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

Critical Illness Clinical Trial

— RELIEVE-AKI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05306964
• Other study ID #: STUDY21080010
• Secondary ID: 1R01DK128100-01A
• Status: Recruiting
• Phase: N/A
• Start date: July 5, 2022
• Est. completion date: June 17, 2024

Study information

• Verified date: September 2023
• Source: University of Pittsburgh
• Contact: Raghavan Murugan, MD, MS, FRCP
• Phone: 412-383-4201
• Email: muruganr[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: June 17, 2024
• Est. primary completion date: June 17, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Acute Kidney Injury
• Critical Illness
• Dialysis; Complications
• Fluid Overload
• Hypotension
• Wounds and Injuries

Intervention

Procedure:
• Restrictive UFnet Rate Strategy
In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal.
• Liberal 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.

Locations

Country	Name	City	State
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (3)

Lead Sponsor	Collaborator
University of Pittsburgh	Mayo Clinic, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	No. of intradialytic hypotension episodes	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.
Other	No. of intradialytic hypertension episodes	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.
Other	No. of episodes of intradialytic cardiac arrhythmias	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.
Other	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.
Other	No. of participants with severe hypophosphatemia	Hypophosphatemia defined by serum phosphate <0.5 mg/dL	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with severe hypokalemia	Hypokalemia defined by serum potassium <3.0 mg/dL	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with severe hypocalcemia	Hypocalcemia defined by serum calcium <1.90 mg/dL or ionized calcium <0.90 mmol/L	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of episodes of stopping of CKRT system due to hemofilter clotting or clogging.	Stopping of CKRT system due to filter clotting and/or clogging.	From study enrollment until termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with discontinuation of fluid removal due to hemodynamic instability.	No. of participants in whom fluid removal is stopped due to hemodynamic instability such as intradialytic hypotension, cardiac arrhythmias, or cardiac arrest.	From study enrollment until termination of continuous kidney replacement therapy or day 28.
Other	No. of participants in whom surgical wounds are left open after surgery due to tissue edema.	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.
Other	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.
Other	No. of participants with worsening of systolic or diastolic cardiac function on echocardiogram from baseline.	Changes in transthoracic echocardiogram will be assessed from baseline (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with worsening of pulmonary edema on chest X Ray and/or CT scan based on radiologist report.	Changes in chest X ray and CT scan will be assessed from baseline (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with worsening of ileus on abdominal X Ray and/or CT scan based on radiologist report.	Changes in abdominal X ray and CT scan will be assessed from baseline (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with bowel ischemia or anastomotic breakdown based on intraoperative findings.	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.
Other	No. of participants with pressure ulceration per nursing records.	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.
Other	No. of participants with new wound infection per nursing records.	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.
Other	No. of participants with new arterial and/or deep vein thrombosis as assessed by doppler studies.	New arterial thrombosis or deep vein thrombosis as assessed by doppler study (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with severe anemia requiring red cell transfusions.	Participants with severe anemia requiring red cell transfusions (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with severe thrombocytopenia requiring platelet transfusions.	No. of participants with severe thrombocytopenia requiring platelet transfusions (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
Other	No. of participants with new secondary infections.	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.
Primary	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.
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Hospital mortality	The proportion of patients who died while in the hospital.	From study enrollment to hospital discharge or day 28.
Secondary	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.