronym>AOSIS</acronym>
    <official_title>Differential Diagnosis of Sterile Systemic Inflammation and Sepsis in Patients Undergoing Thoracic Aortic Surgery</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University Hospital Hradec Kralove</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>American Association for Thoracic Surgery</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University Hospital Hradec Kralove</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of the prospective observational study is to evaluate the immunological background&#xD;
        of inflammatory response often seen after open thoracic aortic surgery. Patients scheduled&#xD;
        for this type of procedure will undergo a series of blood testing (preoperatively, and&#xD;
        several times postoperatively). The blood samples will be used for a wide scale of&#xD;
        immunological tests to better evaluate potential differential markers against infection. A&#xD;
        control group will include patients with active infective endocarditis (preoperatively).&#xD;
  &#xD;
        The main question is if there is a biomarker able to determine a difference between sterile&#xD;
        systemic inflammation and infection after thoracic aortic surgery. The second question is if&#xD;
        there is a difference in dynamics of evaluated biomarkers between sterile postoperative&#xD;
        inflammation and active endocarditis.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        It has been observed in daily clinical practice that patients after thoracic aortic&#xD;
        replacement (of any extent, of any reason) often develop a set of specific symptoms. Those&#xD;
        include fever, weakness and prolonged rise of standard laboratory parameters of inflammation&#xD;
        (CRP and leucocyte level) in absence of infection. Those symptoms may, but do not have to,&#xD;
        coincide with typical signs of postcardiotomy syndrome, rather characteristic by pericardial&#xD;
        / pleural effusion and indifferent chest pain. They rather resemble a so called&#xD;
        &quot;postimplantation&quot; syndrome, described after endovascular aortic repair. As a reaction to&#xD;
        foreign vascular graft material, pro-inflammatory cytokines are being released, thus leading&#xD;
        to flu-like symptoms in absence of true infection. Those occur in the short-term&#xD;
        postoperatively, usually in the first 2 weeks after the surgery.&#xD;
  &#xD;
        Patients after thoracic aortic surgery represent a high-risk patient cohort vulnerable to&#xD;
        infections of any kind, mostly respiratory, urinary, wound infections, and, last but not&#xD;
        least, early valve endocarditis / endoaortitis being the most feared of them. While&#xD;
        clinicians (and patients) are often afraid of the abovementioned complications, the patients&#xD;
        are forced to undergo complex diagnostic process including repeated echocardiography,&#xD;
        collection of microbiology cultures and blood samples, chest computer tomography imaging with&#xD;
        extensive radiation burden. The prolonged broad-spectrum empiric antibiotic treatment is&#xD;
        often in place together with prolonged hospital stay and limited patient satisfaction. The&#xD;
        question of starting the immunosuppressive treatment is often weighed against the potential&#xD;
        aggravation of infection with eventual fatal consequences.&#xD;
  &#xD;
        In absence of a specific biomarker to distinguish between the sterile systemic inflammation&#xD;
        and infection, the clinicians must rely on complex evaluation of patient symptoms, clinical&#xD;
        examination, imaging modalities, standard laboratory measures of inflammation and&#xD;
        microbiology cultures (with some delay). However, in the era of molecular biology and&#xD;
        extensive progress in immunology research, there has been a long row of potential biomarkers&#xD;
        able to specify the etiology of inflammatory process significantly sooner.&#xD;
  &#xD;
        The potential biomarkers of inflammation suitable for this issue are mentioned in detail&#xD;
        further. Conventional biomarkers include CRP, leukocyte count, differential blood count,&#xD;
        recently also procalcitonin (PCT), tumor necrosis factor-α (TNF- α) and interleukin-6 (IL-6).&#xD;
        Hematology tests have reported novel early markers of sepsis, e.g. mean neutrophil volume or&#xD;
        neutrophil-to-lymphocyte ratio. Novel serology markers (mostly assessed by ELISA) include&#xD;
        soluble triggering receptor expressed on myeloid cell-1 (sTREM-1), presepsin, serum&#xD;
        amyloid-A, pentraxin 3, hemoxygenase-1 (HO-1), soluble CD64 (sCD64), soluble CD163 (sCD163),&#xD;
        high mobility group box-1 (HMGB-1), lipopolysaccharide-binding protein (LBP) and others.&#xD;
        Newly, the molecules expressed on the surface of circulating blood cells may be examined&#xD;
