Clinical trial NCT05306964: Restrictive Versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury
Official title: REstrictive Versus LIberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute Kidney Injury
Fluid Overload
Hypotension
Dialysis; Complications
Critical Illness
Keywords: Fluid overload
Acute kidney injury
Net ultrafiltration
Intensive care unit
Intradialytic hypotension
Complications
Feasibility Trial
Cardiac arrhythmias
Mortality
Dialysis dependence
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2022-04-01
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial.
Primary purpose: TREATMENT

Brief summary: 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: "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.

Eligibility criteria: Inclusion Criteria:

1. Age 18 years or older
2. Stage 3 acute kidney injury according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria
3. Started or intending to start CKRT for volume management
4. Attending intensivist or nephrologist intending to remove net fluid using CKRT for at least 48 hours

Exclusion Criteria:

1. Respiratory distress due to pulmonary edema or fluid overload in unintubated patients
2. Massive volume infusion (i.e., \>200 mL/h for \>6 hours of continuous infusion)
3. No intention to remove net fluid as determined by attending intensivist or nephrologist
4. Attending intensivist or nephrologist believes that the protocol will not be followed
5. Continuous net fluid removal for \>48 hours prior to study enrollment
6. Patients on chronic outpatient hemodialysis
7. Patients with history of, or current admission for kidney transplantation
8. Patients on comfort measures only orders.
9. Moribund not expected to survive \>24 hours
10. Confirmed pregnancy
11. Patients treated with extracorporeal membrane oxygenation, ventricular assist device, or intra-aortic balloon pump
12. Organ donors with neurological determination of death (i.e., brain dead donors)
13. Drug overdose requiring CKRT for drug clearance
14. Enrollment in a concurrent interventional clinical trial with direct impact on fluid balance (e.g., \>500 mL study drug administration)

