Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study

Abstract

Background: Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae. We undertook a randomised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria.

Methods: Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo. Clinical tolerance was assessed at the start of the trial, with particular reference to respiratory depression and hypotension. Seizures were timed and recorded, and treated in a standard way. Plasma phenobarbital concentrations were measured. Analyses were by intention to treat.

Findings: 440 children with cerebral malaria were admitted to the hospital; 100 were not recruited to the study. Of the remaining 340, 170 received phenobarbital and 170 placebo. The drug was adequately absorbed and well tolerated. Seizure frequency was significantly lower in the phenobarbital group than in the placebo group (18 [11%] vs 46 [27%] children had three or more seizures of any duration; odds ratio 0.32 [95% CI 0.18-0.58]) but mortality was doubled (30 [18%] vs 14 [8%] deaths; 2.39 [1.28-4.64]). The frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam (odds ratio 31.7 [1.2-814]).

Interpretation: In children with cerebral malaria, phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality. Use of this dose cannot, therefore, be recommended.

PIP: This randomized, placebo-controlled study assesses whether a single intramuscular dose of phenobarbital (20 mg/kg) given on admission to Kenyan children with cerebral malaria could lower the frequency of seizures, which complicate cerebral malaria by increasing the risk of death and neurological sequelae. A total of 340 children with cerebral malaria were admitted to the hospital; 170 received phenobarbital and 170 received placebo. The drug was adequately absorbed and well tolerated. Findings revealed a significantly lower frequency of seizures in the phenobarbital group than in the placebo group (18 [11%] vs. 46 [27%] children had 3 or more seizures of any duration; odds ratio (OR), 0.32; 95% confidence interval (CI), 0.18-0.58). However, mortality was doubled (30 [18%] vs. 14 [8%] deaths; OR, 2.39; 95% CI, 1.28-4.64) in the phenobarbital group. In addition, the frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus 3 or more doses of diazepam. In conclusion, although the phenobarbital dose of 20 mg/kg given to children with cerebral malaria provides highly effective seizure prophylaxis, an unacceptable increase in mortality is noted; hence, use of this dosage is not recommended.