Balanced crystalloids are gaining ground in sepsis?

Brown RM, Wang L, Coston TD , Krishnan NI et el published a secondary analysis of patients from SMART (Isotonic Solutions and Major Adverse Renal Events Trial) admitted with sepsis to ICU.

Original  smart trial  was published in 2017,  which is discussed here .  A total of 15,802 patients  were enrolled in the trial.  It was a pragmatic, cluster-level allocation, cluster-level crossover trial  which compared  normal saline with balance crystalloid (lactated Ringer’s solution or Plasma-Lyte A)  in patient with sepsis.

Authors performed a secondary analysis of the patients with sepsis who was admitted in Medical ICU only(1641 PATIENTS). Original trial looked at the all patients with sepsis admitted to hospital.  They showed that 217 patients (26.3%) in the balanced crystalloids group experienced 30-day in-hospital morality compared with 255 patients (31.2%) in the saline group (adjusted odds ratio [aOR], 0.74; 95% confidence interval [CI], 0.59–0.93; P = 0.01). Patients in the balanced group experienced a lower incidence of major adverse kidney events within 30 days (35.4% vs. 40.1%; aOR, 0.78; 95% CI, 0.63–0.97) and a greater number of vasopressor-free days (20 ± 12 vs. 19 ± 13; aOR, 1.25; 95% CI, 1.02–1.54) and renal replacement therapy–free days (20 ± 12 vs. 19 ± 13; aOR, 1.35; 95% CI, 1.08–1.69) compared with the saline group.

This secondary analysis trial alone was enough to tilt the balance in favor of balance crystalloids, then Hammond DA, Lam SW, Rech MA et el  published meta-analysis of 13 trials of critically ill patients , which included more than 30,000 patients.


  1. Balanced crystalloids had lower hospital or 28-/30-day mortality (risk ratio [RR] = 0.86; 95% CI = 0.75-0.99; I2 = 82%) overall, in observational studies (RR = 0.64; 95% CI = 0.41-0.99; I2 = 63%).
  2. Approached significance in randomized trials (RR = 0.94; 95% CI = 0.88-1.02; I2 = 0%).
  3. New acute kidney injury occurred less frequently with balanced crystalloids (RR = 0.91; 95% CI = 0.85-0.98; I2 = 0%)
  4. Progression to renal replacement therapy was similar (RR = 0.91; 95% CI = 0.79-1.04; I2 = 38%).

Mortality did not reach significance in sepsis cohort.


The use of 0.9% saline is believed to have originated during the cholera pandemic that swept across Europe in 1831. It is recommended by surviving sepsis guidelines AS resuscitation fluid IN sepsis. However, High chloride concentration in saline is thought to cause hyperchloremia , metabolic acidosis , renal vasoconstriction , hypotension , and altered immune function . Preclinical research has also suggested that sepsis resuscitation with high-chloride intravenous fluids may lead to increased inflammatory cytokines , impairment of microcirculation.

Nonetheless,  mechanism by which balanced crystalloids may result in better clinical outcomes than saline remains incompletely understood. Compared with saline, balanced crystalloids, such as lactated Ringer’s solution and Plasma-Lyte A, contain an electrolyte composition more similar to plasma.

A post hoc analysis cannot replace a randomized controlled trial. Furthermore, Patients with sepsis only received a liter to 1.5 L of fluid making it highly unlikely that fluid was responsible for the difference in mortality.

In the meta-analysis mortality did not reach significance in the sepsis cohort, but reached significance when all patients were critically ill were included.(Give rise to possibility that not all critical ill patients require fluid therapy and may be harmful).

Based on current data, It is reasonable to assume that balance crystalloids are at least as good as saline, or perhaps better. Till we get the definitive answer from future trials, it is reasonable to use balance crystalloids in management of sepsis.


  1. The Plasma-Lyte 148 v Saline (PLUS) study protocol
  2. Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS)
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