Rectal artemether versus intravenous quinine for the treatment of cere
http://www.100md.com
《英国医生杂志》
1 Department of Paediatrics and Child Health, Makerere Medical School, PO Box 7072, Kampala, Uganda
Corresponce to: J K Tumwine jtumwine@imul.com
Abstract
Cerebral malaria is the most severe and life threatening complication of Plasmodium falciparum malaria and carries a case fatality rate1 of 5-40%, with most deaths occurring within the first 24 hours.2 Although the recommended treatment of cerebral malaria is intravenous quinine,1 alternative drugs are necessary where intravenous treatment is not possible.3 Most studies comparing rectal artemether with intravenous quinine were carried out in adults.4-6 The results were variable, and information on the use of artemether in children is limited.6 One recent study found that a single dose of rectal artesunate is associated with rapid reduction in parasite density in children and adults with moderately severe malaria.7
If found effective, rectal artemether might be particularly useful for treating severely ill children at peripheral health units,2 where facilities for intravenous treatment are often lacking.3 8 Using rectal formulations might prevent potentially life threatening complications arising from delays in administering effective antimalarial treatment to children with cerebral malaria. We compared the efficacy and safety of rectal artemether with that of intravenous quinine in the treatment of children, aged 6 months to 5 years, with cerebral malaria.
Methods
From July 2002 to February 2003, we enrolled 103 patients with cerebral malaria and randomly assigned them to treatment with either intravenous quinine or rectal artemether (fig 1). The patients in the two groups were comparable in sociodemographic, clinical, and laboratory characteristics.
Fig 1 Flow of participants through the trial
The distribution of the patients' clinical symptoms and signs were comparable on admission between the two treatment groups (tables 1 and 2).
Table 1 Baseline symptoms and signs of patients in both treatment arms on admission. Values are numbers (percentages) of patients
Table 2 Baseline clinical and laboratory characteristics before treatment for patients with cerebral malaria for both treatment arms. Values are means with standard deviations unless otherwise indicated
The main outcome measures were comparable between the two groups (table 3). Kaplan-Meier curves (fig 2) and the log rank test for parasite clearance time showed no significant difference between the two groups. The times to regaining consciousness and fever clearance did not differ significantly between the two groups ((P = 0.01 and P = 0.08, respectively).
Table 3 Clinical and parasitological outcomes of treatment for patients with cerebral malaria in the two treatment arms. Values are means with standard deviations
Fig 2 Kaplan-Meier survival curve for parasite clearance time for children receiving artemether or quinine. The difference in parasite clearance rates between the two treatment groups did not reach significance by the log rank test (P=0.666)
Adverse effects
We did not observe drug side effects such as skin rash, hypotension, jaundice, and diarrhoea in either treatment arm. Five children developed vomiting when they regained consciousness: three (7.1%) receiving quinine and two (4.4%) receiving artemether (P = 0.235, Fisher's exact test). This did not last for more than 24 hours. None of the children showed allergy to either drug, complained of tenesmus, or had rectal bleeding. Liver and renal function tests, altered on admission, had normalised by discharge (table 4).
Table 4 Comparison of admission with discharge biochemical characteristics of children treated for cerebral malaria for the two treatment groups. Values are means with standard deviations
Mortality was higher in the quinine group than in the artemether group (10/52 v 6/51, relative risk 1.29, 95% confidence interval 0.84 to 2.01). Postmortem findings in eight of the children who died included intense petechial haemorrhages affecting the white matter and cerebellar surface; parasitised red blood cells and malaria pigment in the brain tissue; and parasitised red blood cells in the liver.
Discussion
Warrell D, ME M, Beales P. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990;84: 1-65.
D'Alessandro U. Treating severe and complicated malaria. BMJ 2004;328: 155.
Simoes E, Peterson S, Gamatie Y, Kisanga F, Mukasa G, Nsungwa-Sabiiti J, et al. Management of severely ill children at first-level health facilities in sub-Saharan Africa when referral is difficult. Bull World Health Organ 2003;81: 522-3.
Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemesinin with intravenous quinine in the treatment of severe malaria in Ethiopia. East Afr Med J 1999;76: 154-9.
Hien T, Arnold K, Vinh H, Cuong B, Phu N, Chau T, et al. Comparison of artemesinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Trans R Soc Trop Med Hyg 1992;86: 582-3.
Esamai F, Ayuo P, Owino-Ongor W, Rotich J, Ngindu A, Obala A, et al. Rectal dihyroartemesinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial. East Afr Med J 2000;77: 273-8.
