Outcomes Research in Review

Balanced Crystalloids in the Critically Ill

Semler MW, Self WH, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical
Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl J Med



Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.


Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

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