CLOVERS: Restrictive vs. Liberal Fluid in Sepsis-Induced Hypotension (2023)

“Among patients with sepsis-induced hypotension, a restrictive fluid strategy was not associated with a significant difference in 90-day mortality as compared with a liberal fluid strategy.”

  • The CLOVERS Trial Investigators

1. Publication Details

  • Trial Title: Restrictive versus Liberal Fluid Regimens in Early Septic Shock
  • Citation: National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Restrictive versus Liberal Fluid Regimens in Early Septic Shock. N Engl J Med. 2023;388(6):499-510. DOI: 10.1056/NEJMoa2212663
  • Published: February 9, 2023, in The New England Journal of Medicine
  • Author: The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network
  • Funding: National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Sepsis, Septic Shock, Fluid Resuscitation, Fluid Restriction, Crystalloids, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with sepsis-induced hypotension (Population), does a restrictive fluid strategy (Intervention) compared to a liberal fluid strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early, aggressive fluid resuscitation has been a cornerstone of sepsis management for decades. However, a large positive fluid balance is associated with harm and increased mortality in critically ill patients. This created significant clinical uncertainty regarding the optimal fluid strategy in the initial 24 hours of sepsis care.
  • Knowledge Gap: There was no high-quality evidence from a large randomized trial to determine if a restrictive fluid strategy was superior to a more liberal approach during the initial phase of resuscitation for septic shock.
  • Proposed Hypothesis: The authors hypothesized that a restrictive fluid strategy would be superior to a liberal fluid strategy in reducing 90-day mortality in patients with sepsis-induced hypotension.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 60 medical centers in the United States.
  • Trial Period: Enrollment ran from March 2018 to January 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) in the emergency department or ICU with sepsis-induced hypotension who had received between 1 and 3 liters of intravenous crystalloids.
    • Exclusion Criteria: Included fluid overload, uncontrolled hemorrhage, or severe electrolyte abnormalities.
  • Intervention: A restrictive fluid strategy, where the priority was to use vasopressors to maintain blood pressure, and fluids were given only as “rescue” for specific signs of severe hypoperfusion.
  • Control: A liberal fluid strategy, where the priority was to administer a 2-liter fluid bolus and give additional fluids as needed to treat hypotension before and alongside vasopressors.
  • Management Common to Both Groups: Both strategies were protocolized for the first 24 hours. All other aspects of sepsis management were at the discretion of the treating clinicians according to best practices.
  • Power and Sample Size: The authors calculated that a sample size of 2320 patients would provide 90% power to detect a 4.5% 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 ventilator-free days, vasopressor-free days, and the incidence of major adverse kidney events.

6. Key Results

  • Enrollment and Baseline: 1563 patients were randomized (782 to the restrictive group and 781 to the liberal group). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for futility, as it was highly unlikely that a significant difference would be found between the groups.
  • Primary Outcome: There was no significant difference in 90-day mortality. 109 of 775 patients (14.0%) in the restrictive group died, compared with 116 of 775 patients (14.9%) in the liberal group (p=0.61).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including ventilator-free days or vasopressor-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 Bayesian model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The posterior probability that the restrictive strategy was superior to the liberal strategy was low (0.08).
  • Interpretation of Key Statistic(s):
    • Bayesian Analysis: A posterior probability of 0.08 (or 8%) is very low and provides strong evidence against the hypothesis that the restrictive strategy is superior.
    • P-value (for context): The frequentist p-value of 0.61 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 large, multicenter, randomized controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The pragmatic design and inclusion of 60 diverse medical centers make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful 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 unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was from a single, high-income country, and the results may not be fully generalizable to lower-resource settings.
  • Other: The separation in the volume of fluid administered between the two groups was modest (a median difference of about 2.1 liters at 24 hours), which may have been insufficient to show a true difference in outcomes.

10. Conclusion of the Authors

  • Among patients with sepsis-induced hypotension, a restrictive fluid strategy did not result in a significantly lower 90-day mortality than a liberal fluid strategy.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that in the initial 24 hours of resuscitation for sepsis, a restrictive fluid strategy is not superior to a more liberal approach.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis-induced hypotension in the emergency department or ICU.
    • Actionable Intervention: The results suggest that either a restrictive or a liberal fluid strategy is an acceptable approach in the first 24 hours, with no evidence of superiority for the restrictive strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that fluid overload is harmless. It only addresses the initial 24-hour period and does not provide guidance on fluid management in the subsequent days of critical illness.
  • Implementation Caveats: The key to fluid management remains careful and frequent reassessment of the individual patient’s volume status and perfusion, rather than rigid adherence to a “liberal” or “restrictive” protocol.

12. Context and Related Studies

  • Building on Previous Evidence: The CLOVERS trial (2023) was designed to provide a definitive answer to the question of early fluid volumes in sepsis, a question raised by observational studies suggesting harm from fluid overload (e.g., Bouchard et al. 2009).
  • Influence on Subsequent Research: The neutral finding of this trial, along with the concurrent CLASSIC trial (2022) which also found no difference between a restrictive and standard strategy after initial resuscitation, has been highly influential. It suggests that the focus of fluid research may need to shift from simple volume targets to more personalized approaches.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal fluid strategy in specific subgroups of patients (e.g., those with pre-existing heart or kidney failure) remains an area of investigation.
  • Future Directions: Future research is focused on identifying which patients are likely to be “fluid responders” and on using more advanced hemodynamic monitoring to guide fluid therapy in a more personalized way, rather than relying on protocolized volume targets.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical dilemma in the initial management of septic shock.
  • Methods: The large, multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. A key point for interpretation is the modest separation in fluid volumes between the two groups.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that was narrow and centered on the null value. This provides strong evidence against a meaningful clinical benefit of a routine restrictive fluid strategy 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 CLASSIC, provides strong evidence that a one-size-fits-all approach to fluid restriction is not beneficial and that the focus should be on individualized patient assessment.

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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