FLUID: Hospital-Wide Lactated Ringer’s versus Normal Saline (2025)

“In this cluster-randomized, crossover trial involving a heterogenous group of patients in academic and community hospitals, the use of lactated Ringer’s solution as compared with normal saline did not result in a significant difference in the incidence of death or readmission to the hospital within 90 days.”

— The FLUID Trial Investigators

1. Publication Details

  • Trial Title: Hospital-Wide Lactated Ringer’s versus Normal Saline: A Cluster-Randomized, Crossover Trial.
  • Citation: Billia M, Zaltzman J, Bialach T, et al; for the FLUID Trial Investigators. Hospital-Wide Lactated Ringer’s versus Normal Saline: A Cluster-Randomized, Crossover Trial. N Engl J Med. 2025; Published online July 16. doi:10.1056/NEJMoa2406529.
  • Published: July 16, 2025, in The New England Journal of Medicine.
  • Author: Michael Billia, M.D.
  • Funding: Canadian Institutes of Health Research and others.

2. Keywords

Intravenous Fluids, Crystalloids, Lactated Ringer’s, Normal Saline, Hospital-Wide, Readmission.

3. The Clinical Question

In a general population of hospitalized adult patients (Population), does a hospital-wide policy of using Lactated Ringer’s solution (Intervention) compared to a policy of using normal saline (Comparison) affect the composite outcome of death or hospital readmission within 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The choice between balanced crystalloids (like Lactated Ringer’s) and normal saline is a long-standing debate. Trials like SMART suggested a benefit for balanced fluids in critically ill patients by reducing kidney injury, but subsequent large trials (BaSICS, PLUS) did not find a mortality benefit.
  • Knowledge Gap: The effect of a hospital-wide default fluid strategy on a broad, unselected patient population (not just ICU patients) was unknown. It was unclear if the findings from ICU-specific trials would translate to general medical and surgical patients.
  • Proposed Hypothesis: The authors hypothesized that a hospital-wide strategy of using Lactated Ringer’s would be superior to normal saline in reducing a composite of death or hospital readmission at 90 days.

5. Study Design and Methods

  • Design: A large, pragmatic, cluster-randomized, multiple-crossover trial. Hospitals (the “clusters”) were randomized to a sequence of using either Lactated Ringer’s or normal saline as the default fluid, with crossover periods.
  • Setting: 7 hospitals (both academic and community) in Ontario, Canada.
  • Trial Period: Enrollment from May 2021 to January 2024.
  • Population:
    • Inclusion Criteria: All adult patients with an index hospital admission (i.e., not a readmission within the last 90 days).
    • Exclusion Criteria: Patients younger than 1 month or missing a birth date.
  • Intervention: A hospital-wide policy to use Lactated Ringer’s solution as the default intravenous crystalloid.
  • Control: A hospital-wide policy to use normal saline as the default intravenous crystalloid.
  • Management Common to Both Groups: The default fluid was implemented through automatic substitution in electronic medical records or by bedside nurses. Clinicians could override the assigned fluid for specific clinical reasons.

6. Key Results

  • Enrollment and Baseline: 43,626 patients were included in the final analysis (22,017 in the Lactated Ringer’s group and 21,609 in the normal saline group). The patient populations were diverse, including medical, surgical, and obstetrical admissions.
  • Trial Status: The trial was completed but did not reach its intended sample size due to the COVID-19 pandemic.
  • Primary Outcome: There was no significant difference in the primary composite outcome of death or hospital readmission within 90 days between the two groups (20.3% in the LR group vs. 21.4% in the NS group; adjusted mean difference, -0.53 percentage points; P=0.35).
  • Secondary Outcomes: There were no significant differences in any of the secondary outcomes, including 90-day mortality, 90-day readmission, or the initiation of dialysis.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed, accounting for the cluster-randomized design.
  • Statistical Tests Used: The primary outcome was analyzed using a mixed-effects linear regression model.
  • Key Statistic(s) Reported: Adjusted mean difference for the primary outcome: -0.53 (95% CI, -1.85 to 0.79; P=0.35).
  • Interpretation of Key Statistic(s):
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was -1.85 to 0.79 percentage points.
      • Clinical Meaning: The confidence interval is wide and crosses zero. This means the true effect could be anywhere from a 1.85% benefit for Lactated Ringer’s to a 0.79% harm. Because the range includes the possibility of no effect (zero) and potential harm, the result is not statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.35.
      • Clinical Meaning: The p-value of 0.35 is much higher than the conventional threshold of 0.05. This indicates that the small difference observed between the groups is very likely to be due to chance, further confirming the lack of a statistically significant effect.
  • Clinical Impact Measures (Interpreted with caution as the primary outcome was not significant):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 21.4% – 20.3% = 1.1%.
      • Clinical Meaning: The observed, non-significant absolute difference in the primary outcome was 1.1%. This suggests that for every 100 patients treated with Lactated Ringer’s instead of saline, about 1 fewer patient might experience death or readmission, but this finding could be due to chance.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.011 ≈ 91.
      • Clinical Meaning: If the observed 1.1% risk reduction were a true effect, approximately 91 patients would need to be treated with Lactated Ringer’s instead of saline to prevent one additional event of death or readmission.

