Balanced Crystalloids versus Saline in Critically Ill Adults

Abstract

BACKGROUND:: Both balanced crystalloids and saline are used for intravenous fluid administration among critically ill adults. Which results in better clinical outcomes remains unknown.

METHODS:: In a pragmatic, cluster-randomized, multiple-crossover trial in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A®), according to the randomization of the unit to which they were admitted. The primary outcome was Major Adverse Kidney Events within 30 days (MAKE30), i.e., the composite of death, new renal replacement therapy, or persistent creatinine elevation ≥ 200% of baseline – all censored at the first of hospital discharge or 30 days.

RESULTS:: In the balanced crystalloid group, 1,139 patients (14.3%) experienced MAKE30, compared to 1,211 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval, 0.84–0.99; conditional odds ratio, 0.90; 95% confidence interval, 0.82–0.99; P=0.04). Thirty-day in-hospital mortality was 10.3% in the balanced crystalloid group and 11.1% in the saline group (P=0.06). The incidence of new renal replacement therapy was 2.5% and 2.9% respectively (P=0.08), and the incidence of persistent creatinine elevation was 6.4% and 6.6% respectively (P=0.60).

CONCLUSIONS:: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration appeared to reduce the composite outcome of in-hospital mortality, new renal replacement therapy, and persistent renal dysfunction compared with the use of saline. (SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779.)

Conflict of interest statement

Conflicts of Interest: All authors completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. W.H.S. reported serving on advisory boards for Venaxis Inc, Cempra Pharmaceuticals, Ferring Pharmaceuticals, and BioTest AG, serving as a consultant for Abbott Point of Care, and receiving travel funds from Gilead Pharmaceuticals. A.K.M. reported receiving funding from Atoxbio Ltd. L.We. reported receiving funding from Medtronic Inc. T.W.R. reported serving on an advisory board for Avisa Pharma, LLC and as the Director of Medical Affairs for Cumberland Pharmaceuticals, Inc.

Figures

Figure 1. Volume of Intravenous Isotonic Crystalloid by Study Arm.

For patients assigned to the balanced crystalloid group (left) and saline group (right), the cumulative volume (mean and 95% confidence interval) of intravenous balanced crystalloid and 0.9% sodium chloride ordered between ICU admission and hospital discharge is displayed over time.

Figure 2. Plasma Chloride and Bicarbonate Concentration by Study Arm.

The mean and 95% confidence interval for the first plasma chloride (left) or bicarbonate (right) measurement each day are displayed for patients in the balanced crystalloid (blue) and saline (red) groups using locally weighted scatterplot smoothing. Plasma chloride and bicarbonate concentrations were similar between groups at hospital presentation (Table S3 in the Supplementary Appendix), but, because fluid therapy in the emergency department and operating room was coordinated with the ICU to which patients were being admitted, plasma chloride concentration differed between the balanced crystalloid and saline groups at ICU admission.

Figure 3. Subgroup Analyses.

For each pre-specified subgroup, the figure displays the number and percentage of patients in each study group who experienced MAKE30, the odds ratio and 95% confidence interval for experiencing MAKE30 in the balanced crystalloid group compared with the saline group, and the P values within the subgroup and for the test of interaction derived from a generalized linear mixed-effects model adjusting only for ICU as a random effect (analyses adjusting for additional covariates are displayed in Table 2). TBI is traumatic brain injury. Normal kidney function at enrollment is defined as the absence of acute kidney injury (AKI), chronic kidney disease (CKD), or renal replacement therapy prior to enrollment. AKI refers to patients without CKD whose first creatinine after enrollment was at least 200% of the baseline value OR both (1) greater than 4.0 mg/dL and (2) increased at least 0.3 mg/dL from the baseline value. CKD refers to patents with a glomerular filtration rate less than 60 ml/min per 1.73 m2 as calculated by the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation using the patient’s baseline creatinine value. Prior renal replacement therapy (RRT) refers to patients known to have received any form of RRT prior to enrollment.