CLASSIC: Restrictive vs. Standard Fluid in Septic Shock (2022)

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

  • The CLASSIC Trial Investigators

1. Publication Details

  • Trial Title: Restriction of Intravenous Fluid in ICU Patients with Septic Shock
  • Citation: Meyhoff TS, Hjortrup PB, Wetterslev J, et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022;386(26):2459-2470. DOI: 10.1056/NEJMoa2202707
  • Published: June 24, 2022, in The New England Journal of Medicine
  • Author: Theis S. Meyhoff, M.D., Ph.D.
  • Funding: The Novo Nordisk Foundation and others.

2. Keywords

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

3. The Clinical Question

  • In adult patients with septic shock in the ICU (Population), does a restrictive intravenous fluid strategy (Intervention) compared to a standard, more liberal fluid strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: While early fluid resuscitation is a cornerstone of sepsis management, a positive fluid balance and fluid overload are associated with harm and increased mortality in critically ill patients. This created a clinical dilemma: how much fluid is enough, and when should fluid administration be restricted?
  • Knowledge Gap: Previous trials on fluid resuscitation had focused on the initial bolus phase. There was no high-quality evidence from a large randomized trial to guide fluid management after initial resuscitation, and it was unknown if a restrictive fluid strategy would be beneficial or harmful.
  • Proposed Hypothesis: The authors hypothesized that a restrictive fluid strategy would be superior to a standard fluid strategy in reducing 90-day mortality in patients with septic shock.

5. Study Design and Methods

  • Design: A multicenter, international, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 31 intensive care units (ICUs) in 8 European countries.
  • Trial Period: Enrollment ran from June 2018 to November 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) in the ICU with septic shock who had received at least 1 liter of intravenous fluid.
    • Exclusion Criteria: Included patients with uncontrolled hemorrhage or severe burns.
  • Intervention: A restrictive fluid strategy, where intravenous fluids (isotonic crystalloids) were only given in specific situations: for severe hypoperfusion, to replace documented losses, or for maintenance if oral/enteral intake was impossible. The use of fluid boluses was strongly discouraged.
  • Control: A standard fluid strategy, where clinicians could give intravenous fluids according to local guidelines and clinical judgment, with specific triggers for fluid boluses allowed.
  • Management Common to Both Groups: All other aspects of sepsis management, including the use of vasopressors and antibiotics, were at the discretion of the treating clinicians according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1554 patients would provide 80% power to detect a 7% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included the incidence of severe AKI, ischemic events, and the number of days alive without life support.

6. Key Results

  • Enrollment and Baseline: 1554 patients were randomized (770 to the restrictive group and 784 to the standard 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. 322 of 763 patients (42.2%) in the restrictive group died, compared with 329 of 776 patients (42.4%) in the standard group (p=0.96).
  • Secondary Outcomes: There were no significant differences between the groups in the incidence of severe AKI, ischemic events, or in the number of days alive without life support.
  • 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: Adjusted Odds Ratio (OR) for death at 90 days: 0.99 (95% CI, 0.80 to 1.21; P-value: 0.96).
  • 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 adjusted 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 0.80 to 1.21.
      • 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 20% benefit to a 21% harm.
    • P-value: The p-value of 0.96 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 31 diverse ICUs across Europe make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • 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 open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was predominantly from high-income European countries, 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 difference of about 2 liters over 5 days), which may have been insufficient to show a true 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 standard fluid strategy.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that a restrictive fluid strategy, once initial resuscitation is complete, is not superior to a more standard approach in a general population of ICU patients with septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients in the ICU with septic shock who have received initial fluid resuscitation.
    • Actionable Intervention: The results suggest that either a restrictive or a standard fluid strategy is an acceptable approach, 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 suggests that in this study, the difference in fluid volumes between the two groups was not large enough to impact mortality.
  • 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 CLASSIC trial (2022) was designed to provide a definitive answer to the question of post-resuscitation fluid management, 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 CLOVERS trial (2023) which also found no difference between a restrictive and liberal strategy in the first 24 hours, 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 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 CLOVERS, 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.
Scroll to Top