Annane et al: Steroids for Septic Shock (2002)

“Treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency.”

  • Annane D, et al.

1. Publication Details

  • Trial Title: Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock
  • Citation: Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. DOI: 10.1001/jama.288.7.862
  • Published: August 21, 2002, 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, Fludrocortisone, Adrenal Insufficiency, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock (Population), does treatment with low-dose hydrocortisone and fludrocortisone (Intervention) compared to placebo (Comparison) reduce 28-day mortality, particularly in those who are non-responders to a corticotropin stimulation test (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Following the negative results of high-dose steroid trials in the 1980s (e.g., Sprung et al. 1984), interest shifted towards “stress-dose” or physiologic steroid replacement. It was hypothesized that many patients in septic shock develop relative adrenal insufficiency, and that replacing corticosteroids to physiologic levels could improve outcomes.
  • Knowledge Gap: It was unknown if low-dose corticosteroids provided a survival benefit in septic shock, and whether this benefit was limited to patients with demonstrable adrenal insufficiency (so-called “non-responders” to a corticotropin stimulation test).
  • Proposed Hypothesis: The authors hypothesized that a 7-day course of low-dose hydrocortisone and fludrocortisone would reduce 28-day mortality in patients with septic shock, especially in those classified as non-responders.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 19 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from October 1995 to March 1999.
  • Population:
    • Inclusion Criteria: Adult patients with septic shock, defined by clinical signs of infection, hyperthermia or hypothermia, tachycardia, hypotension requiring vasopressors for at least 1 hour, and evidence of organ dysfunction.
    • Exclusion Criteria: Included age <18 years, pregnancy, and terminal illness.
  • Intervention: Patients received intravenous hydrocortisone (50 mg every 6 hours) plus oral fludrocortisone (50 μg once daily) for 7 days.
  • Control: Patients received matching intravenous and oral placebos for 7 days.
  • 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 300 patients would be required to have 80% power to detect a 15% 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 ICU length of stay.

6. Key Results

  • Enrollment and Baseline: 300 patients were randomized (151 to steroids and 149 to placebo). Of these, 229 (76%) were classified as non-responders. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: In the primary analysis of the 229 non-responders, after adjusting for baseline variables, treatment with hydrocortisone and fludrocortisone was associated with a significant reduction in 28-day mortality (hazard ratio, 0.67; 95% CI, 0.47-0.95; p=0.02). The unadjusted mortality was 63% in the placebo group vs. 53% in the steroid group.
  • Secondary Outcomes: In the overall population (responders and non-responders), there was no significant difference in 28-day mortality. However, patients in the steroid group had a significantly faster reversal of shock.
  • Adverse Events: There were no significant differences in the rates of major adverse events, including secondary infections or gastrointestinal bleeding.

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 Cox proportional-hazards model, adjusted for baseline covariates.
  • Primary Outcome Analysis: The primary outcome was a time-to-event analysis of 28-day mortality in the subgroup of non-responders.
  • Key Statistic(s) Reported: Adjusted Hazard Ratio for death at 28 days in non-responders: 0.67 (95% CI, 0.47 to 0.95; P-value: 0.02).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the adjusted result as 0.67.
      • Clinical Meaning: The HR of 0.67 means that non-responder patients in the steroid group had a 33% lower risk of dying at any given time point compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.47 to 0.95.
      • Clinical Meaning: Since this entire range is below the line of no effect (1.0), it confirms that the result is statistically significant.
    • P-value: The p-value of 0.02 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the unadjusted mortality in non-responders):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 63% – 53% = 10%.
      • Clinical Meaning: For every 100 non-responder patients treated with this steroid regimen, about 10 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.10 = 10.
      • Clinical Meaning: You would need to treat 10 non-responder patients with this regimen to prevent one additional death.
  • Subgroup Analyses: The entire trial’s primary outcome was a subgroup analysis (non-responders). The treatment was not shown to be effective in the smaller group of responders.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design was a major strength for its time.
  • Generalizability: The inclusion of 19 centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome (in the non-responder subgroup).
  • 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 primary outcome was a subgroup analysis, which is generally considered hypothesis-generating. The fact that the benefit was not seen in the overall population is a significant limitation. The reliability and clinical utility of the corticotropin stimulation test to guide therapy is also a major point of controversy.
  • External Validity (Generalizability): The findings are only applicable to patients identified as “non-responders,” a classification that is not routinely used in modern practice.
  • Other: The sample size was relatively small by modern standards.

10. Conclusion of the Authors

  • A 7-day treatment with low doses of hydrocortisone and fludrocortisone reduced the risk of death in patients with septic shock and relative adrenal insufficiency (defined as a poor response to a corticotropin test).

11. To Summarize

  • Impact on Current Practice: This was a highly influential trial that revived interest in the use of low-dose corticosteroids for septic shock after the negative results of the high-dose era. It led to the widespread practice of considering stress-dose steroids, particularly in patients with refractory shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock who are poorly responsive to fluids and vasopressors.
    • Actionable Intervention: The trial supports the use of low-dose hydrocortisone and fludrocortisone in this population.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with septic shock benefit from steroids. The benefit was only seen in the “non-responder” subgroup.
  • Implementation Caveats: The use of the corticotropin stimulation test to guide therapy is not supported by subsequent evidence and is not recommended in current guidelines.

12. Context and Related Studies

  • Building on Previous Evidence: The Annane et al. trial (2002) was a direct response to the negative high-dose steroid trials of the 1980s (e.g., Sprung et al. 1984), testing a new hypothesis about physiologic replacement.
  • Influence on Subsequent Research: The positive but controversial findings of this trial directly led to the larger CORTICUS trial (2008), which failed to confirm a mortality benefit. This ongoing uncertainty was later addressed by the very large APROCCHSS (2018) and ADRENAL (2018) trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the key question of whether the corticotropin stimulation test is a useful tool to guide therapy unresolved. It also raised the question of whether the benefit was from the hydrocortisone, the fludrocortisone, or the combination.
  • Future Directions: The entire subsequent history of steroid research in sepsis, from CORTICUS to APROCCHSS and ADRENAL, can be seen as the future direction that followed from this study’s pivotal but debated findings.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a new and plausible hypothesis for an old and controversial therapy.
  • Methods: The multicenter, double-blind RCT design was a strength. However, defining the primary outcome based on a subgroup analysis (the non-responders) is a significant methodological limitation, as such analyses are prone to false-positive results.
  • Results: The study reported a statistically significant benefit in its primary (subgroup) outcome, but not in the overall population. The clinical significance of this finding is debated due to the methodological limitations.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their primary analysis, but its applicability is limited by the controversy surrounding the corticotropin stimulation test. While this trial was hugely influential in reviving the use of low-dose steroids, subsequent, larger trials have not supported the strategy of using a stimulation test to guide therapy.

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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