Cerebral Malaria Clinical Trial
Official title:
Effect of Mannitol as Adjunct Therapy on the Clinical Outcome of Childhood Cerebral Malaria in Mulago Hospital: A Randomised Clinical Trial
Cerebral malaria is a life-threatening complication of Plasmodium falciparum infection in African children and nonimmune travellers despite availability of quinine, the current drug of choice. Several reports have suggested that raised intracranial pressure (ICP) is a major cause of death among children with cerebral malaria. Mannitol, an osmotic diuretic, effectively lowers ICP and is used to treat post traumatic raised ICP. There have been some case reports of reduction in mortality and morbidity in African children with cerebral malaria following administration of mannitol, but as these were not randomized controlled trials it is difficult to evaluate their significance. This study seeks to establish whether a single dose of intravenous mannitol given to children with cerebral malaria will significantly reduce the coma recovery time.
Cerebral malaria is a life-threatening complication of Plasmodium falciparum infection
accounting for significant morbidity and mortality in African children despite availability
of quinine, the current drug of choice. The case fatality ranges from 5 to 40% with almost
10% of survivors experiencing neurological sequelae.
Several reports have suggested that raised intracranial pressure (ICP) may be a feature of
cerebral malaria. There is evidence of brain swelling on computer tomography, magnetic
resonance imaging and at necropsy. It has been postulated that raised intracranial pressure
can cause death by transtentorial herniation or by compromising cerebral blood flow. In
fact, most children who died of cerebral malaria in a Kenyan study, had clinical signs
compatible with transtentorial herniation and all those who had severe ICP (maximum ICP >
40mmHg) either died or survived with neurological sequelae.
Mannitol, an osmotic diuretic, effectively lowers ICP and is used to treat post traumatic
raised intracranial pressure. There have been some case reports of reduction in mortality
and morbidity in African children with cerebral malaria following administration of
mannitol, but as these were not randomized controlled trials it is difficult to evaluate
their significance. Currently the WHO contends that there is insufficient evidence for using
mannitol as adjunct therapy for cerebral malaria.
A recent Cochrane review found no randomized or quasi-randomized controlled trial to support
or refute the use of mannitol as adjunct therapy for cerebral malaria.
Hypothesis: A single dose of intravenous mannitol (1g/kg) given to children with cerebral
malaria will reduce mean coma recovery time from 22.5 to 13.1 hours.
We calculated a sample size of 78 patients in each group for 90% power and 95% confidence.
In the calculation, we assumed that the children receiving intravenous mannitol would have a
mean coma recovery time of 13.1 (SD 18.5) hours and those receiving placebo would have a
mean coma recovery time of 22.5 (SD 18.5) hours (42.3% effect size), according to a recent
study by Aceng, Byarugaba and Tumwine in the same hospital.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
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