<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/NCT04496583</url>
  </required_header>
  <id_info>
    <org_study_id>1200248</org_study_id>
    <nct_id>NCT04496583</nct_id>
  </id_info>
  <brief_title>Fluid unLoading On Weaning (FLOW)</brief_title>
  <acronym>FLOW</acronym>
  <official_title>Preload Responsiveness as a Signal to Start an Spontaneous Breathing Trial in Mechanically Ventilated Critically Ill Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pontificia Universidad Catolica de Chile</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Pontificia Universidad Catolica de Chile</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 purpose of this study is to determine if testing preload responsiveness, the normal&#xD;
      physiologic state that means that changes in preload determine changes in cardiac output,&#xD;
      allows an earlier and physiologically safer weaning from mechanical ventilation in critically&#xD;
      ill patients with fluid overload, when compared to a strategy of fluid removal aimed at&#xD;
      obtaining a predetermined negative fluid balance.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Fluid overload is a state of global body accumulation of fluids with a deleterious impact in&#xD;
      organ function. This condition is frequently found in critically ill patients after acute&#xD;
      resuscitation. Its adverse impact is well demonstrated on weaning-induced heart failure,&#xD;
      pulmonary and visceral edema, intraabdominal hypertension, etc., which results in longer&#xD;
      mechanical ventilation and length of stay, and worse clinical outcomes. Despite these&#xD;
      well-known facts, there are no guidelines on how to implement depletive strategies on this&#xD;
      phase. The usual approach is to set in advance a desired negative fluid balance for the&#xD;
      upcoming days, initiating diuretics or ultrafiltration in preparation for weaning from&#xD;
      mechanical ventilation. Unfortunately, this strategy frequently results in excessive and&#xD;
      detrimental fluid removal.&#xD;
&#xD;
      A more physiologic approach to guide fluid removal is testing preload responsiveness, which&#xD;
      is the normal physiologic state, and means that changes in preload determine changes in&#xD;
      cardiac output, with mild or null increment in filling pressures. In contrast, preload&#xD;
      unresponsiveness corresponds to a state in which preload increases do not increase stroke&#xD;
      volume but produce large increments in filling pressures. This altered state is usually&#xD;
      present in patients with fluid overload. Preload responsiveness can be tested routinely in&#xD;
      the ICU by assessing the interactions between preload and cardiac output.&#xD;
&#xD;
      Now, in usual clinical practice, weaning from mechanical ventilation is accomplished through&#xD;
      a process called the spontaneous breathing trial (SBT), which is a standardized test to mimic&#xD;
      the real conditions of breathing without the ventilator, before extubation. One-third of&#xD;
      patients fail the initial SBT, which determines a prolonged or difficult weaning and longer&#xD;
      stay on mechanical ventilation. Importantly, one of the main determinants of this problem is&#xD;
      fluid overload. The pathophysiologic explanation lays in that when switching from positive&#xD;
      pressure ventilation to spontaneous breathing, intrathoracic pressure goes from being&#xD;
      steadily positive across the ventilatory cycle to markedly negative, promoting increased&#xD;
      preload and impeding left ventricular ejection, and this phenomenon is associated to preload&#xD;
      unresponsiveness. Interestingly, in most patients with fluid overload, preload responsiveness&#xD;
      can be restored just a few hours after starting fluid removal, while modifying fluid balance&#xD;
      may take several days. Notably, some patients may persist with preload unresponsiveness even&#xD;
      after achieving significant fluid removal.&#xD;
&#xD;
      The investigators hypothesized that in mechanically ventilated patients with fluid overload,&#xD;
      a fluid removal strategy aimed at attaining a state of preload responsiveness associates with&#xD;
      a decreased incidence of weaning failure from cardiovascular origin, shorter weaning time,&#xD;
      and less depletion-induced hypoperfusion events, metabolic derangements and kidney stress&#xD;
      compared to patients depleted with a fluid removal strategy aimed at obtaining a&#xD;
      predetermined negative fluid balance.&#xD;
&#xD;
      To confirm this hypothesis, the investigators propose a prospective randomized study on 46&#xD;
      critically ill mechanically ventilated patients with fluid overload, comparing these two&#xD;
      strategies of depletion and their impact on weaning development and other related systemic&#xD;