Barnes KI, Mwenechanya J, Tembo M, McIlleron P, Folb P, Ribeiro I, et al. Efficacy orf rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 2004;363: 1598-605.
Peterson S, Nsungwa-Sabiiti J, Were W, Nsabagasani X, Magumba G, Nambooze J, et al. Coping with paediatric referral—Ugandan parents' experience. Lancet 2004;363: 1955-6.
Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke S, et al. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria. Lancet 2002;360: 2031-8.
Newton C, Chokwe T, Schellenberg J, Winstanley P, Forster D, Peshu N, et al. Coma scales for children with severe falciparum malaria. Trans R Soc Trop Med Hyg 1997;91: 161-5.
Jiang J, Li G, Guo X, Kong Y, Arnold K. Antimalarial activity of mefloquine and qinghaosu. Lancet 1982;2: 285-8.
Pe Than Myint TS. The efficacy of artemether (qinghaosu) in Plasmodium falciparum and P. vivax in Burma. Southeast Asian J Trop Med Public Health 1986;17: 19-22.
Shwe T, Myint P, Htut Y, Myint W, Soe L. The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. Trans R Soc Trop Med Hyg 1988;82: 665-6.
Alin M, Kihamia C, Bjorkman A, Bwijo B, Premji Z, Mtey G, et al. Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemesinin, chloroquine, and mefloquine. Am J Trop Med Hyg 1995;53: 693-45.
Hien T, White N. Qinghaosu. Lancet 1993;341: 603-8.
Kwiatkowski D, Bate C. Inhibition of tumour necrosis factor (TNF) production by antimalarial drugs used in cerebral malaria. Trans R Soc Trop Med Hyg 1995;89: 215-6.
Walker O, Salako L, Omokhodion I, Sowunmi A. An open randomized comparative study of intramuscular artemether and intravenous quinine in cerebral malaria in children. Trans R Soc Trop Med Hyg 1993;87: 564-6.
van Hensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335: 69-75.
Taylor T, Wills B, Kazembe P, Chisale M, Wirima J, Ratsma E, et al. Rapid coma resolution with artemether in Malawian children with cerebral malaria. Lancet 1993;341: 661-2.(Jane Ruth Aceng, registrar1, Justus S By)
Corresponce to: J K Tumwine jtumwine@imul.com
Abstract
Cerebral malaria is the most severe and life threatening complication of Plasmodium falciparum malaria and carries a case fatality rate1 of 5-40%, with most deaths occurring within the first 24 hours.2 Although the recommended treatment of cerebral malaria is intravenous quinine,1 alternative drugs are necessary where intravenous treatment is not possible.3 Most studies comparing rectal artemether with intravenous quinine were carried out in adults.4-6 The results were variable, and information on the use of artemether in children is limited.6 One recent study found that a single dose of rectal artesunate is associated with rapid reduction in parasite density in children and adults with moderately severe malaria.7
If found effective, rectal artemether might be particularly useful for treating severely ill children at peripheral health units,2 where facilities for intravenous treatment are often lacking.3 8 Using rectal formulations might prevent potentially life threatening complications arising from delays in administering effective antimalarial treatment to children with cerebral malaria. We compared the efficacy and safety of rectal artemether with that of intravenous quinine in the treatment of children, aged 6 months to 5 years, with cerebral malaria.
Methods
From July 2002 to February 2003, we enrolled 103 patients with cerebral malaria and randomly assigned them to treatment with either intravenous quinine or rectal artemether (fig 1). The patients in the two groups were comparable in sociodemographic, clinical, and laboratory characteristics.
Fig 1 Flow of participants through the trial
The distribution of the patients' clinical symptoms and signs were comparable on admission between the two treatment groups (tables 1 and 2).
Table 1 Baseline symptoms and signs of patients in both treatment arms on admission. Values are numbers (percentages) of patients
Table 2 Baseline clinical and laboratory characteristics before treatment for patients with cerebral malaria for both treatment arms. Values are means with standard deviations unless otherwise indicated
The main outcome measures were comparable between the two groups (table 3). Kaplan-Meier curves (fig 2) and the log rank test for parasite clearance time showed no significant difference between the two groups. The times to regaining consciousness and fever clearance did not differ significantly between the two groups ((P = 0.01 and P = 0.08, respectively).
