<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/NCT03810118</url>
  </required_header>
  <id_info>
    <org_study_id>REFILL</org_study_id>
    <nct_id>NCT03810118</nct_id>
  </id_info>
  <brief_title>Fluid Challenge Infusion and Response</brief_title>
  <acronym>REFILL</acronym>
  <official_title>Rate of Fluid Challenge Administration and Fluid Responsiveness: an Open-label, Multicentric, Randomized Clinical Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Humanitas Clinical and Research Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Humanitas Clinical and Research Center</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>
      It is unclear if the rate of administration of the fluid challenge could affect the rate of&#xD;
      fluid responsiveness.&#xD;
&#xD;
      The role of this small-dose (the so called mini-FC) has been recently tested to assess if the&#xD;
      infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of&#xD;
      the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and&#xD;
      150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV&#xD;
      and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high&#xD;
      sensitivity and specificity in predicting the final outcome of the FC.&#xD;
&#xD;
      The primary aim of the present study is assess whether the does the rate of infusion of fluid&#xD;
      challenge affect fluid responsiveness in neurosurgical supine patients.&#xD;
&#xD;
      The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a&#xD;
      mini-FC test in predicting the final fluid responsiveness.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Dedicated algorithms and protocols of anaesthetic care regarding fluid therapy are key&#xD;
      factors to prevent perioperative hypovolaemia and/or hypervolemia, which are known to&#xD;
      increase morbidity and length of hospital stay.&#xD;
&#xD;
      Fluid therapy is commonly used in critically ill and surgical patients to restore&#xD;
      hemodynamics. The aim of volume expansion is to increase cardiac index and oxygen delivery&#xD;
      and to improve tissue oxygenation. However, this occurs only in a situation of preload&#xD;
      dependency (i.e. when the ventricle operates on the steep part of the Frank-Starling's&#xD;
      curve). Moreover, giving fluids to a non-volume-responsive patient (preload independency) can&#xD;
      result in detrimental pulmonary and interstitial oedema. Fluid responsiveness (i.e., increase&#xD;
      in stroke volume, SV, after fluid challenge, FC, administration) can be detected in 35-50% of&#xD;
      both critically ill and surgical patients. The FC consists in assessing the hemodynamic&#xD;
      effects of giving a small amount of fluid in a short period of time. The FC allows restoring&#xD;
      fluid depletion when indicated, while minimizing the risk of overloading, which makes it the&#xD;
      gold standard for assessing fluid depletion in patients undergoing surgery.&#xD;
&#xD;
      Then, FC administration should be based on predictors of fluid responsiveness. Static&#xD;
      indexes, such as the central venous pressure, do not seem appropriate, whereas dynamic&#xD;
      indexes, such as pulse pressure variation (PPV) and stroke volume variation (SVV), reliably&#xD;
      predict the effect of FC administration during controlled mechanical ventilation only in case&#xD;
      of a tidal volume (VT) of at least 8 mL/kg, which unfortunately are rarely found in both&#xD;
      critically ill and surgical patients.&#xD;
&#xD;
      To overcome this VT-related limitation of PPV and SVV, the prediction of fluid responsiveness&#xD;
      can be also achieved by applying functional hemodynamic tests aiming at increasing venous&#xD;
      return and enhancing right ventricle preload dependence.&#xD;
&#xD;
      For example, when a FC is performed using a rapid infusion rate and a relatively &quot;small&quot;&#xD;
      dose, its effect is sufficient to test whether the patient is on the ascending part of the&#xD;
      cardiac function curve, hence showing an increase in cardiac output (CO).&#xD;
&#xD;
      The role of this small-dose (the so called mini-FC) has been recently tested to assess if the&#xD;
      infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of&#xD;
      the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and&#xD;
      150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV&#xD;
      and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high&#xD;
      sensitivity and specificity in predicting the final outcome of the FC. However, the mini-FC&#xD;
      has been tested, insofar, only in small-sized studies, needing further investigations to be&#xD;
      confirmed.&#xD;
&#xD;
      Moreover, the response to the FC is transitory, and as such also its clinical effect. The&#xD;
      study of Aya et al. pointed out that the effect of the FC is dissipated in about 10 minutes&#xD;
      in both responders and non-responders and that a dose of 4 ml/kg of crystalloids is the&#xD;
      lowest one to evocate a significant hemodynamic effect. It remains unclear, however, what the&#xD;
      best approach to FC administration should be and, in fact, wide variability exists at this&#xD;
      regard among studies performed both in the perioperative setting and in the intensive care&#xD;
      unit (ICU). In fact, the rate of fluid administration is not fixed. A recent systematic&#xD;
      review showed a significant heterogeneity. In a subgroup of 35 studies three (8.6%) reported&#xD;
      an infusion rate of 1 ml/kg/min. In another group of 32 studies, the FC was administered in&#xD;
      30 minutes in 7 (21.8%) studies, in 20 minutes in 2 (6.2%) studies, in 13 minutes in 1 (3.1%)&#xD;
