A previously healthy 25 year old female was admitted with low GCS and a fever. She had a 24 history of viral symptoms including sore throat and a headache. On admission she had a GCS of 3, temperature of 38.9°C and raised inflammatory markers. She was intubated but did not require vasopressor support. A CT brain showed diffuse cerebral swelling, effacement of the sulci, sylvian fissures, basal cisterns and 3rd/4th ventricles, and early cerebellar tonsillar herniation. Lumbar puncture was not performed due to CT appearances. She was commenced on intravenous (IV) ceftriaxone 2g twice daily, IV acyclovir 800mg three times daily, and IV dexamethasone 10mg four times daily. Unfortunately, her pupils remained fixed and dilated on sedation hold 36 hours later, and she was making no respiratory efforts. She subsequently became a DBD organ donor.
What is the evidence for dexamethasone in bacterial meningitis?
Mirae Shin
Bacterial meningitis is a life threatening condition with high rates of long term morbidity and mortality (1) despite improved knowledge of its pathophysiology, likely causative organisms, and the availability of antibiotics.
The mainstay of treatment is early administration of effective antimicrobial therapy while providing systemic support. As well as administration of antibiotics, adjunctive treatment with corticosteroids is recommended in hospital protocols. NICE guidelines advocate early use of corticosteroids (ideally before antibiotic therapy or within four hours of first dose of antibiotics). There is biological plausibility in using steroids in this context; the inflammatory response in the subarachnoid space can be dampened (2), thereby reducing the damage from subsequent increased intracranial pressure.
Corticosteroids may therefore protect against intracranial complications of meningitis which occurs as part of the host response to infection (3) such as cerebral oedema leading to cerebral or cerebellar herniation, as well as neurological complications such as hearing loss.
The potential benefits of using high dose corticosteroids were initially reported in 1950s in the form of single case reports but it was not until 2002 when a randomised controlled trial was conducted in Europe (4). A significant beneficial effect of IV dexamethasone was seen when given before or with the first dose of antibiotics and continued for four days. Namely, there was a significant reduction in mortality (RR 0.48, p=0.04) as well as a reduction in all “unfavourable outcomes” including neurological deficits and hearing loss (RR 0.59, p=0.03).
An interesting aspect of this study is the long term follow up of the same cohort of patients in 2006 (5), and again in 2012 (6). The earlier follow up study with median follow up period of 99 months focused on the neurological sequelae only and revealed no long term difference between the survivors of the two treatment arms. The latter study with median follow up of 13 years showed a significant difference between survival rate to 13 years with log-rank p=0.029. However, further analysis show that the main benefits from steroid therapy is in reduction of mortality within the acute phase of the disease (first 8 weeks). After the primary end point of the original study, there is no significant difference between the treatment arms in mortality rate over the following 13 years (log-rank p=0.27).
Based on the initial works of de Ganz et al (4), there was an international uptake of dexamethasone into bacterial meningitis management protocols around the world.
In an updated Cochrane review published in 2013 (7) which included 25 studies involving 4121 patients, steroids were shown to significantly reduce hearing loss (RR 0.67, 95% CI 0.51 to 0.88) with suggestion of further effect on neurological sequelae. The effect on overall mortality was non-significant although there is some trend towards significance (17.8% vs 19.9%, p=0.07). When the subgroups (which were pre-defined) were analysed, there was a significant reduction in mortality in streptococcus pneumoniae meningitis (RR 0.84, 95% CI 0.72 to 0.98) but not in Haemophilus influenza or Neisseria meningitidis.
Controversially, trial results have been inconsistent between developing and developed world. A randomised controlled trial conducted in sub-Saharan Africa (8) with an adjusted steroid regimen (16mg twice daily dexamethasone for 4 days) with primary outcome of death at 40 days showed no significant difference (OR 1.14, 95% CI 0.79-1.64). Similarly, there were no significant differences in secondary outcomes. Both groups had extremely high mortality rates compared to the Dutch studies and the interpretation of the results should also take into consideration the comorbidities the population are likely to have had.
The inconclusive results from large trials suggest that some people may benefit from corticosteroids but the patient factors that determine this effect are not at all clear. When the large studies from Europe (4), Africa (8), South America (9), and Asia (10) were combined using individual patient data, none of the predefined subgroups clearly benefited from corticosteroid use, although there was also no clear signal of harm (11).
The enthusiastic uptake of corticosteroid use in 2003 in the Netherlands where de Gans and colleagues’ initial positive study took place allow retrospective comparison of morbidity and mortality before and after its widespread introduction. Retrospective evaluation of bacterial meningitis from 1998 to 2012 showed that in-hospital mortality was not affected by the implementation of dexamethasone in 2003 (12).
In summary, early administration of IV corticosteroids have been recommended as therapy that can potentially reduce neurological sequelae as well as mortality. This effect seems to be the strongest with pneumococcal meningitis but should be instituted early before any information on the organism is available. Despite pooling of evidence, no clear patient group has been identified that would benefit from dexamethasone therapy. Based on the lack of signal of harm and potential positive effect on long term hearing loss in survivors, corticosteroids remain a key recommendation in treatment of bacterial meningitis despite larger and more recent data supporting no treatment effect on mortality.
Lessons learnt:
Although there is a widespread use of corticosteroids in bacterial meningitis, the evidence is weak.
References:
1. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, Harrison LH, Farley MM, Reingold A, Bennett NM, Craig AS, Schaffner W, Thomas A, Lewis MM, Scallan E, Schuchat A. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011. 364(21):2016
2. Lutnar I, Friedland IR, Jafri HS, Wubbel L, Ahmed A, Trujillo M, McCoig CC, McCracken GH Jr. Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis. J Antimicrob Chemother. 2003. 52(4):651
3. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Inf Dis. 2002. 2(12):721-36
4. De Gans J, Van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002. 347(20):1549
5. Weisfelt M, Hoogman M, Van de Beek D, de Gans J, Dreschler WA, Schmand BA. Dexamethasone and long-term outcome in adults with bacterial meningitis. Ann Neurol. 2006. 60(4):456
6. Fritz D, Brouwer MC, Van de Beek D. Dexamethasone and long-term survival in bacterial meningitis. Neurology. 2012. 79(22):2177-9
7. Brower MC, McIntyre P, Prasad K, Van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2013. Jun 4:6
8. Scarborough M, Gordon SB, Whitty CJ et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med. 2007. 357:2441-2450
9. Peltola H, Roine I, Fernandez J et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2007. 45:1277-1286
10. Nguyen TH, Tran TH, Thwaites G et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med. 2007. 357:2431-2440
11. Van de Beek D, Farrar JJ, de Gans J et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol. 2010. 9:254-63
12. Bodilsen J, Dalager-Pedersen M, Schonheyder HC, Nielsen H. Dexamethasone treatment and prognostic factors in community-acquired bacterial meningitis: a Danish retrospective population-based cohort study. Scand J Infect Dis. 2014. 46(6):418-25
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