Dexamethasone & long-term survival on bacterial meningitis

Zulfa Indah K. Fadhly

Fritz D, Brouwer et al. Dexamethasone and long-term survival on bacterial meningitis. American Academy of Neurology: Vol 79, No 22, November 27, 2012, p. 2177

ABSTRACT

BACKGROUND Data on long term effect of dexamethasone on survival in

bacterial meningitis are lacking

METHODS A long term follow up study of the European Dexamethasone

in Adulthood Bacterial Meningitis Study

Double-blind, RCT301 patients randomly assigned receive adjunctive dexamethasone (n=157) or placebo (n=114)

between June 1993 & December 2001.

Obtaining the data using the Dutch Municipal Population Register

RESULTS Death had occurred in 32 of 301 included patients (11%) at the

primary outcome measurement 8 weeks after randomization

Follow up was obtained for 228 of 246 evaluable patients (93%), with median follow up of 13 years.

Overall, 31 of 114 patients (22%) in the dexamethasone group died 44 of 134 patients (33%) in the placebo group died

(log-rank p=0.029)

After the primary end point of the study at 8 weeks: 20 patients in the dexamethasone group died 23 patients in the placebo group died (log rank p = 0.27), with age being the sole predictor of death (p<0.001)

CONCLUSION In adults with community-acquired bacterial meningitis, the

survival benefit from adjunctive dexamethasone therapy is obtained in the acute phase of the disease and remains for years

CLASSIFICATION OF EVIDENCE This study of a population of Dutch patients shows Class III

evidence that dexamethasone provides an extended survival benefit in patients treated for bacterial meningitis, and this survival benefit extends as long as 20 years

Infectious diseases of the CNS lead to overwhelming inflammatory processes within the brain & spinal cord that contribute substantially to patient morbidity & mortality

Many pharmacologic strategies to modulate inflammation have been investigated and steroids have been proposed as adjunctive treatments for bacterial meningitis, tuberculous meningitis & herpes simplex virus encephalitis.

RCT have been performed on the efficacy & safety of adjunctive dexamethasone in bacterial & tuberculous meningitis, with conflicting results.

Data on long term effect of dexamethasone in bacterial meningitis are lacking

In 2002, we published results of a RCT showing that early treatment with dexamethasone improved the outcome in adults with acute bacterial meningitis.

Recently, a long term follow up of a RCT in patients with TBM showed that the initial beneficial effect of dexamethasone was abolished because of delayed mortality within 5 years.

Current European Study

showed that adjunctive dexamethasone therapy reduced the rate of unfavorable outcomes in adults with bacterial meningitis from 25% to 15% (relative risk 0.59, 95% CI 0.37 – 0.94; p = 0.03)

Investigating the influence of dexamethasone on long term survival of adults with bacterial meningitis

Kaplan-Meier survival estimates according to study group (adjunctive dexamethasone therapy vs placebo)

for adult patients with community-acquired bacterial meningitis

MethodsEuropean Dexamethasone in Adulthood Bacterial Meningitis Study

301 patients w/ community acquired bacterial meningitis randomly assigned to a treatment group (June 1993 & December 2001)

157 to dexamethasone group & 144 to the placebo group

Baseline characteristics 2 groups were similar

Dexamethasone (10 mg) OR placebo was administered 15 to 20 minutes before or with the first dose of antibiotic

& was given every 6 hours for 4 days

The primary outcome measure was the score on the Glasgow Outcome Scale at 8 weeks

(a score of 5, indicating favorable outcome, vs a score of 1-4, indicating an unfavorable outcome)

Obtaining survival data of patients using the Dutch Municipal Population Register

Exclusion: patients who were enrolled in centers outside the Netherlands

Survival data Kaplan-Meier curves Data analysis log-rank test & Cox regression Subanalyses were performed for causative bacteria.

whether dexamethasone provides an extended survival benefit in patients treated for bacterial meningitis

The primary research question?

RESULTS

23 patients were enrolled in centers outside the Netherlands & were excluded from this follow up study

8 weeks after enrollment

32 of 301 patients (11%) had died:

11 of 157 (7%) in the dexamethasone group 21 of 144 (15%) in the placebo group

(relative risk 0.48, 95% CI 0.24 – 0.96; p = 0.04)

Among the patients with pneumococcal meningitis:

14% of those who received dexamethasone34% of those who received placebo died.

Of the remaining 246 surviving patients at 8 weeks after enrollment, 228 (93%) could be identified using the Dutch Municipal Population Register

Patients who could not be identified were censored at the primary outcome measure time point at 8 weeks after enrollment (n=18).

Patients who left the Netherlands to settle in another country were censored at the date of emigration (n = 7).

The median follow up time of the 278 patients was 13 years (range 0 – 18 years).

The causative organism were: Streptococcus pneumoniae in 104 patients (37%) Nisseria meningitidis in 92 patients (33%) Other bacteria or negative CSF cultures in 82 patients (29%)

By October 31, 2011 31 of 144 patients (22%) in dexa group had died 44 of 134 patients (33%) in the placebo group had died

(figure; log-rank p = 0.029)

The beneficial effect was not apparent in the patients with pneumococcal meningitis (p= 0.009).

After the primary outcome measurement at 8 weeksthe slopes of the survival curve did not differ between the 2 treatment groups or causative organisms & age was the sole predictor of death (log rank p < 0.001).

Survival after the primary outcome measurement was independent of the score on the GOS that was assessed 8 weeks after enrollment.

Long-time survival in adults with bacterial meningitis according to treatment group

(adjunctive dexamethasone therapy vs Placebo)

DISCUSSION

This study shows survival benefit by adjunctive dexamethasone therapy obtained in the acute phase of the disease remain for years.

The lower mortality in the dexamethasone group did not result in an increased rate of severe neurologic sequelae in this group at the primary outcome measurement.

Age was the sole predictor of death on long-term follow up.

After publication of the results of our trial in 2002, trials from Malawi, South America & Vietnam showed no beneficial effect of dexamethasone in bacterial meningitis.

What are the studies say?

In an individual patient data meta analysis of 2.029 patients from 5 large trials, treatment with adjunctive dexamethasone did not significantly reduce mortality, neurologic disability, or severe hearing loss in patients with bacterial meningitis.

Nevertheless, current guidelines recommend the use of adjunctive dexamethasone in patients with suspected or proven bacterial meningitis, but only in high-income countries.

In a nationwide observational cohort study in the Netherlands, the drug was administered in 92% of meningitis episodes in the period 2006 – 2009 a decrease in mortality from 30% to 20% after introduction of adjunctive dexamethasone therapy (absolute risk difference 10%, 95% CI 4% - 17%, p = 0.001)

We previously showed that treatment with adjunctive dexamethasone is not associated with an increased risk for cognitive impairment.

The finding in our current long-term survival follow up study:

Beneficial effect of dexamethasone is not abolished because of long term complications of dexamethasone or delayed mortality

after the primary outcome time point, further support the use of dexamethasone in higher income countries.

Thank You