      study, in 10 minutes in 15 studies (46.8%), in 5 minutes in 4 (12.5%) studies, in 3 minutes&#xD;
      in 1 (3.1%) study, and in 2 minutes in 2 (6.2%) studies. The median (IQR) time of infusion&#xD;
      was 10 (5-20) minutes.&#xD;
&#xD;
      After the indication of Aya et al., 4 ml/kg of crystalloids is the standard dose for the FC&#xD;
      in our center. However, it is unclear if the rate of administration could affect the rate of&#xD;
      fluid responsiveness. We, therefore, will perform a study to address this issue in a sample&#xD;
      of neurosurgical patients.&#xD;
&#xD;
      The primary aim of the present study is assess whether the does the rate of infusion of fluid&#xD;
      challenge affect fluid responsiveness in neurosurgical patients.&#xD;
&#xD;
      The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a&#xD;
      mini-FC test in predicting the final fluid responsiveness.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 8, 2019</start_date>
  <completion_date type="Actual">May 1, 2020</completion_date>
  <primary_completion_date type="Actual">February 21, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A single group of patient will receive 4 ml/kg fluid challenge in either 10 or 20 minutes</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of fluid responders</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>Percentage of patients showing an increase in the stroke volume above the predefined threshold of fluid responsiveness after the infusion of the fluid challenge (&gt;10%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic effect of the FC</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>AUC</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic effect of the FC</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>dmax</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic effect of the FC</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>Tmax</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic effect of the FC</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>d1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic effect of the FC</measure>
    <time_frame>10 or 20 minutes from the start</time_frame>
    <description>d5</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Neurosurgery</condition>
  <condition>Cardiovascular System</condition>
  <condition>Anesthesia, General</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All the enrolled patients will receive the same mini-fluid challenge test of 100ml and then will complete the 4 ml/kg fluid challenge in either 10 or 20 minutes</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>fluid challenge</intervention_name>
    <description>4 ml/kg fluid challenge infused over in either 10 or 20 minutes</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients aged ≥ 18 years;&#xD;
&#xD;
          2. Scheduled for elective supine neurosurgery and requiring invasive arterial monitoring;&#xD;
&#xD;
          3. Glasgow coma scale 15 at recruitment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any recurrent cardiac arrhythmias;&#xD;
&#xD;
          2. Reduced left (ejection fraction &lt;30%) or right (systolic peak velocity of tricuspid&#xD;
             annular motion &lt;0.17 m/s) ventricular systolic function;&#xD;
&#xD;
          3. Intra-operative use of vasopressors or inotropes before FC administration or between&#xD;
             the first and the second bolus of fluids.&#xD;
&#xD;
          4. Chronic use beta-blocking agents.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Humanitas Research Hospital</name>
      <address>
        <city>Rozzano</city>
        <state>Milano</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <results_reference>
    <citation>Mahjoub Y, Lejeune V, Muller L, Perbet S, Zieleskiewicz L, Bart F, Veber B, Paugam-Burtz C, Jaber S, Ayham A, Zogheib E, Lasocki S, Vieillard-Baron A, Quintard H, Joannes-Boyau O, Plantefeve G, Montravers P, Duperret S, Lakhdari M, Ammenouche N, Lorne E, Slama M, Dupont H. Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study. Br J Anaesth. 2014 Apr;112(4):681-5. doi: 10.1093/bja/aet442. Epub 2013 Dec 29.</citation>
    <PMID>24374504</PMID>
  </results_reference>
  <results_reference>
    <citation>Biais M, de Courson H, Lanchon R, Pereira B, Bardonneau G, Griton M, Sesay M, Nouette-Gaulain K. Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. Anesthesiology. 2017 Sep;127(3):450-456. doi: 10.1097/ALN.0000000000001753.</citation>
    <PMID>28640019</PMID>
  </results_reference>
  <results_reference>
    <citation>Muller L, Toumi M, Bousquet PJ, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye JE, Molinari N, Lefrant JY; AzuRea Group. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011 Sep;115(3):541-7. doi: 10.1097/ALN.0b013e318229a500.</citation>
    <PMID>21792056</PMID>
  </results_reference>
  <results_reference>
    <citation>Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-91. doi: 10.1097/CCM.0000000000001517.</citation>
    <PMID>26683506</PMID>
  </results_reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 16, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>May 26, 2020</last_update_submitted>
  <last_update_submitted_qc>May 26, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Humanitas Clinical and Research Center</investigator_affiliation>
    <investigator_full_name>Antonio Messina</investigator_full_name>
    <investigator_title>ICU senior consultant</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03810118
org study id: REFILL
nct id: NCT03810118
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
It is unclear if the rate of administration of the fluid challenge could affect the rate of
      fluid responsiveness.

