REstrictive versus LIberal rate of Extracorporeal Volume removal Evaluation in Acute Kidney Injury (RELIEVE-AKI)

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Abstract Two-thirds of critically ill patients with acute kidney injury have a fluid overload at the time of initiation of kidney replacement therapy in the intensive care unit. Although “net ultrafiltration (UFNET),” also known as net fluid removal during kidney replacement therapy, has been used in the treatment of fluid overload for more than seven decades, the optimal rate of UFNET remains uncertain, complications such as hypotension and cardiac arrhythmias occur frequently, and more than 40% of critically ill patients die. Emerging evidence from observational studies suggests a “J” shaped association between UFNET rate and mortality in critically ill patients with acute kidney injury and treated with kidney replacement therapy. Higher UFNET rates are associated with an increased risk of death compared with moderate and lower UFNET rates. Understanding the causal effects of UFNET rate on outcomes is critical to design interventions to reduce mortality, develop evidence-based clinical practice guidelines, and implement quality measures for UFNET. In the absence of such knowledge, optimizing UFNET to improve outcomes will remain problematic. Thus, we will conduct a pilot clinical trial entitled REstrictive versus LIberal rate of Extracorporeal Volume removal Evaluation in Acute Kidney Injury (RELIEVE-AKI) to examine the feasibility of restrictive compared with a liberal UFNET rate strategy. The study is a stepped-wedge cluster-randomized trial involving 144 critically ill patients with acute kidney injury and treated with continuous kidney replacement therapy in six intensive care units across two hospital systems. The intensive care units will be randomized 1:1 in which patients will receive either a restrictive or a liberal UFNET rate strategy. Both strategies are standards of care and are commonly used in current clinical practice. In the restrictive group, the UFNET rate will be titrated and maintained between 0.5-1.5 mL/kg/h. In the liberal group, the UFNET rate will be titrated and maintained between of 2.0-5.0 mL/kg/h. The primary feasibility outcomes are between-group differences in patient mean delivered UFNET rates, protocol adherence, and rate of patient recruitment (Aim 1). We will also explore the effects of alternative UFNET rate strategies on secondary outcomes including hypotensive episodes, and cardiac arrhythmias; emergent use of rescue UFNET rates higher than the assigned treatment arm for fluid overload; duration of kidney replacement therapy and mechanical ventilation; intensive care unit and hospital length of stay, and independence from kidney replacement therapy and hospital mortality (Aim 2). This pragmatic clinical trial will be used to support the rationale, assess feasibility, and design a phase III multicenter randomized trial to examine the effects of alternative UFNET rate strategies on patient-centered clinical outcomes. Our study will have a direct impact on the care of critically ill patients with acute kidney injury and thus will influence clinical practice, physicians, and policymakers.