<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/NCT03814564</url>
  </required_header>
  <id_info>
    <org_study_id>HUS/420/2018</org_study_id>
    <nct_id>NCT03814564</nct_id>
  </id_info>
  <brief_title>ASSESSment of Perfusion, Oxygen Saturation, Endothelial Function and Coagulation in Circulatory SHOCK</brief_title>
  <acronym>ASSESS-SHOCK</acronym>
  <official_title>ASSESSment of Peripheral Perfusion, Tissue Oxygen Saturation, Endothelial Function and Coagulation Disorder in Circulatory SHOCK, the ASSESS - SHOCK Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tampere University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kuopio University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medtronic</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Helsinki University Central Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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 objective of the observational cohort study is (1) to deduce whether measurements of&#xD;
      peripheral near-infrared spectroscopy (NIRS) (lower limb) associate with the development of&#xD;
      organ dysfunction as assessed by daily Sequential Orfgan Failure Score (SOFA) in the&#xD;
      Intensive Care Unit (ICU), (2)whether cerebral (frontal) tissue haemoglobin oxygen saturation&#xD;
      (StO2) values are associated with delirium in the ICU and (3) the association of frontal and&#xD;
      peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4)&#xD;
      to deduce the associations between shock, endotheliopathy, disseminated intravascular&#xD;
      coagulation (DIC) and tissue perfusion and, last, the feasibility of central and peripheral&#xD;
      NIRS monitoring in shock patients in the ICU using the Medtronic INVOS NIRS StO2 appliances.&#xD;
      In addition, the investigators target to evaluate (5) the incidence, evolution, and outcome&#xD;
      of sepsis-associated DIC, and (6) the associations between a) continuous hemodynamic data, b)&#xD;
      laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73,&#xD;
      heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests,blood&#xD;
      count d-dimer, international normalized ratio (INR), neuron specific enolase and metabolomics&#xD;
      data) (7) and study associations of singlenucleotide polymorphisms with developing organ&#xD;
      dysfunction and 90-day mortality. To compare the hemodynamic alterations of burn patients to&#xD;
      septic patients with the intention to find new ways to monitor and manage hemodynamic and&#xD;
      particularly microcirculation in burn patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Circulatory shock is a frequent condition in the intensive care unit, comprising roughly one&#xD;
      of three patients in the intensive care unit (ICU), and associated with high mortality rates.&#xD;
      Current treatment guidelines state that one of the main goals for therapeutic interventions&#xD;
      is to improve tissue perfusion to prevent subsequent organ dysfunction and death. In acute&#xD;
      critical illness, up to one fourth of the patients develop severe hemostatic aberrations and&#xD;
      coagulopathy, called disseminated intravascular coagulation (DIC), which is associated with&#xD;
      excess mortality.&#xD;
&#xD;
      Despite differences in the underlying cause, acutely critically ill patients share similar&#xD;
      features that may be driven by shock. This response, potentially escalating to&#xD;
      life-threatening conditions, is relatively homogenous. The shock induced sympatho-adrenal&#xD;
      hyperactivation may be a critical driver this endotheliopathy. If allowed to proceed&#xD;
      uncontrollably, damages to the microcirculation and organ dysfunction may follow.&#xD;
&#xD;
      Near-infrared spectroscopy (NIRS), a non-invasive method based on the principles of light&#xD;
      transmission and absorption, offers a non-invasive and continuous bedside method to assess&#xD;
      tissue haemoglobin oxygen saturation (StO2), which may serve as an indirect measure of the&#xD;
      adequacy of tissue perfusion. NIRS could potentially be used for early identification of&#xD;
      patients with tissue hypoperfusion and therefore high risk of developing organ dysfunction,&#xD;
      and may also be used for assessing frontal cerebral oxygen saturation in circulatory failure&#xD;
      and its use is well documented in general anaesthesia in many patient groups. There are some&#xD;
      data showing an association between low frontal StO2 values and delirium in the ICU. The use&#xD;
      of near-infrared spectroscopy to measure tissue oxygenation in healthy humans has been well&#xD;
      validated. However, assessing tissue oxygenation using NIRS in critically ill patients is&#xD;
