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

Abstract

Importance: Net ultrafiltration (NUF) is frequently used to treat fluid overload among critically ill patients, but whether the rate of NUF affects outcomes is unclear.

Objective: To examine the association of NUF with survival among critically ill patients with acute kidney injury being treated with continuous venovenous hemodiafiltration.

Design, setting, and participants: The Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy trial was conducted between December 30, 2005, and November 28, 2008, at 35 intensive care units in Australia and New Zealand among critically ill adults with acute kidney injury who were being treated with continuous venovenous hemodiafiltration. This secondary analysis began in May 2018 and concluded in January 2019.

Exposures: Net ultrafiltration rate, defined as the volume of fluid removed per hour adjusted for patient body weight.

Main outcomes and measures: Risk-adjusted 90-day survival.

Results: Of 1434 patients, the median (interquartile range) age was 67.3 (56.9-76.3) years; 924 participants (64.4%) were male; median (interquartile range) Acute Physiology and Chronic Health Evaluation III score was 100 (84-118); and 634 patients (44.2%) died. Using tertiles, 3 groups were defined: high, NUF rate greater than 1.75 mL/kg/h; middle, NUF rate from 1.01 to 1.75 mL/kg/h; and low, NUF rate less than 1.01 mL/kg/h. The high-tertile group compared with the low-tertile group was not associated with death from day 0 to 6. However, death occurred in 51 patients (14.7%) in the high-tertile group vs 30 patients (8.6%) in the low-tertile group from day 7 to 12 (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.13-2.02); 45 patients (15.3%) in the high-tertile group vs 25 patients (7.9%) in the low-tertile group from day 13 to 26 (aHR, 1.52; 95% CI, 1.11-2.07); and 48 patients (19.2%) in the high-tertile group vs 29 patients (9.9%) in the low-tertile group from day 27 to 90 (aHR, 1.66; 95% CI, 1.16-2.39). Every 0.5-mL/kg/h increase in NUF rate was associated with increased mortality (3-6 days: aHR, 1.05; 95% CI, 1.00-1.11; 7-12 days: aHR, 1.08; 95% CI, 1.02-1.15; 13-26 days: aHR, 1.11; 95% CI, 1.04-1.18; 27-90 days: aHR, 1.13; 95% CI, 1.05-1.22). Using longitudinal analyses, increase in NUF rate was associated with lower survival (β = .056; P < .001). Hypophosphatemia was more frequent among patients in the high-tertile group compared with patients in the middle-tertile group and patients in the low-tertile group (high: 308 of 477 patients at risk [64.6%]; middle: 293 of 472 patients at risk [62.1%]; low: 247 of 466 patients at risk [53.0%]; P < .001). Cardiac arrhythmias requiring treatment occurred among all groups: high, 176 patients (36.8%); middle: 175 patients (36.5%); and low: 147 patients (30.8%) (P = .08).

Conclusions and relevance: Among critically ill patients, NUF rates greater than 1.75 mL/kg/h compared with NUF rates less than 1.01 mL/kg/h were associated with lower survival. Residual confounding may be present from unmeasured risk factors, and randomized clinical trials are required to confirm these findings.

Trial registration: ClinicalTrials.gov identifier: NCT00221013.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Murugan reported receiving grants and personal fees from La Jolla Inc; grants from Bioporto, Inc, and the National Institute of Diabetes and Digestive and Kidney Diseases; and personal fees from Beckman Coulter and AM Pharma, Inc, outside the submitted work. Dr Chang reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Gallagher reported receiving speaking fees from Amgen outside the submitted work. Dr Clermont reported receiving personal fees from UpToDate and grants from the National Institutes of Health and the National Science Foundation outside the submitted work. Dr Palevsky reported receiving personal fees from Novartis, GE Healthcare, HealthSpan Dx, and Baxter International and grants from Dascena outside the submitted work. Dr Kellum reported receiving personal fees from NxStage and grants and personal fees from Baxter International during the conduct of the study. Dr Bellomo reported receiving grants from Baxter International outside the submitted work. No other disclosures were reported.

Figures

Figure.. Net Ultrafiltration (NUF) Rate and Survival From Gray Model

Hazard ratios (blue solid lines) are shown with 95% CIs (blue dotted lines). The orange line indicates a hazard ratio of 1. A hazard ratio less than 1 suggests that the NUF rate is associated with lower mortality, and a hazard ratio greater than 1 suggests that the NUF is associated with higher mortality. A, The risk of death associated with an NUFrate greater than 1.75 mL/kg/h compared with an NUFrate slower than 1.01 mL/kg/h was 51% for day 7 to 12, 52% for day 13 to 26, and 66% for day 27 to 90. B, An NUFrate from 1.01 to 1.75 mL/kg/h was not associated with death. C, For an NUFrate greater than 1.75 mL/kg/h compared with an NUFrate from 1.01 to 1.75 mL/kg/h, the risk of death was 44% for day 7 to 12, 42% for day 13 to 26, and 77% for day 27 to 90. D, Every 0.50-mL/kg/h increase in NUFrate was associated with death: 5% for day 3 to 6, 8% for day 7 to 12, 11% for day 13 to 26, and 13% for day 27 to 90.