Table 3 Clinical and parasitological outcomes of treatment for patients with cerebral malaria in the two treatment arms. Values are means with standard deviations
Fig 2 Kaplan-Meier survival curve for parasite clearance time for children receiving artemether or quinine. The difference in parasite clearance rates between the two treatment groups did not reach significance by the log rank test (P=0.666)
Adverse effects
We did not observe drug side effects such as skin rash, hypotension, jaundice, and diarrhoea in either treatment arm. Five children developed vomiting when they regained consciousness: three (7.1%) receiving quinine and two (4.4%) receiving artemether (P = 0.235, Fisher's exact test). This did not last for more than 24 hours. None of the children showed allergy to either drug, complained of tenesmus, or had rectal bleeding. Liver and renal function tests, altered on admission, had normalised by discharge (table 4).
Table 4 Comparison of admission with discharge biochemical characteristics of children treated for cerebral malaria for the two treatment groups. Values are means with standard deviations
Mortality was higher in the quinine group than in the artemether group (10/52 v 6/51, relative risk 1.29, 95% confidence interval 0.84 to 2.01). Postmortem findings in eight of the children who died included intense petechial haemorrhages affecting the white matter and cerebellar surface; parasitised red blood cells and malaria pigment in the brain tissue; and parasitised red blood cells in the liver.
Discussion
Warrell D, ME M, Beales P. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990;84: 1-65.
D'Alessandro U. Treating severe and complicated malaria. BMJ 2004;328: 155.
Simoes E, Peterson S, Gamatie Y, Kisanga F, Mukasa G, Nsungwa-Sabiiti J, et al. Management of severely ill children at first-level health facilities in sub-Saharan Africa when referral is difficult. Bull World Health Organ 2003;81: 522-3.
Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemesinin with intravenous quinine in the treatment of severe malaria in Ethiopia. East Afr Med J 1999;76: 154-9.
Hien T, Arnold K, Vinh H, Cuong B, Phu N, Chau T, et al. Comparison of artemesinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Trans R Soc Trop Med Hyg 1992;86: 582-3.
Esamai F, Ayuo P, Owino-Ongor W, Rotich J, Ngindu A, Obala A, et al. Rectal dihyroartemesinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial. East Afr Med J 2000;77: 273-8.
Barnes KI, Mwenechanya J, Tembo M, McIlleron P, Folb P, Ribeiro I, et al. Efficacy orf rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 2004;363: 1598-605.
Peterson S, Nsungwa-Sabiiti J, Were W, Nsabagasani X, Magumba G, Nambooze J, et al. Coping with paediatric referral—Ugandan parents' experience. Lancet 2004;363: 1955-6.
Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, Staedke S, et al. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria. Lancet 2002;360: 2031-8.
Newton C, Chokwe T, Schellenberg J, Winstanley P, Forster D, Peshu N, et al. Coma scales for children with severe falciparum malaria. Trans R Soc Trop Med Hyg 1997;91: 161-5.
Jiang J, Li G, Guo X, Kong Y, Arnold K. Antimalarial activity of mefloquine and qinghaosu. Lancet 1982;2: 285-8.
Pe Than Myint TS. The efficacy of artemether (qinghaosu) in Plasmodium falciparum and P. vivax in Burma. Southeast Asian J Trop Med Public Health 1986;17: 19-22.
Shwe T, Myint P, Htut Y, Myint W, Soe L. The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. Trans R Soc Trop Med Hyg 1988;82: 665-6.
Alin M, Kihamia C, Bjorkman A, Bwijo B, Premji Z, Mtey G, et al. Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemesinin, chloroquine, and mefloquine. Am J Trop Med Hyg 1995;53: 693-45.
Hien T, White N. Qinghaosu. Lancet 1993;341: 603-8.
Kwiatkowski D, Bate C. Inhibition of tumour necrosis factor (TNF) production by antimalarial drugs used in cerebral malaria. Trans R Soc Trop Med Hyg 1995;89: 215-6.
Walker O, Salako L, Omokhodion I, Sowunmi A. An open randomized comparative study of intramuscular artemether and intravenous quinine in cerebral malaria in children. Trans R Soc Trop Med Hyg 1993;87: 564-6.
van Hensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335: 69-75.
Taylor T, Wills B, Kazembe P, Chisale M, Wirima J, Ratsma E, et al. Rapid coma resolution with artemether in Malawian children with cerebral malaria. Lancet 1993;341: 661-2.(Jane Ruth Aceng, registrar1, Justus S By)