      less well established. The hemodynamic and other systemic responses in burns are similar to&#xD;
      those in septic shock. However, the mechanisms behind these responses have not been compared&#xD;
      between burn and septic shock patients to our knowledge. Overall, the knowledge of&#xD;
      microcirculation and how to monitor it in burn patients is limited.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      The objective of the observational cohort study is (1) to deduce whether measurements of&#xD;
      peripheral NIRS (lower limb registered proximal of the knee cap) associate with the&#xD;
      development of organ dysfunction as assessed by daily sequential organ failure assessment&#xD;
      score (SOFA) in the ICU during days 1 to 7 in the ICU, (2) whether cerebral (frontal) StO2&#xD;
      values are associated with delirium in the ICU and (3) the association of frontal and&#xD;
      peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4)&#xD;
      to deduce the associations between shock, endotheliopathy, DIC and tissue perfusion and,&#xD;
      last, the feasibility of central and peripheral NIRS monitoring in shock patients in the ICU&#xD;
      using the INVOS tm NIRS StO2 appliances. In addition, the investigators target to evaluate&#xD;
      (5) the incidence, evolution, and outcome of sepsis-associated disseminated intravascular&#xD;
      coagulation (DIC), and (6) the associations between a) continuous hemodynamic data, b)&#xD;
      laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73,&#xD;
      heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests, blood&#xD;
      count d-dimer, INR, neuron specific enolase and metabolomics data) (7) and study associations&#xD;
      of singlenucleotide polymorphisms with developing organ dysfunction and 90-day mortality. To&#xD;
      compare the hemodynamic alterations of burn patients to septic patients with the intention to&#xD;
      find new ways to monitor and manage hemodynamic and particularly microcirculation in burn&#xD;
      patients.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Observational multi-center study&#xD;
&#xD;
      Patient population:&#xD;
&#xD;
      Patients with circulatory shock admitted to the intensive care units (ICU) fulfilling the&#xD;
      inclusion criteria.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      A minimum of 250patients with circulatory shock with NIRS registration A minimum of 400&#xD;
      patients with sepsis for evaluation of incidence of DIC and metabolomics and genetic tests&#xD;
      (genome-wide association study, GWAS)&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Patients with circulatory shock admitted to the intensive care unit (ICU) fulfilling the&#xD;
      inclusion criteria but none of the exclusion criteria within 4 hours of vasopressor&#xD;
      inititation in the ICU and signs of clinical hypoperfusion or elevated lactate levels.&#xD;
      Frontal and peripheral NIRS StO2 registration is performed using the Medtronic INVOS&#xD;
      appliances and bilateral central and peripheral sensors for 48 hours from study inclusion.&#xD;
      The INVOS NIRS registration is blinded and cannot be used for clinical decision making. The&#xD;
      frontal and peripheral StO2 registrations will be collected for further analyses. Blood&#xD;
      samples will be taken from an arterial cannula at inclusion, and at 12 h, 24h and 48h, blood&#xD;
      gas samples will be drawn every 2 hours. Data on demographic data, health status, chronic&#xD;
      illnesses and medications prior to ICU admission will be collected during the study.&#xD;
      Hemodynamic data, information on vasopressor and inotrope medication, need and use of&#xD;
      sedatives, fluid balance and specific ICU interventions during the ICU stay will also be&#xD;
      collected, as well as daily intensive care delirium screening checklist (ICDSC) and&#xD;
      SOFA-score registrations. An electronic case report form (CRF) will be used in the study. In&#xD;
      addition to clinical data, data of feasibility and reported problems considering the use of&#xD;
      NIRS StO2 registrations will be collected. Blood samples will be frozen and stored locally&#xD;
      for further processing and analyses.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in severity of Organ dysfunction during the first week in ICU (study period)</measure>
    <time_frame>At 7 days in ICU</time_frame>
    <description>Change in the total Sequential Organ Failure Assessment (SOFA) score from day 1 to day 7 in the ICU, higher SOFA score indicates greater severity of organ failure, the total SOFA score ranges from 0-24 points</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Average severity of Organ dysfunction during the first 7 days in the ICU (study period)</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Average Sequential Organ Failure Assessment (SOFA) during days 1 to day 7 in the ICU, higher SOFA score indicates greater severity of organ failure, the total SOFA score ranges from 0-24 points</description>
