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Three Part Question

In [children aged between 6 months and 5 years with severe malaria], does [co-administration of im artemether with iv quinine]versus therapy with iv quinine alone [improve morbidity and mortality?]

Clinical Scenario

The review aimed to find evidence for the outcome of those children with severe malaria under the age of 5 years who underwent co-administration of arteusnate preparations with traditional iv quinine versus treatment with iv quinine alone.
Outcome was assessed as risk of death, parasite clearance and hypoglycaemia.

Search Strategy

Cochrane Infectious Diseases Group Specialized Register (January 2007), CENTRAL (The Cochrane Library 2006 Issue 4), MEDLINE (1966 to January 2007) and the WHO using [artemisin] AND [artemisin plus quinine] AND [cerebral malaria] LIMIT [human and english language].
Randomized controlled trials comparing intravenous, intramuscular or rectal artesunate with intravenous or intramuscular quinine for treating children with severe malaria were selected for inclusion in the search. Two authors assessed the eligibility and methodological quality or trials, extracted and analysed data and drafted the review. Mortality was the primary outcome although dichotomous outcomes were summarized using relative risks and continuous outcomes by mean differences. Some data was combined in meta-analyses. Heterogeneity was investigated for the primary outcome using subgroup analyses.
Three trials enrolling 198 participants (all children below the age of 5 years) met the inclusion criteria. All trials were conducted in Asia. All trials used intramuscular artesunate and two of the trials used intravenous quinine.
Treatment with artesunate significantly reduced the risk of death (RR 0.62, 95% CI 0.51 to 0.75; three trials, 198 participants), reduced parasite clearance time (WMD 8.14 HRS. 95% CI 11.55 to 4.73; 198 participants, 3 trials) and hypoglycaemia detected by routine monitoring (RR 0.46, 95% CI 0.25 to 0.87; 198 participants, 3 trials).
There appeared to be no evidence of a difference in neurological sequelae, coma recovery time, time to hospital discharge, fever clearanbce time or adverse effects other than hypoglycaemia.

Search Outcome

Combination therapy with both artesunate and quinine appears to be preferable to treatment with intravenous quinine alone in children with cerebral malaria in Asia.
The review does not identify sufficient data to make firm conclusions about the treatment of African children with falciparum infection.
The applicability of these results to children and the ethics of further research are points of debate.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses

Comment(s)

Artesunate drugs have long been known to be better used in combination therapy for treating uncomplicated malaria in various adult population subgroups in both Africa and Asia. The preparations work quickly and few side effects have been reported compared with the traditional incidences of hypoglycaemia and resistance seen with quinine. All trials identified were conducted in Asia, with a single artemisin derivative artemether, making extrapolation and relevance of data to the African population and use of other artemisin derivatives theoretical. As with most studies conducted on the paediatric population, the ethical limitations and low study numbers involved make the power of the trials low compared with evidence to support the use of combination therapy with artemisin derivatives and quinine based preparation in the adult population.

Editor Comment

more data to be added in the next 7/7 (BB admin team 1/10/08)

Clinical Bottom Line

Sufficient evidence to support the use of artesunate based preparations above quinine is significantly lacking in Africa. However, studies carried out in Asia seem to indicate that use of artesunate improves survival in this patient subgroup. In my present clinical practice, I have found that because the medications work using different pathways, improved survival and outcome as assessed with GCS, temperature patterns and seizure frequency is significantly improved when artemether is added to the treatment regimen of iv quinine of those children under 5 years suffering with severe malaria.

References

1. Umberto D'Alessandro et al. Severe and complicated malaria Trans R Sic Trop Med Hyg 2000; 94 (Supp1); 1-90
2. Faiz MA A randomized controlled trial comparing artemether and quinine in the treatment of cerebral malaria in Bangladesh Indian J Malariology 2001; 38: 9- 18
3. Falade C et al Artemether - lumefantrine combination therapy in children with uncomplicated malaria Trans R Soc Trop Hyg 2005;99:459-467
4. Adjuik M, Babiker A, Garner P et al. International Artemisinin Study Group. Artesunate combinations for treatment of malaria: a meta analysis Lancet 2004; Jan 3;363(9402):9-17.