From Pages to Practice

By Rebecca Berger, MD

Published July 20, 2022


Mr. Strickland is a 77-year-old man who presents to the emergency department with fever and dysuria. He is febrile to 38.5°C, has a heart rate of 130 beats per minute and blood pressure of 80/50 mmHg. His white blood cell count is elevated at 16,000/mm3 and urinalysis demonstrates >50 white blood cells per high power field and 3+ leukocyte esterase. You order broad spectrum antibiotics to treat him for sepsis from a urinary tract infection and request a bed in the intensive care unit (ICU). As you place an order for 2 liters of normal saline to begin fluid resuscitation for sepsis, a colleague asks why you didn’t choose Plasma-Lyte, a balanced multielectrolyte solution (BMES). What are the data that inform this clinical decision?

Intravenous fluid selection in the ICU has been examined at great length and certain fluids, such as albumin and hydroxyethyl starch, have been associated with worse patient outcomes. Normal saline is the most common IV fluid administered in ICUs worldwide, although some data raise concern about increased risk of acute kidney injury and death from what some have coined “abnormal saline” due to an electrolyte composition that differs from human plasma.

To help answer the question of whether a BMES, specifically Plasma-Lyte 148, leads to better patient outcomes in ICU patients, investigators randomized 5037 patients from 53 ICUs in Australia and New Zealand to receive either BMES or normal saline. Although randomization determined the assigned fluid type for each patient, decisions about the timing and amount of fluid were left to the discretion of the treating clinician.

No differences were reported in the primary outcome (death within 90 days of randomization) between the BMES and saline groups (21.8% vs. 22.0%, respectively), as well as in several secondary outcomes, including initiation of new renal-replacement therapy and maximum increase in serum creatinine.

These results must be interpreted in the context of both the study’s limitations and the body of existing evidence. Limitations of the study include a failure to meet the initial target for patient recruitment, requiring adjustment in the estimated absolute difference in mortality that could be assessed based on the trial’s power. In addition, although the investigators did not track the total amount of fluid given to patients prior to randomization, more patients in the BMES group received at least 500 mL of normal saline than patients in the saline group received at least 500 mL of BMES (55.5% vs.23.5%). Further, significant and asymmetric cross-over occurred between the groups after randomization, with more patients in the BMES group receiving normal saline, purportedly because of medication delivery that was only compatible with normal saline.

Although the results of the primary outcome (death) did not show a difference between BMES and saline in this trial, an updated meta-analysis published in NEJM Evidence that included the data from this study showed that the overall weight of existing evidence still suggests a high probability that balanced salt solutions reduce mortality among adults in the ICU.

These results do not support superiority of BMES over normal saline but may not be sufficient to overturn the body of pre-existing evidence that suggests a potential benefit of BMES. Based on this conclusion, you thank your colleague for the reminder about BMES, change the order from normal saline to Plasma-Lyte, and stabilize Mr. Strickland for transfer to the ICU.

The following NEJM Journal Watch summary provides further details of the study.


Similar Mortality in Patients Resuscitated with Normal Saline or Balanced Crystalloid

Patricia Kritek, MD, reviewing Finfer S et al. N Engl J Med 2022 Jan 18

In 2018, a large, pragmatic, single-center trial demonstrated lower mortality and fewer renal injuries in patients who received balanced crystalloid (a solution with chloride levels closer to plasma levels) than in those who received normal saline (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:819, 829). Although the differences were small, the results prompted many clinicians to change practice and preferentially use balanced crystalloid for resuscitation. A subsequent multicenter trial from Brazil did not confirm these results (JAMA 2021; 326:1. opens in new tab).

In this latest trial from Australia and New Zealand, investigators randomized more than 5000 critically ill patients who required fluid resuscitation to receive either normal saline or Plasmalyte (contains 140 mEq of sodium and 98 mEq of chloride). The median volume of fluid administered was 3.8 L. Three quarters of patients were supported with mechanical ventilation, and about 40% had sepsis. Renal replacement therapy, organ failure, and mortality at 90 days were similar between groups. Although chloride levels were higher and pH was lower in the normal-saline group, no difference in renal function was noted between groups. The results were similar in subgroup analysis of patients with sepsis.

Comment: Conflicting results in clinical trials are not uncommon. My sense is that the choice of resuscitation fluid generally does not make a big difference for individual patients. In specific clinical settings, saline or balanced crystalloid might have unique benefits; for example, saline might be favored in patients with traumatic brain injury. However, in most cases, picking the most easily available and least expensive resuscitation fluid makes sense. 

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Rebecca Berger, MD, was a 2016-2017 NEJM Editorial Fellow and is a hospitalist at New York Presbyterian-Weill Cornell Medicine. She graduated from Columbia University College of Physicians and Surgeons in 2013, completed internal medicine residency at Massachusetts General Hospital (MGH) in 2016, and worked as a hospitalist at MGH from 2016-2018. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.
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