PLUS: Balanced Solution vs. Saline in Critically Ill Adults (2022)

“Among critically ill adults, the use of a balanced multielectrolyte solution (Plasma-Lyte 148), as compared with saline, did not lead to a lower risk of death at 90 days.”

  • The PLUS Investigators and the ANZICS Clinical Trials Group

1. Publication Details

  • Trial Title: Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults
  • Citation: Finfer S, Micallef S, Hammond N, et al. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022;386(9):817-828. DOI: 10.1056/NEJMoa2114464
  • Published: March 3, 2022, in The New England Journal of Medicine
  • Author: Simon Finfer, M.D., on behalf of the PLUS Investigators
  • Funding: The National Health and Medical Research Council of Australia; and others.

2. Keywords

  • Critical Care, Fluid Resuscitation, Balanced Crystalloids, Saline, Acute Kidney Injury (AKI), Randomized Controlled Trial

3. The Clinical Question

  • In a broad population of critically ill adult patients requiring fluid therapy in the ICU (Population), does the use of a balanced crystalloid solution (Plasma-Lyte 148) (Intervention) compared to 0.9% saline (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The choice between balanced crystalloids and 0.9% saline for fluid resuscitation was a major clinical debate. Saline’s high chloride content was known to cause hyperchloremic metabolic acidosis and was associated with an increased risk of acute kidney injury (AKI) in observational studies. The SMART trial (2018) had suggested a benefit for balanced solutions in reducing major adverse kidney events, but the BaSICS trial (2021) found no difference in mortality.
  • Knowledge Gap: A large, definitive, multicenter trial was needed to provide a clear answer on whether the choice of crystalloid fluid had a significant impact on survival in a general ICU population.
  • Proposed Hypothesis: The authors hypothesized that the use of a balanced solution would be superior to saline in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, double-blind, controlled trial (used to test the effectiveness of interventions).
  • Setting: 53 intensive care units (ICUs) in Australia and New Zealand.
  • Trial Period: Enrollment ran from September 2017 to December 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who required intravenous crystalloid fluid therapy.
    • Exclusion Criteria: Included patients at imminent risk of death, those with a contraindication to either fluid, or those with established end-stage kidney disease on dialysis.
  • Intervention: Fluid therapy with a balanced multielectrolyte solution (Plasma-Lyte 148).
  • Control: Fluid therapy with 0.9% saline.
  • Management Common to Both Groups: The assigned study fluid was used for all subsequent fluid needs (resuscitation, maintenance, and dilution). All other aspects of ICU care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 8800 patients would be required to have 90% power to detect a 2.9% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included the incidence of new renal-replacement therapy (RRT), maximal SOFA score, and ventilator-free days.

6. Key Results

  • Enrollment and Baseline: 5037 patients were randomized (2515 to the balanced-solution group and 2522 to the saline group). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for futility after a pre-planned interim analysis, as it was highly unlikely that a significant difference would be found.
  • Primary Outcome: There was no significant difference in 90-day mortality. 530 of 2433 patients (21.8%) in the balanced-solution group died, compared with 530 of 2413 patients (22.0%) in the saline group (p=0.90).
  • Secondary Outcomes: There were no significant differences between the groups in the need for new RRT, maximal SOFA scores, or ventilator-free days.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for death at 90 days: 0.99 (95% CI, 0.86 to 1.14; P-value: 0.90).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the result as 0.99.
      • Clinical Meaning: An OR of 0.99 indicates virtually no difference in the odds of death between the two groups.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.86 to 1.14.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 14% benefit to a 14% harm.
    • P-value: The p-value of 0.90 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of ICU patients make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: Although stopped early, the study was very large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The study was conducted in Australia and New Zealand, and the results may not be fully generalizable to all healthcare systems.
  • Other: The median volume of fluid administered was relatively low (around 3L over the ICU stay), which may have been insufficient to show a difference between the fluid types.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults, the use of a balanced multielectrolyte solution did not lead to a lower risk of death at 90 days than the use of saline.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that in a general ICU population, there is no significant survival difference between using a balanced crystalloid and 0.9% saline.
  • Specific Recommendations:
    • Patient Selection: For a broad population of adult ICU patients requiring fluid therapy.
    • Actionable Intervention: The results suggest that either balanced crystalloids or saline are acceptable choices for fluid therapy.
  • What This Trial Does NOT Mean: This trial does NOT mean that saline is harmless. The potential for hyperchloremic acidosis and kidney injury with large volumes of saline is still a valid concern, even if it did not translate to a mortality difference in this trial.
  • Implementation Caveats: While the choice of fluid may not affect mortality in a general population, a balanced solution may still be preferred in patients at high risk for acidosis or kidney injury, or those expected to receive very large volumes of fluid.

12. Context and Related Studies

  • Building on Previous Evidence: The PLUS trial (2022) was designed to provide a more definitive answer to the question raised by the SMART trial (2018), which had suggested a benefit for balanced solutions.
  • Influence on Subsequent Research: The neutral findings of PLUS, along with the concurrent BaSICS trial (2021) which also found no difference, have largely settled the “crystalloid wars.” They suggest that while there may be small physiological differences, the choice between balanced solutions and saline does not appear to have a major impact on survival for most ICU patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether there are specific subgroups of patients (e.g., those with severe sepsis or traumatic brain injury) who might still benefit from one type of crystalloid over another.
  • Future Directions: Future research is focused on more nuanced questions, such as the optimal volume and timing of fluid administration, rather than just the type of fluid.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and fundamental aspect of ICU care.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality. The pragmatic design ensured high external validity.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of balanced solutions in this population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This trial, along with BaSICS, provides strong evidence that for the majority of ICU patients, the choice between balanced crystalloids and saline is unlikely to have a major impact on patient-centered outcomes.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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