• 1

    Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI, 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434 :214–217.

    • Search Google Scholar
    • Export Citation
  • 2

    World Health Organization Communicable Diseases Cluster, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–90.

  • 3

    World Health Organization Division of Control of Tropical Diseases, 1990. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2):1–65.

    • Search Google Scholar
    • Export Citation
  • 4

    World Health Organization, 2006. Guidelines for the Treatment of Malaria. Geneva: WHO.

  • 5

    Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K, 1999. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. Q J Med 92 :151–157.

    • Search Google Scholar
    • Export Citation
  • 6

    Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K, 1999. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 93 :283–286.

    • Search Google Scholar
    • Export Citation
  • 7

    Evans JA, Adusei A, Timmann C, May J, Mack D, Agbenyega T, Horstmann RD, Frimpong E, 2004. High mortality of infant bacteraemia clinically indistinguishable from severe malaria. Q J Med 97 :591–597.

    • Search Google Scholar
    • Export Citation
  • 8

    Yen LM, Dao LM, Day NP, Waller DJ, Bethell DB, Son LH, Hien TT, White NJ, 1994. Role of quinine in the high mortality of intramuscular injection tetanus. Lancet 344 :786–787.

    • Search Google Scholar
    • Export Citation
  • 9

    White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, Williamson DH, Turner RC, 1983. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 309 :61–66.

    • Search Google Scholar
    • Export Citation
  • 10

    White NJ, Miller KD, Marsh K, Berry CD, Turner RC, Williamson DH, Brown J, 1987. Hypoglycaemia in African children with severe malaria. Lancet 1 :708–711.

    • Search Google Scholar
    • Export Citation
  • 11

    White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Chanthavanich P, Bunnag D, Harinasuta T, 1983. Quinine loading dose in cerebral malaria. Am J Trop Med Hyg 32 :1–5.

    • Search Google Scholar
    • Export Citation
  • 12

    Krishna S, White NJ, 1996. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet 30 :263–299.

    • Search Google Scholar
    • Export Citation
  • 13

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 :717–725.

    • Search Google Scholar
    • Export Citation
  • 14

    Artemether–Quinine Meta-analysis Study Group, 2001. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 95 :637–650.

    • Search Google Scholar
    • Export Citation
  • 15

    Murphy SA, Mberu E, Muhia D, English M, Crawley J, Waruiru C, Lowe B, Newton CR, Winstanley P, Marsh K, Watkins WM, 1997. The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study. Trans R Soc Trop Med Hyg 91 :331–334.

    • Search Google Scholar
    • Export Citation
  • 16

    Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J, 2004. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother 48 :4234–4239.

    • Search Google Scholar
    • Export Citation
  • 17

    Magill A, Panosian C, 2005. Making antimalarial agents available in the United States. N Engl J Med 353 :335–337.

  • 18

    Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG, 1994. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 88 (Suppl 1):S33–S36.

    • Search Google Scholar
    • Export Citation
  • 19

    Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ, 2003. Neuropathological assessment of artemether-treated severe malaria. Lancet 362 :295–296.

    • Search Google Scholar
    • Export Citation
  • 20

    Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ, 2002. Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 67 :423–429.

    • Search Google Scholar
    • Export Citation
  • 21

    Clark RL, White TE, A Clode S, Gaunt I, Winstanley P, Ward SA, 2004. Developmental toxicity of artesunate and an arte-sunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 71 :380–394.

    • Search Google Scholar
    • Export Citation
  • 22

    White TE, Bushdid PB, Ritter S, Laffan SB, Clark RL, 2006. Artesunate-induced depletion of embryonic erythroblasts precedes embryolethality and teratogenicity in vivo. Birth Defects Res B Dev Reprod Toxicol 77 :413–429.

    • Search Google Scholar
    • Export Citation
  • 23

    Hien TT, Arnold K, Vinh H, Cuong BM, Phu NH, Chau TT, Hoa NT, Chuong LV, Mai NT, Vinh NN, et al., 1992. Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Trans R Soc Trop Med Hyg 86 :582–583.

    • Search Google Scholar
    • Export Citation
  • 24

    Cao XT, Bethell DB, Pham TP, Ta TT, Tran TN, Nguyen TT, Pham TT, Nguyen TT, Day NP, White NJ, 1997. Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Trans R Soc Trop Med Hyg 91 :335–342.

    • Search Google Scholar
    • Export Citation
  • 25

    Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P, Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisiddhi T, 1998. Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Am J Trop Med Hyg 58 :11–16.

    • Search Google Scholar
    • Export Citation
  • 26

    Barnes KI, Mwenechanya J, Tembo M, McIlleron H, Folb PI, Ribeiro I, Little F, Gomes M, Molyneux ME, 2004. Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 363 :1598–1605.

    • Search Google Scholar
    • Export Citation
  • 27

    Karunajeewa HA, Reeder J, Lorry K, Dabod E, Hamzah J, Page-Sharp M, Chiswell GM, Ilett KF, Davis TM, 2006. Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea. Antimicrob Agents Chemother 50 :968–974.

    • Search Google Scholar
    • Export Citation
  • 28

    Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S, McIlleron H, Miller R, Molyneux M, Mwenechanya J, Navaratnam V, Nosten F, Olliaro P, Pang L, Ribeiro I, Tembo M, van Vugt M, Ward S, Weerasuriya K, Win K, White NJ, 2006. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med 3 :e444.

    • Search Google Scholar
    • Export Citation
  • 29

    Gerardin P, Rogier C, Ka AS, Jouvencel P, Diatta B, Imbert P, 2007. Outcome of life-threatening malaria in African children requiring endotracheal intubation. Malar J 6 :51.

    • Search Google Scholar
    • Export Citation
  • 30

    Newton CR, Crawley J, Sowumni A, Waruiru C, Mwangi I, English M, Murphy S, Winstanley PA, Marsh K, Kirkham FJ, 1997. Intracranial hypertension in Africans with cerebral malaria. Arch Dis Child 76 :219–226.

