Restrictive Versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI)

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.

"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.

Fluid overload, Acute kidney injury, Net ultrafiltration, Intensive care unit, Intradialytic hypotension, Complications, Feasibility Trial, Cardiac arrhythmias, Mortality, Dialysis dependence

Prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial.

In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal.

In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal.

A minimum separation of 0.53-0.57 mL/kg/h in mean delivered UFnet rates between the two intervention arms.

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.

Intradialytic hypotension will be defined as a new mean arterial pressure <65 mmHg, systolic blood pressure <90 mmHg or a decline in systolic blood pressure >40 mmHg, and/or a >30% increase in dose of existing vasopressors, initiating a new vasopressor, or administration of fluid bolus with a goal to maintain mean arterial pressure >=65 mmHg, systolic blood pressure >=90 mmHg.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

Intradialytic hypertension will be defined as new onset systolic blood pressure >=160 mmHg or mean arterial pressure >=80 mmHg for more than 1 hour in the absence of any vasopressor or inotrope use.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

New onset intradialytic cardiac arrhythmias including supraventricular tachycardia, bradycardia, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, asystole/pulseless electrical activity will be diagnosed as per American Heart Association.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants who receive UFnet rates higher than the assigned intervention arm for treatment of fluid overload emergencies.

No. of participants in whom emergent use of UFnet rates higher than the assigned treatment arm for more than 3 consecutive hours will be noted.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants in whom fluid removal is stopped due to hemodynamic instability such as intradialytic hypotension, cardiac arrhythmias, or cardiac arrest.

This will be determined as per the primary surgeon. Abdominal wounds left open for a second look or for abdominal re-exploration will not be counted unless there is concurrent tissue edema precluding abdominal closure.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with new organ dysfunction as assessed by change in Sequential Organ Failure Assessement (SOFA) scoring system from baseline.

New organ dysfunction will be assessed by changes in SOFA scores from the baseline across the five organ systems of central nervous system, cardiovascular, respiratory, coagulation, and liver.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with worsening of systolic or diastolic cardiac function on echocardiogram from baseline.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with worsening of pulmonary edema on chest X Ray and/or CT scan based on radiologist report.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with worsening of ileus on abdominal X Ray and/or CT scan based on radiologist report.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

Intraoperative findings of bowel ischemia or anastomotic breakdown will be noted as determined by the surgeon (if available).

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with new diagnosis of pressure ulcerations as documented by the nursing staff in the electronic medical record (if available)

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

No. of participants with new diagnosis of wound infection as documented by the nursing staff in the electronic medical record (if available)

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

New diagnosis of secondary infections occurring after initiation of study intervention will be collected based on culture data, antibiotic use and suspected sepsis as per clinician judgment (if available).

From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

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)

The RELIEVE-AKI study investigators will review the request for data from other investigators. The investigators will execute a data-sharing agreement with the University of Pittsburgh to share de-identified data with other investigators for research purposes only. The data-sharing agreement will ensure: i.) a commitment to using the data only for research purposes and not to identify any individual participant; ii.) a commitment to securing the data using appropriate computer technology; and iii.) a commitment to destroying or returning the data after analyses are completed on a specific date. The investigators will not release any patient identifiers in any of the data files shared with other researchers. The investigators will also require appropriate confidentiality agreements and approvals from the Institutional Review Boards of other investigators before the data are shared.

Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

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