El concepto de competencia y la formación integral en este trabajo

Introduction

If anticonvulsant prophylaxis can reduce the incidence of seizures complicating cerebral malaria, this may in turn reduce the risk of death and neurological sequelae (Molyneux 1989; Brewster 1990; Jaffar 1997; van Hensbroek 1997), and have an important impact on the educational potential of children in sub-Saharan Africa (Holding 1999). This chapter describes a randomised, controlled intervention study of anticonvulsant prophylaxis in childhood cerebral malaria.

Phenobarbitone has been used as an anticonvulsant for many years, and is highly effective in the treatment of both partial and generalised seizures (Shorvon 1994b). It is cheap and, unlike the majority of anticonvulsant drugs used for seizure prophylaxis, widely available throughout Africa. It may be given by intramuscular injection, which is a further advantage, since intravenous therapy is not possible in many health facilities throughout the continent. The loading dose recommended for children is 10-20 mg/kg (Rylance 1990; Bone 1993).

The three published studies of phenobarbitone prophylaxis in cerebral malaria have yielded disparate results. In a small, randomised, controlled study on Thai adults, a single intramuscular dose of phenobarbitone 3.5 mg/kg reduced the incidence of seizures by 40% (White 1988a). A single intramuscular dose of phenobarbitone 10 mg/kg given to Indian adults in an open study reduced the incidence of seizures by 20% (Kochar 1997) while, in an open study on Kenyan children, the same dose failed to produce therapeutic blood concentrations, and had no effect on seizure frequency (Winstanley 1992). The randomised, placebo controlled study presented here was designed to assess whether a single intramuscular dose of phenobarbitone 20 mg/kg given on admission to Kenyan children with cerebral malaria could reduce the incidence of seizures complicating the clinical course in hospital. The safety and clinical tolerance of this dose was assessed at the start of the trial.

Methods

Patients

Children aged 9 months to 13 years with cerebral malaria (see Chapter 2) were eligible for the study. Those who had pre-existing afebrile epilepsy or significant neurodevelopmental problems, and those who had received treatment with phenobarbitone or phenytoin during the current illness were excluded.

Sample size

A sample size calculation, assuming 90% power and a significance level of 5%, suggested that a total of 320 children would be required to detect a 50% reduction in seizures occurring prior to recovery of consciousness in the phenobarbitone-treated group. The following seizure categories were considered to be of particular clinical importance:

• Three or more seizures of any duration • Any seizures lasting for 5 minutes or more

• Any episodes of status epilepticus (defined as seizure activity lasting for 30 minutes or more, or 6 or more seizures within a period of 2 hours).

Randomisation

Using a sequentially numbered register, children were randomised as soon as possible after admission to receive a single intramuscular injection o f phenobarbitone 2 0 mg/kg, or the same volume of identical placebo (90% propylene glycol, the normal vehicle for parenteral preparations o f phenobarbitone). Numbered 5ml ampoules of phenobarbitone and placebo were prepared by the pharmacy department of Torbay Hospital, UK. The code identifying drug and placebo was kept at Torbay Hospital, and therefore none of the clinical or scientific staff involved in the study knew which patients had received phenobarbitone. Since previous work (Crawley 1996) had shown an increased frequency

of seizures among younger children with cerebral malaria, randomisation was stratified into two age groups of 24 months or below and above 24 months.

Clinical tolerance

The clinical tolerance of phenobarbitone 20 mg/kg was assessed at the start of the trial. Twenty three children received the study drug (phenobarbitone or placebo) by constant rate intravenous infusion over 4 hours instead of by intramuscular injection. The intravenous route was chosen because the infusion could have been stopped should any adverse events have occurred. As in the main study, the clinical investigators were unaware of which patients had received phenobarbitone. Pulse, respiratory rate, blood pressure, and transcutaneous oxygen saturation were measured at baseline, and at thirty- minute intervals for 5 hours. Blood was taken at the same times for phenobarbitone level, and at hourly intervals for venous gas and lactate. The trial was then unblinded for these 23 patients only, and the phenobarbitone and placebo groups compared with respect to all clinical and biochemical findings.

Investigations

Baseline blood samples were taken for parasite count, full blood count, glucose, electrolytes, blood gas, blood culture, and phenobarbitone level. Further blood samples were taken for phenobarbitone level at 1,2, 4, 8, 12, 24, 36, and 48 hours. Parasite counts were repeated every 8 hours until discharge, death, or clearance of parasitaemia.

Treatment

Patients received standard therapy for cerebral malaria, as described in Chapter 2. The number and duration of all seizures were recorded using timers pre-set to alarm at 5, 15, and 30 minutes. Seizures lasting for 5 minutes or more were treated in a standardised manner, with intravenous diazepam 0.3 mg/kg, and, as second line therapy, intramuscular paraldehyde 0.2 ml/kg. Anticonvulsants were administered at 5, 15, 30, and 45 minutes, if seizure activity persisted. Intravenous phenytoin 20 mg/kg was given to children who, following randomisation, had received 2 doses of both diazepam and paraldehyde, or had experienced 6 or more seizures within a period of 2 hours.

Follow up

A neurological examination was performed on all patients at the time o f discharge from hospital. All patients were asked to return 3 months later for full neurodevelopmental assessment.

Pharmacokinetics

Serial blood samples for phenobarbitone concentration were taken from all patients. Whole blood phenobarbitone concentrations were subsequently assayed by reversed- phase high performance liquid chromatography (Winstanley 1992) in Nairobi. Derived pharmacokinetic parameters, namely maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the concentration / time curve (AUCo-12 hours) were obtained after every 1 0 profiles on patients who had received phenobarbitone by intramuscular injection. Since there was very little variability in the data, with no significant change in the mean derived pharmacokinetic profiles as numbers increased, it was decided that profiles on 50 patients would provide a good representation of the phenobarbitone group as a whole.

Stastisticai analysis

This is described in Chapter 2. An interim analysis was performed by an independent statistician in January 1997, at which stage 170 patients had been recruited. The results of the analysis were reviewed by the trial monitor, but were not made available to the clinical investigators. The trial was continued until the calculated sample size had been achieved.

Figure 13. Whole-blood phenobarbitone concentrations according to