    • Search Google Scholar
    • Export Citation
  • 31

    Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CR, Levin M, 2005. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ 331 :337–343.

    • Search Google Scholar
    • Export Citation
  • 32

    Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma D, Winstanley P, Peto T, Marsh K, 2000. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 355 :701–706.

    • Search Google Scholar
    • Export Citation
  • 33

    White NJ, Looareesuwan S, Phillips RE, Chanthavanich P, Warrell DA, 1988. Single dose phenobarbitone prevents convulsions in cerebral malaria. Lancet 2 :64–66.

    • Search Google Scholar
    • Export Citation
  • 34

    Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM, Chau TT, Mai NT, Waller DJ, White NJ, 1992. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis 15 :874–880.

    • Search Google Scholar
    • Export Citation
  • 35

    Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, Winearls C, Farrar J, White N, Day N, 2002. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 347 :895–902.

    • Search Google Scholar
    • Export Citation
  • 36

    Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 :76–83.

    • Search Google Scholar
    • Export Citation
  • 37

    Bruneel F, Gachot B, Timsit JF, Wolff M, Bedos JP, Regnier B, Vachon F, 1997. Shock complicating severe falciparum malaria in European adults. Intensive Care Med 23 :698–701.

    • Search Google Scholar
    • Export Citation
  • 38

    Day NP, Phu NH, Bethell DP, Mai NT, Chau TT, Hien TT, White NJ, 1996. The effects of dopamine and adrenaline infusions on acid–base balance and systemic haemodynamics in severe infection. Lancet 348 :219–223.

    • Search Google Scholar
    • Export Citation
  • 39

    Planche T, Onanga M, Schwenk A, Dzeing A, Borrmann S, Faucher JF, Wright A, Bluck L, Ward L, Kombila M, Kremsner PG, Krishna S, 2004. Assessment of volume depletion in children with malaria. PLoS Med 1 :e18.

    • Search Google Scholar
    • Export Citation
  • 40

    Planche T, 2005. Malaria and fluids—balancing acts. Trends Parasitol 21 :562–567.

  • 41

    Maitland K, 2006. Severe malaria: lessons learned from the management of critical illness in children. Trends Parasitol 22 :457–462.

  • 42

    Day N, 2006. Fluid resuscitation in malaria: the need for new randomised clinical trials. PLoS Clin Trials 1 :e24.

  • 43

    Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CF, Nosten F, Chapman D, Brewster D, Holloway PA, et al., 1994. Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg 88 :67–73.

    • Search Google Scholar
    • Export Citation
  • 44

    Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ, 2000. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 28 :1833–1840.

    • Search Google Scholar
    • Export Citation
  • 45

    Dondorp AM, Chau TT, Phu NH, Mai NT, Loc PP, Chuong LV, Sinh DX, Taylor A, Hien TT, White NJ, Day NP, 2004. Unidentified acids of strong prognostic significance in severe malaria. Crit Care Med 32 :1683–1688.

    • Search Google Scholar
    • Export Citation
  • 46

    Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Supputamongkol Y, Davis TM, Holloway PA, White NJ, 1994. Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. Metabolism 43 :974–981.

    • Search Google Scholar
    • Export Citation
  • 47

    Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Henderson GN, Hutson AD, Derendorf H, Krishna S, Stacpoole PW, 2003. Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children. J Clin Pharmacol 43 :386–396.

    • Search Google Scholar
    • Export Citation
  • 48

    World Health Organization, 2001. The Prevention and Management of Severe Anaemia in Children in Malaria-Endemic Regions of Africa: A Review of Research. Geneva: WHO.

  • 49

    Enwere G, 2005. A review of the quality of randomized clinical trials of adjunctive therapy for the treatment of cerebral malaria. Trop Med Int Health 10 :1171–1175.

    • Search Google Scholar
    • Export Citation
  • 50

    van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S, Kwiatkowski D, Greenwood B, 1996. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis 174 :1091–1097.

    • Search Google Scholar
    • Export Citation
  • 51

    Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intara-prasert R, Bunnag D, Harinasuta T, 1982. Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med 306 :313–319.

    • Search Google Scholar
    • Export Citation
  • 52

    Hoffman SL, Rustama D, Punjabi NH, Surampaet B, Sanjaya B, Dimpudus AJ, McKee KT Jr, Paleologo FP, Campbell JR, Marwoto H, et al., 1988. High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial. J Infect Dis 158 :325–331.

    • Search Google Scholar
    • Export Citation
  • 53

    Prasad K, Garner P, 2000. Steroids for treating cerebral malaria. Cochrane Database Syst Rev CD000972.

  • 54

    Smith HJ, Meremikwu M, 2003. Iron chelating agents for treating malaria. Cochrane Database Syst Rev CD001474.

  • 55

    Powell VI, Grima K, 2002. Exchange transfusion for malaria and Babesia infection. Transfus Med Rev 16 :239–250.

  • 56

    Riddle MS, Jackson JL, Sanders JW, Blazes DL, 2002. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 34 :1192–1198.

    • Search Google Scholar
    • Export Citation
  • 57

    Watt G, Jongsakul K, Ruangvirayuth R, 2002. A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria. Q J Med 95 :285–290.

    • Search Google Scholar
    • Export Citation
  • 58

    Dondorp AM, Silamut K, Charunwatthana P, Chuasuwanchai S, Ruangveerayut R, Krintratun S, White NJ, Ho M, Day NPJ, 2007. Levamisole inhibits sequestration of infected red blood cells in patients with falciparum malaria. J Int Dis 196 :460–466.

    • Search Google Scholar
    • Export Citation
  • 59

    Yipp BG, Robbins SM, Resek ME, Baruch DI, Looareesuwan S, Ho M, 2003. Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow. Blood 101 :2850–2857.

