Description of the condition
Malaria remains an important global health challenge. In 2009, approximately 225 million clinical cases and 781,000 malaria-related deaths occurred worldwide (WHO 2010a). The greatest burden of disease occurs in sub-Saharan Africa where the highest risk is in children below the age of five years and the dominant parasite species, Plasmodium falciparum, accounts for over 95% of cases. The disease is frequently over-diagnosed because the symptoms of malaria are usually non-specific, with the added risk of delays in recognizing other potentially life-threatening illness (Chandler 2008; Koram 2007; Reyburn 2004). However, progression to severe disease often occurs rapidly, especially in patients with P. falciparum infections, and death may occur within a few hours of onset (Marsh 1995).
Severe or complicated malaria is a medical emergency requiring urgent and specialised care. Effective drug treatment of infected patients is required as quickly as possible to prevent severe neurological deficit and death (WHO 2010b). Patients are often unable to take drugs by mouth because of repeated vomiting or a reduced level of consciousness. Therefore parenteral treatment with either intravenous (IV) or intramuscular (IM) injections is the preferred route for administering antimalarial drugs. However, this potentially restricts treatment to facilities where the skill and equipment for parenteral drug administration are available. In many malaria endemic countries, especially in areas with the greatest burden of disease, access to such care is a major challenge. The resulting delays in accessing treatment could account for the huge proportion of deaths associated with the disease (Marsh 1995). Indeed, results of verbal autopsy studies have demonstrated that the majority of patients with severe malaria never reach the hospital (Kamugisha 2007; Kaatano 2009; Mudenda 2011) and emphasize the need for effective pre-referral treatment in the community.
Addressing this situation requires improvements in the initial emergency response package for identifying and treating cases of suspected severe malaria disease. Specifically, this would involve the use of effective drugs in formulations that can be easily administered by health staff at the point of first contact, taking into account the level of skill available at such points.
Description of the intervention
Two classes of drugs are available for the parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (dihydroartemisinin, artesunate and artemether). The current treatment guideline for severe malaria recommends the use of IV or IM artesunate in both children and adults (WHO 2011). In addition, artemisinin preparations are available as suppositories for rectal administration. Notably, the artesunate suppository has been reported as having the potential to reduce mortality rates in children with cerebral malaria if administered early enough in the disease, before the patient is able to receive definitive therapy (Karunajeewa 2007).
The time to response following the use of a drug is largely influenced by its route of administration. A review of 19 pharmacokinetic studies of rectal artemisinin derivatives (artesunate, dihydroartemisinin and artemether) revealed that conventional doses of artesunate achieved an earlier time to maximum plasma concentrations (T
Rectal artesunate has the advantage of not having a first pass effect through the liver so bioavailability after administration is high. In children, the rate of absorption is modified by the body temperature, with rates of absorption positively correlated with rising body temperature (Karunajeewa 2004). The volume of distribution is also influenced by body weight which in this context, is a proxy for age (Karunajeewa 2004; Stepniewska 2009). Its role in management of severe disease is based on observation of a dose-dependent but prompt parasite clearance following use (Karunajeewa 2007).
How the intervention might work
The risk of death from severe malaria is greatest within the first 24 hours of onset (Marsh 1995). Treatment should therefore start as soon as possible, preferably before the referral process is completed in those needing it. Ideally, the drug should be given via the IV route, though recommendations allow for the IM or rectal route where this is not possible or available (WHO 2010b). In most malaria endemic countries, injectable formulations of artesunate and quinine and the necessary skill to give them are concentrated in large health facilities. The transit time to these facilities is often prolonged due to long distances and a lack of adequate transport.
In this context, artesunate suppositories offer a distinct advantage as a means of initiating treatment of severe malaria in rural settings before patients are referred to distant facilities for definitive IV or IM treatment (Tozan 2010). They are easy to administer by individuals with minimal training.
Why it is important to do this review
Intravenous or intramuscular artesunate significantly reduces the risk of death compared to quinine and has the added advantage of not requiring rigorous monitoring. Rectal preparations of artesunate may provide an additional advantage because of their ease of administration and the minimal skill required to administer them. They could therefore be a significant adjunct to reduce the time to start of effective treatment of patients with malaria so severe as to make treatment by mouth impossible.
The exact role of rectal artesunate in the management of malaria has remained the subject of discussion. While it provides a pragmatic solution for early onset of treatment, its impact on mortality and morbidity is less clear. Also, this route of treatment may not be universally acceptable (Inthavilay 2010).