        using flow cytometry: CD64 on polymorphonuclears (PMN CD64 index) or monocytes, CD163, CD167,&#xD;
        HLA-DR etc. Cell function assays which test ability of blood cells to respond to microbial&#xD;
        stimuli (represented by LPS, flagellin, etc.) may reveal changes in soluble biomarkers, such&#xD;
        as IL-18 or IFN-γ that reflect nature of inflammation in patients.&#xD;
  &#xD;
        Recently, several scoring systems have emerged combining panels of various biomarkers. There&#xD;
        is a promising evidence for a composite of serum and cell-expressed parameters, called&#xD;
        &quot;Bioscore&quot;, including procalcitonin, sTREM-1 and PMN CD64 index. A composite of 5&#xD;
        hematological parameters has proven to be a reliable marker of early sepsis, being called&#xD;
        intensive care infection score (ICIS). Another scoring systems have been developed by group&#xD;
        of Kofoed et al. Nevertheless, most of these scoring systems have been tested in the settings&#xD;
        of unstable patients in the intensive care unit. The issue of inflammatory response described&#xD;
        above is mostly a matter of stable patients in the standard ward who develop signs of&#xD;
        undetermined inflammation. Eventual diagnostic modalities in these settings have been only&#xD;
        scarcely evaluated before. The topic of inflammatory response after aortic surgery (IRAS) has&#xD;
        not been studied in the literature yet.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">April 1, 2022</start_date>
    <completion_date type="Anticipated">September 30, 2023</completion_date>
    <primary_completion_date type="Anticipated">September 30, 2023</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Case-Control</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Serum concentration of sCD64</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute value or dynamics of serum concentrations of sCD64 between the study groups to help distinguish between the specified clinical syndromes.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Expression of CD64 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD64 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Cell function assay of INF-γ</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the outcomes of cell function assay of INF-γ between the study groups to distinguish between the specified clinical syndromes.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Serum concentration of sTREM-1</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute value or dynamics of serum concentrations of sTREM-1 between the study groups to help distinguish between the specified clinical syndromes.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum concentration of calprotectin</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute value or dynamics of serum concentrations of calprotectin between the study groups to help distinguish between the specified clinical syndromes.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum concentration of pentraxin 3</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute value or dynamics of serum concentrations of pentraxin 3 between the study groups to help distinguish between the specified clinical syndromes.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of HLA-DR on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of HLA-DR on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of CD-14 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD-14 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of CD-16 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD-16 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of CD-40 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD-40 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of CD-45 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD-45 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Expression of CD-163 on granulocytes</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A statistically significant difference in absolute values or dynamics of the expression of CD-163 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cell function assay of IL-18</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the outcomes of cell function assay of IL-18 between the study groups to distinguish between the specified clinical syndromes.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ICIS score</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of ICIS (intensive care infection score) score value between the study groups.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Serum concentration of C-Reactive protein</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of C-Reactive protein serum concentrations value between the study groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>Serum concentration of procalcitonin</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of procalcitonin serum concentrations value between the study groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>Serum concentration of IL-6</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of IL-6 serum concentrations value between the study groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>Leukocyte blood count</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of leukocyte blood count values between the study groups. Differential blood count will also be included in analysis.</description>
