DE GANS 2002: Dexamethasone in Adults with Bacterial Meningitis (2002)

“Early treatment with dexamethasone is associated with a reduction in the risk of an unfavorable outcome and, in particular, a reduction in the risk of death.”

— The European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators

1. Publication Details

  • Trial Title: Dexamethasone in Adults with Acute Bacterial Meningitis.
  • Citation: de Gans J, van de Beek D; for the European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with acute bacterial meningitis. N Engl J Med. 2002;347(20):1549-1556. doi:10.1056/NEJMoa021334.
  • Published: November 14, 2002, in The New England Journal of Medicine.
  • Author: Jan de Gans, M.D., Ph.D.
  • Funding: Dutch Meningitis Foundation and others.

2. Keywords

Bacterial Meningitis, Dexamethasone, Corticosteroids, Neurological Complications, Hearing Loss, Streptococcus pneumoniae.

3. The Clinical Question

In adult patients with acute bacterial meningitis (Population), does adjunctive therapy with dexamethasone (Intervention) compared to placebo (Comparison) improve functional outcome at 8 weeks (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The intense subarachnoid inflammatory response in bacterial meningitis is a major contributor to neuronal damage, leading to high rates of death and severe neurological disability, such as hearing loss. Corticosteroids were known to dampen this inflammatory response.
  • Knowledge Gap: While animal studies and pediatric trials (specifically for H. influenzae meningitis) had shown a benefit for adjunctive corticosteroids, their efficacy in adults with bacterial meningitis caused by other pathogens (like S. pneumoniae) was unproven. A large, definitive trial was needed.
  • Proposed Hypothesis: The authors hypothesized that early treatment with dexamethasone would reduce morbidity and mortality in adults with acute bacterial meningitis.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, placebo-controlled trial.
  • Setting: 52 medical centers in the Netherlands.
  • Trial Period: Enrollment from June 1998 to December 2001.
  • Population:
    • Inclusion Criteria: Adult patients (≥17 years) with suspected bacterial meningitis, based on clinical signs and abnormal cerebrospinal fluid (CSF) analysis.
    • Exclusion Criteria: Recent head trauma or neurosurgery, known contraindications to steroids, or prior antibiotic treatment for more than 12 hours.
  • Intervention: Dexamethasone, 10 mg intravenously, administered 15-20 minutes before or with the first dose of antibiotics, and continued every 6 hours for 4 days.
  • Control: Matching placebo (saline) administered in the same manner.
  • Management Common to Both Groups: All patients received standard antibiotic therapy according to national guidelines.
  • Power and Sample Size: The trial was powered to detect a 15% absolute reduction in the rate of unfavorable outcomes, requiring 300 patients.
  • Outcomes:
    • Primary Outcome: Score on the Glasgow Outcome Scale at 8 weeks, dichotomized as favorable (score of 5) or unfavorable (score of 1-4).
    • Secondary Outcomes: Included mortality, focal neurological abnormalities, and hearing loss.

6. Key Results

  • Enrollment and Baseline: 301 patients were randomized (157 to dexamethasone, 144 to placebo). The groups were well-matched at baseline. Streptococcus pneumoniae was the most common pathogen.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The rate of an unfavorable outcome was significantly lower in the dexamethasone group compared to the placebo group (15% vs 25%; P=0.03).
  • Secondary Outcomes: All-cause mortality was significantly lower in the dexamethasone group (7% vs 15%; P=0.04). The benefit was most pronounced in the large subgroup of patients with pneumococcal meningitis.
  • Adverse Events: The rates of adverse events, including gastrointestinal bleeding, were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of patients with an unfavorable outcome at 8 weeks was compared between the two groups.
  • Key Statistic(s) Reported: Unfavorable outcome: 15% (dexamethasone) vs 25% (placebo); RR 0.59 (95% CI, 0.37 to 0.94); P=0.03.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of unfavorable outcome in Dexamethasone Group) / (Risk in Placebo Group).
      • Calculation: The paper reports the RR as 0.59.
      • Clinical Meaning: An RR of 0.59 means there was a 41% lower relative risk of having an unfavorable outcome in the dexamethasone group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.37 to 0.94.
      • Clinical Meaning: Since the 95% CI ranges from a 63% benefit to a 6% benefit and does not cross 1.0, the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.03.
      • Clinical Meaning: The p-value of 0.03 is less than the conventional threshold of 0.05, indicating that the observed difference is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 25% – 15% = 10%.
      • Clinical Meaning: For every 100 adults with bacterial meningitis treated with dexamethasone, about 10 were prevented from having an unfavorable outcome.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.10 = 10.
      • Clinical Meaning: Approximately 10 patients with acute bacterial meningitis need to be treated with adjunctive dexamethasone to prevent one additional unfavorable outcome.
  • Subgroup Analyses: The benefit was clear and significant for patients with pneumococcal meningitis (unfavorable outcome 26% vs 52%), but not for those with meningococcal meningitis.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence.
  • Generalizability: The pragmatic inclusion of patients with suspected meningitis before the causative organism was known increases the real-world applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome of functional status on the Glasgow Outcome Scale is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial was conducted in a high-income country with a specific bacterial epidemiology and low rates of HIV. The findings may not be fully generalizable to low-income settings where the causes and comorbidities of meningitis differ.
  • Other: The benefit was not seen in patients with meningococcal disease, which is a key nuance.

10. Conclusion of the Authors

“Early treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal bleeding.”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It definitively established adjunctive dexamethasone as the standard of care for adults with suspected bacterial meningitis in high-income countries. It provided clear evidence that this simple, inexpensive intervention significantly reduces both morbidity and mortality.
  • Specific Recommendations:
    • Patient Selection: For adult patients in high-income settings with suspected acute bacterial meningitis.
    • Actionable Intervention: Administer 10 mg of dexamethasone intravenously just before or with the first dose of antibiotics, and continue for 4 days.
    • Expected Benefit: A significant reduction in unfavorable outcomes (NNT ~10) and mortality, particularly for patients with pneumococcal meningitis.
  • What This Trial Does NOT Mean: This trial does not mean that dexamethasone is beneficial in all settings or for all pathogens. The benefit in low-income countries and in patients with non-pneumococcal meningitis is less certain.
  • Implementation Caveats: The key to effectiveness is early administration, ideally before or with the very first dose of antibiotics, to dampen the inflammatory cascade triggered by bacterial lysis.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to provide a definitive answer for adults, building on the positive but specific findings from pediatric trials in the era of H. influenzae.
  • Influence on Subsequent Research: The findings of this trial have been a cornerstone of international meningitis guidelines for two decades. Subsequent research and meta-analyses have largely confirmed the benefit in high-income settings but have raised questions about its utility in low-income settings with high HIV prevalence, where the risks might outweigh the benefits.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the true risk-benefit ratio of dexamethasone in low-income countries with different pathogen profiles and high rates of HIV and tuberculosis?
  • Future Directions: Research is focused on understanding the role of corticosteroids in different global settings and on developing other adjunctive therapies to target neuroinflammation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, testing a simple, inexpensive intervention for a common and devastating neurological emergency.
  • Methods: The study’s design (multicenter, randomized, double-blind, placebo-controlled) was of the highest quality.
  • Results: The trial had a clear and statistically significant positive result for its primary, patient-centered outcome, as well as for mortality. The NNT of 10 represents a highly effective intervention.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to practice in high-income countries and have definitively established a new standard of care for adult bacterial meningitis.

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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