      The role of this small-dose (the so called mini-FC) has been recently tested to assess if the
      infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of
      the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and
      150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV
      and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high
      sensitivity and specificity in predicting the final outcome of the FC.

      The primary aim of the present study is assess whether the does the rate of infusion of fluid
      challenge affect fluid responsiveness in neurosurgical supine patients.

      The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a
      mini-FC test in predicting the final fluid responsiveness.
Dedicated algorithms and protocols of anaesthetic care regarding fluid therapy are key
      factors to prevent perioperative hypovolaemia and/or hypervolemia, which are known to
      increase morbidity and length of hospital stay.

      Fluid therapy is commonly used in critically ill and surgical patients to restore
      hemodynamics. The aim of volume expansion is to increase cardiac index and oxygen delivery
      and to improve tissue oxygenation. However, this occurs only in a situation of preload
      dependency (i.e. when the ventricle operates on the steep part of the Frank-Starling's
      curve). Moreover, giving fluids to a non-volume-responsive patient (preload independency) can
      result in detrimental pulmonary and interstitial oedema. Fluid responsiveness (i.e., increase
      in stroke volume, SV, after fluid challenge, FC, administration) can be detected in 35-50% of
      both critically ill and surgical patients. The FC consists in assessing the hemodynamic
      effects of giving a small amount of fluid in a short period of time. The FC allows restoring
      fluid depletion when indicated, while minimizing the risk of overloading, which makes it the
      gold standard for assessing fluid depletion in patients undergoing surgery.

      Then, FC administration should be based on predictors of fluid responsiveness. Static
      indexes, such as the central venous pressure, do not seem appropriate, whereas dynamic
      indexes, such as pulse pressure variation (PPV) and stroke volume variation (SVV), reliably
      predict the effect of FC administration during controlled mechanical ventilation only in case
      of a tidal volume (VT) of at least 8 mL/kg, which unfortunately are rarely found in both
      critically ill and surgical patients.

      To overcome this VT-related limitation of PPV and SVV, the prediction of fluid responsiveness
      can be also achieved by applying functional hemodynamic tests aiming at increasing venous
      return and enhancing right ventricle preload dependence.

      For example, when a FC is performed using a rapid infusion rate and a relatively "small"
      dose, its effect is sufficient to test whether the patient is on the ascending part of the
      cardiac function curve, hence showing an increase in cardiac output (CO).

      The role of this small-dose (the so called mini-FC) has been recently tested to assess if the
      infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of
      the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and
      150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV
      and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high
      sensitivity and specificity in predicting the final outcome of the FC. However, the mini-FC
      has been tested, insofar, only in small-sized studies, needing further investigations to be
      confirmed.

