BMJ  2005;330:334 (12 February), doi:10.1136/bmj.330.7487.334

Paper

Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial

¹ Department of Paediatrics and Child Health, Makerere Medical School, PO Box 7072, Kampala, Uganda

Abstract

Objective To compare the efficacy and safety of rectal artemether with intravenous quinine in the treatment of cerebral malaria in children.

Design Randomised, single blind, clinical trial.

Setting Acute care unit at Mulago Hospital, Uganda's national referral and teaching hospital in Kampala.

Participants 103 children aged 6 months to 5 years with cerebral malaria.

Intervention Patients were randomised to either intravenous quinine or rectal artemether for seven days.

Main outcome measures Time to clearance of parasites and fever; time to regaining consciousness, starting oral intake, and sitting unaided; and adverse effects.

Results The difference in parasitological and clinical outcomes between rectal artemether and intravenous quinine did not reach significance (parasite clearance time 54.2 (SD 33.6) hours v 55.0 (SD 24.3) hours, P = 0.90; fever clearance time 33.2 (SD 21.9) hours v 24.1(SD 18.9 hours, P = 0.08; time to regaining consciousness 30.1 (SD 24.1) hours v 22.67 (SD 18.5) hours, P = 0.10; time to starting oral intake 37.9 (SD 27.0) hours v 30.3 (SD 21.1) hours, P = 0.14). 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). No serious immediate adverse effects occurred.

Conclusion Rectal artemether is effective and well tolerated and could be used as treatment for cerebral malaria.

Introduction

The recommended treatment of cerebral malaria is intravenous quinine, but alternative drugs are necessary where intravenous treatment is not possible. Studies comparing rectal artemether with intravenous quinine have been carried out in adults,^{1 2 3} but results were variable, and information in children is limited.³ A single dose of rectal artesunate has been found to be associated with rapid reduction in parasite density in children and adults with moderately severe malaria.⁴

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

This study was carried out in Mulago Hospital, Uganda's national referral and teaching hospital, from July 2002 to February 2003. We recruited patients from the acute care unit and followed them for seven days.

Randomisation and blinding
This was a single blind study using placebo; treatment nurses but not patients were aware of the treatment allocations. Patients were randomised to either rectal artemether or intravenous quinine. Rectal artemether "suppogels" were similar in appearance and packaging to the rectal placebo.

Both groups had intravenous lines and received 5% dextrose until they regained consciousness, when patients receiving rectal artemether were given oral placebo, and patients receiving intravenous quinine oral quinine.

Patients
We recruited children aged 6 months to 5 years, with cerebral malaria (seizures and unarousable coma lasting more than 30 minutes after seizures have stopped, with asexual forms of P falciparum on the blood film, with no other cause of coma). We excluded children who had received derivatives of artemesinin or quinine or had had more than four bowel motions in the 24 hours before admission.

Drug administration
Patients in the quinine arm received a loading dose of 20 mg/kg of intravenous quinine in 20 ml/kg of 5% dextrose in water for two to four hours. This was reduced to 10 mg/kg in 10 ml/kg of 5% dextrose in water every eight hours until a patient regained consciousness. Quinine was then given orally (10 mg/kg, every eight hours) until seven days of treatment had been completed.

Patients receiving rectal artemether were treated according to the manufacturer's guidelines. Children weighing up to 8.9 kg received 40 mg immediately (one suppository) and continued to be given 40 mg daily for seven days. Children weighing 9-18.9 kg received 80 mg immediately and continued to be given 40 mg daily for seven days, and those weighing 19-27.9 kg received 120 mg immediately and continued to be given 80 mg daily.

Laboratory tests
We used Giemsa stained thick films to determine the density of asexual malaria parasites, which we counted per 200 white blood cells and expressed as parasites per µl—assuming a total white blood cell count of 8000x10⁶/l. We recorded parasite density at 0 hours, and microscopists who were blinded to the patients' clinical situation or treatment examined subsequent smears in two independent laboratories every 12 hours. We recorded a smear as negative when we found no asexual forms.

Main outcome measures
We used six outcome measures. Parasite clearance time was the time from starting antimalarial treatment to the first negative blood slide. Fever clearance time was from the start of antimalarial treatment until the patient had a body temperature below 37.5°C for 24 hours. We used the Blantyre coma scale daily to assess time to regain consciousness⁵ and took this as the time from onset of treatment to the time when the patient regained consciousness. We recorded time to starting oral intake of feeds and time to sitting up unaided as time from onset of treatment to beginning of these activities. We recorded complications and side effects of the drugs.