    • Search Google Scholar
    • Export Citation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

The Management of Patients with Severe Malaria

View More View Less
  • 1 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and the Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom

Severe malaria is a global problem, claiming at least 1 million lives annually. Few adequately powered clinical studies have been directed at improving the management of severe malaria over the years, but this situation is slowly changing. The antimalarial treatment of severe disease is being transformed by the development and deployment of the water-soluble artemisinin derivative artesunate. Parenteral artesunate is now the treatment of choice in low-transmission areas and in the 2nd and 3rd trimesters of pregnancy, and research is underway into whether it should replace quinine as the treatment of choice in African children. Development of good manufacturing practice (GMP) formulations should make parenteral artesunate more widely available in the near future. The development of artesunate suppositories offers another exciting prospect, the ability to treat patients with severe disease in remote rural settings, delaying the evolution of disease and buying them time to reach a health care facility. No adjunctive therapy has been shown to improve the outcome of severe malaria, but most studies have been underpowered. Future trials of interventions shown to be promising in pilot studies should be large and adequately powered. This will require multi-center designs and necessitate close collaboration between groups, as well as agreement on the research agenda. We suggest a list of candidate interventions for debate.

INTRODUCTION

Falciparum malaria remains a major cause of morbidity and mortality throughout the tropical world, with as many as 500 million cases annually causing 1–3 million deaths.1 Most cases of malaria are uncomplicated and can be treated successfully with appropriate oral antimalarial drugs. However, in a proportion of patients, particularly in nonimmune individuals and/or where treatment has been delayed or ineffective drugs (chloroquine in most areas of the world) or substandard counterfeited drugs given, life-threatening severe disease can evolve requiring hospitalization, parenteral antimalarial therapy, and the treatment of complications. Severe malaria is often a multisystem disorder, presenting with multiple complications, each requiring specific management. In most of the malaria-endemic world, sophisticated intensive care facilities are not available and treatment is necessarily resource-limited. The mortality associated with severe malaria remains high, ranging from 10% to 50% depending on the setting. In this context, the main objective of the management of severe malaria is to prevent the patient from dying. Prevention of long-term sequelae and recrudescence (the usual primary endpoint of antimalarial trials in uncomplicated malaria) are secondary objectives.

The World Health Organization coordinated the production of guidelines for the management of severe and complicated malaria in 1990 and again in 2000, which also contain strict definitions of severe malaria, useful for standardizing clinical research.2,3 More recently, in 2006, WHO published evidence-based guidelines for the treatment of malaria, which include extensive advice on the management of severe malaria as well as a clinically useful distillation of the WHO severe malaria definitions (Table 1).4

Unfortunately, the clinical evidence base on which to base guidelines is small, as most of the clinical trials on severe malaria management have been either negative, underpowered, or both. Until the SEAQUAMAT trial in 2005, no proposed intervention in severe malaria had ever been shown to reduce mortality. This review will briefly recapitulate the evidence for current “best practice” but will also concentrate on the many gaps in our knowledge and how they might be addressed.

INITIAL ASSESSMENT AND MANAGEMENT

Severe malaria is a medical emergency. Initial management is based on that of any acutely and severely ill patient. The initial rapid clinical assessment should focus on the airway and circulation and include assessments of conscious level, respiratory status, and state of hydration. Hypoglycemia should be ruled out or, if the patient is comatose, treated empirically. Convulsions, which can present with subtle symptoms, especially in children, should be treated promptly. Intravenous rehydration should be commenced if indicated, oxygen given if there is clinical or blood gas evidence of respiratory distress or hypoxia, and an appropriate antimalarial drug administered. If the presence of severe malaria is suspected (Table 1), the patient should be transferred to the highest level of care available (preferably an intensive care unit).2,4

In areas of high transmission, peripheral parasitemia is common and relatively uninformative unless very high, and other common infections may produce clinical pictures similar to the spectrum of syndromes produced by severe malaria. In cases with impaired consciousness, a lumbar puncture should be performed to exclude meningitis5 and the possibility of bacterial sepsis considered in all seriously ill individuals. Blood cultures are rarely available in endemic areas, but where they have been done systematically, bacteremias were found in a significant proportion of clinically severe patients with parasitemia.6,7 Clearly if there are focal signs suggesting a bacterial infection (such as pneumonia), broad-spectrum antibiotic cover should be given. However, at present there is no robust method of excluding bacterial sepsis in patients with parasitemia and “severe malaria” in high-transmission areas. In the absence of such a test, a strong case can be made for a broader use of empirical antibiotics (in addition to the antimalarials), although so far no clinical trials have addressed this issue.

ANTIMALARIAL TREATMENT

For most of the last 300 years, the cinchona alkaloid quinine has been the drug of choice for severe malaria. In the 1950s, it was supplanted by the synthetic 4-aminoquinoline antimalarial chloroquine, but with the inexorable worldwide rise of chloroquine resistance, quinine returned to widespread use in the last decades of the 20th century. The situation is now rapidly changing once more with the rediscovery and development by Chinese scientists of the artemisinin derivatives, the most rapidly acting of all antimalarial drugs.

Quinine.

Parenteral quinine remains at present the drug of choice for treating severe malaria in African children. Because of its cardiotoxicity, intravenous infusion should be carried out over 4 hours. Where intravenous infusion is not practical, quinine can be given by deep intramuscular injection, although this can cause sterile abscesses, which in turn have been associated with a lethal form of tetanus.8 Injection into the buttocks can also cause sciatic nerve damage. Quinine is a relatively toxic drug with a narrow therapeutic ratio. Quinine-induced hyperinsulinemic hypoglycemia is a particular problem in patients with severe malaria, especially during pregnancy, and is impossible to diagnose clinically in the already unconscious patient.9,10 Frequent monitoring of blood glucose concentrations is therefore essential. It is also important that parasitocidal drug levels are obtained as quickly as possible, so in patients who have not been given recent (< 24 hours before admissions) doses of quinine, an initial loading dose of 20 mg/kg should be administered.11 The total apparent volume of distribution of quinine and its systemic clearance are both reduced in proportion to disease severity, and in severe malaria the dose should be reduced by one-third after 48 hours if there is no clinical improvement or if there is renal failure.12

Artemisinin derivatives.

