Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial

Abstract

Rationale: Saline is the intravenous fluid most commonly administered to critically ill adults, but it may be associated with acute kidney injury and death. Whether use of balanced crystalloids rather than saline affects patient outcomes remains unknown.

Objectives: To pilot a cluster-randomized, multiple-crossover trial using software tools within the electronic health record to compare saline to balanced crystalloids.

Methods: This was a cluster-randomized, multiple-crossover trial among 974 adults admitted to a tertiary medical intensive care unit from February 3, 2015 to May 31, 2015. The intravenous crystalloid used in the unit alternated monthly between saline (0.9% sodium chloride) and balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A). Enrollment, fluid delivery, and data collection were performed using software tools within the electronic health record. The primary outcome was the difference between study groups in the proportion of isotonic crystalloid administered that was saline. The secondary outcome was major adverse kidney events within 30 days (MAKE30), a composite of death, dialysis, or persistent renal dysfunction.

Measurements and main results: Patients assigned to saline (n = 454) and balanced crystalloids (n = 520) were similar at baseline and received similar volumes of crystalloid by 30 days (median [interquartile range]: 1,424 ml [500-3,377] vs. 1,617 ml [500-3,628]; P = 0.40). Saline made up a larger proportion of the isotonic crystalloid given in the saline group than in the balanced crystalloid group (91% vs. 21%; P < 0.001). MAKE30 did not differ between groups (24.7% vs. 24.6%; P = 0.98).

Conclusions: An electronic health record-embedded, cluster-randomized, multiple-crossover trial comparing saline with balanced crystalloids can produce well-balanced study groups and separation in crystalloid receipt. Clinical trial registered with www.clinicaltrials.gov (NCT 02345486).

Trial registration: ClinicalTrials.gov NCT02345486.

Keywords: acute kidney injury; critical illness; crystalloid; intravenous fluid; saline.

Figure 1.

Flow of participants through the trial. All 974 patients admitted to the medical intensive care unit (ICU) during the 4-month study period were enrolled, assigned to a balanced crystalloid group, followed through hospital discharge, and included in the intention-to-treat analysis. A total of 51 patients assigned to saline remained in the ICU through a crossover to balanced crystalloids, and 53 patients assigned to balanced crystalloids remained in the ICU through a crossover to saline. Median days spent in the ICU after a crossover in crystalloid assignment were 0 (range, 0–0) overall and 3.0 (range, 2.3–6.4) among the 104 patients who remained in the ICU through a crossover.

Figure 2.

Crystalloid receipt in the intensive care unit. For patients assigned to the saline group (left) and balanced crystalloid group (right), the cumulative volume of intravenous 0.9% sodium chloride (diamonds) and balanced crystalloid (circles) is displayed over time. Cumulative volume (mean and 95% confidence interval) includes fluids given in the intensive care unit as a bolus, as maintenance, or to accompany medications. Day 0 is the day of study enrollment. Fluid received before the time of enrollment on Day 0 includes fluid received between hospital admission and intensive care unit admission but does not include fluid given before hospital admission by the emergency medical system, emergency department, or transferring facility.

Figure 3.

Daily laboratory values by saline (red) and balanced crystalloid (blue) group. The first value each day is displayed as mean (95% confidence interval) for each study group using locally weighted scatterplot smoothing. Values on Day 0 represent the first available laboratory measurement after enrollment and may not precede the receipt of the assigned crystalloid. A P value for the difference between groups in the laboratory value overall (main effect) and the difference between groups in the change in the laboratory value over time (interaction) were generated using generalized estimating equations. The number of patients with laboratory values available declined from 882 on Day 1 to 311 on Day 7. Note that the highest and lowest serum values each day are available in Figures E3 and E4 of the online supplement.

Figure 4.

Heterogeneity of treatment effect. The incidence of major adverse kidney events within 30 days (MAKE30) is compared between patients assigned to the saline (red) and balanced crystalloid (blue) groups across the spectrum of exposure to the study crystalloids (upper left), baseline risk of death (upper right), and prespecified subgroups (bottom). Colored vertical bars display a histogram of the proportion of patients in each group who received a given volume of crystalloid (upper left) or possessed a given predicted in-hospital mortality (upper right). For each prespecified subgroup, the lower panel displays the unadjusted number and percentage of patients in each study arm who experienced MAKE30, the unadjusted odds ratio for experiencing MAKE30 with 95% confidence interval (CI), and the P values within the subgroup and for the test of interaction. Normal kidney function at enrollment is defined as the absence of acute kidney injury (AKI), chronic kidney disease (CKD), or renal replacement therapy (RRT) before enrollment. AKI refers to patients without CKD whose first creatinine after enrollment was at least 200% of the baseline value or both (1) >4.0 mg/dl and (2) increased at least 0.3 mg/dl from the baseline value (22). CKD refers to patents with a glomerular filtration rate <60 ml/min per 1.73 m² as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation using the patient’s baseline creatinine value (41). RRT refers to patients who received any form of RRT before enrollment.