Therapy Dexamethasone in Adults with Bacterial Meningitis
This review may be edited
Summary
Posted By:	Todd Fraser
E-Mail:	lil_frog@bigpond.net.au
Posted Date:	1/12/02
Title:	Dexamethasone in Adults with Bacterial Meningitis
Authors:	de Gans, J, van de Beek, D.
Reference:	NEJM 2002; 347:1549-56
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	Background : Mortality and morbidity rates are high among adults with acute bacterial meningitis, especially those with pneumococcal meningitis. In studies of bacterial meningitis in animals, adjuvant treatment with corticosteroids has beneficial effects. Methods : We conducted a prospective, randomized, double-blind, multicenter trial of adjuvant treatment with dexamethasone, as compared with placebo, in adults with acute bacterial meningitis. Dexamethasone (10 mg) or placebo was administered 15 to 20 minutes before or with the first dose of antibiotic and was given every 6 hours for four days. The primary outcome measure was the score on the Glasgow Outcome Scale at eight weeks (a score of 5, indicating a favorable outcome, vs. a score of 1 to 4, indicating an unfavorable outcome). A subgroup analysis according to the causative organism was performed. Analyses were performed on an intention-to-treat basis. Results : A total of 301 patients were randomly assigned to a treatment group: 157 to the dexamethasone group and 144 to the placebo group. The base-line characteristics of the two groups were similar. Treatment with dexamethasone was associated with a reduction in the risk of an unfavorable outcome (relative risk, 0.59; 95 percent confidence interval, 0.37 to 0.94; P=0.03). Treatment with dexamethasone was also associated with a reduction in mortality (relative risk of death, 0.48; 95 percent confidence interval, 0.24 to 0.96; P=0.04). Among the patients with pneumococcal meningitis, there were unfavorable outcomes in 26 percent of the dexamethasone group, as compared with 52 percent of the placebo group (relative risk, 0.50; 95 percent confidence interval, 0.30 to 0.83; P=0.006). Gastrointestinal bleeding occurred in two patients in the dexamethasone group and in five patients in the placebo group. Conclusions : Early treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal bleeding.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes. The authors state that "balanced treatment assignmentes wihtin each hospital were achieved with the use of a computer-generated list of random numbers in blocks of six." This list was distributed to all centres in opaque, sealed envelopes.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Figure 1 documents the flow and follow-up of all patients. 7 patients were lost to follow up, 3 in the treatment group and 4 in the control group. Followup was conducted at 8 weeks, and for the 7 lost patients, their condition at discharge was substituted for the 8-week measurement. Only one of these patients was considered an unfavourable outcome for the purposes of analysis. Treating the 3 patients in the treatment group as poor outcomes would not significanly change the outcome of the trial. 8 week mortality and morbidity estimates would seem appropriate for this condition.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes.
3. Were patients, health workers, and study personnel blind to treatment?
	Yes. Placebo preparations were administered to maintain blinding. The code was broken on two occasions in emergent deteriorations in the patients condition, once in each arm.
4. Were the groups similar at the start of the trial?
	Table 1 demonstrates that there were no significant differences between the groups.
5. Aside from the experimental intervention, were the groups treated equally?
	No details were given with regards to supportive therapy. We do not know if ventilation rates or inotrope use differed between the two groups AFTER the onset of treatment.
What are the Results?
1. How large was the treatment effect?
	Mortality at 8 weeks was significantly lower in the dexamthasone group by 8% (7% vs. 15%, p=0.04, 95% CI 1% to 15%). Morbidity, as detirmined by the Glascow Outcome Score, was measured at 8 weeks. An unfavourable outcome was defined as any patient who scored 4 or less on this assessment (ie, was independently living but unable to return to school or work due to disability, or worse). Unfavourable outcome was significantly reduced by 10% in the dexamethasone group (15% vs. 25%, p=0.03, 95%CI 1% to 19%). Dexamethasone treated patients were also significanly less likely to develop impaired consciousness (11% vs. 25%, p=0.002), to have seizures (5% vs. 12%, p=0.04) or to develop cardiorespiratory failure (10% vs. 20%, p=0.02).
2. How precise was the estimate of the treatment effect?
	The 95% confidence intervals for all estimates are reported above.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	The inclusion criteria are quite restrictive, as all patients must have one of a) cloudy CSF, b) bacteria seen on CSF gram stain or c)CSF white cell count > 1000/ml, however if the patient you are considering treating would qualify for entry into this study, it is likely they would benefit. It should be noted that in this population, all Strep pneumoniae isolates were sensitive to penicillin. In some populations where Penicillin resistance in Strep pneumoniae is higher, vancomycin is added to empiric therapy. There is some suggestion that steroids reduce the CSF penetration of vancomycin. Consequently, the results of this trial may not be applicable to those patients.
2. Were all clinically important outcomes considered?
	The authors considered mortality, disability, focal neurological deficits and hearing loss as the outcomes of interest. The authors also considered adverse treatment effects potentially attributable to steroids such as opportunistic superinfections, hyperglycaemia and GIT bleeding. The authors could have considered costs or used a quality of life tool that is more refined than the GOS however we are relatively confident in the outcomes that were reported.
3. Are the likely treatment benefits worth the potential harms and costs?
	The overall study outcome was positive, with a significant reduction in both mortality and morbidity. A bad outcome occured in 25% of all patients in the control group - this figure was almost halved by treatment with dexamethasone. Importantly, the reduction in mortality did not result in more patients with a severe disability.
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