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In the Vietnamese study, Hien et al. used a broader definition of severe disease than that recommended by the World Health Organization.4 They chose limits of 11 instead of 9 for the score on the Glasgow Coma Scale used to define cerebral malaria, a hematocrit of 20 percent instead of 15 percent to indicate anemia, and systolic blood pressure of 80 instead of 70 mm Hg to indicate shock. They failed to mention acute lung injury, which has a high fatality rate.5 A substantial number of patients in this study therefore probably had moderately severe malaria.
Despite the imperfections in the studies, artemether appears effective in the treatment of moderate-to-severe malaria, but its superiority to quinine remains to be established. The main concern with this compound is potential neurotoxicity, which has been clearly demonstrated in animals.6 The prolonged duration of coma and the increased incidence of convulsions in artemether-treated patients in the study of Gambian children by Boele van Hensbroek et al. are alarming. We think that intravenous quinine remains the drug of choice for the treatment of severe malaria, especially since relative resistance to quinine is still limited to Southeast Asia.
Bertrand Gachot, M.D., Ph.D.
Françoise Doyon, M.Sc.
Catherine Hill, Ph.D.
Gustave Roussy Institute
94805 Villejuif, France
References
Oren Fruchter, M.D.
29 Greenbaum St.
Haifa 34987, Israel
References
Arthur Newmark, M.D.
Veterans Affairs Medical Center
Philadelphia, PA 19104
To the Editor: As pointed out by Dr. Gachot and colleagues, in our study of Gambian children the artemether group had a slightly prolonged time to recovery from coma and an increased incidence of convulsions while in the hospital, but the study provides no evidence that these were of consequence in the longer term. For both mortality and residual neurologic sequelae, which were the primary end points of the study, the artemether group had a marginally better outcome than the quinine group. Though not statistically significant, this trend was remarkably similar to that observed in the study of Vietnamese adults by Hien et al. Our conclusion was cautious — namely, that artemether is about as effective as quinine in the treatment of cerebral malaria.
Gachot and colleagues are unhappy with the suggestion that artemether might replace quinine in the management of severe malaria. They overlook the practical consideration that intramuscular artemether requires fewer injections and is better tolerated than intramuscular quinine. This makes it an attractive alternative for tropical health centers that lack the resources for carefully controlled intravenous infusions of quinine. We agree that there is a strong argument for limiting the distribution of artemether while quinine remains effective, to avoid the development of simultaneous resistance to both compounds. How to accomplish this is a complex and important question.
As Dr. Fruchter implies, serious consideration needs to be given to adjunctive therapy. A trial of murine monoclonal antibody against tumor necrosis factor (BC7) was conducted concurrently with the comparison of artemether and quinine in the Gambia, but this reagent proved to be of no benefit.1 There is preliminary evidence that pentoxifylline treatment may be a more effective way of suppressing excessive tumor necrosis factor activity in cerebral malaria, since the drug hastens recovery from coma.2 Deferoxamine also appears to hasten recovery from coma, but the available data show little effect on mortality.3 Studies are either planned or ongoing of different strategies of anticonvulsant therapy and fluid management,4 and of dichloroacetate therapy to reduce the lactic acidosis that commonly accompanies fatal malaria.5 We need an infrastructure for multicenter studies that can properly evaluate each of these treatment options, using mortality and sequelae as the primary outcome measures.
Michaël Boele van Hensbroek, M.D.
Academic Medical Center
1105 AZ Amsterdam, the Netherlands
Brian Greenwood, M.D.
London School of Hygiene and Tropical Medicine
London WC1E 7HT, United Kingdom
Dominic Kwiatkowski, M.D.
John Radcliffe Hospital
Oxford OX3 9DU, United Kingdom
References
We presented a prospectively designed multivariate analysis in which artemether treatment was associated with a significantly lower mortality rate than quinine. If the same logistic-regression analysis is applied only to the post hoc subgroup who fulfilled the World Health Organization criteria, the difference in mortality between quinine and artemether increases, with an odds ratio for a fatal outcome associated with quinine of 2.4 (95 percent confidence interval, 1.3 to 4.5). Nevertheless, our conclusion — that artemether is a satisfactory alternative to quinine for the treatment of severe malaria — was circumspect. As we stated in our report, the cause of the prolongation of coma in artemether recipients is unclear. Studies in animals have shown that both artemether and the closely related compound arteether induce a selective pattern of damage principally to the brain-stem nuclei involved in auditory processing.3 If the prolongation of coma observed in our study and in the accompanying study from the Gambia was caused by neurotoxicity, then it was reversible. There was no associated neurologic deficit in survivors, and no evidence of auditory abnormalities. The incidence of neurologic sequelae in the Gambian trial was also similar in the two treatment groups. We believe that a definitive statement regarding the relative merits of artemether and quinine should await a systematic overview of many randomized, controlled trials. If this confirms that artemether treatment is associated with a lower mortality rate than quinine, and there is no associated increase in neurologic sequelae, then any effect on the duration of coma will have secondary importance.
Dr. Newmark is correct; an error crept into the manuscript. The line should have read, "the correlated QT interval was prolonged to more than 0.5 second."
Tran Tinh Hien, M.D.
Nicholas P.J. Day, B.M., B.Ch.
Nicholas J. White, M.D., D.Sc.
Center for Tropical Diseases
Ho Chi Minh City, Vietnam
References
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