EBQ:De Gans - Steroids for Bacterial Meningitis
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Clinical Question
In patients with acute bacterial meningitis does dexamethasone improve outcomes when given in addition to standard antibiotic therapy?
Conclusion
Early treatment with dexamethasone in adults with acute bacterial meningitis improves outcomes, specifically neurologic sequalae in patient with Strep. Pneumonia Meningitis with no increase in GI Bleed
Major Points
- Dexamethasone may reduce the mortality of patients with S. pneumonia Meningitis. Specifically in the this study, patients with any of the following:
- Cloudy cerebrospinal fluid
- Bacteria in cerebrospinal fluid on Gram’s staining
- Cerebrospinal fluid leukocyte count of more than 1000/mL
were given an empiric 10mg of Dexamethasone 20min prior or during the first dose of antibiotic administration. The goal was to both reduce mortality as well as neurologic sequelae.
- The main benefit was demonstrated with the S. pneumonia meningitis group especially those with a GCS between 8-11. However the mortality benefits have not been replicated in non developed countries and there is concern for decreased CSF penetration of antibiotics. Regardless there is a demonstrated benefit to decreased hearing loss and short term neurologic sequelae with a NNT of 21 to prevent hearing loss[1]
*The Infectious Disease Society of America recommends the use of dexamethasone in all patients with suspected Strep. Pneumoniae meningitis. [2] and continuation of the dexamethasone as an in-patient can be based on the culture and gram stain results of the CSF
Study Design
Prospective, randomized, double-blinded, multi-center, controlled trial
Population
- N=301; randomly assigned to 1 of 2 groups
- 157 in dexamethasone group
- 144 in placebo group
Patient Demographics
Group Characteristic | Dexamethasone | Placebo |
Age (yr) | 44+/-18 | 46+/-20 |
Bacteria + in gram stain of CSF | 74% | 69% |
CSF WBC >1000/gram stain neg | 24% | 29% |
Cloudy CSF only | 2% | 2% |
Duration of symp prior to admission(median) | 24 | 24 |
Seizures | 10% | 5% |
CSF opening pressure | 37+/-13 | 34+/-14 |
GCS (median) | 12 | 12 |
Papilledema | 7% | 10% |
CN palsy | 9% | 12% |
Hemiparesis | 6% | 8% |
CSF Strep Pneumo | 37% | 35% |
CSF Nisseria | 32% | 33% |
CSF other | 8% | 12% |
CSF negative | 24 | 24 |
CSF WBC (mean) | 8185 | 7438 |
CSF Protein | 4.3+/-3.0 | 4.7+/-3.2 |
CSF Glucose | 27+/-31 | 27+/-29 |
Blood Cx + | 53% | 47% |
Inclusion Criteria
- Age 17 yrs or older AND
- Suspected meningitis with:
- Cloudy CSF OR
- Bacteria in CSF on gram stain OR
- CSF leukocyte count >1000
Exclusion Criteria
- Hypersensitivity to B-lactam antibiotics or steroids
- Pregnancy
- Cerebrospinal shunt
- Treatment with antibiotics within past 48 hours
- Active TB or fungal infection
- Recent head trauma, neurosurgery, or PUD
- Enrollment in other trial
Interventions
- Randomized to receive Dexamethasone or placebo
- Interventions looked identical and were blinded from provider and patient
- Given 15-20 min prior to antibiotics, but amended to allow simultaneous administration of antibiotics and intervention after interim analysis
- 10 mg IV q6 hrs x 4 days of Dexamethasone sodium or placebo
- Initially treated with amoxicillin 2 g IV q4 x7-10 days
- Antibiotic was changed according to susceptibility if needed
Outcomes
- Analyzed with an intention to treat analysis and last-observation-carried-forward procedure
Primary Outcome
- Glasgow Outcome Scale 8 weeks after intervention
- Score of 5 = favorable outcome
- Score of 1-4 = unfavorable outcome
- Dexamethasone: 15%
- Placebo: 25%
- p value = 0.03
- CI 0.37–0.94
- RR 0.59
Secondary Outcomes
- Death
- Dexamethasone: 7%
- Placebo: 15%
- p value = 0.04
- CI 0.24–0.96
- RR 0.48
- Focal neurological abnormalities
- Dexamethasone: 13%
- Placebo: 20%
- p value = 0.13
- CI 0.36–1.09
- RR 0.62
- Hearing loss
- Dexamethasone: 9%
- Placebo: 12%
- p value = 0.54
- CI 0.38–1.58
- RR 0.77
- GI bleed
- Dexamethasone: 2 patients
- Placebo: 5 patients
- p value = 0.27
- Fungal infection
- p value = 0.24
- Herpes Zoster
- p value = 0.75
- Hyperglycemia
- p value = 0.38
Subgroup analysis
- Causes of meningitis
- Streptococcus pneumoniae
- Neisseria meningitidis
- Other bacteria
- Culture negative CSF
- Statistically significant decrease in GOS unfavorable outcomes and death with dexamethasone in strep pneumo subgroup
- No other subgroup reached statistical significance
Criticisms & Further Discussion
- The goal of early glucocorticoids for bacterial meningitis, is to reduce the neurologic morbidity, particularly with Streptococcus pneumoniae
- Early animal research demonstrated a decrease in hearing loss in rabbits[3] and shown in adults in Europe to reduce mortality in patient with Streptococcus pneumoniae Meningitis[4]
- However meta-analysis demonstrated no mortality difference overall and only in the subgroup with cultures positive for Streptococcus pneumoniae and not those for Haemophilus influenzae or Neisseria meningitidis[5]
- Dexamethasone has been shown to decrease blood-brain permeability and therefore antibiotic penetration into subarachnoid space specifically with Vancomycin[6] However increasing the serum concentration of Vancomycin may increase the CSF levels and can possibly counteract the effects from dexamethasone
- The Infectious Disease Society of America recommends the use of dexamethasone in all patients with suspected Strep. Pneumoniae meningitis. [7] and continuation of the dexamethasone as an in-patient can be continued based on the culture and gram stain results of the CSF
- Suspicion for pneumococcal meningitis can be based on the inclusion criteria from the De Gans Study
Funding
Supported in part by a grant from NV Organon, which also supplied the study medication.
Sources
- ↑ The NNT - Steroids in bacterial meningitis http://www.thennt.com/nnt/steroids-for-meningitis/
- ↑ Tunkel AR et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267
- ↑ Bhatt SM et al. Progression of hearing loss in experimental pneumococcal meningitis: correlation with cerebrospinal fluid cytochemistry. J Infect Dis. 1993;167(3):675
- ↑ EBQ:De Gans - Steroids for Bacterial Meningitis
- ↑ Brouwer MC, McIntyre P, de Gans J, Prasad K, van de Beek D. Corticosteroids for Acute Bacterial Meningitis. Cochrane Database of Systematic Reviews 2010, Issue 9.
- ↑ Ricard JD et al. Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study. Clin Infect Dis. 2007;44(2):250
- ↑ Tunkel AR et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267