Dexamethasone in Adults with Bacterial Meningitis - By: Dr. D.S. Merchant

Abstract:
• Mortality and morbidity rates are high among adults with acute bacterial meningitis, especially those with pneumococcal meningitis.

Methods:
• a prospective, randomized, double-blind, multicenter trial of adjuvant treatment with dexamethasone, as compared with placebo, in adults with acute bacterial meningitis.
• Dexamethasone (10 mg) or placebo was administered 15 to 20 minutes before or with the first dose of antibiotic and was given every 6 hours for four days.
• The primary outcome measure was the score on the Glasgow Outcome Scale at eight weeks (a score of 5, indicating a favorable outcome, vs. a score of 1 to 4, indicating an unfavorable outcome).
• The mortality rate among adults with acute bacterial meningitis and the frequency of neurologic sequelae among those who survive are high, especially among patients with pneumococcal meningitis.
• Unfavorable neurologic outcomes are not the result of treatment with inappropriate antimicrobial agents, since cerebrospinal fluid cultures are sterile 24 to 48 hours after the start of antibiotic therapy
• Studies in animals have shown that bacterial lysis, induced by treatment with antibiotics, leads to inflammation in the subarachnoid space, which may contribute to an unfavorable outcome.
• These studies also show that adjuvant treatment with antiinflammatory agents, such as dexamethasone, reduces both cerebrospinal fluid inflammation and neurologic sequelae.
• Many controlled trials have been performed to determine whether adjuvant corticosteroid therapy is beneficial in children with acute bacterial meningitis.
• A meta-analysis of randomized controlled trials performed since 1988 showed a beneficial effect of adjunctive dexamethasone therapy in terms of severe hearing loss in children with Haemophilus influenzae type b meningitis and suggested a protective effect in those with pneumococcal meningitis if the drug was given before or with parenteral antibiotics.
• There are few data on the use of adjunctive dexamethasone therapy in adults with bacterial meningitis.
• The paucity of data precludes a recommendation that dexamethasone be administered routinely in adults with bacterial meningitis.
• We conducted a study to determine whether adjunctive dexamethasone treatment improves the outcome in such patients.
• Patients referred to one of the participating centers were eligible for the study if they were
• 17 years of age or older
• Suspected meningitis in combination with cloudy cerebrospinal fluid, bacteria in cerebrospinal fluid on Gram's staining.
Cerebrospinal fluid leukocyte count of more than 1000 per cubic millimeter.

Patients were excluded:
• If they had a history of hypersensitivity to beta lactam antibiotics or corticosteroids.
• If they were pregnant
• If they had a cerebrospinal shunt
• Been treated with oral or parenteral antibiotics in the previous 48 hours.
• History of active tuberculosis or fungal infection.
• Had a recent history of head trauma, neurosurgery, or peptic ulcer disease
• Assessment of Outcome
• The primary outcome measure was the score on the Glasgow Outcome Scale eight weeks after randomization, as assessed by the patient's physician.
• A score of 1 indicates death.
• 2, a vegetative state (the patient is unable to interact with the environment).
• 3, severe disability (the patient is unable to live independently but can follow commands).
• 4 Moderate disability (the patient is capable of living independently but unable to return to work or school).
• 5 Mild or no disability (the patient is able to return to work or school.
• A favorable outcome was defined as a score of 5, and an unfavorable outcome as a score of 1 to 4.

Statistical Analysis:
• Calculation of the required sample size was based on the assumption that dexamethasone would reduce the proportion of patients with an unfavorable outcome from 40 to 25 percent.
• With a two-sided test, an alpha level of 0.05, and a power of 80 percent, the analysis required 150 patients per group.
• The analysis of outcomes was performed on an intention-to-treat basis with the use of a last-observation-carried-forward procedure.
• Two-tailed P values of less than 0.05 were considered to indicate statistical significance.
• Parametric and nonparametric values were tested with Student's t-test and the Mann–Whitney U test, respectively. The results are expressed as relative risks for the dexamethasone group as compared with the placebo group, with a relative risk of less than 1.0 indicating a beneficial effect.

Results:
• A total of 301 patients were randomly assigned to a study group.
• 157 to the dexamethasone group and 144 to the placebo group.
• Two patients (one in each group) did not meet the inclusion criteria because they were too young.
• Seven patients in the dexamethasone group and nine in the placebo group each met one exclusion criterion, one patient in the dexamethasone group met two exclusion criteria
• Four patients were withdrawn because they did not meet the inclusion criteria (three in the dexamethasone group and one in the placebo group), and five because of adverse events (four in the dexamethasone group and one in the placebo group).
• Eight weeks after admission, neurologic examinations were performed in 262 of 269 patients (97 percent). Seven patients were lost to follow-up, three in the dexamethasone group and four in the placebo group.
• At discharge, six of these seven patients had a score of 5 on the Glasgow Outcome Scale, and one had a score of 4. These last-observation scores were carried forward to eight weeks, so that all 301 patients were included in the analyses of the primary outcome and mortality

Efficacy:
• Eight weeks after enrollment, the percentage of patients with an unfavorable outcome was significantly smaller in the dexamethasone group than in the placebo group (15 percent vs. 25 percent).
• The proportion of patients who died was significantly smaller in the dexamethasone group than in the placebo group (7 percent vs. 15 percent).
• Among the patients with pneumococcal meningitis, 14 percent of those who received dexamethasone and 34 percent of those who received placebo died.

Adverse Events:
• Adverse events resulted in the early withdrawal of four patients in the dexamethasone group and one in the placebo group.
• In the dexamethasone group, two patients were withdrawn because of severe hyperglycemia, one because of suspected stomach perforation (which was not the case), and one because of agitation and flushing.
• One patient in the placebo group was withdrawn because of suspected cerebral abscess.
• In one patient in the dexamethasone group, gastrointestinal bleeding was complicated by stomach perforation, which required surgery.

Clinical Course:
• Impairment of consciousness was significantly less likely to develop in the patients who received dexamethasone than in those who received placebo (18 of 157 patients [11 percent] vs. 36 of 144 [25 percent].
• The patients in the dexamethasone group were also significantly less likely to have seizures (8 [5 percent] vs. 17 [12 percent].

Discussion:
• The results of our controlled prospective trial show that early treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis.
• Adjunctive treatment with dexamethasone reduced the risks of both an unfavorable outcome and death.
• However, neurological sequelae were seen predominantly in the most severely ill patients, and the proportion of severely ill patients who survived to be tested was larger in the dexamethasone group than in the placebo group.
• Two important issues are the duration and timing of dexamethasone therapy.
• Data suggest that two-day and four-day regimens are equally effective, the four-day regimen has been used in most clinical trials involving children with bacterial meningitis.
• In this study, we used the four-day regimen and also started it early. Therefore, a four-day regimen is recommended, with dexamethasone therapy started before or with the first dose of antibiotics.
• Cognitive impairment occurs frequently in adults who survive bacterial meningitis
• Dexamethasone (10 mg every six hours for four days) should be given to all such adults, and the regimen should be initiated before or with the first dose of antibiotics. This treatment does not increase the risk of gastrointestinal bleeding.

About the Author

Dr. D.S. Merchant is a Gold Medalist in (Anatomy & Histology), Resident AKUH, Pakistan. For more information on Gastroenterology or visit http://health.update.pk is a popular website that offers information on Acute Bacterial Meningitis, Pneumococcal Meningitis and Dexamethasone Therapy.

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