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Q J Med 1995; 88: 341-349
© 1995 Association of Physicians

Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria

S. KRISHNA1,2,, T. AGBENYEGA2,3, B. J. ANGUS1,4, G. BEDU-ADDO3, G. OFORI-AMANFO3, G. HENDERSON5, I.S.F. SZWANDT6, R. O'BRIEN7 and P.W. STACPOOLE5,8

1 Division of Communicable Diseases, St George's Hospital Medical School London, UK 2 Department of Physiology, University of Science and Technology, School of Medical Sciences Kumasi, Ghana 3 Departments of Paediatrics and Medicine, Komfo-Anokye Teaching Hospital Kumasi, Ghana 4 Wellcome-Mahidol Oxford Tropical Medicine Research Programme, Mahidol University Bangkok, Thailand 5 Department of Medicine, University of Florida USA 6 Department of Pharmacology and Therapeutics, University of Liverpool UK 7 Department of Statistics USA 8 Department of Biochemistry and Molecular Biology, University of Florida College of Medicine USA

Address correspondence to Dr S. Krishna, Division of Communicable Diseases, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE

Received 14 October 1994 Accepted for publication 23 January 1995.


  Abstract

Lactic acidosis frequently complicates severe malaria in African children, and is a strong independent predictor of mortality. We tested the hypothesis that sodium dichloroacetate (DCA), an activator of pyruvate dehydrogenase, rapidly reduces hyperlactataemia in this patient population. Eighteen children with severe malaria and capillary plasma lactate 5≥5 mM were randomized to receive either intramuscular quinine plus a single 50 mg/kg intravenous infusion of DCA in saline, or quinine plus intravenous saline alone. Two patients in each treatment group died following randomization. Thirty minutes after treatment, the mean plasma lactate was 28% below pretreatment baseline values in the DCA group, but was unchanged in the placebo group. Throughout the first 4 h after treatment, mean plasma lactate in the DCA-treated patients was significantly less than that in controls (p = 0.003). Thereafter, mean plasma lactate declined in both groups and was <2 mM 10 h after treatment. DCA was well tolerated and did not alter quinine pharmacokinetics. A single intravenous dose of DCA rapidly improved lactic acidosis in African children with severe malaria, suggesting that DCA may be a useful adjunct in the initial treatment of these patients, and may increase their chance of survival by improving a major complication of their illness.


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