ADRENAL: Hydrocortisone in Septic Shock (2018)

“In patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.”

  • The ADRENAL Trial Investigators

1. Publication Details

  • Trial Title: Adjunctive Glucocorticoid Therapy in Patients with Septic Shock
  • Citation: Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. DOI: 10.1056/NEJMoa1705835
  • Published: March 1, 2018, in The New England Journal of Medicine
  • Author: Balasubramanian Venkatesh, M.D.
  • Funding: National Health and Medical Research Council of Australia; and others.

2. Keywords

  • Sepsis, Septic Shock, Corticosteroids, Hydrocortisone, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock undergoing mechanical ventilation (Population), does a continuous infusion of hydrocortisone (Intervention) compared to placebo (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The role of corticosteroids in septic shock was a long-standing controversy. While they were known to reverse shock more quickly, previous trials had yielded conflicting results regarding a survival benefit, and concerns about potential side effects persisted.
  • Knowledge Gap: A large, high-quality, multicenter trial was needed to provide a more definitive answer on whether hydrocortisone improved survival in a broad population of patients with septic shock.
  • Proposed Hypothesis: The authors hypothesized that treatment with a continuous infusion of hydrocortisone would reduce 90-day mortality in patients with septic shock.

5. Study Design and Methods

  • Design: A multicenter, parallel-group, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 69 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Saudi Arabia, and Denmark.
  • Trial Period: Enrollment ran from March 2013 to April 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with septic shock who were receiving vasopressor support.
    • Exclusion Criteria: Included a decision to withhold life-sustaining treatment, a high probability of death within 90 days from an underlying condition, and treatment with systemic corticosteroids.
  • Intervention: Patients received a continuous intravenous infusion of hydrocortisone at a dose of 200 mg per 24 hours for up to 7 days.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All other aspects of care, including fluid resuscitation and antibiotic therapy, were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 3800 patients would provide 90% power to detect a 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 time to resolution of shock, duration of mechanical ventilation, incidence of new-onset bacteremia or fungemia, and need for renal replacement therapy.

6. Key Results

  • Enrollment and Baseline: 3658 patients were randomized (1832 to hydrocortisone and 1826 to placebo). 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. 511 of 1832 patients (27.9%) in the hydrocortisone group died, compared with 526 of 1826 patients (28.8%) in the placebo group (p=0.50).
  • Secondary Outcomes: Patients in the hydrocortisone group had a significantly faster resolution of shock (median, 3 days vs. 4 days; p<0.001) and a shorter duration of initial mechanical ventilation.
  • Adverse Events: The overall incidence of adverse events was similar between the groups. However, hyperglycemia was more common in the hydrocortisone group.

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. Time-to-event outcomes were analyzed with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for death at 90 days: 0.95 (95% CI, 0.82 to 1.10; P-value: 0.50).
  • 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 result as 0.95.
      • Clinical Meaning: The OR of 0.95 suggests a non-significant 5% lower odds of death in the hydrocortisone group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.82 to 1.10.
      • 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 an 18% benefit to a 10% harm.
    • P-value: The p-value of 0.50 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 very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and producing high-quality evidence.
  • Generalizability: The inclusion of 69 diverse ICUs across five countries increases the external validity, making the results highly applicable to a broad range of clinical settings.
  • Statistical Power: The large sample size provided excellent statistical power to confidently rule out a modest but clinically important mortality benefit.
  • Patient-Centered Outcomes: The study focused on 90-day mortality, a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are specific to a continuous infusion of hydrocortisone and may not apply to regimens that use bolus dosing or include fludrocortisone.
  • Other: The mortality rate in the placebo group (28.8%) was lower than anticipated, which can make it more difficult to show a treatment benefit.

10. Conclusion of the Authors

  • In patients with septic shock undergoing mechanical ventilation, treatment with a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that a routine hydrocortisone infusion does not improve survival in a broad population of patients with septic shock, though it does lead to a faster resolution of shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock requiring mechanical ventilation and vasopressor support.
    • Actionable Intervention: The results do not support the routine use of hydrocortisone for the sole purpose of reducing mortality. It may be considered to expedite shock resolution.
  • What This Trial Does NOT Mean: This trial does NOT mean that steroids should never be used in septic shock. It specifically tested a hydrocortisone-only strategy and does not refute the potential benefit of a combined hydrocortisone-fludrocortisone regimen as seen in the APROCCHSS trial.
  • Implementation Caveats: If hydrocortisone is used, clinicians should be prepared to actively manage hyperglycemia.

12. Context and Related Studies

  • Building on Previous Evidence: The ADRENAL trial (2018) was designed to be a larger and more definitive successor to previous, smaller trials like CORTICUS (2008).
  • Influence on Subsequent Research: The findings of this trial must be considered alongside the concurrent APROCCHSS trial (2018), which was published at the same time and did find a mortality benefit with a combination of hydrocortisone and fludrocortisone. This has led to an ongoing debate and further research into whether the mineralocorticoid effect of fludrocortisone is a crucial component of any potential benefit.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is why the results of ADRENAL (neutral) and APROCCHSS (positive) were different. This discrepancy has not been fully resolved.
  • Future Directions: Future research is focused on identifying specific phenotypes or biomarkers that might predict which septic shock patients are most likely to benefit from corticosteroid therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing one of the most persistent controversies in critical care.
  • Methods: The study design was of the highest quality (large, multicenter, double-blind RCT), providing a very low risk of bias. The patient population was broad and representative of typical ICU patients with septic shock.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that was centered on the null value. The positive findings for secondary outcomes (faster shock resolution) were statistically significant but did not translate to improved survival.
  • 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. The main point of discussion is how to reconcile these neutral findings with the positive findings of the APROCCHSS trial, which suggests that the choice of steroid regimen (with or without fludrocortisone) may be a critical factor.

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