Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled
J Crawley1, C Waruiru, S Mithwani
1Kenya Medical Research Institute/Wellcome Trust Centre for Geographic Medicine Research (Coast), Kilifi. jane.crawley@ndm.ox.ac.uk
Insights
Phenobarbital effectively prevents seizures in childhood cerebral malaria but significantly increases mortality. This high-dose treatment is not recommended due to unacceptable safety risks.
Area of Science:
- Pediatric Neurology
- Infectious Diseases
- Clinical Pharmacology
Background:
- Seizures are a common and dangerous complication of cerebral malaria in children.
- This complication is linked to higher mortality and long-term neurological issues.
Purpose of the Study:
- To evaluate the effectiveness of intramuscular phenobarbital in preventing seizures in children with cerebral malaria.
Main Methods:
- A randomized controlled trial was conducted involving children with cerebral malaria.
- Participants received either a single intramuscular dose of phenobarbital (20 mg/kg) or a placebo.
- Seizure frequency, mortality, and drug tolerance (respiratory depression, hypotension) were assessed.
Main Results:
- Phenobarbital significantly reduced seizure frequency compared to placebo (11% vs. 27%).
- However, mortality was more than doubled in the phenobarbital group (18% vs. 8%).
- Increased mortality was observed with phenobarbital, particularly when combined with multiple diazepam doses.
Conclusions:
- While phenobarbital at 20 mg/kg is effective for seizure prophylaxis in cerebral malaria, it carries an unacceptable mortality risk.
- The use of this phenobarbital dosage is not recommended due to safety concerns.
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.
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