      functions. Throughout all the protocol, patients will receive general monitoring and&#xD;
      management according to ICU standards, plus protocol-specific monitoring that will be added&#xD;
      since randomization and before and after SBT attempts, for up to 72 h. Patients will be&#xD;
      followed-up for 28 days.&#xD;
&#xD;
      If the investigators' hypothesis is confirmed, it may generate a change in the paradigm of&#xD;
      managing fluid overload in critically ill patients, since the physiologic endpoint preload&#xD;
      responsiveness may suffice as the valid target and safety parameter to appropriately&#xD;
      discontinue mechanical ventilation, shortening the days on mechanical ventilation, the ICU&#xD;
      length of stay, and many other costs associated, among additional benefits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 1, 2021</start_date>
  <completion_date type="Anticipated">June 2023</completion_date>
  <primary_completion_date type="Anticipated">June 2023</primary_completion_date>
  <phase>N/A</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>Randomized prospective controlled study of parallel groups</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients on each study group presenting weaning-induced pulmonary edema or weaning failure from cardiovascular origin</measure>
    <time_frame>72 hours</time_frame>
    <description>Development of signs of cardiac failure and acute pulmonary edema during the spontaneous breathing trial.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean and standard deviation of T time between the starting of fluid depletion and consolidated weaning from mechanical ventilation on each study group.</measure>
    <time_frame>7 days</time_frame>
    <description>Time between the starting of fluid depletion and consolidated weaning from mechanical ventilation, measured in hours and days.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients on each study group presenting weaning-induced global and regional hypoperfusion (lactate, capillary refill time, ScvO2, dCO2)</measure>
    <time_frame>72 hours</time_frame>
    <description>Development of clinical and laboratory signs of global and regional hypoperfusion due to depletive measures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients on each study group presenting depletion-induced renal dysfunction assessed by renal stress biomarkers variation.</measure>
    <time_frame>72 hours</time_frame>
    <description>Development of laboratory signs of renal compromise due to fluid depletion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients on each study group presenting depletion-induced acid-base and electrolyte disturbances.</measure>
    <time_frame>72 hours</time_frame>
    <description>Development of laboratory signs of acid-base and electrolyte derangements due to fluid depletion.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">46</enrollment>
  <condition>Weaning Failure</condition>
  <condition>Fluid Overload</condition>
  <condition>Cardiac Failure Acute</condition>
  <arm_group>
    <arm_group_label>Fluid Balance Depletive Strategy Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with fluid overload under a depletive strategy to attain a predetermined negative balance</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Preload Responsiveness Depletive Strategy Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with fluid overload under a depletive strategy to attain a state of preload responsiveness</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Fluid depletion strategy</intervention_name>
    <description>The fluid depletion strategy will be individualized depending on the response to the standardized furosemide test (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) with a urinary output (UO) cutoff of 200 ml at 2 hours. The desired depletion endpoint will be targeted by using diuretics (40 mg q6h iv initially, adjusting dose by UO) or ultrafiltration (UF) if UO &lt;200 ml/2h</description>
    <arm_group_label>Fluid Balance Depletive Strategy Group</arm_group_label>
    <arm_group_label>Preload Responsiveness Depletive Strategy Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Mechanical ventilation for &gt;24 hours and &lt;7 days&#xD;
&#xD;
          2. Patients who on the daily evaluation to assess their potential for weaning present&#xD;
             fluid overload and, in consequence, require fluid depletion before the spontaneous&#xD;
             breathing trial&#xD;
&#xD;
          3. Clinical condition resolving or hemodynamically stable condition with acceptable&#xD;
             ventilatory status that allows an spontaneous breathing trial according to attending's&#xD;
             criteria.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy&#xD;
&#xD;
          2. Do-not-resuscitate status&#xD;
&#xD;
          3. Child B or C liver cirrhosis&#xD;
&#xD;
          4. Circulatory instability&#xD;
