In children with bacterial meningitis, does the addition of dexamethasone to an antibiotic treatment regimen result in a better clinical outcome than the antibiotic regimen alone?

Despite the development of new antibiotics, acute bacterial meningitis remains a relatively common serious childhood illness with significant mortality and long-term morbidity, including neurological sequelae, such as severe hearing loss. The pathophysiology of neurological injury in meningitis appears to correlate with the severity of inflammation in the cerebrospinal fluid (CSF), which is attenuated by the use of systemic corticosteroids (1,2), and dexamethasone has been shown to decrease the incidence of severe hearing loss in Haemophilus influenzae type b (Hib) meningitis (3,4). However, there have been major shifts in causative organism and antibiotic resistance in the past 10 years, largely due to the introduction of the Hib vaccine in the developed world, and many paediatricians disagree about whether dexamethasone should be used routinely. The best available evidence indicates that while adjuvant dexamethasone therapy has no effect on mortality in children, this intervention significantly reduces the incidence of severe hearing loss in both Hib meningitis and non-Hib meningitis (5) (grade of recommendation: A, based on a systematic review of randomized controlled trials [RCTs] [6]). However, it is no longer possible to answer questions concerning the efficacy of dexamethasone in reducing neurological damage or the risk of side effects of such therapy because of widespread use of Hib and pneumococcal vaccines in First World countries, which have markedly reduced the incidence of meningitis. Answers that may come from Third World countries, where the incidence of meningitis is still high, will be difficult to apply to First World populations because of the fact that such a large proportion of children and adults come to hospital late in the course of their illness in Third World countries. To determine the efficacy of adjuvant dexamethasone therapy in paediatric bacterial meningitis, a thorough search of three major databases – PubMed, EMBASE and the Cochrane Library – was performed. The search terms were ‘meningitis and dexamethasone or corticosteroid’, and the search was limited to paediatric populations and to RCTs or meta-analyses of RCTs. The most recent meta-analysis of RCTs was published in the Cochrane Library in 2003 by van de Beek et al (5); currently, one RCT involving children, published by Molyneux et al (7) in The Lancet in 2002, has not been considered in the Cochrane review. The quality of the studies used in the Cochrane review was high, with an average Jadad score of 4 out of 5 (points are awarded on a scale up to 5 for randomization, blinding, and reporting of withdrawals or losses to follow-up [8]). One problem encountered by the reviewers was that studies to date have been heterogeneous in the type of corticosteroid used, the dose amount and timing, and the outcomes measured. While it was generally agreed that to be most effective, steroids should be initiated before or with the first dose of antibiotic, the review did not break down the results in terms of when the dexamethasone was administered. Of 18 studies included by van de Beek et al (5), 15 tested dexamethasone; in most of those studies, the dose ranged from 0.4 mg/kg to 0.6 mg/kg divided into four doses daily for a duration of four days. In the remaining three studies, hydro-cortisone, prednisolone or a combination was given. Ten studies were used to calculate mortality in children, and only one of the studies (9) used a nondexamethasone regimen. That study showed a trend toward increased mortality with steroid use, and thus its removal from the meta-analysis favoured dexamethasone treatment. Of 12 studies used to calculate severe hearing loss and 10 studies used to calculate severe hearing loss in non-H influenzae species, all used dexamethasone as the intervention (5). van de Beek et al (5) found that adjuvant therapy with dexamethasone has no effect on the mortality rate of acute bacterial meningitis in children (relative risk of mortality with intervention [RR] 0.95, 95% CI 0.65 to 1.37). The reduction in severe hearing loss from 9.8% to 2.9% was significant (RR 0.31, 95% CI 0.18 to 0.54). However, there have been major shifts in causative organism and antibiotic resistance since 1988, when Lebel et al (10) showed a clear advantage of dexamethasone treatment. The most important change was the decrease in Hib meningitis after the introduction of the Hib vaccine in the early 1990s (11). Even so, the number of children with severe hearing loss in meningitis caused by pathogens other than Hib was significantly smaller in the dexamethasone group than in the placebo group (six of 191 [3.1%] versus 19 of 203 [8.3%], RR 0.42, 95% CI 0.20 to 0.89) (5). This means that the adjuvant dexamethasone treatment of 20 children would prevent one case of severe hearing loss. One issue that has complicated the debate is the suggestion that the use of anti-inflammatory steroids may decrease the CSF concentration of antibiotics. While this is not an issue for ceftriaxone, a third-generation cephalosporin with dependable penetration of the blood-brain barrier, it is a potential problem when dexamethasone is used with vancomycin. Vancomycin, the antibiotic of choice in penicillin-resistant pneumococcal meningitis, may rely on the inflammation in the subarachnoid space to increase penetration across the blood-brain barrier – inflammation that may be attenuated by the use of corticosteroids. A 1999 animal study (12) examining this topic suggested that there is a decreased rate of bacterial clearance from the CSF when adjunctive dexamethasone is used, but this was circumvented when the rabbits were given a higher dose (40 mg/kg instead of 20 mg/kg) of vancomycin. The issue was further laid to rest by a study (13) in children with acute meningitis, which demonstrated that dexamethasone does not attenuate either the penetration of vancomycin (15 mg/kg four times daily) into the CSF or the synergistic action of vancomycin with ceftriaxone. Dexamethasone also appears to be a safe adjunct to antimicrobial therapy. The Cochrane review defined adverse events as either clinically evident gastrointestinal (GI) tract bleeding or ‘other’, where the ‘other’ category included reactive arthritis, pericarditis, herpes zoster or herpes simplex virus infection, fungal infection, secondary fever or persistent fever. The 2003 Cochrane meta-analysis (5) found no significant increase in all adverse events in all participants as a group (RR 1.06, 95% CI 0.88 to 1.27). The review did not separate adults and children, but did suggest that the majority of study participants were paediatric: “in adults…there were few data” (5). Another problem with the review was that no absolute numbers were supplied in the GI bleed category. The study only states that the relative risk of GI tract bleeding was higher in the steroid group (RR 1.16) but did not reach statistical significance (5). No confidence intervals were supplied, and without absolute numbers to confirm the results, we do not know the full range of the potential risk. Steroids appear to be of no benefit for patients with late-stage meningitis. In patients with septic shock, corti-costeroids may also be detrimental and should not be administered (14). According to a well-done RCT (Jadad score of 5) conducted in Malawi (7), dexamethasone is not a useful adjunct to therapy. That study was done in a developing country where underlying disease is common and patients often present in a late stage of infection and often with initial mistreatment. Molyneux et al (7) found no difference in mortality with the use of dexamethasone (RR 1.00, 95% CI 0.80 to 1.25) and no effect on the proportion of participants with normal hearing (86 of 305 [28%] versus 92 of 293 [31%]) (7). The trial included mainly children who were presenting late, had HIV or AIDS, or were receiving inappropriate antibiotic therapy. Consequently, van de Beek et al (5) did not include that trial in their Cochrane review because they believed its results were not representative of the typical meningitis population in industrialized countries. In summary, dexamethasone (0.4 mg/kg to 0.6 mg/kg given every 6 h for four days) as an adjunct to antimicrobial therapy in acute bacterial meningitis, when initiated with or before antibiotic therapy, benefits children with meningitis caused by Hib or other bacterial pathogens. Dexamethasone significantly decreases the incidence of severe sensorineural hearing loss, with no significant increase in the risk of GI bleeding or other adverse effects, but should not be given to patients with late-stage meningitis or septic shock.

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