Sample size and data analysis
We calculated a sample size of 50 patients in each group for 90% power and 95% confidence (see bmj.com). We compared the differences in means between the two treatment groups using Student's t test and the log rank test for continuous outcomes, and ² and Fisher's exact tests for categorical outcomes.

Results

We enrolled 103 patients with cerebral malaria. Fifty two were randomly assigned to treatment with intravenous quinine and 51 to rectal artemether. The patients in the two groups were comparable in sociodemographic, clinical, and laboratory characteristics (see bmj.com).

The distribution of the patients' clinical symptoms and signs were comparable on admission between the two treatment groups.

The main outcome measures were comparable between the two groups (table). Kaplan-Meier curves (figure) 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.

View this table: [in this window] [in a new window]   Clinical and parasitological outcomes of treatment for patients with cerebral malaria in the two treatment arms. Values are means with standard deviations

 

View larger version (22K): [in this window] [in a new window]   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 in either treatment arm. Five children developed vomiting for less than 24 hours when they regained consciousness: three (7.1%) receiving quinine and two (4.4%) receiving artemether (P = 0.235). 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.

What is already known on this topic Rectal artemether has a faster parasite clearance time than quinine Patients with higher parasite density clear their parasites more slowly than patients with lower density parasite Intravenous quinine is the treatment of choice for cerebral malaria What this study adds Rectal artemether could be used to treat cerebral malaria in settings where qualified staff and equipment for intravenous therapy is not readily available Rectal artemether is easy to administer

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).

Discussion

Rectal artemether is effective and well tolerated and could be used to treat cerebral malaria. The clinical and parasitological outcomes of rectal artemether and intravenous quinine were similar.

Parasite clearance time
The mean parasite clearance time for rectal artemether was shorter than for intravenous quinine, although the difference did not reach significance. This agrees with similar studies,^1-3 although the parasite clearance time for artemether in our study was slightly higher. This could be due to thick blood films for asexual parasitaemia being taken every 12 hours, whereas other studies took them every four hours, every six hours, and then every 12 hours. The parasite clearance time after oral, intramuscular, or rectal artemether is shorter in patients with uncomplicated malaria than in those with complicated malaria.⁶

Fever clearance time
The longer fever clearance time with artemether could be due to the time it took to reach therapeutic plasma concentrations or because of artemether's less inhibitory activity against tumour necrosis factor .⁷ Some studies reported a faster clearance with artemether than with quinine,^{1 2} whereas others found no difference.^{3 8 9}

Time to start oral intake and time to sit unsupported
The clinical outcomes of times to starting oral intake and sitting unsupported were similar in both groups. There are no studies with which to compare these results.

Adverse events
Both drugs had few side effects. Vomiting was more common in the quinine group, but the difference did not reach significance. Renal and liver function tests and haematological variables, which were altered on admission, improved in both groups. This agrees with other studies,^{2 3 8 9} and reiterates the fact that neither drug has any adverse effects on these functions.

We did not observe unwanted side effects of artemether suppogels, such as tenesmus after bowel irritation. This finding is at odds with observations on adults receiving rectal artemether in Ethiopia,¹ possibly because adults are more likely to report variations in their body function.

The reason for the lower death rate with artemether is not clear. Several trials in south east Asian adults with severe malaria indicated that treatment with artemesinin derivatives might halve mortality.^{10 11}

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This is the abridged version; the full version is on bmj.com

Editorial by Whitty et al and p 347

We thank the doctors, nurses, doctors, laboratory staff, and Paul Ekwaru for help with statistical issues.

Contributors: See bmj.com

Funding: World Health Organization, Uganda country office; Uganda Malaria surveillance Project; Regional Center for Quality of Health Care; Ministry of Health, Uganda; and the Nuffield Foundation, United Kingdom, provided financial support. Dafra Pharma (Belgium) supplied the suppogels (rectal artemether and rectal placebos). Rene Pharmaceuticals (Uganda) provided the oral placebos.

Competing interests: None declared.

Ethical approval: Makerere Faculty of Medicine Ethics and Research Committee and Uganda National Council for Science and Technology.

References

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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.[Web of Science][Medline]
4. 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.[CrossRef][Web of Science][Medline]
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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.
7. 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.[CrossRef][Web of Science][Medline]
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10. 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.
11. 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.[CrossRef][Web of Science][Medline]

(Accepted 17 December 2004)

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