<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/NCT03280745</url>
  </required_header>
  <id_info>
    <org_study_id>201706011.1</org_study_id>
    <nct_id>NCT03280745</nct_id>
  </id_info>
  <brief_title>Hypertonic Saline for Fluid Resuscitation After Cardiac Surgery</brief_title>
  <acronym>HERACLES</acronym>
  <official_title>Hypertonic Saline for Fluid Resuscitation After Cardiac Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Volume replacement strategies and type of fluid used in patients undergoing&#xD;
      cardiac surgery have changed during the last years. Currently used crystalloid solutes have a&#xD;
      variable composition and a major impact on organ function and outcome. Additionally&#xD;
      critically ill patients are prone to fluid overload, which is despite common perception, not&#xD;
      a benign occurrence as it is associated with prolonged ICU- and hospital length of stay and&#xD;
      increased mortality rates. Fluid resuscitation using bolus or continuous infusion of&#xD;
      hypertonic saline was used for more than thirty years. Only a few studies have been conducted&#xD;
      so far, but they showed that infusion of hypertonic saline results in less volume&#xD;
      administered, increased renal function less weight gain in critically ill patients when&#xD;
      compared to other crystalloids.&#xD;
&#xD;
      Aim: This preliminary randomized controlled double-blind study aims to identify whether fluid&#xD;
      resuscitation using hypertonic saline (HS) when used in addition to lactated Ringers solution&#xD;
      results in less total fluid amount administered in patients following cardiac surgery.&#xD;
      Additionally we want to evaluate whether the use of hypertonic saline results less need for&#xD;
      pharmacological cardiocirculatory support, increased renal function, less postoperative&#xD;
      volume overload shortened post-cardiac bypass immune suppression and increased postoperative&#xD;
      outcomes.&#xD;
&#xD;
      Study intervention: At admission to the ICU patients will receive 5ml/kg body weight of 7.3%&#xD;
      NaCl or 0.9% NaCl by infusion pump over 60 minutes. If necessary, fluid resuscitation will&#xD;
      thereafter be performed with Ringer's lactate to normalize peripheral perfusion and to allow&#xD;
      weaning of vasopressors.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 27, 2018</start_date>
  <completion_date type="Actual">September 30, 2019</completion_date>
  <primary_completion_date type="Actual">May 27, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl or 0.9% NaCl by infusion pump over 60 minutes. If necessary, fluid resuscitation will be performed with Ringer's lactate to normalize peripheral perfusion and to allow weaning of vasopressors.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>total cumulative amount of fluids infused</measure>
    <time_frame>daily until ICU discharge, max until postoperative day 90</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>postoperative weight gain</measure>
    <time_frame>until postoperative day 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total postoperative cumulative urinary output</measure>
    <time_frame>daily until ICU discharge, max until postoperative day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total cumulative dose of inopressors per kg bodyweight /hour</measure>
    <time_frame>until ICU discharge, max until postoperative day 90</time_frame>
    <description>cumulation of norepinephrine and epinephrine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time on inopressors</measure>
    <time_frame>from ICU admission until stop of inopressors, max until postoperative day 90</time_frame>
    <description>norepinephrine and/or epinephrine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>variation in renal function markers</measure>
    <time_frame>until postoperative day 6</time_frame>
    <description>renal damage maker (TIMP2-IGFB, creatinine)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>variation in acid-base homeostasis</measure>
    <time_frame>until postoperative day 6</time_frame>
    <description>pH, base excess, lactate, bicarbonate, electrolytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>variation in immune function</measure>
    <time_frame>until postoperative day 6</time_frame>
    <description>mHLA-DR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time on the ventilator</measure>
    <time_frame>from ICU admission until time of extubation, maximum 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurence of infection</measure>
    <time_frame>occurence of infection during the index hospitalisation or subsequent admissions due to infection upto 90 postoperative days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>length of stay</measure>
    <time_frame>time to ICU/hospital-discharge however long this may take, maximum 90 days</time_frame>
    <description>time to ICU/hospital-discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>readmissions to the ICU</measure>
    <time_frame>readmissions to the ICU within postoperative 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>mortality</measure>
    <time_frame>until postoperative day 90</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">165</enrollment>
  <condition>Cardiovascular Diseases</condition>
  <condition>Valvular Heart Disease</condition>
  <arm_group>
    <arm_group_label>7.3% NaCl (intervention)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl NaCl by infusion pump over 60 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>0.9% NaCl (comparator)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>At admission to the ICU patients will receive 5ml/kg body weight of 0.9% NaCl by infusion pump over 60 minutes.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hypertonic saline</intervention_name>
    <description>At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl by infusion pump over 60 minutes.</description>
    <arm_group_label>7.3% NaCl (intervention)</arm_group_label>
    <other_name>7.9% NaCl</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.9% saline</intervention_name>
    <description>At admission to the ICU patients will receive 5ml/kg body weight of 0.9% NaCl by infusion pump over 60 minutes.</description>
    <arm_group_label>0.9% NaCl (comparator)</arm_group_label>
    <other_name>normal saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients undergoing cardiac surgery for ischemic or valvular heart disease&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients unable to give informed consent&#xD;
