Fluid Balance Neutralization During CRRT (Continuous Renal Replacement Therapy)

Study Overview
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Brief Summary
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Fluid overload is associated with increased mortality in critically ill patients with acute kidney injury. Fluid balance controlled is associated with improved outcome in observational studies, and is deemed safe in interventional trials. The objective of the study is to keep fluid balance neutral by matching the net ultrafiltration rate to fluid inputs in patients with vasoplegia, and treated with continuous renal replacement therapy (CRRT), while insuring its security using advanced hemodynamic monitoring with continuous cardiac output monitoring.

Official Title
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Hemodynamic-guided Fluid Balance Neutralization During Continuous Renal Replacement Therapy in Critically Ill Patients: the GO NEUTRAL Randomized Controlled Multi-center Study

Conditions
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Fluid Overload

Intervention / Treatment
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* Procedure: Increased net ultrafiltration with advanced hemodynamic monitoring
* Procedure: Zero or near-zero net ultrafiltration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient 18 yo or more, affiliated to a social security system Treated with vasopressors for acute circulatory failure With KDIGO stage 3 acute kidney injury Treated with continuous renal replacement therapy for less than 24 jours Monitored with a calibrated continuous cardiac output device Exclusion Criteria: Treatment by ECMO (extracorporeal membrane oxygenation) Active hemorrhage necessitating transfusion Maintenance dialysis or renal graft recipient Switch to intermittent hemodialysis is scheduled in the next 72 hours Acute cerebral stroke complicated by coma and under mechanical ventilation Acute fulminant hepatitis Postural maneuver (passive leg raising or Trendelenburg) cannot be performed (amputation, inferior vena cava obstruction) Pregnancy or lactating Withdrawal or limitation of care Moribund patient Patient under protective measures/wardship Inclusion in another trial whose main outcome is cumulative fluid balance, or whose intervention targets hemodynamic physiology, fluid balance or net ultrafiltration. Patient previously enrolled in the same study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluid balance neutralization<br>Fluid balance neutralization using increased net ultrafiltration, aiming to neutralize the cumulative fluid input received over the first 72 hours of study participation. | Procedure: Increased net ultrafiltration with advanced hemodynamic monitoring<br>* A net ultrafiltration rate of 100 ml/h or more will be applied during the first 72 hours of study participation. To insure the hemodynamic security of the intervention, it is associated with an advanced hemodynamic monitoring protocol which encompasses cardiac index, preload dependence assessment (using postural maneuvers), lactate levels and central venous pressure evaluation. The hemodynamic monitoring protocol allows the decrease or suspension of the neutral ultrafiltration rate in case of hemodynamic instability or of hemodynamic status considered at risk of worsening if net ultrafiltration rate is maintained.<br>|
| Active Comparator: Standard care<br>Active control group of positive fluid balance during the first 72 hours of study participation with zero or near-zero net ultrafiltration. | Procedure: Zero or near-zero net ultrafiltration<br>* The active control group aims to represent the present standard of care of net ultrafiltration management in the first 72 hours of study participation in patients with critical illness. This will be performed by setting the net ultrafiltration rate to 0 up to 25 ml/h.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative fluid balance | The cumulative fluid balance (in ml) will be calculated as the total amount of input received by the patients (including IV fluids and medications, blood products, hydration and nutrition), minus the total output over the same period of time (including urine output, net ultrafiltration, and drains). The cumulative fluid balance at H72 will be compared between study groups in alive patients at H72. | 72 hours from study inclusion (H72) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of hemodynamic episodes | Hemodynamic instability is defined as the appearance of mottles, a mean arterial pressure < 65 mm Hg and requiring urgent intervention, a decrease in cardiac index > 15%, or tachycardia > 120 beats per minute (bpm). | 72 hours from study inclusion | 