    </other_outcome>
    <other_outcome>
      <measure>Neutrophil-to-lymphocyte ratio</measure>
      <time_frame>After completion of the study - until the end of 2023</time_frame>
      <description>A significant difference in the absolute values or dynamics of neutrophil-to-lymphocyte values between the study groups.</description>
    </other_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">60</enrollment>
    <condition>Systemic Inflammatory Response Syndrome</condition>
    <condition>Infections</condition>
    <condition>Thoracic Aortic Aneurysm</condition>
    <condition>Aortic Diseases</condition>
    <condition>Immunological Abnormality</condition>
    <arm_group>
      <arm_group_label>Study group</arm_group_label>
      <description>Patients undergoing elective thoracic aortic surgery.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control group</arm_group_label>
      <description>Patients admitted to our institution with active infectious endocarditis.</description>
    </arm_group>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Blood sample test</intervention_name>
      <description>The following groups of biomarkers will be examined:&#xD;
  standard panel of inflammation markers: CRP, PCT, IL-6, Leukocyte count, differential blood count&#xD;
  microbiology cultures according to the clinical status&#xD;
  serum biomarkers: sCD64, sTREM-1, calprotectin, pentraxin 3&#xD;
  flow cytometry: HLA-DR, CD14, CD16, CD40, CD45, CD64, CD163 expression on granulocytes and monocytes&#xD;
  cell function assay: IL-18 and IFN-γ&#xD;
  hematology: ICIS, Neutrophil-to-lymphocyte ratio - examined together with conventional hematological parameters.&#xD;
  The schedule of blood sample taking will be as follows:&#xD;
  A. the study group: preoperatively (T-1), 1st postoperative day (T1), 3rd postoperative day (T2), 7th postoperative day (T3), 10th postoperative day (T4)&#xD;
  B. the control group: at admission or the next day (T1), 3rd day of hospital stay (T2), 7th day of hospital stay (T3), 10th day of hospital stay (T4)</description>
      <arm_group_label>Control group</arm_group_label>
      <arm_group_label>Study group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Thoracic Aortic Surgery</intervention_name>
      <description>Scheduled surgical intervention, i.e. replacement of pre-specified part of thoracic aorta by a vascular prosthesis.</description>
      <arm_group_label>Study group</arm_group_label>
    </intervention>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Blood samples&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          Study group is defined as patients scheduled for elective replacement of thoracic aorta of&#xD;
          any extent by artificial vascular graft, including Bentall procedure,valve-sparing root&#xD;
          replacement, supracoronary aortic replacement, also Ross procedure with supracoronary&#xD;
          aortic replacement, hemiarch and total aortic arch replacement.&#xD;
  &#xD;
          Control group is defined as patients admitted to our institution with active infectious&#xD;
          endocarditis.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria (for study group):&#xD;
  &#xD;
            -  patient scheduled for elective replacement of thoracic aorta of any extent by&#xD;
               artificial vascular graft, including Bentall procedure, Yacoub procedure,&#xD;
               supracoronary aortic replacement, also Ross procedure with supracoronary aortic&#xD;
               replacement, hemiarch and total aortic arch replacement&#xD;
  &#xD;
            -  signature of informed patient consent&#xD;
  &#xD;
          Exclusion Criteria (for study group):&#xD;
  &#xD;
            -  active endocarditis or other infection&#xD;
  &#xD;
            -  unstable preoperative condition&#xD;
  &#xD;
          Inclusion Criteria (for control group):&#xD;
  &#xD;
            -  patient with active infectious endocarditis&#xD;
  &#xD;
            -  signature of informed patient consent&#xD;
  &#xD;
          Exclusion Criteria (for control group):&#xD;
  &#xD;
            -  more than 5 days since diagnosis&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>85 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Jan Vojacek, Prof. MD</last_name>
      <role>Study Chair</role>
      <affiliation>University Hospital Hradec Kralove</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Jan Gofus, MD, PhD</last_name>
      <phone>+420 722 301 527</phone>
      <email>jan.gofus@gmail.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Andrej Myjavec, MD</last_name>
