Restrictive Versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury

Study Overview
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Brief Summary
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Critically ill patients with acute kidney injury and fluid overload who are frequently treated by fluid removal during dialysis are at an increased risk of complications and death. Both slower and faster rates of fluid removal may cause injury to the vital organs. This proposed clinical trial will examine the feasibility of restrictive compared with a liberal rate of fluid removal in order to develop effective treatments for fluid overload and to improve the health of critically ill patients.

Detailed Description
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Net ultrafiltration (UFnet), also known as net fluid removal during kidney replacement therapy, has been used in the treatment of fluid overload among critically ill patients with acute kidney injury (AKI) for more than seven decades. However, the optimal rate of fluid removal (i.e., UFnet rate) remains uncertain, complications such as hypotension and cardiac arrhythmias occur frequently, and more than 40% of patients die. Observational studies in critically ill patients receiving continuous kidney replacement therapy (CKRT) show that UFnet rate has a J shaped association with mortality with both slower and faster UFnet rates associated with increased risk of death compared with moderate UFnet rates. The overall objective of this randomized trial is to establish the feasibility of maintaining patients in the restrictive UFnet rate strategy during treatment with CKRT. The investigator's central hypothesis is that a restrictive UFnet rate strategy embracing a slow and steady approach to fluid removal is associated with fewer complications, including cardiac arrhythmias, hypotension, and death, compared with a more liberal sprint and pause strategy among critically ill patients. The trial is a prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial among 112 critically ill patients with AKI treated with CKRT in 10 ICUs across two hospital systems. The trial will be conducted at 5 ICUs at University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania, as well as 5 ICUs at Mayo Clinic, Rochester, Minnesota. ICUs will be randomized 1:1 to either a restrictive or a liberal UFnet rate strategy. During the first six months, all ICUs will continue with a liberal UFnet rate strategy. Every two months thereafter or when 10 patients have been enrolled, whichever occurs first, one ICU will be randomized to deploy the restrictive UFnet rate strategy. In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal. In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal. The UFnet rates used in both strategies are used in current clinical practice.This feasibility trial will be used to support the rationale and design of a future multicenter phase III randomized trial to examine the effects of alternative UFnet rate strategies on patient-centered clinical outcomes.

Official Title
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REstrictive Versus LIberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury

Conditions
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Acute Kidney Injury, Fluid Overload, Hypotension, Dialysis; Complications, Critical Illness

Intervention / Treatment
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* Procedure: Restrictive UFnet Rate Strategy
* Procedure: Liberal UFnet Rate Strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Stage 3 acute kidney injury according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria Started or intending to start CKRT for volume management Attending intensivist or nephrologist intending to remove net fluid using CKRT for at least 48 hours Exclusion Criteria: Respiratory distress due to pulmonary edema or fluid overload in unintubated patients Massive volume infusion (i.e., >200 mL/h for >6 hours of continuous infusion) No intention to remove net fluid as determined by attending intensivist or nephrologist Attending intensivist or nephrologist believes that the protocol will not be followed Continuous net fluid removal for >48 hours prior to study enrollment Patients on chronic outpatient hemodialysis Patients with history of, or current admission for kidney transplantation Patients on comfort measures only orders. Moribund not expected to survive >24 hours Confirmed pregnancy Patients treated with extracorporeal membrane oxygenation, ventricular assist device, or intra-aortic balloon pump Organ donors with neurological determination of death (i.e., brain dead donors) Drug overdose requiring CKRT for drug clearance Enrollment in a concurrent interventional clinical trial with direct impact on fluid balance (e.g., >500 mL study drug administration)

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Restrictive UFnet Strategy<br>Fluid removal will be titrated to keep net ultrafiltration rate between 0.5-1.5 mL/kg/h | Procedure: Restrictive UFnet Rate Strategy<br>* In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal.<br>|
| Active Comparator: Liberal UFnet Strategy<br>Fluid removal will be titrated to keep net ultrafiltration rate between 2.0-5.0 mL/kg/h | Procedure: Liberal UFnet Rate Strategy<br>* In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delivered UFnet rates. | A minimum separation of 0.53-0.57 mL/kg/h in mean delivered UFnet rates between the two intervention arms. | Until the end of continuous kidney replacement therapy or day 28. | 
| No. of participants with protocol deviation. | Protocol deviation defined as delivered UFnet rate that lies >0.5 mL/kg/h outside of the target UFnet rate range for greater than six consecutive hours. | Until the end of continuous kidney replacement therapy or day 28. | 
| Participant recruitment rate over 21 months | An enrollment rate of 1 patient per ICU per time window. | Through study completion, an average of 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily fluid balance | Patient daily fluid balance will be measured while on continuous kidney replacement therapy. | Daily from enrollment to ICU discharge or until day 28. | 
| Cumulative fluid balance | Patient cumulative fluid balance will be measured while on continuous kidney replacement therapy. | Daily from enrollment to ICU discharge or until day 28. | 
| Duration of kidney replacement therapy | The number of days the patient received kidney replacement therapy while in the hospital. | Daily from enrollment to hospital discharge or until day 28. | 
| Duration of mechanical ventilation | The number of days the patient received mechanical ventilation while in hospital. | Daily from study enrollment to ICU discharge or until day 28. | 
| Organ failure free days | The no. of days the patient remained free of organ failure while in the ICU. | Daily from study enrollment to ICU discharge or until day 28. | 
| ICU length of stay | The number of days patients need to stay in the ICU | Daily from study enrollment to ICU discharge or day 28. | 
| Hospital length of stay | The number of days patients need to stay in the hospital | Daily from study enrollment to hospital discharge or day 28. | 
| Hospital mortality | The proportion of patients who died while in the hospital. | From study enrollment to hospital discharge or day 28. | 
| Dependence on kidney replacement therapy | The proportion of patients who were on dialysis at hospital discharge. | From study enrollment until hospital discharge or day 28. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mortality, Fluid overload, Acute kidney injury, Net ultrafiltration, Intensive care unit, Intradialytic hypotension, Complications, Feasibility Trial, Cardiac arrhythmias, Dialysis dependence