Description of the condition
Malaria is caused by Plasmodium parasites transmitted to humans through the bite of infected female Anopheles mosquitoes. Plasmodium falciparum is the most common species worldwide, and is responsible for almost all of the severe disease and deaths (WHO 2000; WHO 2008).
Severe malaria is diagnosed in very sick people with a positive blood slide or antigen test for malaria including impaired consciousness, coma, convulsions, respiratory distress, shock (systolic blood pressure < 70 mmHg in adults, < 50 mmHg in children), jaundice, haemoglobinuria, hypoglycaemia, severe metabolic acidosis, or anaemia (WHO 2013). Cerebral malaria is a specific type of severe malaria where patients are in a coma. Even with correct treatment, cerebral malaria can have a mortality rate approaching 20%, and persistent neurological problems are seen in some survivors (Jaffar 1997). People living in endemic regions can develop a naturally acquired immunity to malaria through repeated exposure over 5 to 10 years (Doolan 2009). This partial immunity is protective against the most severe forms of the disease, and as a consequence, in high transmission settings mortality from severe malaria is highest in young children, and decreases with increasing age (WHO 2013).
The World Health Organization (WHO) currently recommends parenteral artesunate as the first-line treatment for severe malaria, followed by a complete course of an effective artemisinin-based combination therapy (ACT) as soon as the patient can take oral medications (WHO 2013), based on a series of important large trials, summarised in a Cochrane review (Sinclair 2011). The review estimates that treating severe malaria with artesunate instead of quinine would reduce the risk of death by 39% in adults and 24% in children (Sinclair 2011).
Description of the intervention
Artesunate is one of a number of antimalarial drugs derived from artemisinin, the active ingredient in a Chinese herbal remedy for fever, Artemesia annua. Once ingested or injected, all the artemisinin derivatives undergo conversion to dihydroartemisinin, the active metabolite, which has a broad spectrum of activity against the asexual blood stage of plasmodium parasites (ter Kuile 1993; Navaratnam 2000). The artemisinin derivatives have been shown to clear parasites from the peripheral blood quicker than other antimalarials.
Unlike artesunate, artemether is poorly soluble in water, and only available parenterally as a pre-mixed oil-based solution for intramuscular injection (80 mg/ml for use in adults and 40 mg/ml for children). The standard dose is 3.2 mg/kg on admission followed by 1.6 mg/kg once daily until oral therapy is tolerated (WHO 2013). Peak plasma concentrations typically occur at around six hours after intramuscular injection, but in severely ill children, with poor peripheral perfusion, absorption can be highly erratic (Karbwang 1997; Murphy 1997; Mithwani 2004).
Conversely, artesunate is supplied as a dry powder for mixing with sodium bicarbonate prior to either intravenous or intramuscular injection (WHO 2013), and compared to artemether the absorption of artesunate is more reliable, with peak plasma concentrations following intramuscular injection occurring at around one hour (Illet 2002; Nealon 2002; Hien 2004). These more favourable pharmacokinetic properties of artesunate moved research attention away from artemether, and with strong research evidence of artesunate reducing mortality compared to quinine, WHO now recommend it for both adults and children (Sinclair 2011; WHO 2013).
Why it is important to do this review
Despite the current recent global policy recommending artesunate in children, artemether and quinine still remain acceptable alternatives where parenteral artesunate is not available. Systematic reviews had concluded that intramuscular artemisinin derivatives (including both artesunate and artemether), were non-inferior to quinine in preventing deaths from malaria, but were safer and easier to administer (McIntosh 2000; AQMSG 2001; Kyu 2009).
Thus it is important to have an up to date summary of intramuscular artemether in managing severe malaria in children.
To assess the efficacy and safety of parenteral artemether versus any other parenteral medication in the treatment of severe malaria in children.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials
Types of participants
Children (less than 15 years of age) with severe malaria who are unable to take medication by mouth.
Types of interventions
- Intramuscular artemether
- Any other parenteral medication for the treatment of severe malaria
Types of outcome measures
- Death from any cause
- Coma resolution time
- Neurological sequelae (such as blindness, deafness, hemiplegia and others)
- Time to hospital discharge
- Fever clearance
- Parasite clearance
- Need for blood transfusion
- Severe anaemia
- Adverse events (hypoglycaemia, tinnitus, nausea, and vomiting, haematological and cardiac-related adverse events.)
Search methods for identification of studies
We will attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press and in progress).
We will search the following databases using the search terms detailed in Appendix 1: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE and LILACS. We will also search the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials using 'artemether', 'severe malaria', 'complicated malaria', 'artesunate', 'arteether', and 'child*' as search terms.
Searching other resources
We will search relevant proceedings of the following meetings for trial information; Multilateral Initiative on Malaria (MIM) Pan-African Malaria Conference, European Congress of Tropical Medicine and American Society of Tropical Medicine and Hygiene.
We will contact researchers working in the field and the WHO for unpublished and ongoing trials.
We will check the reference lists of existing reviews and of all trials identified by the above methods.
Data collection and analysis
Selection of studies
Two authors (EE & AU), will independently screen the results of the literature search for potentially relevant trials and obtain the full reports of such potentially relevant trials. Two authors (EE & EEE) will independently apply the inclusion criteria to the full reports using an eligibility form and scrutinize publications to ensure each trial is included in the review only once. We will contact trial authors for clarification if eligibility is unclear. We will resolve disagreements through discussion with a third author and when necessary, by consulting a member of the Cochrane Infectious Disease Group editorial team. We will list the excluded studies and the reasons for their exclusion.