      <email>andrej.myjavec@fnhk.cz</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University Hospital Hradec Králové</name>
        <address>
          <city>Hradec Králové</city>
          <state>Královehradecký Kraj</state>
          <zip>500 02</zip>
          <country>Czechia</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Ján Gofus, MD, PhD</last_name>
        <phone>+420495832422</phone>
        <email>jan.gofus@fnhk.cz</email>
      </contact>
      <investigator>
        <last_name>Andrej Myjavec, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Jan Vojacek, Prof, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Pavla Paterova, MD, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Radek Pelouch, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Martina Kolackova, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Ondrej Soucek, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Ilona Sejkorova, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Czechia</country>
    </location_countries>
    <reference>
      <citation>Gabaldo K, Sutlic Z, Miskovic D, Knezevic Pravecek M, Prvulovic D, Vujeva B, Cvitkusic Lukenda K, Hadzibegovic I. Postpericardiotomy syndrome incidence, diagnostic and treatment strategies: experience AT two collaborative centers. Acta Clin Croat. 2019 Mar;58(1):57-62. doi: 10.20471/acc.2019.58.01.08.</citation>
      <PMID>31363326</PMID>
    </reference>
    <reference>
      <citation>Daye D, Walker TG. Complications of endovascular aneurysm repair of the thoracic and abdominal aorta: evaluation and management. Cardiovasc Diagn Ther. 2018 Apr;8(Suppl 1):S138-S156. doi: 10.21037/cdt.2017.09.17.</citation>
      <PMID>29850426</PMID>
    </reference>
    <reference>
      <citation>Raveendran AV, Kumar A, Gangadharan S. Biomarkers and newer laboratory investigations in the diagnosis of sepsis. J R Coll Physicians Edinb. 2019 Sep;49(3):207-216. doi: 10.4997/JRCPE.2019.308.</citation>
      <PMID>31497788</PMID>
    </reference>
    <reference>
      <citation>Gibot S, Bene MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, Bollaert PE, Faure G, Charles PE. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012 Jul 1;186(1):65-71. doi: 10.1164/rccm.201201-0037OC. Epub 2012 Apr 26.</citation>
      <PMID>22538802</PMID>
    </reference>
    <reference>
      <citation>Nierhaus A, Linssen J, Wichmann D, Braune S, Kluge S. Use of a weighted, automated analysis of the differential blood count to differentiate sepsis from non-infectious systemic inflammation: the intensive care infection score (ICIS). Inflamm Allergy Drug Targets. 2012 Apr;11(2):109-15. doi: 10.2174/187152812800392841.</citation>
      <PMID>22280231</PMID>
    </reference>
    <reference>
      <citation>Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care. 2007;11(2):R38. doi: 10.1186/cc5723.</citation>
      <PMID>17362525</PMID>
    </reference>
    <reference>
      <citation>Djebara S, Biston P, Fosse E, Daper A, Joris M, Boudjeltia KZ, Lelubre C, Cauchie P, Piagnerelli M. Time Course of CD64, a Leukocyte Activation Marker, During Cardiopulmonary Bypass Surgery. Shock. 2017 Feb;47(2):158-164. doi: 10.1097/SHK.0000000000000751.</citation>
      <PMID>27648690</PMID>
    </reference>
    <reference>
      <citation>Kolackova M, Kudlova M, Kunes P, Lonsky V, Mandak J, Andrys C, Jankovicova K, Krejsek J. Early expression of FcgammaRI (CD64) on monocytes of cardiac surgical patients and higher density of monocyte anti-inflammatory scavenger CD163 receptor in &quot;on-pump&quot; patients. Mediators Inflamm. 2008;2008:235461. doi: 10.1155/2008/235461.</citation>
      <PMID>18320015</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>May 22, 2023</study_first_submitted>
    <study_first_submitted_qc>August 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 8, 2023</study_first_posted>
    <last_update_submitted>August 31, 2023</last_update_submitted>
    <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>systemic inflammatory response syndrome</keyword>
    <keyword>infection</keyword>
    <keyword>thoracic aortic surgery</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Aneurysm</mesh_term>
      <mesh_term>Aortic Aneurysm</mesh_term>
      <mesh_term>Aortic Aneurysm, Thoracic</mesh_term>
      <mesh_term>Aortic Diseases</mesh_term>
      <mesh_term>Systemic Inflammatory Response Syndrome</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06028789
  org study id: 202202 P02
  nct id: NCT06028789
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of the prospective observational study is to evaluate the immunological background
        of inflammatory response often seen after open thoracic aortic surgery. Patients scheduled
        for this type of procedure will undergo a series of blood testing (preoperatively, and
        several times postoperatively). The blood samples will be used for a wide scale of
        immunological tests to better evaluate potential differential markers against infection. A
        control group will include patients with active infective endocarditis (preoperatively).