In the single largest trial on this subject, Gomes and colleagues (Gomes 2009) evaluated the effect of a single dose rectal artesunate given before referral on death and permanent disability. The trial showed a significant reduction in the risk of mortality and permanent disability but only where arrival at an appropriate point-of-care was delayed for over six hours. The trial received wide acclaim and helped to form recommendations for use in this context (WHO 2010b).
There has been recent criticisms of the trial findings and by extension, the evidence in support of the recommendation as pre-referral treatment in severe malaria. Notably, Hirji and Premji (Hirji 2011) cite deficiencies in the design, implementation, analysis and interpretation of the trial data. Other questions have arisen over the rational for the use of a placebo in patients considered to be critically ill (Bello 2009).
There are other studies that have previously evaluated the role of rectal artesunate preparations (Awad 2003; Barnes 2004; Gomes 2008; Kitua 2010; Pengsaa 2005; Wilairatana 1997) and the study by Gomes and colleagues was designed to address some of the questions raised (Gomes 2011). The concerns that have followed the Gomes trial therefore indicate a real interest in this field and makes this review timely. Given the importance of early intervention on the outcome of severe malaria, it is vital that we have a concise summary of the available evidence regarding the use of rectal artesunate at an important and defining period in the management of severe malaria.
To evaluate the effect of pre-referral treatment with rectal artesunate on mortality and morbidity in people with severe malaria.
Criteria for considering studies for this review
Types of studies
We will include both individual and cluster randomized controlled trials.
Types of participants
Children and adults with severe malaria based on the definitions by the World Health Organization (WHO 2000). We will also include studies where additional criteria such as inability to swallow oral drugs or need for hospitalization are used to define entry to the study.
Types of interventions
Comparison 1: Artesunate given rectally before referral to a health facility versus placebo.
Comparison 2: Artesunate given rectally before referral to a health facility versus intramuscular or intravenous injections of an antimalarial drug.
Types of outcome measures
- Malaria related deaths.
- All cause mortality.
- Neurodisability defined as any neurological deficit persisting beyond the acute phase of illness.
- Proportion of patients with severe malaria reaching a secondary health care facility.
- Proportion of patients with parasitaemia on admission in the secondary health care facility.
- Average parasite count per group on admission in the secondary health care facility.
- Time to presentation at health facility.
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 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 and the metaRegister of Controlled Trials (mRCT) for ongoing trials.
Searching other resources
We will contact individual researchers working in the field for unpublished and ongoing trials. We will also check the reference lists of all studies identified by the above methods.
Data collection and analysis
Selection of studies
Two of the authors (JO and ME) will independently screen titles and abstracts of the search result for eligible studies using a study selection form. We will reconcile discrepancies through discussion and by consulting a third author (JN) if required. We will obtain full text articles of all selected abstracts and we will check them for eligibility using the pre-specified eligibility criteria. If there is any ambiguity, we will seek clarification in discussion with the third author. We will use reference manager software to detect multiple publications of the same study and we will summarize the reasons for excluding studies in the "Characteristics of excluded studies" table.
Data extraction and management
JO and ME will independently extract data from the studies using a pre-piloted data extraction form. We will reconcile any differences in results of data extraction by discussion with a third author (JN).
We will extract the following study information:
- Study details: citation, start and end dates, location and details of the study design.
- Participant details: study population eligibility (inclusion and exclusion) criteria, ages, population size and attrition rate.
- Details about the interventions for malaria treatment given: what type of suppository was used and at what dose per kg, what intravenous or intramuscular medication was given; dose per kg body weight of participants used and how long after disease onset.
- Person giving the treatment: who applied the medication.
- Diagnosis of malaria: what was the method used to diagnose malaria.
- Diagnosis of diseases other than malaria in participants.
- Supportive treatment(s) given other than antimalarial drugs.
- Outcome details: we will record outcomes including malaria related mortality, long term neurodisability and all-cause mortality. For each outcome, we will note the number of participants randomized and the number of participants analysed for each treatment group. For dichotomous outcomes, we will record the number experiencing the event and the number of patients in each treatment group. For continuous outcomes, we will record the arithmetic mean and standard deviation and the numbers of patients in each group (if medians are used, we will extract medians and ranges). For count data, we will extract the number of events in the treatment and control group and the total person time at risk in each group or the rate ratio and a measure of variance (standard error, for example) directly from the trial report.