Data extraction and management
Two authors (EE & MMM), will independently extract data using specifically developed piloted data extraction form. We will resolve disagreements through discussion by all reviewers and, when necessary, by consulting a member of the Cochrane Infectious Diseases Group editorial team. We will contact the corresponding publication author in the case of unclear information or missing data.
For each outcome we will aim to extract the number of participants randomized and the number analysed in each treatment group. For dichotomous outcomes, we will record the number of participants experiencing the event and the number assessed in each treatment group. For continuous outcomes, we will extract arithmetic means and standard deviations for each treatment group, together with the numbers assessed in each group.
Assessment of risk of bias in included studies
Two authors (MMM & EEE), will independently assess the risk of bias of each trial using a risk of bias form. We will attempt to contact the authors if this information is not specified or if it is unclear. We will resolve any disagreements by discussion between review authors. Six components will be assessed: generation of the randomization sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other biases (such as the trial stopped early). We will categorise our judgements as low risk of bias, high risk of bias, or unclear risk of bias, and describe our reasons for doing so.
Measures of treatment effect
we will calculate results using risk ratio for dichotomous data, and mean difference for continuous data. We will present these effect estimates with 95% confidence intervals (CI). We will treat time-to-event outcomes as continuous data and, accordingly, mean difference will be calculated from mean time in intervention versus control groups. For time-to-event data presented as Kaplan-Meier curves in trial reports, we will calculate Peto hazard ratios and include in the fixed-effects meta-analysis using generic inverse variance methods.
Unit of analysis issues
For multiple arm trials, we shall combine all relevant experimental intervention groups of the study into a single group, and also combine all relevant control intervention groups into a single control group. For dichotomous outcomes, both the sample sizes and the numbers of people with events will be summed across groups. For continuous outcomes, we will combine means and standard deviations using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane 2011).
Dealing with missing data
We shall aim to analyse data according to the intention-to treat principle (all randomized participants should be analysed in the groups to which they were originally assigned). If there is discrepancy between the number randomized and the number analysed, we will calculate the percentage loss to follow up for each treatment group and report this information.
However, if for some trials it is unclear whether there is loss to follow up, we will enter the number analysed into Review Manager 5.2 whenever these figures are available. By attempting to carry out a complete case analysis we will avoid making assumptions about the outcomes of participants that are lost to follow up. Where possible, we will contact authors for missing data.
Assessment of heterogeneity
We will look for statistical heterogeneity by inspecting the forest plots for overlapping CIs, applying the Chi
Assessment of reporting biases
We will construct funnel plots to look for evidence of publication bias provided there are sufficient included trials to make this informative.
We will analyse the data using Review Manager 5.2. In the first instance, we will apply a fixed-effect meta-analysis. However, if we detect moderate heterogeneity but still consider it appropriate to combine the trials, we will then use a random-effects approach. Where heterogeneity is very high, such that meta-analysis is not appropriate, we will display the results in forest plots or tables, but not combine the results. Where data are only presented as medians and ranges, we will present the results in tables.
The main results of the review, alongside a GRADE appraisal of the quality of evidence, will be presented in a 'Summary of findings table'.
Subgroup analysis and investigation of heterogeneity
When heterogeneity is detected we will explore possible causes using a series of pre-specified subgroup analyses. The potential sources of heterogeneity might be differences in drug regimen, type of severe malaria (cerebral versus non-cerebral malaria), time since admission to hospital, length of follow up, and geographical region.
We will conduct a sensitivity analysis to investigate the robustness of the results to the risk of bias components by including only trials that conceal the allocation and have low incomplete outcome data (ie <10%).
Assessment of the quality of evidence
The quality of the evidence will be assessed following the GRADE approach. Using this approach 'quality' is defined as an assessment of our confidence in the estimates of effect (Guyatt 2008).
We will appraise the quality of evidence for each outcome against five criteria; risk of bias (an appraisal of the overall risk of bias for trials contributing to the outcome); consistency (an evaluation of explained and unexplained heterogeneity), directness (an appraisal of how directly the included trials address the review question), precision (an assessment of the statistical precision of the result), and publication bias (an assessment of the risk of publication bias). Where we find deficiencies sufficient to decrease our confidence in the estimates of effect we will downgrade the quality of evidence from randomized controlled trials from 'High' to 'Moderate', 'Low', or 'Very Low' and describe our reasons for doing so.
The academic editors for this protocol are Dr Hasifa Bukirwa and Dr David Sinclair.
This document is an output of the Effective Health Care Research Consortium, which is funded by UKaid from the UK Government Department for International Development. The editorial base of the Cochrane Infectious Diseases Group is funded by UKaid from the UK Government for the benefit of developing countries.
Appendix 1. Detailed search strategies
Contributions of authors
Ekpereonne Esu developed and wrote the protocol. Martin Meremikwu, Emmanuel Effa, Oko Opie, and Amirahobu Uwaoma contributed to the conception and design of the protocol and commented on and helped revise the protocol.
Declarations of interest
Sources of support
- University of Calabar, Nigeria.
- Liverpool School of Tropical Medicine, UK.
- Department for International Development, UK.