CORTICUS: Hydrocortisone in Septic Shock (2008)

“Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who had a poor response to corticotropin. However, shock was reversed more quickly in patients treated with hydrocortisone.”

  • The CORTICUS Study Group

1. Publication Details

  • Trial Title: Hydrocortisone Therapy for Patients with Septic Shock
  • Citation: Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. DOI: 10.1056/NEJMoa071366
  • Published: January 10, 2008, in The New England Journal of Medicine
  • Author: Charles L. Sprung, M.D.
  • Funding: European Society of Intensive Care Medicine; and others.

2. Keywords

  • Sepsis, Septic Shock, Corticosteroids, Hydrocortisone, Adrenal Insufficiency, 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 mortality in those who are non-responders to a corticotropin stimulation test (Outcome)?

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 mortality benefit in a subgroup of patients with “relative adrenal insufficiency” (non-responders to a corticotropin test). However, this was a single, relatively small trial, and its findings were not universally accepted.
  • Knowledge Gap: A larger, multicenter trial was needed to confirm or refute the findings of the Annane (2002) trial and to clarify whether the corticotropin stimulation test was a useful tool for guiding therapy.
  • Proposed Hypothesis: The authors hypothesized that low-dose hydrocortisone would reduce 28-day mortality in patients with septic shock who did not have a normal adrenal response to a corticotropin stimulation test.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 52 intensive care units (ICUs) in Europe and Israel.
  • Trial Period: Enrollment ran from November 2002 to August 2005.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock who had evidence of multiple organ dysfunction.
    • Exclusion Criteria: Included moribund patients and those who had received systemic corticosteroids within the previous 4 weeks.
  • Intervention: Patients received intravenous hydrocortisone (50 mg every 6 hours) for 5 days, followed by a taper.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients underwent a short corticotropin stimulation test before randomization. All other aspects of care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample of 800 patients would be required to have 80% power to detect a 10% absolute risk reduction in 28-day mortality among non-responders. (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 in patients who were non-responders to the corticotropin test.
    • Secondary Outcomes: Included 28-day mortality in the overall population, shock reversal, and incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 499 patients were randomized (251 to hydrocortisone and 248 to placebo). Of these, 233 (47%) were classified as non-responders. The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for slow enrollment after recruiting 499 of the planned 800 patients.
  • Primary Outcome: In the primary analysis of non-responders, there was no significant difference in 28-day mortality. 42 of 125 non-responders (33.6%) in the placebo group died, compared with 36 of 108 non-responders (33.3%) in the hydrocortisone group (p=1.00).
  • Secondary Outcomes: There was no significant difference in 28-day mortality in the overall population (34.5% in the hydrocortisone group vs. 31.5% in the placebo group). However, patients in the hydrocortisone group had a significantly faster reversal of shock.
  • Adverse Events: Patients in the hydrocortisone group had a significantly higher incidence of superinfections, including new sepsis or septic shock.

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 two groups in the subgroup of non-responders.
  • 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-value of 1.00 for the primary outcome indicates no difference whatsoever between the groups and is far from the 0.05 threshold for statistical significance (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: The primary outcome of the trial was itself a subgroup analysis.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design was of high quality.
  • Generalizability: The inclusion of 52 diverse ICUs increases the applicability of the findings.
  • 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 study population was less sick than in the Annane (2002) trial, which may have diluted the potential for benefit.
  • Other: The trial was stopped early for slow enrollment and was therefore underpowered to definitively rule out a smaller, but still potentially important, treatment effect. The finding of increased superinfections is a significant safety concern.

10. Conclusion of the Authors

  • The authors concluded that hydrocortisone does not improve survival in patients with septic shock, either in the overall population or in the subgroup of patients who do not respond to a corticotropin stimulation test.

11. To Summarize

  • Impact on Current Practice: This was a highly influential trial that directly contradicted the findings of the Annane (2002) trial. Its neutral result, combined with the signal of harm (superinfections), led to a significant decrease in the routine use of corticosteroids for septic shock and cast serious doubt on the utility of the corticotropin stimulation test.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock.
    • Actionable Intervention: The results do not support the routine use of low-dose hydrocortisone to improve survival in septic shock.
  • What This Trial Does NOT Mean: This trial does NOT mean that corticosteroids are never useful in septic shock. It only suggests that in a broad population, they do not provide a survival benefit and may cause harm.
  • Implementation Caveats: The finding of increased superinfections highlights the potential downside of even “low-dose” steroid therapy in this population.

12. Context and Related Studies

  • Building on Previous Evidence: The CORTICUS trial (2008) was a direct attempt to replicate and validate the findings of the Annane et al. trial (2002).
  • Influence on Subsequent Research: The conflicting results between Annane (2002) (positive) and CORTICUS (2008) (negative) created a state of clinical equipoise and controversy that lasted for a decade. This directly led to the design of the two very large, definitive trials—APROCCHSS (2018) and ADRENAL (2018)—to finally settle the question.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the role of corticosteroids in septic shock highly uncertain, with two major trials showing directly opposing results.
  • Future Directions: The entire subsequent field of research into corticosteroids for sepsis, culminating in the APROCCHSS and ADRENAL trials, can be seen as the future direction that followed from the clinical uncertainty created by the conflicting results of Annane (2002) and CORTICUS (2008).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, as it sought to confirm the findings of a previous, potentially practice-changing trial.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological limitation is that the trial was stopped early and was underpowered, which weakens the strength of its neutral conclusion.
  • Results: The study reported a clear neutral finding for its primary outcome. The finding of faster shock reversal was consistent with previous studies, but the new finding of increased superinfections was a critical safety signal that tempered enthusiasm for the therapy.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data. This trial was profoundly important because it failed to replicate the benefit seen in the Annane (2002) trial, thereby preventing the widespread adoption of a potentially flawed treatment strategy (guiding therapy by corticotropin testing) and highlighting the need for larger, more definitive trials.

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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