- Study site: Prevalence of malaria, available health services, distance to health facilities.
Individually randomized trials
For each dichotomous outcome, we will extract the number of participants experiencing the event and the number of participants in each treatment group. For count data outcomes, we will record the number of events in the treatment and control group, and the total person time at risk in each group.
Cluster randomized trials
For cluster randomized trials, if the trial has been adjusted for clustering we will extract the cluster adjusted measure of effect and a measure of variance. If the trial has not been adjusted for clustering, we will extract the same data as for individually randomized trials. Also, we will record information on the average cluster size and the method used to adjust for clustering.
Assessment of risk of bias in included studies
Two authors (JO and ME) will perform the assessment independently. We will resolve any differences through discussion or, if necessary, by consulting the third author (JN). In the case of missing or unclear information, we will contact publication authors for further information.
Individually randomized trials
We will assess risk of bias of all randomized controlled trials using The Cochrane Collaboration’s tool for assessing the risk of bias. We will include the following assessment categories: sequence generation, allocation sequence concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcome reporting. Using this system, we will assign judgments that are classified as "yes" (low risk of bias), "no" (high risk of bias) or "unclear". The results for the assessment of risk of bias will be summarised using the "Risk of bias summary" and the "Rsk of bias graph" in addition to the "Risk of bias tables" (Higgins 2011).
Cluster randomized trials
For cluster randomized trials, we will assess recruitment bias, baseline imbalance, loss of clusters, incorrect analysis and comparability with individual RCTs.
Measures of treatment effect
For dichotomous data (death from malaria, death from all causes, presence of neurodisability, percentage reaching hospital, percentage with parasitaemia), we will use risk ratios (RR) to measure treatment effect. We will express count data as rate ratios, and for continuous data (average parasite count per group) we will compare arithmetic means using mean differences. Also, we will present the measures presented with 95% confidence intervals (CIs). We will report medians and ranges in table format only.
Unit of analysis issues
We will pay attention to the unit of analysis at the level of randomization (individual or group) and we will analyse the data accordingly. For cluster analysis, we will adjust sample sizes using methods described previously (Higgins 2011) using an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial if possible. Where a multi-arm study contributes multiple comparisons to a particular meta-analysis, we will combine treatment groups or we will split the "shared" group as appropriate.
Dealing with missing data
If there are missing or unclear data, we will contact the trial authors. Where this cannot be resolved, we will check for randomness of the missing data and where this is not present, the information (including losses to follow up) will be excluded from the analysis.
Assessment of heterogeneity
We will evaluate statistical heterogeneity by visually inspecting the forest plots to detect overlapping CIs, applying the Chi
Assessment of reporting biases
We will examine the likelihood of reporting bias using funnel plots if there are sufficient studies (about 10) in the meta-analysis.
JO will analyse the data using Review Manager (RevMan) software. We will stratify the analysis by study design. We will combine cluster randomized trials that adjust for clustering and individually randomized trials in meta-analysis. Also, we will tabulate results from cluster randomized trials that do not adjust for clustering. We will use a random-effects model in the presence of heterogeneity of treatment effects and a fixed-effect model in the absence of heterogeneity. If substantial heterogeneity (I
Subgroup analysis and investigation of heterogeneity
If statistical heterogeneity is present, we will attempt to further investigate potentially influential study characteristics by conducting subgroup analysis with respect to age (under-5 and greater than 5 years), malaria endemicity, type of antimalarial used, and form of training of the health care worker applying the suppository. If there are sufficient trials (at least 10 for each characteristic modelled), we will use meta-regression to investigate sources of heterogeneity.
We will conduct sensitivity analysis on the robustness of the methods used regarding allocation concealment and losses to follow up in the analysis, and we will report where the analysis alters the quantitative result.
The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development for the benefit of developing countries. We thank the Cochrane Infectious Diseases Group for their support of this protocol.
Appendix 1. Search methods: detailed search strategies
a = Cochrane Infectious Diseases Group Specialized Register
b = Search terms to be used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2011).
Protocol first published: Issue 7, 2012
Contributions of authors
JO wrote the background to the protocol and the objectives. ME wrote the methods section and search terms. JN reviewed the draft manuscript. All the authors reviewed the final draft before submission.
Declarations of interest
We have no conflicts of interest to declare.