Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial

JAMA. 2015 Oct 27;314(16):1701-10. doi: 10.1001/jama.2015.12334.


Importance: Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality.

Objective: To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU).

Design and setting: Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients.

Participants: All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed.

Interventions: Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration.

Main outcomes and measures: The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality.

Results: In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40).

Conclusions and relevance: Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality.

Trial registration: clinicaltrials.gov Identifier: ACTRN12613001370796.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / mortality
  • Biomarkers / blood
  • Buffers
  • Creatinine / blood*
  • Cross-Over Studies
  • Crystalloid Solutions
  • Double-Blind Method
  • Feasibility Studies
  • Female
  • Fluid Therapy / adverse effects*
  • Fluid Therapy / methods
  • Fluid Therapy / mortality
  • Hospital Mortality
  • Humans
  • Intensive Care Units
  • Isotonic Solutions / administration & dosage
  • Isotonic Solutions / adverse effects*
  • Male
  • Middle Aged
  • Renal Replacement Therapy / statistics & numerical data
  • Sodium Chloride / administration & dosage
  • Sodium Chloride / adverse effects*
  • Time Factors


  • Biomarkers
  • Buffers
  • Crystalloid Solutions
  • Isotonic Solutions
  • Sodium Chloride
  • Creatinine

Associated data

  • ANZCTR/ACTRN12613001370796