By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

SYNOPSIS: Balanced crystalloids appear to reduce in-hospital mortality in critically ill patients with sepsis or without traumatic brain injury and may reduce in-hospital mortality in the entire cohort of critically ill patients.

SOURCE: Xue M, et al. Effects of chloride content of intravenous crystalloid solutions in critically ill adult patients: A meta-analysis with trial sequential analysis of randomized trials. Ann Intensive Care 2019;9:30.

Critically ill patients with distributive shock are resuscitated most frequently with IV crystalloid and/or colloid solutions. For sepsis in particular, the current Surviving Sepsis Campaign guidelines provide a strong recommendation based on low quality of evidence for initial resuscitation with IV crystalloid fluid. The guidelines also offer a best practice statement for further fluid resuscitation based on reassessment of hemodynamic status with preferential use of dynamic markers of fluid responsiveness.1 Guidelines for the management of distributive shock do not provide preferential recommendations for the type of IV crystalloid fluid. In the last five years, significant contributions to evolving and resolving the debate regarding balanced crystalloid vs. saline in critically ill patients with distributive shock have been made.2-4 However, a contemporary meta-analysis that incorporates these data had not been performed.

Xue et al incorporated all randomized and cluster-randomized trials that compared balanced crystalloids (i.e., those with a near-physiological chloride concentration, such as PlasmaLyte and Ringer’s lactate) to 0.9% saline provided as resuscitative or maintenance fluids in critically ill adults.5 Articles indexed in Medline, EMBASE, Cochrane (Central) database, Elsevier, Web of Science, and by June 2018 were considered for inclusion, resulting in eight trials with 19,301 patients. Four trials were assessed as low risk of bias. Their protocol was registered a priori in the PROSPERO database (CRD42018102661). Researchers performed subgroup analyses for subpopulations of critical illness (e.g., sepsis, traumatic brain injury [TBI]) for primary and secondary outcomes. The authors developed and evaluated fixed effect and random effect models for each outcome.

A difference in in-hospital survival favoring balanced crystalloids to 0.9% saline may exist (10.1% vs. 10.9%; risk ratio [RR], 0.92; 95% confidence interval [CI], 0.85-1.0; P = 0.06; I2, 0%), although the results of a trial sequential analysis suggested the sample size was inadequate to detect a difference. Mortality at 30 and 60 days was similar between groups (RR, 0.92; 95% CI, 0.85-1.01; P = 0.08; and RR, 0.94; 95% CI, 0.87-1.02; P = 0.13, respectively). The evidence for the mortality outcomes was of low quality, according to GRADE criteria. Patients who received balanced crystalloids logged more days without renal replacement therapy (RRT; 25.6 days vs. 24.8 days; standard mean difference [SMD], 0.09; 95% CI, 0.06-0.12; P < 0.001), more days without using a ventilator (SMD, 0.08; 95% CI, 0.05-0.11; P < 0.001), and more days without using a vasopressor (SMD, 0.04; 95% CI, 0.00-0.07; P = 0.02). These patients also were at a lower risk of an increase in serum chloride levels (SMD, -1.23; 95% CI, -1.59 to -0.87; P < 0.001). Receipt of balanced crystalloids was associated with lower in-hospital mortality rates among septic patients (RR, 0.86; 95% CI, 0.75-0.98; P = 0.02) and non-TBI patients (RR, 0.90; 95% CI, 0.82-0.99; P = 0.02).


While surgical subspecialties of critical care have used balanced crystalloids as resuscitative and maintenance fluids predominately for years, recent interest in this practice from the medical critical care community has led to multiple randomized and cluster-randomized trials. This new research has helped reshape the landscape of IV fluid use in critical care. Of note, analyses were driven by the significant weight afforded to the recent cluster-randomized trial by Semler et al, which Xue et al determined to be of high risk of bias.3 This systematic review and meta-analysis helps clarify subpopulations of critical care that appear most susceptible to improved outcomes from balanced crystalloid administration while leaving some questions unanswered or inadequately answered.

The two subpopulations of critical care for which balanced crystalloids were identified confidently as beneficial in reducing in-hospital mortality were those with sepsis and those without TBI, which makes sense pathophysiologically. Balanced crystalloids may help resolve the metabolic acidosis and acute kidney injury that often happens during sepsis and septic shock. Conversely, 0.9% saline is more likely to raise serum sodium concentrations than balanced crystalloids, which may help alleviate raised intracranial pressure that often is present in TBI patients. Additionally, these outcomes may be achievable with relatively small volumes of IV fluids, as evidenced by 99% of patients in these studies receiving 2-3 L of IV fluids during the study period.

The authors described the overall primary outcome of in-hospital mortality as similar (RR, 0.92; 95% CI, 0.85-1.0; P = 0.06), which clinicians should note is based on P > 0.05 using frequentist statistics. Based on the point estimate and narrow confidence interval, there is a high probability (> 80% based on Bayesian statistics) that balanced crystalloids are associated with lower in-hospital mortality rates in the general critical care population. Additionally, although the authors chose not to include high-quality observational studies, those that have been published suggest a mortality benefit with balanced crystalloids.5,6 Better end-organ function (evidenced by greater time without vasopressor, mechanical ventilator, and RRT support) corroborates this finding. More confident statements regarding mortality in the overall critically ill cohort and subgroups of interest should be expected following completion of two ongoing randomized, controlled trials.7,8 At this point, clinicians should feel comfortable and justified using balanced crystalloids for resuscitative and maintenance fluids in critically ill patients (except for those with TBI).


  1. Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-377.
  2. Young P, et al. 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;314:1701-1710.
  3. Semler MW, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829-839.
  4. Semler MW, et al. Balanced crystalloids versus saline in the intensive care unit: The SALT randomized trial. Am J Respir Crit Care Med 2016;195:1362-1372.
  5. Raghunathan K, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med 2014;42:1585-1591.
  6. Shaw AD, et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care 2015;19:334.
  7. Zampieri FG, et al. Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS): A factorial randomised trial. Crit Care Resusc 2017;19:175-182.
  8. Hammond NE, et al. The Plasma-Lyte 148 v Saline (PLUS) study protocol: A multicentre, randomised controlled trial of the effect of intensive care fluid therapy on mortality. Crit Care Resusc 2017;19:239-246.