8. Strengths of the Study

  • Pragmatic Design: The cluster-randomized, hospital-wide design provides high external validity and reflects real-world clinical practice.
  • Large and Diverse Population: The inclusion of over 43,000 patients from a wide range of clinical services (medicine, surgery, obstetrics) makes the findings broadly applicable.
  • Important Clinical Question: The study addresses a fundamental and common clinical decision, providing valuable data to inform hospital policy.

9. Limitations and Weaknesses

  • Internal Validity (Bias): Adherence to the assigned fluid was imperfect and lower in the Lactated Ringer’s group. The study was unblinded.
  • External Validity (Generalizability): The trial was conducted within a single healthcare system in Canada, which may differ from other systems.
  • Other: The trial was underpowered as it did not reach its planned sample size. Patient-level data on the volume and type of fluid received were not collected.

10. Conclusion of the Authors

“In this cluster-randomized, crossover trial involving a heterogenous group of patients in academic and community hospitals, the use of lactated Ringer’s solution as compared with normal saline did not result in a significant difference in the incidence of death or readmission to the hospital within 90 days.”

11. To Summarize

  • Impact on Current Practice: This large, pragmatic trial adds significant weight to the growing body of evidence (including the BaSICS and PLUS trials) suggesting that for a general, unselected hospital population, the choice between balanced crystalloids and saline does not significantly impact major patient-centered outcomes like death or readmission. It challenges the idea that a hospital-wide switch to balanced fluids is necessary to improve outcomes.
  • Specific Recommendations:
    • Patient Selection: For the general population of hospitalized adult patients.
    • Actionable Intervention: A hospital policy of using either Lactated Ringer’s or normal saline as the default crystalloid is a reasonable approach.
    • Expected Benefit: No significant difference in 90-day death or hospital readmission.
  • What This Trial Does NOT Mean: This trial does not nullify the findings of the SMART trial, which focused on a sicker, exclusively ICU population and found a benefit in a kidney-specific outcome. It suggests that any potential benefit of balanced fluids may be limited to specific high-risk subgroups (like sepsis) and is not apparent in a general, lower-acuity hospital population.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to see if the kidney-related benefits of balanced fluids seen in the critically ill in the SMART trial would translate to broader, patient-centered outcomes across an entire hospital system.
  • Influence on Subsequent Research: The results of FLUID, along with BaSICS and PLUS, provide a counterpoint to SMART and SALT-ED. This collection of large trials suggests that while balanced fluids may be beneficial for specific outcomes in specific ICU populations, a hospital-wide, one-size-fits-all approach does not appear to improve overall outcomes.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Does the volume of fluid administered matter? Are there specific subgroups (e.g., patients with sepsis, DKA, or pre-existing kidney disease) within the broader hospital population who still derive a significant benefit from balanced crystalloids?
  • Future Directions: Future research may focus on individualizing fluid choice based on patient-specific factors and biomarkers rather than broad, hospital-wide policies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a simple, scalable intervention with the potential for large public health impact.
  • Methods: The pragmatic, cluster-randomized, crossover design was appropriate and robust for evaluating a hospital-level policy.
  • Results: The trial had a clear “negative” result for its primary outcome. Despite being underpowered, the very small effect size and confidence interval crossing 1.0 make a clinically significant benefit unlikely in this broad population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and appropriate interpretation of the data. The results are highly applicable to hospital systems considering a default fluid policy and suggest that focusing on other quality improvement measures may be more impactful than mandating a specific crystalloid choice for all patients.

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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