  
        The main question is if there is a biomarker able to determine a difference between sterile
        systemic inflammation and infection after thoracic aortic surgery. The second question is if
        there is a difference in dynamics of evaluated biomarkers between sterile postoperative
        inflammation and active endocarditis.
  It has been observed in daily clinical practice that patients after thoracic aortic
        replacement (of any extent, of any reason) often develop a set of specific symptoms. Those
        include fever, weakness and prolonged rise of standard laboratory parameters of inflammation
        (CRP and leucocyte level) in absence of infection. Those symptoms may, but do not have to,
        coincide with typical signs of postcardiotomy syndrome, rather characteristic by pericardial
        / pleural effusion and indifferent chest pain. They rather resemble a so called
        "postimplantation" syndrome, described after endovascular aortic repair. As a reaction to
        foreign vascular graft material, pro-inflammatory cytokines are being released, thus leading
        to flu-like symptoms in absence of true infection. Those occur in the short-term
        postoperatively, usually in the first 2 weeks after the surgery.
  
        Patients after thoracic aortic surgery represent a high-risk patient cohort vulnerable to
        infections of any kind, mostly respiratory, urinary, wound infections, and, last but not
        least, early valve endocarditis / endoaortitis being the most feared of them. While
        clinicians (and patients) are often afraid of the abovementioned complications, the patients
        are forced to undergo complex diagnostic process including repeated echocardiography,
        collection of microbiology cultures and blood samples, chest computer tomography imaging with
        extensive radiation burden. The prolonged broad-spectrum empiric antibiotic treatment is
        often in place together with prolonged hospital stay and limited patient satisfaction. The
        question of starting the immunosuppressive treatment is often weighed against the potential
        aggravation of infection with eventual fatal consequences.
  
        In absence of a specific biomarker to distinguish between the sterile systemic inflammation
        and infection, the clinicians must rely on complex evaluation of patient symptoms, clinical
        examination, imaging modalities, standard laboratory measures of inflammation and
        microbiology cultures (with some delay). However, in the era of molecular biology and
        extensive progress in immunology research, there has been a long row of potential biomarkers
        able to specify the etiology of inflammatory process significantly sooner.
  
        The potential biomarkers of inflammation suitable for this issue are mentioned in detail
        further. Conventional biomarkers include CRP, leukocyte count, differential blood count,
        recently also procalcitonin (PCT), tumor necrosis factor-α (TNF- α) and interleukin-6 (IL-6).
        Hematology tests have reported novel early markers of sepsis, e.g. mean neutrophil volume or
        neutrophil-to-lymphocyte ratio. Novel serology markers (mostly assessed by ELISA) include
        soluble triggering receptor expressed on myeloid cell-1 (sTREM-1), presepsin, serum
        amyloid-A, pentraxin 3, hemoxygenase-1 (HO-1), soluble CD64 (sCD64), soluble CD163 (sCD163),
        high mobility group box-1 (HMGB-1), lipopolysaccharide-binding protein (LBP) and others.
        Newly, the molecules expressed on the surface of circulating blood cells may be examined
        using flow cytometry: CD64 on polymorphonuclears (PMN CD64 index) or monocytes, CD163, CD167,
        HLA-DR etc. Cell function assays which test ability of blood cells to respond to microbial
        stimuli (represented by LPS, flagellin, etc.) may reveal changes in soluble biomarkers, such
        as IL-18 or IFN-γ that reflect nature of inflammation in patients.
