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PLUS RCT – Balanced Fluid vs Normal Saline

March 3, 2022

Written by Laura Murphy

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The PLUS (Plasmalyte 148 vs saline) trial found no evidence that the risk of death or acute kidney injury was higher in critically ill adults who received normal saline compared to those who received balance multielectrolyte solution (BMES).

Why is this important?
IV fluids are a key component of resuscitation and treatment of critically ill patients. There have been increasing concerns that the use of normal saline may increase risk of acute kidney injury and death compared to BMES and several recent studies comparing BMES and saline, with conflicting results: SMART, SALT-ED, and BaSICS.

Another round for saline vs. balanced fluids…
The PLUS trial was a double-blind, multicenter, randomized controlled trial in which 5,037 critically ill patients were assigned to receive BMES (Plasma-Lyte 148) or saline as fluid therapy in the ICU, followed for 90 days. Baseline characteristics of the two groups were well-matched. The median volume of trial fluid administered was 3.9 L (higher than some other studies). 

There was no statistically significant difference in the primary outcome of death within 90 days of randomization in the BMES group compared to the saline group (21.8% vs 22.0%, 95% CI -3.6 to 3.3; P=0.90). The use of saline resulted in significantly higher serum chloride and lower pH compared to BMES, but there was also no significant difference between the two groups with regards to secondary outcomes of initiation of new renal replacement therapy (12.7% vs 12.9%, 95%CI -2.96 to 2.56) or mean (±SD) maximum increase in serum creatinine (36.6±94.0 mmol/L vs 36.1±90.2 mmol/L). Subgroup analyses were conducted based on illness severity before randomization, presence of sepsis, kidney injury, age, sex, and ICU admission after surgery, and did not show a significant difference between the two groups.

The authors discuss the results of a concurrently published meta-analysis including their data which suggests there is a high probability that use of BMES reduces mortality in critically ill adults. This study estimated that the effect of BMES vs saline ranges from a 9% relative reduction to 1% relative increase in risk of death, suggesting a high probability that use of BMES reduces mortality. The authors also point out this probability was even higher in patients with sepsis and suggest that specific patient factors may inform fluid choice.

Given results of the concurrent meta-analysis including the study data, I will likely continue to favor BMES in critically ill patients without traumatic brain injury, though other factors such as cost and availability of fluids as well as drug compatibility may impact fluid choice as well.


Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Jan 18. doi: 10.1056/NEJMoa2114464. Epub ahead of print. PMID: 35041780.

Balanced Crystalloids versus Saline in Critically Ill Adults-A Systematic Review with Meta-Analysis. NEJM Evid 2022; 1(2). Doi: 10.1056/EVIDoa2100010

What are your thoughts?