  </primary_outcome>
  <primary_outcome>
    <measure>New organ dysfunctions</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Number of new organ dysfunctions (new organ dysfunction defined as one of 6 SOFA subscores ≥3 points/ total 4 points, higher points indicate greater severity. Only one new organ dysfunction / each subscore can be used for calculation of total number of new organ dysfunctions in one week</description>
  </primary_outcome>
  <primary_outcome>
    <measure>90-day mortality</measure>
    <time_frame>90 days</time_frame>
    <description>Death within 90 days from ICU admission</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intensive care delirium incidence</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Delirium diagnosis in the ICU assessed by Intensive Care Delirium Scoring Checklist (ICDSC) scoring during days 1-7 defined as ICDSC score value of four points or more ( total score: 0-8 points)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive care delirium severity</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Number of Intensive Care Delirium Scoring Checklist (ICDSC) scores (assessment performed twice daily) of ≥4 points indicating presence of delirium during days 1-7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive care delirium scoring checklist aggregate and average score during first week in intensive care</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Aggregate Intensive Care Delirium Scoring Checklist (ICDSC) scores during days 1-7 . Total score ranges from 0 to 8 points. The aggregate score of all daily ICDSC measurements ( sum of all daily scores performed twice daily) will be divided by number of measurements to adjust for possible differences in number of measurements (= average ICDSC score)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>INVOS NIRS feasibility and safety questionnaire</measure>
    <time_frame>0-48 hours in Intensive Care Unit after enrolment into study</time_frame>
    <description>Feasibility of frontal and peripheral near-infrared spectroscopy tissue (NIRS) haemoglobin oxygen saturation (StO2) assessment in circulatory shock during the 48 h registration. Feasibility and registration issues are assessed using a questionnaire. Feasibility will be assessed every eight hours ( during each nurse's shift assessing feasibility and saefty on a scale from 0 to 5. Higher score indicatesmore severe feasibility issues</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Extubation</measure>
    <time_frame>28 days</time_frame>
    <description>Time to extubation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days off ventilator in 28 days</measure>
    <time_frame>28 days</time_frame>
    <description>Days off ventilator in 28 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days without vasoactive medication in 28 days</measure>
    <time_frame>28 days</time_frame>
    <description>Days without vasopressor or inotropic medication</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days without RRT in 28 days</measure>
    <time_frame>28 days</time_frame>
    <description>Days without renal replacement therapy of any kind in 28 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU length of stay</measure>
    <time_frame>90 days</time_frame>
    <description>ICU length of stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>28-day mortality</measure>
    <time_frame>28 days</time_frame>
    <description>28-day mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive dysfunction after ICU discharge</measure>
    <time_frame>6 months</time_frame>
    <description>Cognitive dysfunction assessed by a set of neuropsychological tests</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Glycocalyx and endothelial injury biomarkers such as: Syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73, heparin binding protein (HBP), angiopoietin-2, endostatin, chromogranin</measure>
    <time_frame>First week in the Intensive Care Unit after admission</time_frame>
    <description>Injury of the endothelium and glycocalyx</description>
  </other_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Circulatory Failure</condition>
  <arm_group>
    <arm_group_label>Circulatory failure / NIRS monitoring</arm_group_label>
    <description>Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring intensive care unit (ICU) care, including both surgical and medical ICU patients with circulatory shock will be included in the (near-infrared spectroscopy) NIRS-substudy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Circulatory Failure / no NIRS monitoring</arm_group_label>
