EBQ:De Gans - Steroids for Bacterial Meningitis

Under Review Journal Club Article

de Gans JD, et al. "Dexamethasone in Adults with Bacterial Meningitis". The New England Journal of Medicine. 2002. 347(20):1549-1556.
PubMed Full text PDF

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. There is no increase in GI bleed.

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

• Inclusion in study group required CSF abnormalities and therefore may have required CT prior to administration of antibiotics/steroids
  • CT should not delay administration of antibiotics or steroids
• Subgroup analysis showed no statistical significance with use of dexamethasone in Nisseria M. or other bacterial infection groups. However, it is difficult to determine benefit or not with such small numbers.
• Further research is required to determine if 2 day duration of dexamethasone is effective
• Dexamethasone has been shown to decrease blood-brain permeability and therefore antibiotic penetration into subarachnoid space
  • May decrease availability of Vancomycin in CSF
• Steroids may potentiate ischemic injury to neurons. Further research is needed which includes cognitive evaluation with and without steroids. The GOS is fairly basic and may not uncover subtle cognitive changes.

Funding

NV Organon

Sources

1. Gans, Jan De, and Diederik Van De Beek. "Dexamethasone in Adults with Bacterial Meningitis." New England Journal of Medicine (2002): 1549-556. New England Journal of Medicine. Web. 4 Nov. 2014. <http://www.nejm.org/doi/pdf/10.1056/NEJMoa021334>.