&#xD;
          -  Patients with age &lt;18 years&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Left-ventricular ejection fraction (LVEF) &lt; 30% preoperatively&#xD;
&#xD;
          -  Preexisting renal insufficiency with an eGFR &lt;30 ml/min/1.73m2&#xD;
&#xD;
          -  Patients with postoperative circulatory support devices such as LVAD, IABP, Impella,&#xD;
             ECMO&#xD;
&#xD;
          -  Preexisting serum sodium of &gt;145mmol/l or &lt;135 mmol/L&#xD;
&#xD;
          -  Preexisting serum chloremia &gt;107mmol/l or &lt; 98 mmol/L&#xD;
&#xD;
          -  Systemic steroid therapy (at any dose at time of inclusion)&#xD;
&#xD;
          -  Chronic liver disease (bilirubin &gt;3 mg.dl)&#xD;
&#xD;
          -  Any signs of infection or sepsis defined as clear clinical evidence for active&#xD;
             infection or current antibiotic therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joerg C Schefold, MD</last_name>
    <role>Study Director</role>
    <affiliation>Department of Intensive Care, Inselspital, Bern University Hospital, Bern, Switzerland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Intensive Care, Bern University Hospital and University of Bern, Bern, Switzerland</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>March 23, 2020</last_update_submitted>
  <last_update_submitted_qc>March 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Heart Valve Diseases</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/NCT03280745
org study id: 201706011.1
nct id: NCT03280745
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Background: Volume replacement strategies and type of fluid used in patients undergoing
      cardiac surgery have changed during the last years. Currently used crystalloid solutes have a
      variable composition and a major impact on organ function and outcome. Additionally
      critically ill patients are prone to fluid overload, which is despite common perception, not
      a benign occurrence as it is associated with prolonged ICU- and hospital length of stay and
      increased mortality rates. Fluid resuscitation using bolus or continuous infusion of
      hypertonic saline was used for more than thirty years. Only a few studies have been conducted
      so far, but they showed that infusion of hypertonic saline results in less volume
      administered, increased renal function less weight gain in critically ill patients when
      compared to other crystalloids.

      Aim: This preliminary randomized controlled double-blind study aims to identify whether fluid
      resuscitation using hypertonic saline (HS) when used in addition to lactated Ringers solution
      results in less total fluid amount administered in patients following cardiac surgery.
      Additionally we want to evaluate whether the use of hypertonic saline results less need for
      pharmacological cardiocirculatory support, increased renal function, less postoperative
      volume overload shortened post-cardiac bypass immune suppression and increased postoperative
      outcomes.

      Study intervention: At admission to the ICU patients will receive 5ml/kg body weight of 7.3%
      NaCl or 0.9% NaCl by infusion pump over 60 minutes. If necessary, fluid resuscitation will
      thereafter be performed with Ringer's lactate to normalize peripheral perfusion and to allow
      weaning of vasopressors.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl or 0.9% NaCl by infusion pump over 60 minutes. If necessary, fluid resuscitation will be performed with Ringer's lactate to normalize peripheral perfusion and to allow weaning of vasopressors.
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: double-blind
measure: total cumulative amount of fluids infused
time frame: daily until ICU discharge, max until postoperative day 90
measure: postoperative weight gain
time frame: until postoperative day 6
measure: total postoperative cumulative urinary output
time frame: daily until ICU discharge, max until postoperative day 90
measure: total cumulative dose of inopressors per kg bodyweight /hour
time frame: until ICU discharge, max until postoperative day 90
description: cumulation of norepinephrine and epinephrine
measure: time on inopressors
time frame: from ICU admission until stop of inopressors, max until postoperative day 90
description: norepinephrine and/or epinephrine
measure: variation in renal function markers
time frame: until postoperative day 6
description: renal damage maker (TIMP2-IGFB, creatinine)
measure: variation in acid-base homeostasis
time frame: until postoperative day 6
description: pH, base excess, lactate, bicarbonate, electrolytes
measure: variation in immune function
time frame: until postoperative day 6
description: mHLA-DR
measure: time on the ventilator
time frame: from ICU admission until time of extubation, maximum 90 days
measure: occurence of infection
time frame: occurence of infection during the index hospitalisation or subsequent admissions due to infection upto 90 postoperative days
measure: length of stay
time frame: time to ICU/hospital-discharge however long this may take, maximum 90 days
description: time to ICU/hospital-discharge
measure: readmissions to the ICU
time frame: readmissions to the ICU within postoperative 90 days
measure: mortality
time frame: until postoperative day 90
arm group label: 7.3% NaCl (intervention)
arm group type: Active Comparator
description: At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl NaCl by infusion pump over 60 minutes.
arm group label: 0.9% NaCl (comparator)
arm group type: Active Comparator
description: At admission to the ICU patients will receive 5ml/kg body weight of 0.9% NaCl by infusion pump over 60 minutes.
intervention type: Drug
intervention name: Hypertonic saline
description: At admission to the ICU patients will receive 5ml/kg body weight of 7.3% NaCl by infusion pump over 60 minutes.
arm group label: 7.3% NaCl (intervention)
other name: 7.9% NaCl
intervention type: Drug
intervention name: 0.9% saline
description: At admission to the ICU patients will receive 5ml/kg body weight of 0.9% NaCl by infusion pump over 60 minutes.
arm group label: 0.9% NaCl (comparator)
other name: normal saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joerg C Schefold, MD
role: Study Director
affiliation: Department of Intensive Care, Inselspital, Bern University Hospital, Bern, Switzerland
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Cardiovascular Diseases
mesh term: Heart Diseases
mesh term: Heart Valve Diseases
sharing ipd: No