  
        Recently, several scoring systems have emerged combining panels of various biomarkers. There
        is a promising evidence for a composite of serum and cell-expressed parameters, called
        "Bioscore", including procalcitonin, sTREM-1 and PMN CD64 index. A composite of 5
        hematological parameters has proven to be a reliable marker of early sepsis, being called
        intensive care infection score (ICIS). Another scoring systems have been developed by group
        of Kofoed et al. Nevertheless, most of these scoring systems have been tested in the settings
        of unstable patients in the intensive care unit. The issue of inflammatory response described
        above is mostly a matter of stable patients in the standard ward who develop signs of
        undetermined inflammation. Eventual diagnostic modalities in these settings have been only
        scarcely evaluated before. The topic of inflammatory response after aortic surgery (IRAS) has
        not been studied in the literature yet.
  observational model: Case-Control
  time perspective: Prospective
  measure: Serum concentration of sCD64
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute value or dynamics of serum concentrations of sCD64 between the study groups to help distinguish between the specified clinical syndromes.
  measure: Expression of CD64 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD64 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Cell function assay of INF-γ
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the outcomes of cell function assay of INF-γ between the study groups to distinguish between the specified clinical syndromes.
  measure: Serum concentration of sTREM-1
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute value or dynamics of serum concentrations of sTREM-1 between the study groups to help distinguish between the specified clinical syndromes.
  measure: Serum concentration of calprotectin
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute value or dynamics of serum concentrations of calprotectin between the study groups to help distinguish between the specified clinical syndromes.
  measure: Serum concentration of pentraxin 3
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute value or dynamics of serum concentrations of pentraxin 3 between the study groups to help distinguish between the specified clinical syndromes.
  measure: Expression of HLA-DR on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of HLA-DR on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Expression of CD-14 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD-14 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Expression of CD-16 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD-16 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Expression of CD-40 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD-40 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Expression of CD-45 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD-45 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Expression of CD-163 on granulocytes
  time frame: After completion of the study - until the end of 2023
  description: A statistically significant difference in absolute values or dynamics of the expression of CD-163 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.
  measure: Cell function assay of IL-18
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the outcomes of cell function assay of IL-18 between the study groups to distinguish between the specified clinical syndromes.
  measure: ICIS score
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of ICIS (intensive care infection score) score value between the study groups.
  measure: Serum concentration of C-Reactive protein
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of C-Reactive protein serum concentrations value between the study groups.
  measure: Serum concentration of procalcitonin
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of procalcitonin serum concentrations value between the study groups.
  measure: Serum concentration of IL-6
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of IL-6 serum concentrations value between the study groups.
  measure: Leukocyte blood count
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of leukocyte blood count values between the study groups. Differential blood count will also be included in analysis.
  measure: Neutrophil-to-lymphocyte ratio
  time frame: After completion of the study - until the end of 2023
  description: A significant difference in the absolute values or dynamics of neutrophil-to-lymphocyte values between the study groups.
  arm group label: Study group
  description: Patients undergoing elective thoracic aortic surgery.
  arm group label: Control group
  description: Patients admitted to our institution with active infectious endocarditis.
  intervention type: Diagnostic Test
  intervention name: Blood sample test
  description: The following groups of biomarkers will be examined:
  standard panel of inflammation markers: CRP, PCT, IL-6, Leukocyte count, differential blood count
  microbiology cultures according to the clinical status
  serum biomarkers: sCD64, sTREM-1, calprotectin, pentraxin 3
  flow cytometry: HLA-DR, CD14, CD16, CD40, CD45, CD64, CD163 expression on granulocytes and monocytes
  cell function assay: IL-18 and IFN-γ
  hematology: ICIS, Neutrophil-to-lymphocyte ratio - examined together with conventional hematological parameters.