The artemisinin derivatives are the most exciting recent development in the treatment of severe malaria. They are rapidly parasitocidal, and—crucially unlike quinine—they kill young circulating parasites before they sequester in the deep microvasculature. To examine whether these advantages over quinine could be translated into a reduction in severe malaria mortality, between 2003 and 2005, 1461 patients (including 202 children) in 4 south and southeast Asian countries were recruited into SEAQUAMAT (South and Southeast Asian Quinine versus Artesunate in severe Malaria Trial), the largest ever clinical drug trial in severe malaria.13 Mortality in those randomized to artesunate was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; a relative reduction of 34.7% (95% CI 18.5–47.6%; P = 0.0002). The NNT (Number Needed to Treat to save one life) was 11.1 (95% CI 5.8–121) in Bangladesh, 12.6 (7.3 to 45) in Burma, 16.6 in Indonesia, and 21.2 in India. The mortality difference was particularly marked in those patients with large numbers of circulating young parasites, consistent with the hypothesis that artesunate’s advantage lies in its ability to kill young parasites before they sequester (unpublished observations). As a result of the SEAQUAMAT study, parenteral artesunate is now recommended by WHO as the drug of choice for the treatment of severe malaria in low-transmission areas and in the second and third trimesters of pregnancy (Table 2).4

The current recommendation for treating severe malaria patients in high-transmission areas is either quinine or an artemisinin derivative. This patient group consists mainly of African children, who bear the largest part of the global malaria disease burden and for whom the potential advantage for parenteral artesunate is not as clear-cut as in southeast Asian adults. Severe malaria in children progresses more rapidly than in adults, leaving a smaller time window for the killing of young parasites by artesunate to deliver a clinical advantage. In the 1980s and 1990s under WHO oversight, a number of studies were carried out in both Africa and Asia comparing quinine with artemether, a lipid-soluble artemisinin derivative administered intramuscularly (it can also be given rectally, but not intravenously). An individual patient data meta-analysis showed that, whereas overall there was no significant difference in mortality between the two drugs [14% vs. 17%, odds ratio (95% confidence interval) 0.8 (0.62 to 1.02), P = 0.08], there was substantial heterogeneity in the treatment effect; in the Asian patients (mainly adults), artemether was associated with a modest, but significantly lower mortality than quinine [OR (99% CI) 0.59 (0.35 to 1.01), P = 0.012], but this effect was not seen in African patients (mainly children).14 Intramuscular artemether has since been shown to be erratically absorbed (unlike intramuscular artesunate, which was rapidly absorbed and quickly hydrolyzed to DHA); it is unclear whether artemether’s lack of effect on mortality in African children is due to this or to the absence of a true difference in efficacy between quinine and the artemisinin derivatives in African childhood severe malaria15,16; hence the need for evidence from randomized clinical trials comparing quinine and artesunate in African children. AQUAMAT (African Quinine versus Artesunate in severe Malaria Trial), a multicenter study based on the SEAQUAMAT design, is currently underway. This trial plans to recruit 5,306 patients by 2010, and is powered to detect a 25% reduction in mortality from 8% to 6%.

The only widely available parenteral artesunate formulation is made by Guilin Pharmaceutical factory in China. Although it is effective (it was used in the SEAQUAMAT study) and is registered in many countries, it is manufactured to Chinese GMP (Good Manufacturing Practice) standards and is not yet “international GMP certified” (although there are plans for this). It is currently particularly difficult to treat severe malaria in the United States, as both parenteral artesunate and quinine are unlicensed, and intravenous quinidine, the mainstay of severe malaria therapy in the U.S., is increasingly unavailable as its use in cardiology declines.17 A new GMP formulation of artesunate is being developed by the U.S. Army and will hopefully obtain FDA approval in the next year or so.

Animal toxicity studies have raised concerns about possible neurotoxicity with high doses of the artemisinin derivative drugs, but so far, despite widespread use, neurotoxicity has not been reported in humans.18,19 The animal neurotoxicity appears particularly related to high sustained levels produced by administration of lipophilic artemisinin derivatives such as artemether, which suggests that if a problem with neurotoxicity did exist (and there is no evidence of this to date), then water-soluble derivatives such as artesunate would be much safer.20 Animal studies have also shown some reproductive toxicity, with fetal resorption in rats and rabbits.21,22 There is no evidence that this occurs in humans, but such a problem would by its nature be difficult to detect. As severe malaria is a potentially fatal illness for the mother, until further evidence becomes available, the 2006 WHO guidelines regard both quinine and artesunate as treatment options in the first trimester (Table 2).4

Artesunate suppositories.

Most patients with malaria in the rural tropics live far from the nearest health clinic or hospital, and many develop severe disease and die before reaching a health facility where parenteral treatment can be given. Deployment of artesunate suppositories in rural areas offers the prospect of effective early treatment of malaria, preventing clinical deterioration and buying time to reach a hospital. The use of suppositories containing artemisinin or one of its derivatives for the treatment of severe malaria in both adults and children was pioneered in Viet Nam in the early 1990s.23,24 Subsequently, the WHO sponsored the development of GMP-manufactured rectal artesunate capsules, which appear to be reasonably well absorbed and are effective for the treatment of moderately severe malaria.2528 A large phase III study of early deployment has been completed and will report soon, and it appears likely that rectal artesunate will obtain U.S. FDA registration in the near future.1 Home-or village-based deployment of rectal artesunate in rural areas of the tropics may play an important role in reducing malaria-associated morbidity and mortality. Further research needs to be conducted on how best to achieve this, in particular, at what level to deploy the suppositories (family, village health worker, etc.), whether they will be socially and culturally acceptable, and assessment of practical problems concerning their administration (early passing of suppository, multiple dosing, potential paradoxical delays in referral, etc.). As a high proportion of sick individuals will have severe bacterial sepsis rather than severe malaria, the question of antibiotic cover arises. A suppository containing both artesunate and an antibiotic (preferably one with some antimalarial activity) may be the next logical step and is currently the subject of preliminary research into its feasibility.

