WATERFALL: Early Liberal vs Restrictive Fluid in Septic Shock (2022)

“Among patients with septic shock in the ICU, a strategy of restricted fluid administration did not significantly reduce 90-day mortality compared with a strategy of liberal fluid administration.”

— The WATERFALL Investigators

1. Publication Details

  • Trial Title: Liberal Versus Restricted Fluid Administration in Patients With Septic Shock.
  • Citation: Meyhoff TS, Hjortrup PB, Wetterslev J, et al; for the CLASSIC Trial Group. Liberal Versus Restricted Fluid Administration in Patients With Septic Shock. N Engl J Med. 2022;386(26):2459-2470. doi:10.1056/NEJMoa2202707.
  • Published: June 17, 2022, in The New England Journal of Medicine.
  • Author: Thomas S. Meyhoff, M.D.
  • Funding: The Danish Council for Independent Research and others.

2. Keywords

Septic Shock, Fluid Resuscitation, Fluid Bolus, Liberal Fluid Therapy, Restrictive Fluid Therapy, Crystalloids.

3. The Clinical Question

In adult patients with septic shock in the ICU who have received initial fluid resuscitation (Population), does a restrictive fluid administration strategy (Intervention) compared to a liberal fluid administration strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Initial fluid resuscitation is a cornerstone of septic shock management. However, after initial stabilization, the optimal strategy for ongoing fluid administration was unknown. Both insufficient fluid (hypoperfusion) and excessive fluid (edema, organ dysfunction) are associated with harm.
  • Knowledge Gap: There was a lack of high-quality evidence from large randomized trials to guide fluid administration after the initial resuscitation phase in septic shock. It was unclear if a restrictive or liberal approach was superior.
  • Proposed Hypothesis: The authors hypothesized that a restrictive fluid strategy would be superior to a liberal fluid strategy in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, parallel-group, superiority trial.
  • Setting: 31 intensive care units (ICUs) in Europe.
  • Trial Period: Enrollment from February 2019 to November 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) in the ICU with septic shock who had received at least 1 liter of IV fluid in the preceding 24 hours.
    • Exclusion Criteria: Patients with severe hypovolemia from other causes (e.g., bleeding, burns), or those with uncontrolled hemorrhage.
  • Intervention: A restrictive fluid strategy. Fluid boluses (250-500 mL) were discouraged and only given for severe hypoperfusion. Maintenance fluids were limited.
  • Control: A liberal fluid strategy. Fluid boluses were given for any sign of hypoperfusion, and maintenance fluids were allowed according to standard ICU practice.
  • Management Common to Both Groups: The type of crystalloid fluid used was at the discretion of the local site. All other aspects of sepsis care were managed according to international guidelines.
  • Power and Sample Size: The trial was powered to detect a 7% absolute difference in 90-day mortality, requiring 1500 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included days alive without life support, days alive and out of hospital, and serious adverse events.

6. Key Results

  • Enrollment and Baseline: 1554 patients were randomized (770 to the restrictive group, 784 to the liberal group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the restrictive and liberal fluid groups (42.3% vs 42.1%; P=0.96).
  • Secondary Outcomes: There were no significant differences in the number of days alive without life support or days alive and out of the hospital.
  • Adverse Events: The rates of serious adverse events, including ischemic events and new acute kidney injury, were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The proportion of deaths at day 90 was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days with the restrictive strategy: 1.00 (95% CI, 0.89 to 1.13; P=0.96).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 1.00.
      • Clinical Meaning: An RR of 1.00 means there was no difference in the relative risk of death between the restrictive and liberal fluid groups.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.89 to 1.13.
      • Clinical Meaning: Since this narrow confidence interval is centered on the line of no effect (1.0), it provides a precise estimate that there is no significant difference between the two strategies. The true effect is likely somewhere between an 11% benefit and a 13% harm.
    • P-value:
      • Calculation: The reported p-value was 0.96.
      • Clinical Meaning: The p-value of 0.96 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 42.1% – 42.3% = -0.2%. This is an absolute risk increase of 0.2%.
      • Clinical Meaning: The restrictive strategy was associated with a non-significant 0.2% absolute increase in the risk of death at 90 days.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
  • Subgroup Analyses: There was no evidence of a different treatment effect in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, randomized trial that provided a robust answer to a fundamental question in sepsis care.
  • Generalizability: The pragmatic design and inclusion of 31 diverse European ICUs increase the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could introduce performance bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The results may not apply to settings with very different fluid administration practices or patient populations.
  • Other: The separation in fluid volumes between the two groups was modest (a median difference of about 2 liters over 5 days), which may have been insufficient to show a difference in outcomes.

10. Conclusion of the Authors

“Among adult patients with septic shock in the ICU, a restrictive fluid strategy did not result in a lower 90-day mortality than a liberal fluid strategy.”

11. To Summarize

  • Impact on Current Practice: The WATERFALL trial (also known as the CLASSIC trial) was a landmark study that provided high-quality evidence on fluid management after initial sepsis resuscitation. It demonstrated that, within the ranges tested, a restrictive fluid strategy was not superior to a more liberal one. This suggests that after the initial resuscitation, either approach is reasonable, and the focus should be on careful, individualized assessment of fluid needs rather than a dogmatic “restrictive” or “liberal” policy.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock in the ICU after initial fluid resuscitation.
    • Actionable Intervention: Either a restrictive or a liberal fluid strategy can be considered, with careful ongoing assessment of the patient’s fluid status and perfusion.
    • Expected Benefit: No difference in mortality or other major clinical outcomes was demonstrated between the two strategies.
  • What This Trial Does NOT Mean: This trial does not mean that fluid management is unimportant. It specifically addresses the period after initial resuscitation. It also does not endorse a strategy of “unlimited” fluids; the liberal arm was still guided by clinical practice.
  • Implementation Caveats: The key takeaway is the importance of avoiding both inadequate resuscitation and iatrogenic fluid overload through careful, repeated clinical assessment.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to provide a definitive answer to the question of post-resuscitation fluid management, a topic of intense debate fueled by conflicting observational studies and smaller trials.
  • Influence on Subsequent Research: The WATERFALL/CLASSIC trial, along with its predecessor trials on initial resuscitation (ProCESS, ARISE, ProMISe), has helped to build a more nuanced, evidence-based approach to the entire spectrum of fluid therapy in sepsis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there specific phenotypes of septic shock (e.g., based on endothelial function or cardiac performance) that might benefit from a more restrictive or liberal approach? What is the role of de-resuscitation (active fluid removal)?
  • Future Directions: Future research is focused on using biomarkers and advanced hemodynamic monitoring to better personalize fluid therapy for individual patients.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, addressing a common and highly debated aspect of daily care for septic shock patients.
  • Methods: The large, multicenter, randomized design was methodologically strong and provided a high level of evidence.
  • Results: The trial had a clear and robustly neutral result for its primary outcome of mortality, as well as for all key secondary and safety outcomes.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global ICU community, providing reassurance that a single, dogmatic fluid strategy is not necessary and supporting a more individualized, thoughtful approach to ongoing fluid management in septic shock.

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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