  The schedule of blood sample taking will be as follows:
  A. the study group: preoperatively (T-1), 1st postoperative day (T1), 3rd postoperative day (T2), 7th postoperative day (T3), 10th postoperative day (T4)
  B. the control group: at admission or the next day (T1), 3rd day of hospital stay (T2), 7th day of hospital stay (T3), 10th day of hospital stay (T4)
  arm group label: Control group
  arm group label: Study group
  intervention type: Procedure
  intervention name: Thoracic Aortic Surgery
  description: Scheduled surgical intervention, i.e. replacement of pre-specified part of thoracic aorta by a vascular prosthesis.
  arm group label: Study group
  Blood samples
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 85 Years
  healthy volunteers: No
  last name: Jan Vojacek, Prof. MD
  role: Study Chair
  affiliation: University Hospital Hradec Kralove
  last name: Jan Gofus, MD, PhD
  phone: +420 722 301 527
  email: jan.gofus@gmail.com
  last name: Andrej Myjavec, MD
  email: andrej.myjavec@fnhk.cz
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  country: Czechia
  citation: Gabaldo K, Sutlic Z, Miskovic D, Knezevic Pravecek M, Prvulovic D, Vujeva B, Cvitkusic Lukenda K, Hadzibegovic I. Postpericardiotomy syndrome incidence, diagnostic and treatment strategies: experience AT two collaborative centers. Acta Clin Croat. 2019 Mar;58(1):57-62. doi: 10.20471/acc.2019.58.01.08.
  PMID: 31363326
  citation: Daye D, Walker TG. Complications of endovascular aneurysm repair of the thoracic and abdominal aorta: evaluation and management. Cardiovasc Diagn Ther. 2018 Apr;8(Suppl 1):S138-S156. doi: 10.21037/cdt.2017.09.17.
  PMID: 29850426
  citation: Raveendran AV, Kumar A, Gangadharan S. Biomarkers and newer laboratory investigations in the diagnosis of sepsis. J R Coll Physicians Edinb. 2019 Sep;49(3):207-216. doi: 10.4997/JRCPE.2019.308.
  PMID: 31497788
  citation: Gibot S, Bene MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, Bollaert PE, Faure G, Charles PE. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012 Jul 1;186(1):65-71. doi: 10.1164/rccm.201201-0037OC. Epub 2012 Apr 26.
  PMID: 22538802
  citation: Nierhaus A, Linssen J, Wichmann D, Braune S, Kluge S. Use of a weighted, automated analysis of the differential blood count to differentiate sepsis from non-infectious systemic inflammation: the intensive care infection score (ICIS). Inflamm Allergy Drug Targets. 2012 Apr;11(2):109-15. doi: 10.2174/187152812800392841.
  PMID: 22280231
  citation: Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care. 2007;11(2):R38. doi: 10.1186/cc5723.
  PMID: 17362525
  citation: Djebara S, Biston P, Fosse E, Daper A, Joris M, Boudjeltia KZ, Lelubre C, Cauchie P, Piagnerelli M. Time Course of CD64, a Leukocyte Activation Marker, During Cardiopulmonary Bypass Surgery. Shock. 2017 Feb;47(2):158-164. doi: 10.1097/SHK.0000000000000751.
  PMID: 27648690
  citation: Kolackova M, Kudlova M, Kunes P, Lonsky V, Mandak J, Andrys C, Jankovicova K, Krejsek J. Early expression of FcgammaRI (CD64) on monocytes of cardiac surgical patients and higher density of monocyte anti-inflammatory scavenger CD163 receptor in "on-pump" patients. Mediators Inflamm. 2008;2008:235461. doi: 10.1155/2008/235461.
  PMID: 18320015
  responsible party type: Sponsor
  mesh term: Aneurysm
  mesh term: Aortic Aneurysm
  mesh term: Aortic Aneurysm, Thoracic
  mesh term: Aortic Diseases
  mesh term: Systemic Inflammatory Response Syndrome
  sharing ipd: No