Primary outcomes:
measure: Delivered UFnet rates.
timeFrame: Until the end of continuous kidney replacement therapy or day 28.
measure: No. of participants with protocol deviation.
timeFrame: Until the end of continuous kidney replacement therapy or day 28.
measure: Participant recruitment rate over 21 months
timeFrame: Through study completion, an average of 21 months
Secondary outcomes:
measure: Daily fluid balance
timeFrame: Daily from enrollment to ICU discharge or until day 28.
measure: Cumulative fluid balance
timeFrame: Daily from enrollment to ICU discharge or until day 28.
measure: Duration of kidney replacement therapy
timeFrame: Daily from enrollment to hospital discharge or until day 28.
measure: Duration of mechanical ventilation
timeFrame: Daily from study enrollment to ICU discharge or until day 28.
measure: Organ failure free days
timeFrame: Daily from study enrollment to ICU discharge or until day 28.
measure: ICU length of stay
timeFrame: Daily from study enrollment to ICU discharge or day 28.
measure: Hospital length of stay
timeFrame: Daily from study enrollment to hospital discharge or day 28.
measure: Hospital mortality
timeFrame: From study enrollment to hospital discharge or day 28.
measure: Dependence on kidney replacement therapy
timeFrame: From study enrollment until hospital discharge or day 28.
Other outcomes:
measure: No. of intradialytic hypotension episodes
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of intradialytic hypertension episodes
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of episodes of intradialytic cardiac arrhythmias
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants who receive UFnet rates higher than the assigned intervention arm for treatment of fluid overload emergencies.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with severe hypophosphatemia
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with severe hypokalemia
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with severe hypocalcemia
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of episodes of stopping of CKRT system due to hemofilter clotting or clogging.
timeFrame: From study enrollment until termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with discontinuation of fluid removal due to hemodynamic instability.
timeFrame: From study enrollment until termination of continuous kidney replacement therapy or day 28.
measure: No. of participants in whom surgical wounds are left open after surgery due to tissue edema.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with new organ dysfunction as assessed by change in Sequential Organ Failure Assessement (SOFA) scoring system from baseline.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with worsening of systolic or diastolic cardiac function on echocardiogram from baseline.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with worsening of pulmonary edema on chest X Ray and/or CT scan based on radiologist report.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with worsening of ileus on abdominal X Ray and/or CT scan based on radiologist report.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with bowel ischemia or anastomotic breakdown based on intraoperative findings.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with pressure ulceration per nursing records.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with new wound infection per nursing records.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with new arterial and/or deep vein thrombosis as assessed by doppler studies.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with severe anemia requiring red cell transfusions.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with severe thrombocytopenia requiring platelet transfusions.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
measure: No. of participants with new secondary infections.
timeFrame: From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Raghavan Murugan, MD, MS, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Murugan R, Kerti SJ, Chang CH, Gallagher M, Clermont G, Palevsky PM, Kellum JA, Bellomo R. Association of Net Ultrafiltration Rate With Mortality Among Critically Ill Adults With Acute Kidney Injury Receiving Continuous Venovenous Hemodiafiltration: A Secondary Analysis of the Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy Trial. JAMA Netw Open. 2019 Jun 5;2(6):e195418. doi: 10.1001/jamanetworkopen.2019.5418.
citation: Murugan R, Balakumar V, Kerti SJ, Priyanka P, Chang CH, Clermont G, Bellomo R, Palevsky PM, Kellum JA. Net ultrafiltration intensity and mortality in critically ill patients with fluid overload. Crit Care. 2018 Sep 24;22(1):223. doi: 10.1186/s13054-018-2163-1.
citation: Serpa Neto A, Naorungroj T, Murugan R, Kellum JA, Gallagher M, Bellomo R. Heterogeneity of Effect of Net Ultrafiltration Rate among Critically Ill Adults Receiving Continuous Renal Replacement Therapy. Blood Purif. 2021;50(3):336-346. doi: 10.1159/000510556. Epub 2020 Oct 7.
citation: Naorungroj T, Neto AS, Zwakman-Hessels L, Yanase F, Eastwood G, Murugan R, Kellum JA, Bellomo R. Early net ultrafiltration rate and mortality in critically ill patients receiving continuous renal replacement therapy. Nephrol Dial Transplant. 2021 May 27;36(6):1112-1119. doi: 10.1093/ndt/gfaa032.
citation: Naorungroj T, Neto AS, Zwakman-Hessels L, Fumitaka Y, Eastwood G, Murugan R, Kellum JA, Bellomo R. Mediators of the Impact of Hourly Net Ultrafiltration Rate on Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy. Crit Care Med. 2020 Oct;48(10):e934-e942. doi: 10.1097/CCM.0000000000004508.
citation: Murugan R, Ostermann M, Peng Z, Kitamura K, Fujitani S, Romagnoli S, Di Lullo L, Srisawat N, Todi S, Ramakrishnan N, Hoste E, Puttarajappa CM, Bagshaw SM, Weisbord S, Palevsky PM, Kellum JA, Bellomo R, Ronco C. Net Ultrafiltration Prescription and Practice Among Critically Ill Patients Receiving Renal Replacement Therapy: A Multinational Survey of Critical Care Practitioners. Crit Care Med. 2020 Feb;48(2):e87-e97. doi: 10.1097/CCM.0000000000004092.
citation: Murugan R, Bellomo R, Palevsky PM, Kellum JA. Ultrafiltration in critically ill patients treated with kidney replacement therapy. Nat Rev Nephrol. 2021 Apr;17(4):262-276. doi: 10.1038/s41581-020-00358-3. Epub 2020 Nov 11.
citation: Lumlertgul N, Murugan R, Seylanova N, McCready P, Ostermann M. Net ultrafiltration prescription survey in Europe. BMC Nephrol. 2020 Dec 1;21(1):522. doi: 10.1186/s12882-020-02184-y.
citation: Chen H, Murugan R. Survey of U.S. Critical Care Practitioners on Net Ultrafiltration Prescription and Practice among Critically Ill Patients Receiving Kidney Replacement Therapy. J Crit Care Med (Targu Mures). 2021 Nov 6;7(4):272-282. doi: 10.2478/jccm-2021-0034. eCollection 2021 Oct.
citation: Tehranian S, Shawwa K, Kashani KB. Net ultrafiltration rate and its impact on mortality in patients with acute kidney injury receiving continuous renal replacement therapy. Clin Kidney J. 2019 Dec 17;14(2):564-569. doi: 10.1093/ckj/sfz179. eCollection 2021 Feb.
citation: Naorungroj T, Serpa Neto A, Murugan R, Kellum JA, Bellomo R. Continuous Renal Replacement Therapy: The Interaction between Fluid Balance and Net Ultrafiltration. Am J Respir Crit Care Med. 2021 May 1;203(9):1199-1201. doi: 10.1164/rccm.202011-4097LE. No abstract available.
citation: Kitamura K, Hayashi K, Fujitani S, Murugan R, Suzuki T. Ultrafiltration in Japanese critically ill patients with acute kidney injury on renal replacement therapy. J Intensive Care. 2021 Dec 20;9(1):77. doi: 10.1186/s40560-021-00590-4.