SUPPORTIVE CARE AND MANAGEMENT OF COMPLICATIONS

Good nursing care is essential in the management of severe malaria, with particular attention to fluid balance, management of the unconscious patient, and detection of potentially lethal complications such as hypoglycemia.

Coma.

In Western ICUs, mechanical ventilation is often used in the unconscious cerebral malaria patient to protect the airway, although its efficacy in terms of prevention of mortality and sequelae has not been proven.29 In a small study of Kenyan children with cerebral malaria and raised intracranial pressures, mannitol, an anti-osmotic agent, was successful in reducing intracranial pressure for short periods,30 but no convincing clinical evidence exists to support its routine use.

Convulsions.

Seizures in cerebral malaria should be treated with rectal diazepam, intravenous lorazepam, paraldehyde, or other standard anticonvulsants, after high-flow oxygen and appropriate airway management have been initiated.31 Prophylactic phenobarbitone was shown to reduce seizure incidence in adult cerebral malaria, but a study in children using a single intramuscular dose of 20 mg/kg reduced seizures but increased mortality, possibly through respiratory depression caused by an interaction with diazepam.32,33 Prophylactic anticonvulsive therapy is therefore currently not recommended.

Acute renal failure.

Whereas in African children malaria-associated acute renal failure is extremely rare, it is a relatively common complication of severe malaria in nonimmune adults and children. It has an untreated mortality of > 70% and should be treated with adequate renal replacement therapy—preferably by hemofiltration when available, as this has been shown to be superior to peritoneal dialysis in terms of mortality and cost-effectiveness.34,35 The role of hemodialysis has not been assessed in a randomized trial, but it is likely to be superior to peritoneal dialysis in the hemodynamically stable patient.

Hemodynamic shock.

Shock in severe malaria (“algid malaria”) carries a high mortality in both adults and children.29,36 It should be treated initially with oxygen and fluids (with monitoring of central venous pressure if available), though, as in children, it is unclear how aggressive the volume expansion should be in terms of safety and effectiveness. Massive hemorrhage, from the gastrointestinal tract or rarely a ruptured spleen, should be excluded. A septic screen including blood cultures should be performed and appropriate broad-spectrum antibiotics administered to cover the possibility of bacterial sepsis. If inotropes are necessary, dopamine has been used safely in malaria, and dobutamine and norepinephrine may also be used though there is little experience with them in severe malaria.37 Epinephrine should be avoided as it induces serious lactic acidosis.38

Fluid resuscitation.

The role of aggressive fluid resuscitation in the management of severe malaria, particularly in children, is unclear and currently controversial. The debate centers around whether hypovolemia plays an important role in the pathophysiology of severe malaria, causing poor tissue perfusion, leading to anaerobic glycolysis and consequent acidosis. Advocates of aggressive fluid repletion suggest that the standards of care applied in resource-rich settings for severely ill children with bacterial sepsis should be extrapolated to severe malaria, while those against argue that there is no evidence that severe dehydration occurs in severe malaria and are concerned that overzealous rehydration may lead to pulmonary and cerebral edema.3941 There is at present insufficient evidence either way, as all clinical studies conducted so far have been small and unsatisfactory.42 A large multicenter clinical trial is planned that will hopefully provide some answers, but in the meantime, intravenous fluid regimens should be guided by clinical judgment and, if available, by central venous pressure monitoring.

Acidosis.

Metabolic acidosis, a common complication of severe malaria, is strongly associated with fatal outcome in both adults and children.43,44 Lactic acid is an important contributor, but impaired renal bicarbonate handling and the presence of other as yet unidentified acids also play major roles.45 Dichloroacetate (which stimulates pyruvate dehydrogenase) has been shown to reduce plasma lactate in severe malaria, but to have no effect on pH, possibly because of the multi-factorial etiology of the acidosis.46,47 Hemofiltration has been shown to rapidly eliminate acidosis in malaria patients with renal failure, even in the presence of lactic acidosis.35 Early hemofiltration may be a useful strategy in patients with acidosis and renal impairment who have not yet developed established renal failure, but this has not yet been evaluated in a clinical trial.

Anemia.

This is present in almost all patients with severe malaria but occurs most prominently in young children. Benefits of blood transfusion should outweigh the risks (especially of HIV and other pathogens). There is no clear evidence supporting specific hemoglobin cut-off levels, and a number of figures are quoted in reviews and guidelines. In adults, the threshold for blood transfusion is commonly set at a hematocrit < 20%. Clinical evidence from Kenya has led to proposed threshold hemoglobin levels for African children of 5 g/dL if there is co-existing respiratory distress, impaired consciousness, or hyperparasitemia or at an absolute cut-off of 4 g/dL.48

ARDS.

This feared complication has a high mortality rate and can develop several days after admission and onset of treatment. Clinical research is needed into both the pathophysiology and treatment of this condition. The etiology is poorly understood, and treatment in malaria is currently based on expert opinion and extrapolation from studies on ARDS associated with other conditions.

OTHER ADJUNCTIVE THERAPIES

The malaria literature contains many small trials of potential adjunctive therapies for severe malaria. Most of these studies to date have been underpowered, and in a recent review many were found to have “inadequate methodological quality.”49 In many cases, meta-analyses have been conducted with multiple small trials in attempts to make sense of the data, but still the power was usually insufficient to draw conclusions. An exception is the placebo-controlled trial of anti-TNF trial in the Gambia reported in 1996, which recruited 610 patients, 124 of whom died. There was no mortality difference and a suggestion of an increased incidence of sequelae in the treatment group.50 The classic 1982 dexamethasone study from Thailand on the other hand, although well-conducted and the largest study ever in severe malaria at the time (N = 100), is underpowered by today’s standards and may conceal a type II error.51 A meta-analysis combining it with the second malaria steroid trial from Indonesia concluded that there was insufficient power to exclude a mortality effect either way.52,53 A meta-analysis of trials on the use of iron chelators also concluded that, although no clear benefit was demonstrated, there is not enough data to draw a definitive conclusion.54

