European Dexamethasone Study

From Wiki Journal Club
Jump to: navigation, search
de Gans JD, et al. "Dexamethasone in Adults with Bacterial Meningitis". The New England Journal of Medicine. 2002. 347(20):1549-1556.
PubMedFull textPDF

Clinical Question

In patients with acute bacterial meningitis, does adjunctive therapy with dexamethasone improve outcomes compared to standard antibiotic therapy alone?

Bottom Line

Adjunctive therapy with dexamethasone reduces morbidity and mortality among patients with acute bacterial meningitis, particularly Streptococcus pneumoniae meningitis.

Major Points

Randomized trials of adjuvant dexamethasone therapy for acute bacterial meningitis have demonstrated mixed results between developed and developing countries.

In the developed world, the European Dexamethasone Study demonstrated a 52% mortality benefit and a 41% reduction in unfavorable outcomes at 8 weeks among patients with suspected meningitis randomized to dexamethasone therapy compared with placebo. In subgroup analyses, this benefit was seen only in patients with Streptococcus pneumoniae meningitis and particularly in patients with moderate-to-severe neurologic deficit on admission as defined by GCS 8-11. Dexamethasone conferred no benefit to those with meningitis due to Neisseria meningitidis. There was no evidence of benefit among patients with mild neurologic deficit.

The Dutch Meningitis Cohort Study was a nationwide prospective cohort study of adults with pneumococcal meningitis in the Netherlands, and demonstrated lower rates of mortality and of unfavorable outcomes in the 2006-2009 cohort (84% of which received dexamethasone) compared with the 1998-2002 cohort (3% of which received dexamethasone).

However, in the developing world, the benefit is less clear. In fact, two RCTs in Malawi and in Vietnam found no overall reduction in the outcomes of death or disability with dexamethasone therapy started with or before the first dose of intravenous ceftriaxone.

Together these findings have led to a grade 1B recommendation for the administration of dexamethasone among adults in the developed world with suspected or proven acute pneumococcal meningitis and a grade 1B recommendation against the administration of dexamethasone among adults in the developing world with a high prevalence of HIV infection, poor nutrition, and significant delays in clinical presentation.

Design

  • Multicenter, double-blind, parallel group, randomized, placebo-controlled trial
  • N=301
    • Dexamethasone (n=157)
    • Placebo (n=144)
  • Setting: Multiple sites in Europe
  • Enrollment: June 1993 to December 2001
  • Mean follow-up: 8 weeks
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age ≥17 years
  • Suspected meningitis in combination with:
    • Cloudy CSF
    • Bacteria in CSF on Gram stain
    • CSF WBC count >1000/mm3

Exclusion Criteria

  • Intolerance of β-lactam antibiotics or corticosteroids
  • Pregnancy
  • CSF shunt
  • Antibiotics in previous 48h
  • History of active TB or fungal infection
  • Recent history of head trauma, neurosurgery, or PUD

Baseline Characteristics

Comparisons are dexamethasone vs. placebo.

  • Age: 45 years
  • Male: 57%
  • Basis for elibility:
    • Bacteria in CSF on Gram stain: 74% vs. 69%
    • No bacteria in CSF, but CSF WBC count >1000 per mm3: 24% vs. 29%
    • Cloudy CSF only: 2%
  • Median duration of symptoms before admission: 24 hrs
  • Seizures: 10% vs. 5%
  • Findings on admission:
    • CSF pressure: 37 vs. 34 cm of water
    • Median GCS score: 12
    • Papilledema: 7% vs. 10%
    • Cranial-nerve palsy: 9% vs. 12%
    • Hemiparesis: 6% vs. 8%
  • CSF culture
    • Streptococcus pneumoniae: 37% vs. 35%
    • Neiserria meningitidis: 32% vs. 33%
    • Other bacteria: 8% vs. 12%
    • Negative bacterial culture: 23% vs. 21%
  • Indices of CSF inflammation:
    • Mean WBC: 8185 vs. 7438 mm3
    • Median WBC: 3667 vs. 3498
    • Protein: 4.3 vs. 4.7 g/l
    • Glucose: 27 mg/dl
  • Positive blood culture: 53% vs. 47%

Interventions

  • After cultures of blood and CSF, antibiotic treatment initiated and then adjusted according to GSF gram stain results. Regimens used, in descending frequency of use:
    • Amoxicillin 2g IV q4h for 7-10 days or penicillin (77%)
    • Third-generation cephalosporin (8%)
    • Amoxicillin or penicillin combined with cephalosporin (8%)
  • Randomly assigned to adjunctive therapy with:
    • Dexamethasone sodium phosphate 10mg IV q6h for 4 days
    • Placebo
  • Glasgow Outcome Scale (GOS) performed at 8 weeks
    • Favorable outcome: score of 5 (mild or no disability)
    • Unfavorable outcome: scores 1-4 (1 death, 2 vegetative state, 3 severe disability, 4 moderate disability)
  • In vitro testing of CSF isolates for susceptibility to penicillin
    • 97% vs. 98% susceptibility

Outcomes

Comparisons are dexamethasone vs. placebo at 8 weeks.

Primary Outcomes

Unfavorable GOS score
15% vs. 25% (RR 0.59; 95% CI 0.37-0.94; P=0.03)

Secondary Outcomes

Death
7% vs. 15% (RR 0.48; 95% CI 0.24-0.96; P=0.04)
Focal neurologic abnormalities
13% vs. 20% (RR 0.62; 95% CI 0.36-1.09; P=0.13)
Hearing loss
9% vs. 12% (RR 0.77; 95% CI 0.38-1.58; P=0.54)
Impairment of consciousness
11% vs. 25% (P=0.002)
Seizures
5% vs. 12% (P=0.04)
Cardiorespiratory failure
10% vs. 20% (P=0.02)

Adverse Events

GIB requiring blood transfusion
1% vs. 3% (P=0.43)
Hyperglycemia (blood glucose ≥144 mg/dl)
32% vs. 26% (P=0.24)
Herpes Zoster
4% vs. 3% (P=0.75)
Fungal infection
5% vs. 3% (P=0.38)

Subgroup Analysis

Pneumococcal meningitis

Unfavorable GOS score
26% vs. 52% (RR 0.50; 95% CI 0.30-0.83; P=0.006)
Death
14% vs. 34% (RR 0.41; 95% CI 0.19-0.86; P=0.02)
Focal neurologic abnormalities
22% vs. 33% (RR 0.67; 95% CI 0.33-1.37; P=0.32)
Hearing loss
14% vs. 21% (RR 0.67; 95% CI 0.25-1.69; P=0.55)

Meningococcal meningitis

Unfavorable GOS score
8% vs. 11% (RR 0.75; 95% CI 0.21-2.63; P=0.74)
Death
4% vs. 2% (RR 1.88; 95% CI 0.76-20.1; P=1.00)
Focal neurologic abnormalities
7% vs. 11% (RR 0.57; 95% CI 0.15-2.26; P=0.48)
Hearing loss
7% vs. 11% (RR 0.57; 95% CI 0.15-2.26; P=0.48)

According to Glasgow Coma Scale score on admission

Unfavorable GOS score
Score of 12-14: 10% vs. 10% (RR 1.00; P=1.00)
Score of 08-11: 13% vs. 34% (RR 0.39; P=0.03)
Score of 03-07: 32% vs. 61% (RR 0.53; P=0.08)

Funding

Supported in part by a grant from NV Organon, which also supplied dexamethasone (Oradexon) for the study.