    <description>Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring intensive care unit(ICU) care, including both surgical and medical ICU patients with circulatory shock will be included in the near-infrared spectroscopy (NIRS) substudy. All 400 patients will be analyzed for endotheliopathy incidence, metabolomics, genetic data (without NIRS monitoring). Representation of the study population will be ensured by enrolment of all consecutive patients at the study sites who meet the study enrollment criteria.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Gut dysbiosis, delirium and long term cognition</arm_group_label>
    <description>ASSESS-shock participants that have been treated at Meilahti ICU:s and survived the ICU admission to discharge, who are living in the Helsinki and Uusimaa Hospital District area or reasonable traveling distance to the unit for cognitive testing.&#xD;
Cognitive function testing is performed after ICU discharge and at 3 and 6 months after ICU discharge. Testing of the microbiome is performed by collecting and analyzing fecal samples at ICU admission and at 7 days after ICU admission.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>NIRS monitoring</intervention_name>
    <description>Cerebral and peripheral NIRS monitoring of brain and tissue oxygenation. Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring ICU care, including both surgical and medical ICU patients with circulatory shock will be included in the NIRS-substudy. All 400 patients will be analyzed for endotheliopathy incidence, metabolomics, genetic data Representation of the study population will be ensured by enrolment of all consecutive patients at the study sites who meet the study enrollment criteria</description>
    <arm_group_label>Circulatory failure / NIRS monitoring</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples will be collected for later analysis of metabolomics, patient-related changes&#xD;
      in biomarkers indicating endothelial and myocardial damage, coagulopathies and brain injury&#xD;
      from consenting patients (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1),&#xD;
      CD73, heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests&#xD;
      and regulators (FGF-21 and GDF-15), blood count d-dimer, INR, neuron specific enolase). A&#xD;
      separate sample for genetic analysis will be obtained that will be stored and processed&#xD;
      further only if patient/next of kin provides the separately asked consent for the genetic&#xD;
      analysis.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study population will comprise 400 critically ill patients with circulatory shock from&#xD;
        4 university hospitals during approximately 2 years between April 2019 and December 2021.&#xD;
        Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18&#xD;
        years) requiring ICU care, including both surgical and medical ICU patients with&#xD;
        circulatory shock will be included in the NIRS-substudy. All 400 patients will be analyzed&#xD;
        for endotheliopathy incidence, metabolomics, genetic data (without NIRS monitoring).&#xD;
        Representation of the study population will be ensured by enrolment of all consecutive&#xD;
        patients at the study sites who meet the study enrollment criteria.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age ≥ 18 Critically ill patients requiring Intensive Care Unit (ICU) care with circulatory&#xD;
        shock within 4 hours (≤ hours) of ICU admission or with circulatory shock developing in the&#xD;
        ICU within 24 hours from ICU admission and within 4 hours of initiation of vasopressor&#xD;
        treatment presenting with the below listed signs of for circulatory shock&#xD;
&#xD;
          1. Hypotension - need for vasopressor to achieve mean arterial pressure (MAP) ≥65 mmHg&#xD;
             after 1L of crystalloid solution&#xD;
&#xD;
             and&#xD;
&#xD;
          2. Any sign of hypoperfusion (at least one of the signs below)&#xD;
&#xD;
               -  blood lactate ≥2 mmol/L&#xD;
&#xD;
               -  mottling score ≥ 2&#xD;
&#xD;
               -  Base Excess (BE) ≤ - 5 mEq/L&#xD;
&#xD;
               -  prolonged capillary refill time ≥ 2 s&#xD;
&#xD;
               -  cool periphery beyond elbows or knees bilaterally&#xD;
&#xD;
               -  altered mentation&#xD;
&#xD;
             OR&#xD;
&#xD;
             Confirmed or suspected infection and anti-microbial treatment&#xD;
&#xD;
             OR as an independent criteria for the ASSESS-SHOCK BURNS substudy&#xD;
&#xD;
          3. Burn injury ≥30% total body surface area(TBSA), ICU admission within 12h of the&#xD;
             injury, with or without hypotension and signs of hypoperfusion within 4 hours of ICU&#xD;