Exchange blood transfusion is a popular adjunctive therapy, particularly in well-resourced settings. There are a number of rationales for its use in severe malaria, including removal of parasitized erythrocytes, removal of cytokines and other soluble toxins and mediators, and improving the rheology of the blood unparasitized erythrocytes by replacing unparasitized erythrocytes with reduced deformability.55 However, no adequately powered randomized controlled clinical trial has been performed, and a meta-analysis of small studies and case series showed no clear benefit (although the transfused patient group was significantly sicker than the control group).56

Two adjuvant candidates aimed at the disease process in general are the antioxidant N-acetylcysteine (NAC) and the antihelminthic drug levamisole. NAC has been the subject of several small studies, in one of which it was shown to increase lactate clearance.57 Levamisole, which inhibits binding of parasitized erythrocytes to CD36 in vitro and in uncomplicated malaria58 has not yet been trialed in severe malaria.59

FUTURE DIRECTIONS

The evidence base for the treatment of severe malaria is lamentably small given the global importance of the disease and the number of deaths it causes. Fewer than 10,000 patients have ever been randomized into treatment trials of severe malaria, an astonishingly small figure given the ≈ 10 million cases of severe malaria annually and our inadequate knowledge of how it should best be managed. Clearly, under-funding has played a major role in the past, but in recent years this problem has begun to be addressed as the global community has started making major investments in tackling the main infectious-disease killers. There has been an associated slow but steady development of clinical research capacity in the malaria-endemic world, and although there is a long way to go, it is for the first time becoming practical to conduct large, adequately powered clinical trials of candidate treatments for severe malaria. Major funding and logistical challenges are still associated with such projects, and research capacity building has to be an integral part of the planning. The considerable problem of agreeing on the research agenda must also be kept in mind, as only a limited number of such multicenter trials can be conducted at any one time. Only by forming multinational collaborations can we hope to address important clinical research questions with sufficient statistical power.

Which new treatments or clinical management strategies warrant assessment in these multi-center studies? In Table 3 we list a number of candidates along with a subjective assessment of the evidence supporting their inclusion and the level of controversy such a trial is likely to generate. Several have been mentioned already in this review, whereas others are more speculative and may require study in smaller trials with surrogate marker endpoints before a larger study can be justified. This is necessarily a personal list, and we are sure to have omitted a number of worthy contenders. The main objective is to stimulate debate and, ultimately, some degree of agreement. This is a prerequisite for the development of collaborations and networks to carry out the studies.

Table 1

WHO criteria for severe malaria

One or more of the following clinical or laboratory features
Taken from WHO Guidelines for the Treatment of Malaria. (WHO, Geneva Switzerland: 2006). Full details of the definitions can be found in “WHO severe falciparum malaria” (Trans R Soc Trop Med Hyg 2000; 94 (Suppl. 1): 1–90).
Clinical manifestations
  • Prostration

  • Impaired consciousness

  • Respiratory distress (acidotic breathing)

  • Multiple convulsions

  • Circulatory collapse

  • Pulmonary edema (radiological)

  • Abnormal bleeding

  • Jaundice

  • Hemoglobinuria

Laboratory test
  • Severe anemia

  • Hypoglycemia

  • Acidosis

  • Renal impairment

  • Hyperlactatemia

  • Hyperparasitemia

Table 2

Extracts from current WHO guidelines for the treatment of severe malaria4 (reproduced with permission)

Summary of recommendations on the treatment of severe malariaLevel of evidence
* Levels of evidence: S, formal systematic reviews, such as a Cochrane Review, including more than one randomized controlled trial; T, comparative trials without formal systematic review; O, observational studies (e.g., surveillance or pharmacological data); E, expert opinion/consensus.
Severe malaria is a medical emergency. After rapid clnical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available.E
Artesunate 2.4 mg/kg body weight (bw) i.v. or i.m. given on admission (time 3 0), then at 12 h and 24 h, then once a day is the recommended choice in low-transmission areas or outside malaria-endemic areas.S
For children in high-transmission areas, the following antimalarial medicines are recommended as there is insufficient evidence to recommend any of these antimalarial medicines over another for severe malaria:
  • Artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time 3 0), then at 12 h and 24 h, then once a day;

  • Artemether 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day;

  • Quinine 20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour.

S, T, O, E
Summary of recommendations on pre-referral treatment for severe falciparum malaria
The following may be given:
• Artesunate or artemisinin by rectal administrationT, E
• Artesunate or artemether i.m.E
• Quinine i.m.O, E
Recommendation for treatment for severe falciparum malaria in pregnant women
Use the parenteral antimalarial treatment locally available for severe malaria in full doses. Where available, AS is the first and artemether the second option in the second and third trimesters. In the first trimester, until more evidence becomes available, both artesunate and quinine may be considered as options.E
Table 3

Suggested list of candidate interventions in severe malaria

Candidate interventionScientific rationaleEvidence from previous studiesPracticalityPotential impact in resource-poor settingsControversyStatus (September 2007)
* Very little; *****very much.
Parenteral artesunate vs. quinine in African children**********************Underway
Aggressive fluid resuscitation in children******************Funded
Levamisole******************Pilot
Exchange blood transfusion*************No plans
Empirical antibiotics in high-transmission areas**********************No plans
Dichloroacetate****************No plans
Early vs. standard hemofiltration************No plans
N-acetylcysteine*************No plans
Ventilation and sedation**************No plans
Mannitol in cerebral malaria*************No plans
Optimal fluid management in adults****************No plans
Feeding strategies****************No plans

*

Address correspondence to Nicholas Day, Wellcome Trust–Mahidol University–Oxford Tropical Medicine Programme, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand. E-mail: nickd@tropmedres.ac

Authors’ addresses: Nicholas Day and Arjen M. Dondorp, Wellcome Trust–Mahidol University–Oxford Tropical Medicine Programme, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand, Telephone: +66 2 3549172, Fax: +66 2 3549169 and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, U.K, E-mail: nickd@tropmedres.ac.

N.D. and A.D. are funded by the Wellcome Trust.

Acknowledgments: We thank Professor Nicholas White for helpful discussions.

