The Journal of Informed Pharmacotherapy 2003;13:201.
Reviewer: Chole Campbell, BSc.
Pharm. (1), Salmaan Kanji, Pharm.D.
(corresponding author) (2)
Reviewer’s e-mail address: email@example.com
Reviewer's profession/specialty: Pharmacy Resident (1), Clinical Pharmacy Specialist (Critical Care) (2)
De Gans J, Van De Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-56. PubMed Citation
The purpose of this study was to determine if adjuvant treatment with dexamethasone improves outcomes in adults with acute bacterial meningitis. Evidence supporting adjunctive treatment of acute bacterial meningitis with corticosteroids is controversial at best. A meta-analysis of studies conducted in children only showed benefit in reducing hearing loss in those with Haemophilus influenzae type b meningitis. (1) Previously published reports involving adults have either been inconclusive, poorly designed, or inadequately powered.
This current study involved 301 patients from five European countries who were enrolled from 1993 to 2001. Adults with suspected meningitis were randomized to receive either dexamethasone or placebo in addition to empiric antibiotic therapy. The dexamethasone was given as a 10 mg dose administered intravenously 15 to 20 minutes prior to, or in combination with, the first dose of antibiotic and then every six hours for four days.
The primary study outcome was the Glasgow Outcome Scale (GOS) score. This was assessed by the patients’ physician at eight weeks following randomization. The secondary outcome measures were death, focal neurological abnormalities, hearing loss, gastrointestinal bleeding, fungal infection, herpes zoster infection and hyperglycemia. An unfavorable outcome was defined as a GOS score of 1 to 4, with a favorable outcome defined as a score of five (1-death; 2-vegetative state; 3-severe disability; 4-moderate disability; 5-mild or no disability).
This study was supported, in part, by a grant from NV Organon, the suppliers of the study medication. No relationship between any member of the European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators and the sponsors of this study was declared.
1. Was assignment of patients randomized?
All 301 patients were accounted for and included in the intention-to-treat analysis. The last recorded observation was carried forward for 32 patients (11 dexamethasone group; 21 placebo group) who died prior to the 8-week evaluation point, and seven patients (3 dexamethasone group; 4 placebo group) were lost to follow-up. In addition, 11 patients in each treatment group withdrew early from treatment but were included in the analysis.
1. How large was the treatment effect?
At the 8-week evaluation point, an unfavorable outcome (GOS value of 1to 4) was observed in 15% of the dexamethasone treated patients and 25% of the placebo treated patients (relative risk reduction [RRR] 41%, P=0.03). Death occurred in 7% of dexamethasone treated patients, as compared to 15% of the placebo treated group (RRR 52%, P =0.04). Therefore the authors concluded that adjuvant therapy with dexamethasone can significantly reduce the risk of an unfavorable neurological outcome as well as provide a mortality benefit in adult patients with bacterial meningitis. Subgroup analyses suggested that these benefits may be more apparent in patients with pneumococcal meningitis, but this study was not powered to address this particular hypothesis. There was no statistically significant difference in the incidence of focal neurological abnormalities, hearing loss, or adverse events (i.e. gastrointestinal bleeding, hyperglycemia, herpes zoster and fungal infections) between the two treatment groups.
2. How precise was the estimate of the treatment effect?
The 95% confidence interval (CI) around the RR of the primary endpoint (unfavorable GOS) of 0.59 was 0.37 - 0.94. The 95 percent CI around the RR of death of 0.48 was 0.24 - 0.96. Therefore, one unfavorable outcome can be prevented for every 10 patients treated (95% CI 6-100) and one death (95% CI 7-100) can be prevented for every 13 patients treated with dexamethasone versus placebo treated patients.
2. Were all clinically important outcomes considered?
In adults 18 to 50 years of age, the most common pathogens responsible for bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitides, and were found to be the most common pathogens isolated in this study (36% and 32% respectively). All of the S. pneumoniae isolates tested for susceptibility to penicillin (72%) and all but one of the N. meningitides isolates tested (83%) were sensitive to penicillin. The prevalence of PRSP is approximately 15% in Canada and 24% in the United States therefore empiric antibiotic regimens containing vancomycin may be warranted. (2,5) The likelihood of steroid therapy compromising the penetration of vancomycin across the blood brain barrier is controversial and was not addressed by this study. Future studies examining the efficacy of adjuvant corticosteroids with empiric vancomycin treatment are needed.
Another issue that warrants consideration is the timing of antibiotic and steroid administration. It may not always be reasonable to delay antimicrobial therapy until the results of the CSF Gram’s stain are reported. Inevitably dexamethasone will be given to patients with non-bacterial meningitis and currently the outcome in this population is unknown. Given the potential mortality benefit of early steroid administration and the relatively low risk of toxicity, it would be reasonable to empirically administer steroids if the suspicion of bacterial meningitis is high and to discontinue the drug if the Gram’s stain suggests a higher likelihood of a viral pathogen. Also, administration of dexamethasone to patients already receiving appropriate antimicrobials cannot be recommended at this time.
The role of dexamethasone therapy for patients who present with both evidence of bacterial meningitis and hemodynamic compromise is unclear. While lower, ‘stress doses’ of corticosteroids have been shown to be beneficial in septic shock (6), higher doses have been shown in meta-analyses (7,8) to be either of no benefit or have a trend towards increased mortality. It is possible that the beneficial effects of dexamethasone in this study may have been confounded by its effect in patients with refractory hypotension or septic shock. The rates of hypotension or septic shock were not reported however hypotension was found to be a predictor of an unfavourable outcome (p=0.03) and significantly fewer patients treated with dexamethasone developed cardiorespiratory failure (10% vs 20%; p=0.02). Until further research is done in this area, lower doses of hydrocortisone should be recommended over high doses of dexamethasone (as used in this study) for patients with both bacterial meningitis and refractory hypotension.
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