             admission&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Pregnant or lactating&#xD;
&#xD;
          -  Known refusal to any clinical study or this specific study&#xD;
&#xD;
          -  Consent not obtained (according to local regulatory statements for ethical conduct of&#xD;
             research)&#xD;
&#xD;
          -  Out-of-hospital cardiac arrest (OHCA) patients&#xD;
&#xD;
          -  Terminal illness and not considered for full intensive care support&#xD;
&#xD;
          -  Planned postoperative admission&#xD;
&#xD;
          -  Postoperative intensive care after organ transplantation&#xD;
&#xD;
          -  Patients who are likely to be transferred to the ward in 24 hours&#xD;
&#xD;
          -  Defects of skin, underlying tissues or extremities preventing the use of the central&#xD;
             or peripheral NIRS probes (the first 250 enrolled patients)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Erika Wilkman, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Helsinki University Central Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Erika Wilkman, MD, PhD</last_name>
    <phone>+358504279155</phone>
    <email>erika.wilkman@hus.fi</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Johanna Hästbacka, MD, PhD</last_name>
    <phone>+35894711</phone>
    <email>johanna.hastbacka@hus.fi</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Helsinki University Hospital</name>
      <address>
        <city>Helsinki</city>
        <zip>00029</zip>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Erika Wilkman, MD, PhD</last_name>
      <phone>+358504279155</phone>
      <email>erika.wilkman@hus.fi</email>
    </contact>
    <contact_backup>
      <last_name>Johanna Hästbacka, MD, PhD</last_name>
      <phone>+358504286701</phone>
      <email>johanna.hastbacka@hus.fi</email>
    </contact_backup>
    <investigator>
      <last_name>Suvi T Vaara, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maria Heliste, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Elina Varis, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ville Pettilä, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Minna Bäcklund, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Johanna Hästbacka, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marjatta Okkonen, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Markus Skrifvars, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Laura Lindahl, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tero Varpula, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tuomas Oksanen, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Heriikka Ollila, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sanna K Koskinen, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Laura Hokkanen, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Reetta Satokari, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kuopio University Hospital</name>
      <address>
        <city>Kuopio</city>
        <zip>70029 KYS</zip>
        <country>Finland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Stepani Bendel, MD, PhD</last_name>
      <email>stepani.bendel@kuh.fi</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Tampere University Hospital</name>
      <address>
        <city>Tampere</city>
        <zip>33521 Tampere</zip>
        <country>Finland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Anne Kuitunen, MD, PhD</last_name>
      <email>anne.kuitunen@pshp.fi</email>
    </contact>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>February 27, 2023</last_update_submitted>
  <last_update_submitted_qc>February 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Helsinki University Central Hospital</investigator_affiliation>
    <investigator_full_name>Erika Wilkman, MD PhD</investigator_full_name>
    <investigator_title>Doctor, Adjunct Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT03814564
org study id: HUS/420/2018
nct id: NCT03814564
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The objective of the observational cohort study is (1) to deduce whether measurements of
      peripheral near-infrared spectroscopy (NIRS) (lower limb) associate with the development of
      organ dysfunction as assessed by daily Sequential Orfgan Failure Score (SOFA) in the
      Intensive Care Unit (ICU), (2)whether cerebral (frontal) tissue haemoglobin oxygen saturation
      (StO2) values are associated with delirium in the ICU and (3) the association of frontal and
      peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4)
      to deduce the associations between shock, endotheliopathy, disseminated intravascular
      coagulation (DIC) and tissue perfusion and, last, the feasibility of central and peripheral
      NIRS monitoring in shock patients in the ICU using the Medtronic INVOS NIRS StO2 appliances.