| Number of hemodynamic episodes with preload dependence status | Hemodynamic episodes defined as stated above, that were associated with preload dependence, defined as a significant increase in cardiac index when performing a postural maneuver. This test will be performed every 4 hours as part of the hemodynamic protocol | 72 hours from study inclusion | 
| Number of Major Adverse Kidney Events (MAKE) | MAKE is a composite criterion applied to participants, composed of either the persistence of renal impairment at Day90 (defined as a serum creatinine > 2 x baseline value), renal replacement therapy dependence at Day90, or death at Day90. A separate analysis of each components of the MAKE 90 outcome will be performed. | 90 days from study inclusion | 
| Mean arterial pressure | Repeated measurement or assessment of mean arterial pressure, cardiac index, lactatemia, and vasopressor dose will make it possible to assess the hemodynamic effect of study intervention | Every 4 hours from inclusion to 72 hours after inclusion | 
| Cardiac index | Repeated measurement or assessment of mean arterial pressure, cardiac index, lactatemia, and vasopressor dose will make it possible to assess the hemodynamic effect of study intervention | Every 4 hours from inclusion to 72 hours after inclusion | 
| Lactatemia | Repeated measurement or assessment of mean arterial pressure, cardiac index, lactatemia, and vasopressor dose will make it possible to assess the hemodynamic effect of study intervention | Every 4 hours from inclusion to 72 hours after inclusion | 
| Vasopressor dose administered | Repeated measurement or assessment of mean arterial pressure, cardiac index, lactatemia, and vasopressor dose will make it possible to assess the hemodynamic effect of study intervention | Every 4 hours from inclusion to 72 hours after inclusion | 
| Cumulative fluid balance | The cumulative fluid balance will be calculated as stated for the primary outcome at Hours24. It will be estimated using body weight variation between inclusion and day 7. | 24 hours and day 7 from study inclusion | 
| Cumulative net ultrafiltration | The cumulative net ultrafiltration is reported by CRRT (continuous renal replacement therapy) generators ad collected every 4 hours from inclusion to 72 hours after inclusion. | 24 hours, 72 hours and day 7 from study inclusion | 
| Number of respiratory and circulatory failure free days | Organ failure free days are defined as the number of days without organ support, and censored at 28 days of inclusion. Weaning of mechanical ventilation is defined as being free of IMV for 48 hours or more. Weaning of vasopressor is defined as being free of any vasopressor administration for 48 hours or more. Participant who die are over the 28-day period are assigned a value of 0 organ failure free days. | Day 28 of study inclusion | 
| Severity of organ failures using the SOFA score | Organ failure severity is quantified using the SOFA score (Sepsis-related organ failure assessment), and is collected at inclusion, and daily until Hours 72. The SOFA score assesses 6 physiological systems: respiratory, circulatory, coagulation, liver, renal and neurological. | from inclusion to 72 hours of study inclusion | 
| PaO2/FiO2 ratio | Intensity of pulmonary hydrostatic edema will be quantified using the PaO2/FiO2 ratio variation from inclusion to Hours24, Hours48 and Hours72 of study inclusion | 24 hours, 48 hours, and 72 hours from study inclusion | 
| Extravascular lung water index | Intensity of pulmonary hydrostatic edema will be quantified using the extravascular lung water index reported by the continuous cardiac monitoring device, from inclusion to Hours24, Hours48 and Hours72 of study inclusion | 24 hours, 48 hours, and 72 hours from study inclusion | 
| Hospitalisation duration | Hospitalisation duration will be quantified as the delay between participant admission and discharge from hospital, censored at day 90 from inclusion. | Day 90 of study inclusion | 
| Duration of stay in Intensive Care Unit (ICU) | Duration of stay in ICU will be quantified as the delay between participant admission and discharge from ICU, censored at day 90 from inclusion | Day 90 of study inclusion | 
| Survival | Vital status (death/alive) will be reported at D28 and D90 of study inclusion. | Day 28 and 90 of study inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluid Overload, fluid balance, continuous renal replacement therapy, net ultrafiltration, acute kidney injury, hemodynamic monitoring, preload dependence, hemodynamic instability, acute circulatory failure, shock, deresuscitation