REFERENCES

  • 1

    Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI, 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434 :214–217.

    • Search Google Scholar
    • Export Citation
  • 2

    World Health Organization Communicable Diseases Cluster, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–90.

  • 3

    World Health Organization Division of Control of Tropical Diseases, 1990. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2):1–65.

    • Search Google Scholar
    • Export Citation
  • 4

    World Health Organization, 2006. Guidelines for the Treatment of Malaria. Geneva: WHO.

  • 5

    Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K, 1999. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. Q J Med 92 :151–157.

    • Search Google Scholar
    • Export Citation
  • 6

    Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K, 1999. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 93 :283–286.

    • Search Google Scholar
    • Export Citation
  • 7

    Evans JA, Adusei A, Timmann C, May J, Mack D, Agbenyega T, Horstmann RD, Frimpong E, 2004. High mortality of infant bacteraemia clinically indistinguishable from severe malaria. Q J Med 97 :591–597.

    • Search Google Scholar
    • Export Citation
  • 8

    Yen LM, Dao LM, Day NP, Waller DJ, Bethell DB, Son LH, Hien TT, White NJ, 1994. Role of quinine in the high mortality of intramuscular injection tetanus. Lancet 344 :786–787.

    • Search Google Scholar
    • Export Citation
  • 9

    White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, Williamson DH, Turner RC, 1983. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 309 :61–66.

    • Search Google Scholar
    • Export Citation
  • 10

    White NJ, Miller KD, Marsh K, Berry CD, Turner RC, Williamson DH, Brown J, 1987. Hypoglycaemia in African children with severe malaria. Lancet 1 :708–711.

    • Search Google Scholar
    • Export Citation
  • 11

    White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Chanthavanich P, Bunnag D, Harinasuta T, 1983. Quinine loading dose in cerebral malaria. Am J Trop Med Hyg 32 :1–5.

    • Search Google Scholar
    • Export Citation
  • 12

    Krishna S, White NJ, 1996. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet 30 :263–299.

    • Search Google Scholar
    • Export Citation
  • 13

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 :717–725.

    • Search Google Scholar
    • Export Citation
  • 14

    Artemether–Quinine Meta-analysis Study Group, 2001. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 95 :637–650.

    • Search Google Scholar
    • Export Citation
  • 15

    Murphy SA, Mberu E, Muhia D, English M, Crawley J, Waruiru C, Lowe B, Newton CR, Winstanley P, Marsh K, Watkins WM, 1997. The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study. Trans R Soc Trop Med Hyg 91 :331–334.

    • Search Google Scholar
    • Export Citation
  • 16

    Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J, 2004. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother 48 :4234–4239.

    • Search Google Scholar
    • Export Citation
  • 17

    Magill A, Panosian C, 2005. Making antimalarial agents available in the United States. N Engl J Med 353 :335–337.

  • 18

    Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG, 1994. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 88 (Suppl 1):S33–S36.

    • Search Google Scholar
    • Export Citation
  • 19

    Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ, 2003. Neuropathological assessment of artemether-treated severe malaria. Lancet 362 :295–296.

    • Search Google Scholar
    • Export Citation
  • 20

    Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ, 2002. Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 67 :423–429.

    • Search Google Scholar
    • Export Citation
  • 21

    Clark RL, White TE, A Clode S, Gaunt I, Winstanley P, Ward SA, 2004. Developmental toxicity of artesunate and an arte-sunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 71 :380–394.

    • Search Google Scholar
    • Export Citation
  • 22

    White TE, Bushdid PB, Ritter S, Laffan SB, Clark RL, 2006. Artesunate-induced depletion of embryonic erythroblasts precedes embryolethality and teratogenicity in vivo. Birth Defects Res B Dev Reprod Toxicol 77 :413–429.

    • Search Google Scholar
    • Export Citation
  • 23

    Hien TT, Arnold K, Vinh H, Cuong BM, Phu NH, Chau TT, Hoa NT, Chuong LV, Mai NT, Vinh NN, et al., 1992. Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Trans R Soc Trop Med Hyg 86 :582–583.

    • Search Google Scholar
    • Export Citation
  • 24

    Cao XT, Bethell DB, Pham TP, Ta TT, Tran TN, Nguyen TT, Pham TT, Nguyen TT, Day NP, White NJ, 1997. Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Trans R Soc Trop Med Hyg 91 :335–342.

    • Search Google Scholar
    • Export Citation
  • 25

    Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P, Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisiddhi T, 1998. Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Am J Trop Med Hyg 58 :11–16.

    • Search Google Scholar
    • Export Citation
  • 26

    Barnes KI, Mwenechanya J, Tembo M, McIlleron H, Folb PI, Ribeiro I, Little F, Gomes M, Molyneux ME, 2004. Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 363 :1598–1605.

    • Search Google Scholar
    • Export Citation
  • 27

    Karunajeewa HA, Reeder J, Lorry K, Dabod E, Hamzah J, Page-Sharp M, Chiswell GM, Ilett KF, Davis TM, 2006. Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea. Antimicrob Agents Chemother 50 :968–974.

    • Search Google Scholar
    • Export Citation
  • 28

    Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S, McIlleron H, Miller R, Molyneux M, Mwenechanya J, Navaratnam V, Nosten F, Olliaro P, Pang L, Ribeiro I, Tembo M, van Vugt M, Ward S, Weerasuriya K, Win K, White NJ, 2006. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med 3 :e444.

    • Search Google Scholar
    • Export Citation
  • 29

    Gerardin P, Rogier C, Ka AS, Jouvencel P, Diatta B, Imbert P, 2007. Outcome of life-threatening malaria in African children requiring endotracheal intubation. Malar J 6 :51.

    • Search Google Scholar
    • Export Citation
  • 30

    Newton CR, Crawley J, Sowumni A, Waruiru C, Mwangi I, English M, Murphy S, Winstanley PA, Marsh K, Kirkham FJ, 1997. Intracranial hypertension in Africans with cerebral malaria. Arch Dis Child 76 :219–226.