      In addition, the investigators target to evaluate (5) the incidence, evolution, and outcome
      of sepsis-associated DIC, and (6) the associations between a) continuous hemodynamic data, b)
      laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73,
      heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests,blood
      count d-dimer, international normalized ratio (INR), neuron specific enolase and metabolomics
      data) (7) and study associations of singlenucleotide polymorphisms with developing organ
      dysfunction and 90-day mortality. To compare the hemodynamic alterations of burn patients to
      septic patients with the intention to find new ways to monitor and manage hemodynamic and
      particularly microcirculation in burn patients.
Background:

      Circulatory shock is a frequent condition in the intensive care unit, comprising roughly one
      of three patients in the intensive care unit (ICU), and associated with high mortality rates.
      Current treatment guidelines state that one of the main goals for therapeutic interventions
      is to improve tissue perfusion to prevent subsequent organ dysfunction and death. In acute
      critical illness, up to one fourth of the patients develop severe hemostatic aberrations and
      coagulopathy, called disseminated intravascular coagulation (DIC), which is associated with
      excess mortality.

      Despite differences in the underlying cause, acutely critically ill patients share similar
      features that may be driven by shock. This response, potentially escalating to
      life-threatening conditions, is relatively homogenous. The shock induced sympatho-adrenal
      hyperactivation may be a critical driver this endotheliopathy. If allowed to proceed
      uncontrollably, damages to the microcirculation and organ dysfunction may follow.

      Near-infrared spectroscopy (NIRS), a non-invasive method based on the principles of light
      transmission and absorption, offers a non-invasive and continuous bedside method to assess
      tissue haemoglobin oxygen saturation (StO2), which may serve as an indirect measure of the
      adequacy of tissue perfusion. NIRS could potentially be used for early identification of
      patients with tissue hypoperfusion and therefore high risk of developing organ dysfunction,
      and may also be used for assessing frontal cerebral oxygen saturation in circulatory failure
      and its use is well documented in general anaesthesia in many patient groups. There are some
      data showing an association between low frontal StO2 values and delirium in the ICU. The use
      of near-infrared spectroscopy to measure tissue oxygenation in healthy humans has been well
      validated. However, assessing tissue oxygenation using NIRS in critically ill patients is
      less well established. The hemodynamic and other systemic responses in burns are similar to
      those in septic shock. However, the mechanisms behind these responses have not been compared
      between burn and septic shock patients to our knowledge. Overall, the knowledge of
      microcirculation and how to monitor it in burn patients is limited.

      Objectives:

      The objective of the observational cohort study is (1) to deduce whether measurements of
      peripheral NIRS (lower limb registered proximal of the knee cap) associate with the
      development of organ dysfunction as assessed by daily sequential organ failure assessment
      score (SOFA) in the ICU during days 1 to 7 in the ICU, (2) whether cerebral (frontal) StO2
      values are associated with delirium in the ICU and (3) the association of frontal and
      peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4)
      to deduce the associations between shock, endotheliopathy, DIC and tissue perfusion and,
      last, the feasibility of central and peripheral NIRS monitoring in shock patients in the ICU
      using the INVOS tm NIRS StO2 appliances. In addition, the investigators target to evaluate
      (5) the incidence, evolution, and outcome of sepsis-associated disseminated intravascular
      coagulation (DIC), and (6) the associations between a) continuous hemodynamic data, b)
      laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73,
      heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests, blood
      count d-dimer, INR, neuron specific enolase and metabolomics data) (7) and study associations
      of singlenucleotide polymorphisms with developing organ dysfunction and 90-day mortality. To
      compare the hemodynamic alterations of burn patients to septic patients with the intention to
      find new ways to monitor and manage hemodynamic and particularly microcirculation in burn
      patients.

      Design:

      Observational multi-center study

      Patient population:

      Patients with circulatory shock admitted to the intensive care units (ICU) fulfilling the
      inclusion criteria.

