CAPE COD: Hydrocortisone in Severe Community-Acquired Pneumonia (2023)

“In patients with severe community-acquired pneumonia being treated in the ICU, hydrocortisone reduced the risk of death at 28 days as compared with placebo.”

  • The CAPE COD Trial Group

1. Publication Details

  • Trial Title: Hydrocortisone in Severe Community-Acquired Pneumonia
  • Citation: Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023;388(21):1931-1941. DOI: 10.1056/NEJMoa2215145
  • Published: May 25, 2023, in The New England Journal of Medicine
  • Author: Pierre-François Dequin, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Community-Acquired Pneumonia (CAP), Sepsis, Corticosteroids, Hydrocortisone, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients admitted to the ICU with severe community-acquired pneumonia (Population), does treatment with intravenous hydrocortisone (Intervention) compared to placebo (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Community-acquired pneumonia (CAP) is a leading cause of sepsis and death. The inflammatory response in severe CAP can be profound and lead to organ dysfunction. Corticosteroids, with their potent anti-inflammatory effects, have been studied in CAP for years, but previous trials and meta-analyses had yielded conflicting results, leading to uncertainty and inconsistent recommendations in guidelines.
  • Knowledge Gap: A large, definitive, multicenter randomized controlled trial was needed to clarify whether corticosteroids provide a true survival benefit in the sickest patients with CAP—those requiring ICU admission.
  • Proposed Hypothesis: The authors hypothesized that treatment with hydrocortisone would be superior to placebo in reducing 28-day mortality in patients with severe CAP.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 42 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from October 2015 to March 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with a clinical diagnosis of severe community-acquired pneumonia.
    • Exclusion Criteria: Included septic shock (as this was being studied in other trials), influenza pneumonia (unless there was bacterial co-infection), and contraindications to corticosteroids.
  • Intervention: Patients received a continuous intravenous infusion of hydrocortisone (200 mg per day) for either 4 or 8 days, followed by a taper, with the duration determined by clinical improvement.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients received standard care for severe CAP, including appropriate antibiotic therapy and supportive care, according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1146 patients would be required to have 90% power to detect a 6% absolute risk reduction in 28-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 28 days.
    • Secondary Outcomes: Included mortality at 90 days, need for mechanical ventilation or vasopressors among patients not receiving them at baseline, and length of ICU stay.

6. Key Results

  • Enrollment and Baseline: 800 patients were randomized (401 to hydrocortisone and 399 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for administrative reasons due to the COVID-19 pandemic, after enrolling 70% of the planned sample size.
  • Primary Outcome: 28-day mortality was significantly lower in the hydrocortisone group: 25 of 400 patients (6.2%) died, compared with 47 of 395 patients (11.9%) in the placebo group (p=0.006).
  • Secondary Outcomes: The risk of death at 90 days was also lower in the hydrocortisone group. Among patients not on vasopressors at baseline, those in the hydrocortisone group were significantly less likely to require them.
  • Adverse Events: The incidence of adverse events was similar between the groups. Notably, there was no significant increase in the rate of secondary infections. Patients in the hydrocortisone group required higher doses of insulin for hyperglycemia in the first week.

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.
  • Key Statistic(s) Reported: Absolute difference in 28-day mortality: -5.6 percentage points (95% CI, -9.6 to -1.7; P-value: 0.006).
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.006 is well below the 0.05 threshold, indicating that the observed difference in mortality is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 11.9% – 6.2% = 5.7%.
      • Clinical Meaning: For every 100 patients with severe CAP treated with hydrocortisone, about 6 additional deaths were prevented at 28 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.057 = 17.5, which is rounded down to 17.
      • Clinical Meaning: You would need to treat 17 patients with severe CAP with hydrocortisone to prevent one additional death.
  • Subgroup Analyses: The benefit of hydrocortisone was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and producing high-quality evidence.
  • Generalizability: The inclusion of 42 diverse ICUs increases the external validity of the findings.
  • Statistical Power: Although stopped early, the trial was still large and the observed effect was large enough to be statistically significant.
  • 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 trial specifically excluded patients with septic shock, so the results cannot be directly applied to this population. It also excluded patients with influenza.
  • Other: The trial was stopped early, which can sometimes lead to an overestimation of the true treatment effect. The overall mortality rate was lower than anticipated in the power calculation.

10. Conclusion of the Authors

  • In patients with severe community-acquired pneumonia who were admitted to the ICU, treatment with hydrocortisone for 4 to 8 days resulted in a lower risk of death at 28 days than placebo.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence supporting the use of corticosteroids in patients with severe CAP, helping to resolve a long-standing clinical controversy.
  • Specific Recommendations:
    • Patient Selection: For adult patients admitted to the ICU with severe community-acquired pneumonia who do not have septic shock.
    • Actionable Intervention: Administer intravenous hydrocortisone at a dose of 200 mg per day.
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 17 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that steroids should be given to all patients with pneumonia, only those who are sick enough to require ICU admission.
  • Implementation Caveats: Clinicians should be prepared to actively manage hyperglycemia, a common and expected side effect of this treatment.

12. Context and Related Studies

  • Building on Previous Evidence: The CAPE COD trial (2023) was designed to provide a more definitive answer than previous, smaller trials and meta-analyses on the role of steroids in severe CAP.
  • Influence on Subsequent Research: The definitive positive result of this trial will be highly influential in shaping future international guidelines for the management of severe community-acquired pneumonia.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal duration of steroid therapy (4 vs. 8 days in this trial) remains an area for further investigation. The role of steroids in patients with influenza pneumonia also remains unclear.
  • Future Directions: Future research may focus on identifying which specific inflammatory phenotypes of pneumonia 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 a common and important clinical problem with a controversial but widely available therapy.
  • Methods: The multicenter, double-blind RCT design was of high quality. The exclusion of patients with septic shock is a key methodological point that differentiates this trial from others like APROCCHSS.
  • Results: The study reported a statistically significant and clinically meaningful benefit in its primary outcome (NNT of 17). The finding was consistent and robust.
  • 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 to the care of ICU patients with severe CAP (without shock).

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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