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Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial

l , l , l , a , a , a , b , b , b , d , d , c , c , c , e , e , g , f , f , j , j , h , h , h , i , i , i , k , k , l , l , l , l , l , m , o , p , m , n , l , l , * , for the AQUAMAT group

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      Summary

      Background

      Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.

      Methods

      This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054.

      Findings

      5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63–0·90; relative reduction 22·5%, 95% CI 8·1–36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49–0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66–0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64–0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43–0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects.

      Interpretation

      Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.

      Funding

      The Wellcome Trust.

      Related collections

      Most cited references 39

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      Global, regional, and national causes of child mortality in 2008: a systematic analysis.

      Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in children younger than 5 years. We used multicause proportionate mortality models to estimate deaths in neonates aged 0-27 days and children aged 1-59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world. Of the estimated 8.795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5.970 million), with the largest percentages due to pneumonia (18%, 1.575 million, uncertainty range [UR] 1.046 million-1.874 million), diarrhoea (15%, 1.336 million, 0.822 million-2.004 million), and malaria (8%, 0.732 million, 0.601 million-0.851 million). 41% (3.575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1.033 million, UR 0.717 million-1.216 million), birth asphyxia (9%, 0.814 million, 0.563 million-0.997 million), sepsis (6%, 0.521 million, 0.356 million-0.735 million), and pneumonia (4%, 0.386 million, 0.264 million-0.545 million). 49% (4.294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China. These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions. WHO, UNICEF, and Bill & Melinda Gates Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.
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        Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.

        In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.
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          Pathogenesis, clinical features, and neurological outcome of cerebral malaria.

          Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.
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            Author and article information

            Affiliations
            [a ]Hospital Central da Beira, Beira, Mozambique
            [b ]MRC laboratories, Banjul, The Gambia
            [c ]Komfo Anokye Hospital, Kumasi, Ghana
            [d ]Kilifi District General Hospital, Kilifi, Kenya
            [e ]Magunga District Hospital, NIMR-Korogwe Research Laboratory, Tanga, Tanzania
            [f ]Teule Designated District Hospital, Muheza, Tanzania
            [g ]NIMR-Amani Centre, Tanga, Tanzania
            [h ]Malaria Control Program, Ministry of Health, Kigali, Rwanda
            [i ]University of Ilorin Teaching Hospital, Ilorin, Nigeria
            [j ]Mbarara University of Science and Technology and Epicentre Research Base, Mbarara, Uganda
            [k ]Kinshasa School of Public Health—Kingasani Research Centre, Kinshasa, Democratic Republic of the Congo
            [l ]Mahidol Oxford Tropical MedicineResearch Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
            [m ]Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
            [n ]Menzies School of Health Research, Casuarina, NT, Australia
            [o ]Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
            [p ]KEMRI—CDC Kisumu, Kisumu Kenya
            Author notes
            [* ]Correspondence to: Prof N J White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand nickw@ 123456tropmedres.ac
            [‡]

            Members listed at end of paper.

            Contributors
            Journal
            Lancet
            Lancet
            Lancet
            Lancet Publishing Group
            0140-6736
            1474-547X
            13 November 2010
            13 November 2010
            : 376
            : 9753
            : 1647-1657
            3033534 21062666 LANCET61924 10.1016/S0140-6736(10)61924-1
            © 2010 Elsevier Ltd. All rights reserved.

            This document may be redistributed and reused, subject to certain conditions.

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