      Sample size:

      A minimum of 250patients with circulatory shock with NIRS registration A minimum of 400
      patients with sepsis for evaluation of incidence of DIC and metabolomics and genetic tests
      (genome-wide association study, GWAS)

      Methods:

      Patients with circulatory shock admitted to the intensive care unit (ICU) fulfilling the
      inclusion criteria but none of the exclusion criteria within 4 hours of vasopressor
      inititation in the ICU and signs of clinical hypoperfusion or elevated lactate levels.
      Frontal and peripheral NIRS StO2 registration is performed using the Medtronic INVOS
      appliances and bilateral central and peripheral sensors for 48 hours from study inclusion.
      The INVOS NIRS registration is blinded and cannot be used for clinical decision making. The
      frontal and peripheral StO2 registrations will be collected for further analyses. Blood
      samples will be taken from an arterial cannula at inclusion, and at 12 h, 24h and 48h, blood
      gas samples will be drawn every 2 hours. Data on demographic data, health status, chronic
      illnesses and medications prior to ICU admission will be collected during the study.
      Hemodynamic data, information on vasopressor and inotrope medication, need and use of
      sedatives, fluid balance and specific ICU interventions during the ICU stay will also be
      collected, as well as daily intensive care delirium screening checklist (ICDSC) and
      SOFA-score registrations. An electronic case report form (CRF) will be used in the study. In
      addition to clinical data, data of feasibility and reported problems considering the use of
      NIRS StO2 registrations will be collected. Blood samples will be frozen and stored locally
      for further processing and analyses.
observational model: Cohort
time perspective: Prospective
measure: Change in severity of Organ dysfunction during the first week in ICU (study period)
time frame: At 7 days in ICU
description: Change in the total Sequential Organ Failure Assessment (SOFA) score from day 1 to day 7 in the ICU, higher SOFA score indicates greater severity of organ failure, the total SOFA score ranges from 0-24 points
measure: Average severity of Organ dysfunction during the first 7 days in the ICU (study period)
time frame: First week in the Intensive Care Unit after admission
description: Average Sequential Organ Failure Assessment (SOFA) during days 1 to day 7 in the ICU, higher SOFA score indicates greater severity of organ failure, the total SOFA score ranges from 0-24 points
measure: New organ dysfunctions
time frame: First week in the Intensive Care Unit after admission
description: Number of new organ dysfunctions (new organ dysfunction defined as one of 6 SOFA subscores ≥3 points/ total 4 points, higher points indicate greater severity. Only one new organ dysfunction / each subscore can be used for calculation of total number of new organ dysfunctions in one week
measure: 90-day mortality
time frame: 90 days
description: Death within 90 days from ICU admission
measure: Intensive care delirium incidence
time frame: First week in the Intensive Care Unit after admission
description: Delirium diagnosis in the ICU assessed by Intensive Care Delirium Scoring Checklist (ICDSC) scoring during days 1-7 defined as ICDSC score value of four points or more ( total score: 0-8 points)
measure: Intensive care delirium severity
time frame: First week in the Intensive Care Unit after admission
description: Number of Intensive Care Delirium Scoring Checklist (ICDSC) scores (assessment performed twice daily) of ≥4 points indicating presence of delirium during days 1-7
measure: Intensive care delirium scoring checklist aggregate and average score during first week in intensive care
time frame: First week in the Intensive Care Unit after admission
description: Aggregate Intensive Care Delirium Scoring Checklist (ICDSC) scores during days 1-7 . Total score ranges from 0 to 8 points. The aggregate score of all daily ICDSC measurements ( sum of all daily scores performed twice daily) will be divided by number of measurements to adjust for possible differences in number of measurements (= average ICDSC score)
measure: INVOS NIRS feasibility and safety questionnaire
time frame: 0-48 hours in Intensive Care Unit after enrolment into study
description: Feasibility of frontal and peripheral near-infrared spectroscopy tissue (NIRS) haemoglobin oxygen saturation (StO2) assessment in circulatory shock during the 48 h registration. Feasibility and registration issues are assessed using a questionnaire. Feasibility will be assessed every eight hours ( during each nurse's shift assessing feasibility and saefty on a scale from 0 to 5. Higher score indicatesmore severe feasibility issues
