Cochrane Collaboration researchers conducted a review of the effects of pre-referral rectal artesunate for people with suspected severe malaria, living in rural areas without healthcare services. After searching for all relevant trials up to May 2014 they included only one randomized controlled trial. This trial was conducted at various sites across Ghana, Tanzania and Bangladesh, and enrolled 17,826 children and adults.
What is severe malaria and how might pre-referral rectal artesunate reduce deaths?
Severe malaria is a serious medical condition caused by infection with the Plasmodium parasite which typically causes vomiting, anaemia, fitting, coma, and death. It is treated by giving injections of antimalarial drugs, which need to be started as quickly as possible to reduce the risk of death and brain damage. In some rural areas where malaria is common, people have to travel for several hours to reach healthcare clinics and hospitals, and many die on the way. In these settings, people without formal healthcare education could be trained to give artesunate rectally to start treating malaria before transporting the patient to hospital.
What the research says
Only one trial evaluated rectal artesunate as pre-referral treatment. In the African sites only, children aged 6 to 72 months were included in the trial; while in the Asian trial site, older children and adults were included.
Young children in the African and Asian trial sites (aged 6 to 72 months) had fewer deaths with rectal artesunate than with placebo (moderate quality evidence). However, in Asia among older children and adults, there were more deaths in those that received rectal artesunate (low quality evidence).
In the African sites, 56% of children took longer than six hours to reach hospital whereas over 90% of people in the Asian site reached hospital within six hours.
The unexpected finding of more deaths with rectal artesunate in older children and adults should be taken into account when forming national and local policies about pre-referral treatment.
In rural areas without access to injectable antimalarials rectal artesunate provided before transfer to a referral facility probably reduces mortality in severely ill young children compared to referral without treatment. However, the unexpected finding of possible higher mortality in older children and adults has to be taken into account in forming any national or local policies about pre-referral rectal artesunate.
Severe or complicated malaria is a medical emergency and people die as a result of delays in starting treatment. Most patients need parenteral treatment, and in primary healthcare facilities, where intravenous therapy is not available but intramuscular injections can be given, intramuscular quinine, artesunate, and artemether have been used before transporting patients to hospital.
However, in rural settings with limited access to health care, intramuscular injections may also be unavailable. In these situations, rectal artesunate given prior to transfer to hospital by volunteers with little medical training, may be a feasible option.
To evaluate the effects of pre-referral treatment with rectal artesunate on mortality and morbidity in people with severe malaria.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE and LILACS up to 21 May 2014. We also searched the WHO clinical trial registry platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials.
Individual or cluster-randomized controlled trials comparing pre-referral rectal artesunate with placebo or injectable antimalarials in children and adults with severe malaria.
Two authors independently screened titles and abstracts for potentially eligible trials, and extracted data from the included trials. Dichotomous outcomes were summarized using risk ratios (RR) and presented with 95% confidence intervals (95% CI). Where data allowed, we conducted subgroup analyses by age, trial region and whether participants were included in the trial analysis. We assessed the quality of evidence for the most important outcomes using the GRADE approach.
One trial met the inclusion criteria; a placebo-controlled trial of 17,826 children and adults living in rural villages in Ghana and Tanzania (Africa) and Bangladesh (Asia). Villagers with no previous medical training were trained to recognize the symptoms of severe malaria, administer rectal artesunate and refer patients to hospital. The trained villagers were supervised during the trial period. In the African sites only children aged 6 to 72 months were enrolled, whereas in Bangladesh, older children and adults were also enrolled.
In young children (aged 6 to 72 months) there were fewer deaths following rectal artesunate than with placebo (RR 0.74; 95% CI 0.59 to 0.93; one trial; 8050 participants; moderate quality evidence), while in older children and adults there were more deaths in those given rectal artesunate (RR 2.21; 95% CI 1.18 to 4.15; one trial; 4018 participants; low quality evidence).
In Africa, only 56% of participants reached a secondary healthcare facility within six hours compared to over 90% in Asia. There were no differences between the intervention and control groups in the proportion of participants reaching a healthcare facility within six hours (RR 0.99; 95% CI 0.98 to 1.01; 12,068 participants), or in the proportion with parasitaemia (RR 1.00; 95% CI 0.98 to 1.02; 17,826 participants), or with coma or convulsions on arrival (RR 1.01; 95% CI 0.90 to 1.14; 12,068 participants).
There are no existing trials that compare rectal versus intramuscular artesunate.