    • Search Google Scholar
    • Export Citation
  • 31

    Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CR, Levin M, 2005. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ 331 :337–343.

    • Search Google Scholar
    • Export Citation
  • 32

    Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma D, Winstanley P, Peto T, Marsh K, 2000. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 355 :701–706.

    • Search Google Scholar
    • Export Citation
  • 33

    White NJ, Looareesuwan S, Phillips RE, Chanthavanich P, Warrell DA, 1988. Single dose phenobarbitone prevents convulsions in cerebral malaria. Lancet 2 :64–66.

    • Search Google Scholar
    • Export Citation
  • 34

    Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM, Chau TT, Mai NT, Waller DJ, White NJ, 1992. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis 15 :874–880.

    • Search Google Scholar
    • Export Citation
  • 35

    Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, Winearls C, Farrar J, White N, Day N, 2002. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 347 :895–902.

    • Search Google Scholar
    • Export Citation
  • 36

    Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 :76–83.

    • Search Google Scholar
    • Export Citation
  • 37

    Bruneel F, Gachot B, Timsit JF, Wolff M, Bedos JP, Regnier B, Vachon F, 1997. Shock complicating severe falciparum malaria in European adults. Intensive Care Med 23 :698–701.

    • Search Google Scholar
    • Export Citation
  • 38

    Day NP, Phu NH, Bethell DP, Mai NT, Chau TT, Hien TT, White NJ, 1996. The effects of dopamine and adrenaline infusions on acid–base balance and systemic haemodynamics in severe infection. Lancet 348 :219–223.

    • Search Google Scholar
    • Export Citation
  • 39

    Planche T, Onanga M, Schwenk A, Dzeing A, Borrmann S, Faucher JF, Wright A, Bluck L, Ward L, Kombila M, Kremsner PG, Krishna S, 2004. Assessment of volume depletion in children with malaria. PLoS Med 1 :e18.

    • Search Google Scholar
    • Export Citation
  • 40

    Planche T, 2005. Malaria and fluids—balancing acts. Trends Parasitol 21 :562–567.

  • 41

    Maitland K, 2006. Severe malaria: lessons learned from the management of critical illness in children. Trends Parasitol 22 :457–462.

  • 42

    Day N, 2006. Fluid resuscitation in malaria: the need for new randomised clinical trials. PLoS Clin Trials 1 :e24.

  • 43

    Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J, Craddock CF, Nosten F, Chapman D, Brewster D, Holloway PA, et al., 1994. Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg 88 :67–73.

    • Search Google Scholar
    • Export Citation
  • 44

    Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ, 2000. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 28 :1833–1840.

    • Search Google Scholar
    • Export Citation
  • 45

    Dondorp AM, Chau TT, Phu NH, Mai NT, Loc PP, Chuong LV, Sinh DX, Taylor A, Hien TT, White NJ, Day NP, 2004. Unidentified acids of strong prognostic significance in severe malaria. Crit Care Med 32 :1683–1688.

    • Search Google Scholar
    • Export Citation
  • 46

    Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Supputamongkol Y, Davis TM, Holloway PA, White NJ, 1994. Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. Metabolism 43 :974–981.

    • Search Google Scholar
    • Export Citation
  • 47

    Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Henderson GN, Hutson AD, Derendorf H, Krishna S, Stacpoole PW, 2003. Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children. J Clin Pharmacol 43 :386–396.

    • Search Google Scholar
    • Export Citation
  • 48

    World Health Organization, 2001. The Prevention and Management of Severe Anaemia in Children in Malaria-Endemic Regions of Africa: A Review of Research. Geneva: WHO.

  • 49

    Enwere G, 2005. A review of the quality of randomized clinical trials of adjunctive therapy for the treatment of cerebral malaria. Trop Med Int Health 10 :1171–1175.

    • Search Google Scholar
    • Export Citation
  • 50

    van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S, Kwiatkowski D, Greenwood B, 1996. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis 174 :1091–1097.

    • Search Google Scholar
    • Export Citation
  • 51

    Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intara-prasert R, Bunnag D, Harinasuta T, 1982. Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med 306 :313–319.

    • Search Google Scholar
    • Export Citation
  • 52

    Hoffman SL, Rustama D, Punjabi NH, Surampaet B, Sanjaya B, Dimpudus AJ, McKee KT Jr, Paleologo FP, Campbell JR, Marwoto H, et al., 1988. High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial. J Infect Dis 158 :325–331.

    • Search Google Scholar
    • Export Citation
  • 53

    Prasad K, Garner P, 2000. Steroids for treating cerebral malaria. Cochrane Database Syst Rev CD000972.

  • 54

    Smith HJ, Meremikwu M, 2003. Iron chelating agents for treating malaria. Cochrane Database Syst Rev CD001474.

  • 55

    Powell VI, Grima K, 2002. Exchange transfusion for malaria and Babesia infection. Transfus Med Rev 16 :239–250.

  • 56

    Riddle MS, Jackson JL, Sanders JW, Blazes DL, 2002. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 34 :1192–1198.

    • Search Google Scholar
    • Export Citation
  • 57

    Watt G, Jongsakul K, Ruangvirayuth R, 2002. A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria. Q J Med 95 :285–290.

    • Search Google Scholar
    • Export Citation
  • 58

    Dondorp AM, Silamut K, Charunwatthana P, Chuasuwanchai S, Ruangveerayut R, Krintratun S, White NJ, Ho M, Day NPJ, 2007. Levamisole inhibits sequestration of infected red blood cells in patients with falciparum malaria. J Int Dis 196 :460–466.

    • Search Google Scholar
    • Export Citation
  • 59

    Yipp BG, Robbins SM, Resek ME, Baruch DI, Looareesuwan S, Ho M, 2003. Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow. Blood 101 :2850–2857.

    • Search Google Scholar
    • Export Citation

Footnotes

1

On June 21, 2007, the U.S. FDA approved an Investigational New Drug protocol that will allow the Centers for Disease Control and Prevention to make intravenous artesunate available to clinicians who request it for patients who have severe malaria.

Save