Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

Abstract

Aims Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. Methods Twenty-®ve children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg x1 ) and nine rectally (p.r.; 0.5 mg kg x1 ). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored. Results Median maximum plasma diazepam concentrations of 634 (range 402±1507) ng ml x1 and 423 (range 112±1953) ng ml x1 were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml x1 within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67±169) and 172 (range: 74±393) ng ml x1 , respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension. Conclusions Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without signi®cant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

“…The mean (95% CI) biochemical measurements on admission were: albumin 31.4 (27.2, 35.6) g l −1 , total plasma proteins 60 (56.9, 63.1) g l −1 , haemoglobin 5.9 (4.6, 7.2) g dl −1 , creatinine 56.0 (39.0, 73.0) µmol l −1 , blood glucose 5.1 (3.96, 6.30) mmol l −1 and blood pH 7.34 (7.27, 7.40). These values were typical for children suffering from cerebral malaria [2].…”

“…Convulsions were first treated with diazepam or paraldehyde [2] and then with phenobarbital as a second line anticonvulsant.…”

“…In resource-poor countries, an anticonvulsant that controls seizures and prevents recurrence would be ideal. Diazepam is useful in status epilepticus, but it does not offer prophylaxis following single-dose administration [2], whereas multiple doses can cause respiratory depression [3]. Phenobarbital would be ideal for use in resourcepoor countries, since it is cheap, readily available, fastacting and can be administered i.m.…”

Pediatric Cerebral Malaria: A Scourge of Africa

“…Diazepam administered intravenously achieves therapeutic levels within 5 min. Although there is significant pharmacokinetic variability with rectal administration, this route is crucial in lowresource settings where intravenous access is often not feasible [60]. Benzodiazepines are associated with cardio-respiratory depression (especially when combined with barbiturates such as phenobarbitone) and repetitive administration or continuous infusions are inadvisable without inotropic or ventilator support.…”

“…Up to 60% of children with malaria will experience seizures in the course of their illness [59,60]. Prolonged and repetitive seizures are associated with death and neurological sequelae in children with CM and are a risk factor for the development of epilepsy [10,60].…”