Although 0.9% sodium chloride (“normal” saline) is traditionally the most commonly used intravenous fluid, it is unclear if “normal” saline is the best fluid. Data from prior studies suggests 0.9% saline use may result in hyperchloremic acidosis. Additionally, 0.9% saline is associated with the development of acute kidney injury (AKI). There have been several observational studies and a before-and-after trial comparing 0.9% saline and “balanced” crystalloids like lactated Ringer’s and Plasma-Ltye A, which have compositions closer to that of plasma. The data from these studies showed less AKI, renal replacement therapy, and death with balanced crystalloids use. However other pilot trials have shown no significant difference between the two.

Clinical Question

Does the composition of isotonic crystalloid effect the clinical outcome of critically ill adults, specifically death, need for new renal replacement therapy, and persistent kidney injury?


Adults aged 18 and over admitted to one the five ICUs at Vanderbilt University Medical Center between June 1, 2015 and April 30, 2017.


Use of lactated Ringer’s or Plasmalyte A intravenous fluids


Use of 0.9% sodium chloride intravenous fluid


Primary: Major Adverse Kidney Event at day 30 (MAKE30) – death, new receipt of renal replacement therapy, or persistent renal dysfunction (≥200% baseline creatinine) at hospital discharge or 30 days after enrollment, whichever came first

Secondary: In-hospital death before discharge, or at 30 days or 60 days; ICU-free days; ventilator-free days; vasopressor-free days; days alive and free of renal replacement therapy during the 28 days after enrollment


Pragmatic, unblinded, cluster-randomized, multiple-crossover trial


Patients less than 18 years old

Primary Results

  • 15,802 patients from 5 ICUs were enrolled
  • 7,942 patients were enrolled in the balanced crystalloid arm, and 7860 patients in the saline arm
  • No significant difference in baseline demographic characteristics between the two groups
    • > 1/3 of patients on mechanical ventilation
    • > 1/4 of patients on vasopressors

Critical Findings (95% CI)

  • MAKE30 (Primary outcome)
    • 0.9% saline 15.4% vs. balanced solutions 14.3%
    • Absolute difference of 1.1% (Adjusted OR 0.90 95% CI 0.82-0.99)
    • NNT = 91
    • Results were similar in all 6 sensitivity analyses which excluded various characteristics such as 2nd ICU admission, exposure to both fluids due to crossover date, low volume fluid administration, etc
  • Subgroup Analysis
    • Mortality at 30 days
      • 0.9% saline 11.1% vs. balanced solutions 10.3%
      • Absolute difference of 0.8% (Adjusted OR 0.90 95% CI 0.80-1.01)
    • Mortality at 30 days among patients with sepsis
      • 0.9% saline 29.4% vs. balanced solutions 25.2%
      • Absolute difference of 4.2% (Adjusted OR 0.90 95% CI 0.67-0.97)
      • NNT = 24
    • MAKE 30 among patients with sepsis
      • 0.9% saline 38.9% vs. balanced solutions 33.8%
      • Absolute difference of 6.1% (Adjusted OR 0.80 95% CI 0.67-0.94)
      • NNT = 20
    • Incidence of new RRT
      • 0.9% saline 2.9% vs. balanced solutions 2.5%
      • Not statistically significantly different
    • Persistent renal dysfunction
      • 0.9% saline 6.6% vs. balanced solutions 6.4%
      • Not statistically significantly different


  • The large sample size provided statistical power to detect small differences in patient outcomes
  • Pragmatic, randomized trial
  • Although the authors used a composite outcome (MAKE30) the difference in outcome appears to be driven by mortality
  • The trial design allowed delivery of assigned fluids early in the patient’s critical illness with the coordination with the ED and ORs
  • Enrolling all patients in a given ICU in the same trial arm minimized selection bias and improved generalizability


  • The study was done at a single medical center which limits generalizability
  • The study was not blinded. As the decision to initiate renal replacement therapy is somewhat subjective this creates susceptibility to bias
  • Collecting data at hospital discharge in place of 30 days could potentially underestimate death at 30 days
  • Collecting data at hospital discharge could potentially overestimate the true incidence of persistent renal dysfunction at 30 days
  • The primary outcome was a composite of death, new RRT and persistent renal dysfunction – these outcomes are not of equal importance
  • None of the components of the primary outcome were statistically significantly different when looked at alone (i.e. not as a composite)
  • TBI was a diagnosis that allowed clinicians to deviate from the protocol and opt for saline instead of balanced crystalloids. This study therefore cannot give us accurate data on these patients
  • Hyperkalemia was a relative contraindication to balanced crystalloids and allowed clinicians to deviate from the protocol

Author's Conclusions

” Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.”

Our Conclusions

In this single center study, the use of balanced crystalloids resulted in a lower rate of the composite of death, new RRT, and persistent renal dysfunction compared to the use of 0.9% saline in critically ill adults.

Potential Impact To Current Practice

We are beginning to see a major treatment shift from the use of 0.9% saline to balanced solutions in all patients, particularly those requiring large volume resuscitations.

Bottom Line

Based on the best available data, it is reasonable to opt for balanced crystalloids in place of saline for critically ill patients, especially those with sepsis or requiring large volume resuscitation.

Read More

PulmCrit: Get SMART – Nine Reasons to Quit Using Normal Saline for Resuscitation

REBEL EM: Is the Great Debate Between Balanced vs Unbalanced Crystalloids Finally Over?

REBEL EM: The SPLIT Trial – Saline vs Plasma-Lyte Fluid Therapy

Boring EM: Normal Saline: The Coke of Crystalloid Fluids