measure: Time to Extubation
time frame: 28 days
description: Time to extubation
measure: Days off ventilator in 28 days
time frame: 28 days
description: Days off ventilator in 28 days
measure: Days without vasoactive medication in 28 days
time frame: 28 days
description: Days without vasopressor or inotropic medication
measure: Days without RRT in 28 days
time frame: 28 days
description: Days without renal replacement therapy of any kind in 28 days
measure: ICU length of stay
time frame: 90 days
description: ICU length of stay
measure: 28-day mortality
time frame: 28 days
description: 28-day mortality
measure: Cognitive dysfunction after ICU discharge
time frame: 6 months
description: Cognitive dysfunction assessed by a set of neuropsychological tests
measure: Glycocalyx and endothelial injury biomarkers such as: Syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73, heparin binding protein (HBP), angiopoietin-2, endostatin, chromogranin
time frame: First week in the Intensive Care Unit after admission
description: Injury of the endothelium and glycocalyx
arm group label: Circulatory failure / NIRS monitoring
description: Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring intensive care unit (ICU) care, including both surgical and medical ICU patients with circulatory shock will be included in the (near-infrared spectroscopy) NIRS-substudy.
arm group label: Circulatory Failure / no NIRS monitoring
description: Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring intensive care unit(ICU) care, including both surgical and medical ICU patients with circulatory shock will be included in the near-infrared spectroscopy (NIRS) substudy. All 400 patients will be analyzed for endotheliopathy incidence, metabolomics, genetic data (without NIRS monitoring). Representation of the study population will be ensured by enrolment of all consecutive patients at the study sites who meet the study enrollment criteria.
arm group label: Gut dysbiosis, delirium and long term cognition
description: ASSESS-shock participants that have been treated at Meilahti ICU:s and survived the ICU admission to discharge, who are living in the Helsinki and Uusimaa Hospital District area or reasonable traveling distance to the unit for cognitive testing.
Cognitive function testing is performed after ICU discharge and at 3 and 6 months after ICU discharge. Testing of the microbiome is performed by collecting and analyzing fecal samples at ICU admission and at 7 days after ICU admission.
intervention type: Device
intervention name: NIRS monitoring
description: Cerebral and peripheral NIRS monitoring of brain and tissue oxygenation. Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring ICU care, including both surgical and medical ICU patients with circulatory shock will be included in the NIRS-substudy. All 400 patients will be analyzed for endotheliopathy incidence, metabolomics, genetic data Representation of the study population will be ensured by enrolment of all consecutive patients at the study sites who meet the study enrollment criteria
arm group label: Circulatory failure / NIRS monitoring
Blood samples will be collected for later analysis of metabolomics, patient-related changes
      in biomarkers indicating endothelial and myocardial damage, coagulopathies and brain injury
      from consenting patients (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1),
      CD73, heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests
      and regulators (FGF-21 and GDF-15), blood count d-dimer, INR, neuron specific enolase). A
      separate sample for genetic analysis will be obtained that will be stored and processed
      further only if patient/next of kin provides the separately asked consent for the genetic
      analysis.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Erika Wilkman, MD, PhD
role: Principal Investigator
affiliation: Helsinki University Central Hospital
last name: Erika Wilkman, MD, PhD
phone: +358504279155
email: erika.wilkman@hus.fi
last name: Johanna Hästbacka, MD, PhD
phone: +35894711
email: johanna.hastbacka@hus.fi
facility: 
status: Recruiting
contact: 
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facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Finland
responsible party type: Principal Investigator
investigator affiliation: Helsinki University Central Hospital
investigator full name: Erika Wilkman, MD PhD
investigator title: Doctor, Adjunct Professor
mesh term: Shock
sharing ipd: No