COIITSS: Hydrocortisone in Severe Sepsis (2010)

“In patients with severe sepsis, intravenous hydrocortisone did not reduce mortality at 28 days, irrespective of their response to corticotropin.”

  • The COIITSS Study Investigators

1. Publication Details

  • Trial Title: A multicenter, randomized, placebo-controlled, double-blind study of the efficacy and safety of drotrecogin alfa (activated) in patients with severe sepsis. Correction: The COIITSS trial is on hydrocortisone. The full title is: Corticosteroid Therapy and Intensive Insulin Therapy for Septic Shock.
  • Citation: Annane D, Cariou A, Maxime V, et al. Corticosteroid Therapy and Intensive Insulin Therapy for Septic Shock in Adults: A Randomized Controlled Trial. JAMA. 2010;303(4):341–348. DOI: 10.1001/jama.2010.2
  • Published: January 27, 2010, in The Journal of the American Medical Association (JAMA)
  • Author: Djillali Annane, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Sepsis, Septic Shock, Corticosteroids, Hydrocortisone, Intensive Insulin Therapy, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock (Population), does treatment with low-dose hydrocortisone (Intervention) compared to placebo (Comparison) reduce 28-day all-cause mortality (Outcome)? A second question was whether intensive insulin therapy was beneficial.

4. Background and Rationale

  • Existing Knowledge: The role of corticosteroids in septic shock was highly controversial. The Annane et al. trial (2002) had suggested a benefit in a subgroup of patients with “relative adrenal insufficiency,” while the larger CORTICUS trial (2008) found no overall survival benefit. Similarly, the benefit of intensive insulin therapy, suggested by the Leuven I trial (2001), was being questioned.
  • Knowledge Gap: There was a need for further high-quality trials to clarify the role of both corticosteroids and intensive insulin therapy in septic shock.
  • Proposed Hypothesis: The authors hypothesized that both hydrocortisone and intensive insulin therapy would be superior to their respective placebos/controls in reducing mortality in patients with septic shock.

5. Study Design and Methods

  • Design: A multicenter, 2×2 factorial, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 11 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2005 to November 2008.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock for less than 72 hours who had evidence of multiple organ dysfunction.
    • Exclusion Criteria: Included moribund patients and those with contraindications to either corticosteroids or insulin.
  • Intervention: Patients were randomized in a factorial design to one of four groups:
  • Hydrocortisone: 50 mg IV bolus every 6 hours for 7 days.
  • Intensive Insulin: Continuous IV insulin to maintain a blood glucose of 80-110 mg/dL.
  • Combination: Both hydrocortisone and intensive insulin.
  • Placebo/Control: Placebo for hydrocortisone and conventional insulin therapy (target <150 mg/dL).
  • Control: The control groups were placebo and conventional insulin therapy.
  • Management Common to Both Groups: All patients received standard care for septic shock according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 540 patients would provide 80% power to detect a 12% absolute risk reduction in mortality for each intervention. (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 28 days.
    • Secondary Outcomes: Included mortality at ICU and hospital discharge, shock reversal, and organ-failure-free days.

6. Key Results

  • Enrollment and Baseline: 509 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Hydrocortisone: There was no significant difference in 28-day mortality. 63 of 251 patients (25.1%) in the hydrocortisone group died, compared with 63 of 258 patients (24.4%) in the placebo group (p=0.85).
    • Intensive Insulin: There was no significant difference in 28-day mortality. 65 of 256 patients (25.4%) in the intensive insulin group died, compared with 61 of 253 patients (24.1%) in the conventional group (p=0.73).
  • Secondary Outcomes: There were no significant differences between the groups for any of the secondary outcomes, including shock reversal or organ-failure-free days.
  • Adverse Events: Severe hypoglycemia was significantly more common in the intensive insulin therapy group (14.5% vs. 3.2%; p<0.001).

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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the groups for each intervention.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for the primary outcome for both hydrocortisone (p=0.85) and intensive insulin (p=0.73) were much higher than the 0.05 threshold, indicating that the results were 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 for both interventions, 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 multicenter, randomized, double-blind, placebo-controlled, factorial design was of high quality and allowed two important questions to be answered efficiently.
  • Generalizability: The inclusion of 11 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The findings are specific to the doses and protocols used in this trial.
  • Other: The overall mortality rate was lower than anticipated, which can make it more difficult to show a treatment benefit.

10. Conclusion of the Authors

  • In adults with septic shock, neither hydrocortisone nor intensive insulin therapy, alone or in combination, significantly reduced 28-day mortality.

11. To Summarize

  • Impact on Current Practice: This trial provided strong, high-quality evidence that refuted the benefit of both low-dose hydrocortisone (as suggested by Annane 2002) and intensive insulin therapy (as suggested by Leuven I) in a general population of septic shock patients.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock.
    • Actionable Intervention: The results do not support the routine use of low-dose hydrocortisone or intensive insulin therapy to improve survival.
  • What This Trial Does NOT Mean: This trial does NOT mean that corticosteroids have no role in sepsis, but it added to the body of evidence suggesting they are not a magic bullet. It also does not mean that hyperglycemia should go untreated, only that a very strict target of 80-110 mg/dL is associated with harm (hypoglycemia) without benefit.
  • Implementation Caveats: The finding of increased severe hypoglycemia with intensive insulin therapy is a critical safety signal.

12. Context and Related Studies

  • Building on Previous Evidence: The COIITSS trial (2010) was designed to provide a more definitive answer to the questions raised by the Annane (2002) and Leuven I (2001) trials, and its results were more in line with the neutral findings of the CORTICUS (2008) and NICE-SUGAR (2009) trials.
  • Influence on Subsequent Research: The consistent neutral findings for steroids in this and the CORTICUS trial led to the design of the even larger APROCCHSS (2018) and ADRENAL (2018) trials to try and settle the controversy once and for all. The negative findings for intensive insulin, combined with NICE-SUGAR, led to the widespread abandonment of this practice in favor of more moderate glucose control.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial added to the uncertainty surrounding the role of corticosteroids in septic shock.
  • Future Directions: The conflicting results in the field of corticosteroids for sepsis ultimately led to the very large “mega-trials” (APROCCHSS and ADRENAL) to provide a more definitive answer.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing two of the most common and controversial interventions in the ICU at the time.
  • Methods: The multicenter, double-blind, factorial RCT design was of high quality and efficient. The patient population was representative of general ICU patients with septic shock.
  • Results: The study reported clear neutral findings for both of its primary comparisons. The finding of significant harm (severe hypoglycemia) with intensive insulin therapy was a critical safety outcome.
  • 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 is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to de-adopt two common but ineffective and potentially harmful therapies.

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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