      Moreover, the response to the FC is transitory, and as such also its clinical effect. The
      study of Aya et al. pointed out that the effect of the FC is dissipated in about 10 minutes
      in both responders and non-responders and that a dose of 4 ml/kg of crystalloids is the
      lowest one to evocate a significant hemodynamic effect. It remains unclear, however, what the
      best approach to FC administration should be and, in fact, wide variability exists at this
      regard among studies performed both in the perioperative setting and in the intensive care
      unit (ICU). In fact, the rate of fluid administration is not fixed. A recent systematic
      review showed a significant heterogeneity. In a subgroup of 35 studies three (8.6%) reported
      an infusion rate of 1 ml/kg/min. In another group of 32 studies, the FC was administered in
      30 minutes in 7 (21.8%) studies, in 20 minutes in 2 (6.2%) studies, in 13 minutes in 1 (3.1%)
      study, in 10 minutes in 15 studies (46.8%), in 5 minutes in 4 (12.5%) studies, in 3 minutes
      in 1 (3.1%) study, and in 2 minutes in 2 (6.2%) studies. The median (IQR) time of infusion
      was 10 (5-20) minutes.

      After the indication of Aya et al., 4 ml/kg of crystalloids is the standard dose for the FC
      in our center. However, it is unclear if the rate of administration could affect the rate of
      fluid responsiveness. We, therefore, will perform a study to address this issue in a sample
      of neurosurgical patients.

      The primary aim of the present study is assess whether the does the rate of infusion of fluid
      challenge affect fluid responsiveness in neurosurgical patients.

      The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a
      mini-FC test in predicting the final fluid responsiveness.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A single group of patient will receive 4 ml/kg fluid challenge in either 10 or 20 minutes
primary purpose: Diagnostic
masking: None (Open Label)
measure: Percentage of fluid responders
time frame: 10 or 20 minutes from the start
description: Percentage of patients showing an increase in the stroke volume above the predefined threshold of fluid responsiveness after the infusion of the fluid challenge (>10%).
measure: Pharmacodynamic effect of the FC
time frame: 10 or 20 minutes from the start
description: AUC
measure: Pharmacodynamic effect of the FC
time frame: 10 or 20 minutes from the start
description: dmax
measure: Pharmacodynamic effect of the FC
time frame: 10 or 20 minutes from the start
description: Tmax
measure: Pharmacodynamic effect of the FC
time frame: 10 or 20 minutes from the start
description: d1
measure: Pharmacodynamic effect of the FC
time frame: 10 or 20 minutes from the start
description: d5
arm group label: Treatment
arm group type: Experimental
description: All the enrolled patients will receive the same mini-fluid challenge test of 100ml and then will complete the 4 ml/kg fluid challenge in either 10 or 20 minutes
intervention type: Diagnostic Test
intervention name: fluid challenge
description: 4 ml/kg fluid challenge infused over in either 10 or 20 minutes
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Italy
citation: Mahjoub Y, Lejeune V, Muller L, Perbet S, Zieleskiewicz L, Bart F, Veber B, Paugam-Burtz C, Jaber S, Ayham A, Zogheib E, Lasocki S, Vieillard-Baron A, Quintard H, Joannes-Boyau O, Plantefeve G, Montravers P, Duperret S, Lakhdari M, Ammenouche N, Lorne E, Slama M, Dupont H. Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study. Br J Anaesth. 2014 Apr;112(4):681-5. doi: 10.1093/bja/aet442. Epub 2013 Dec 29.
PMID: 24374504
citation: Biais M, de Courson H, Lanchon R, Pereira B, Bardonneau G, Griton M, Sesay M, Nouette-Gaulain K. Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. Anesthesiology. 2017 Sep;127(3):450-456. doi: 10.1097/ALN.0000000000001753.
PMID: 28640019
citation: Muller L, Toumi M, Bousquet PJ, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye JE, Molinari N, Lefrant JY; AzuRea Group. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011 Sep;115(3):541-7. doi: 10.1097/ALN.0b013e318229a500.
PMID: 21792056
citation: Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-91. doi: 10.1097/CCM.0000000000001517.
PMID: 26683506
responsible party type: Principal Investigator
investigator affiliation: Humanitas Clinical and Research Center
investigator full name: Antonio Messina
investigator title: ICU senior consultant
sharing ipd: Undecided