&#xD;
          5. Acute coronary syndrome&#xD;
&#xD;
          6. Active bleeding&#xD;
&#xD;
          7. Severe concomitant acute respiratory distress syndrome&#xD;
&#xD;
          8. Malnutrition&#xD;
&#xD;
          9. Muscle weakness severe enough to be considered by itself a risk for weaning failure&#xD;
&#xD;
         10. Patient should be excluded based on the opinion of the clinician/investigator&#xD;
             (documented reason)&#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>Ricardo Castro, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>School of Medicine, Pontificia Universidad Católica de Chile</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Eduardo Kattan, MD, MSc</last_name>
    <phone>+56994793024</phone>
    <email>e.kattan@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ricardo Castro</last_name>
    <phone>+56973986588</phone>
    <email>rcastro@ucchristus.cl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hospital Clínico UC CHRISTUS</name>
      <address>
        <city>Santiago</city>
        <state>RM</state>
        <zip>8330077</zip>
        <country>Chile</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>RICARDO CASTRO, MD, MPH</last_name>
      <email>rcastro.med@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Chile</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>July 29, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>September 3, 2021</last_update_submitted>
  <last_update_submitted_qc>September 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2021</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>Heart Failure</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/NCT04496583
org study id: 1200248
nct id: NCT04496583
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to determine if testing preload responsiveness, the normal
      physiologic state that means that changes in preload determine changes in cardiac output,
      allows an earlier and physiologically safer weaning from mechanical ventilation in critically
      ill patients with fluid overload, when compared to a strategy of fluid removal aimed at
      obtaining a predetermined negative fluid balance.
Fluid overload is a state of global body accumulation of fluids with a deleterious impact in
      organ function. This condition is frequently found in critically ill patients after acute
      resuscitation. Its adverse impact is well demonstrated on weaning-induced heart failure,
      pulmonary and visceral edema, intraabdominal hypertension, etc., which results in longer
      mechanical ventilation and length of stay, and worse clinical outcomes. Despite these
      well-known facts, there are no guidelines on how to implement depletive strategies on this
      phase. The usual approach is to set in advance a desired negative fluid balance for the
      upcoming days, initiating diuretics or ultrafiltration in preparation for weaning from
      mechanical ventilation. Unfortunately, this strategy frequently results in excessive and
      detrimental fluid removal.

      A more physiologic approach to guide fluid removal is testing preload responsiveness, which
      is the normal physiologic state, and means that changes in preload determine changes in
      cardiac output, with mild or null increment in filling pressures. In contrast, preload
      unresponsiveness corresponds to a state in which preload increases do not increase stroke
      volume but produce large increments in filling pressures. This altered state is usually
      present in patients with fluid overload. Preload responsiveness can be tested routinely in
      the ICU by assessing the interactions between preload and cardiac output.

      Now, in usual clinical practice, weaning from mechanical ventilation is accomplished through
      a process called the spontaneous breathing trial (SBT), which is a standardized test to mimic
      the real conditions of breathing without the ventilator, before extubation. One-third of
      patients fail the initial SBT, which determines a prolonged or difficult weaning and longer
      stay on mechanical ventilation. Importantly, one of the main determinants of this problem is
      fluid overload. The pathophysiologic explanation lays in that when switching from positive
      pressure ventilation to spontaneous breathing, intrathoracic pressure goes from being
      steadily positive across the ventilatory cycle to markedly negative, promoting increased
      preload and impeding left ventricular ejection, and this phenomenon is associated to preload
      unresponsiveness. Interestingly, in most patients with fluid overload, preload responsiveness
      can be restored just a few hours after starting fluid removal, while modifying fluid balance
      may take several days. Notably, some patients may persist with preload unresponsiveness even
      after achieving significant fluid removal.

      The investigators hypothesized that in mechanically ventilated patients with fluid overload,
      a fluid removal strategy aimed at attaining a state of preload responsiveness associates with
      a decreased incidence of weaning failure from cardiovascular origin, shorter weaning time,
      and less depletion-induced hypoperfusion events, metabolic derangements and kidney stress
      compared to patients depleted with a fluid removal strategy aimed at obtaining a
      predetermined negative fluid balance.

      To confirm this hypothesis, the investigators propose a prospective randomized study on 46
      critically ill mechanically ventilated patients with fluid overload, comparing these two
      strategies of depletion and their impact on weaning development and other related systemic
      functions. Throughout all the protocol, patients will receive general monitoring and
      management according to ICU standards, plus protocol-specific monitoring that will be added
      since randomization and before and after SBT attempts, for up to 72 h. Patients will be
      followed-up for 28 days.

      If the investigators' hypothesis is confirmed, it may generate a change in the paradigm of
      managing fluid overload in critically ill patients, since the physiologic endpoint preload
      responsiveness may suffice as the valid target and safety parameter to appropriately
      discontinue mechanical ventilation, shortening the days on mechanical ventilation, the ICU
      length of stay, and many other costs associated, among additional benefits.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized prospective controlled study of parallel groups
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients on each study group presenting weaning-induced pulmonary edema or weaning failure from cardiovascular origin
time frame: 72 hours
description: Development of signs of cardiac failure and acute pulmonary edema during the spontaneous breathing trial.
measure: Mean and standard deviation of T time between the starting of fluid depletion and consolidated weaning from mechanical ventilation on each study group.
time frame: 7 days
description: Time between the starting of fluid depletion and consolidated weaning from mechanical ventilation, measured in hours and days.
measure: Proportion of patients on each study group presenting weaning-induced global and regional hypoperfusion (lactate, capillary refill time, ScvO2, dCO2)
time frame: 72 hours
description: Development of clinical and laboratory signs of global and regional hypoperfusion due to depletive measures.
measure: Proportion of patients on each study group presenting depletion-induced renal dysfunction assessed by renal stress biomarkers variation.
time frame: 72 hours
description: Development of laboratory signs of renal compromise due to fluid depletion
measure: Proportion of patients on each study group presenting depletion-induced acid-base and electrolyte disturbances.
time frame: 72 hours
description: Development of laboratory signs of acid-base and electrolyte derangements due to fluid depletion.
arm group label: Fluid Balance Depletive Strategy Group
arm group type: Active Comparator
description: Patients with fluid overload under a depletive strategy to attain a predetermined negative balance
arm group label: Preload Responsiveness Depletive Strategy Group
arm group type: Experimental
description: Patients with fluid overload under a depletive strategy to attain a state of preload responsiveness
intervention type: Other
intervention name: Fluid depletion strategy
description: The fluid depletion strategy will be individualized depending on the response to the standardized furosemide test (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) with a urinary output (UO) cutoff of 200 ml at 2 hours. The desired depletion endpoint will be targeted by using diuretics (40 mg q6h iv initially, adjusting dose by UO) or ultrafiltration (UF) if UO <200 ml/2h
arm group label: Fluid Balance Depletive Strategy Group
arm group label: Preload Responsiveness Depletive Strategy Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ricardo Castro, MD, MPH
role: Principal Investigator
affiliation: School of Medicine, Pontificia Universidad Católica de Chile
last name: Eduardo Kattan, MD, MSc
phone: +56994793024
email: e.kattan@gmail.com
last name: Ricardo Castro
phone: +56973986588
email: rcastro@ucchristus.cl
facility: 
status: Recruiting
contact: 
country: Chile
responsible party type: Sponsor
mesh term: Heart Failure
sharing ipd: No