Malaria: severe, life-threatening

Susanne Helena Hodgson; Brian John Angus

. 2011 Mar 7;2011:0913.

Malaria: severe, life-threatening

Susanne Helena Hodgson ^1,^#, Brian John Angus ^2,^#

PMCID: PMC3217801 PMID: 21375787

Abstract

Introduction

Severe malaria mainly affects children under 5 years old, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and neurological sequelae may occur in some survivors. Severe malarial anaemia may have a mortality rate of over 13%.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antimalarial treatments and adjunctive treatment for complicated falciparum malaria in non-pregnant people? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: dexamethasone, exchange blood transfusion, initial blood transfusion, intramuscular artemether, intravenous and intramuscular artesunate, intravenous and intramuscular dihydroartemisinin, quinine, and rectal/intravenous/intramuscular artemisinin and its derivatives.

Key Points

Severe malaria mainly affects children under 5 years old, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria.

Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and neurological sequelae may occur in some survivors.
Severe malarial anaemia may have a mortality rate of over 13%.

International consensus has historically regarded quinine as standard treatment for severe falciparum malaria. RCTs will generally compare new treatments against this standard.

We found no clear evidence on the best quinine treatment regimen or route of administration to use, although high initial dose quinine clears parasites more rapidly compared with lower-dose quinine. However, higher doses increase the risk of adverse effects.
Intravenous artesunate is more effective than quinine in reducing mortality from severe malaria.
Intramuscular artemether and rectal artemisinin, artemether, artesunate, and dihydroartemisinin may be as effective as quinine in reducing mortality from severe malaria.
Routine use of phenobarbitone in cerebral malaria may reduce convulsions compared with placebo, but may be associated with higher mortality.
Dexamethasone has not been shown to reduce mortality from severe malaria, and it increases the risk of gastrointestinal bleeding and seizures.

We don't know whether initial blood transfusion or exchange blood transfusion reduce mortality from severe malaria as no adequate-quality trials have been found. Blood transfusion is associated with adverse effects, but is clinically essential in some circumstances.

We don't know how intravenous or intramuscular dihydroartemisinin compare with quinine, how dihydroartemisinin and artesunate compare with each other when given either intravenously or intramuscularly, or how rectal administration of artemisinin derivatives compares with administering them intramuscularly or intravenously as we found insufficient evidence.

Clinical context

About this condition

Definition

Falciparum malaria is caused by protozoan infection of red blood cells with Plasmodium falciparum and comprises a variety of syndromes. This review deals with clinically complicated malaria (i.e., malaria that presents with life-threatening conditions, including coma, severe anaemia, renal failure, respiratory distress syndrome, hypoglycaemia, shock, spontaneous haemorrhage, and convulsions). The diagnosis of cerebral malaria should be considered when there is encephalopathy in the presence of malaria parasites. A strict definition of cerebral malaria requires the presence of unrousable coma and no other cause of encephalopathy (e.g., hypoglycaemia, sedative drugs), in the presence of P falciparum infection.[1] This review does not currently cover the treatment of malaria in pregnancy.

Incidence/ Prevalence

Malaria is a major health problem in the tropics, with an estimated 250 million clinical cases occurring annually and an estimated 1 million deaths each year as a result of severe malaria.[2] Over 90% of deaths occur in children under 5 years old, mainly from cerebral malaria and anaemia.[2] In areas where the rate of malaria transmission is stable (endemic), those most at risk of acquiring severe malaria are children under 5 years old, because adults and older children have partial immunity, which offers some protection. In areas where the rate of malaria transmission is unstable (non-endemic), severe malaria affects both adults and children. Non-immune travellers and migrants are also at risk of developing severe malaria.

Aetiology/ Risk factors

Malaria is transmitted by the bite of infected female anopheline mosquitoes. Certain haemoglobins such as haemoglobin S[3] and haemoglobin C[4] are protective against severe malaria (see aetiology in review on malaria: prevention in travellers).[5]

Prognosis

In children under 5 years of age with cerebral malaria, the estimated case fatality of treated malaria is 19%, although reported hospital case fatality may be as high as 40%.[1] [6] Neurological sequelae persisting for more than 6 months may occur in some survivors, and include ataxia, hemiplegia, speech disorders, behavioural disorders, epilepsy, and blindness. Severe malarial anaemia may have a case fatality rate higher than 13%.[6] In adults, mortality of cerebral malaria is 20%; this rises to 50% in pregnancy.[7]

Aims of intervention

To prevent death and cure the infection; to prevent long-term disability; to minimise neurological sequelae resulting from cerebral malaria, with minimal adverse effects of treatment.

Outcomes

Mortality; parasite clearance, parasite clearance time; fever clearance time; time to walking and drinking; coma recovery time; neurological sequelae at follow-up; adverse effects. In the option on anticonvulsants, we also report on convulsions.

Methods

Clinical Evidence search and appraisal December 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2009, Embase 1980 to December 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributors for additional assessment. The contributors applied the World Health Organization criteria for severe malaria when deciding which RCTs to include.[1] International consensus has historically recommended quinine for the treatment of severe falciparum malaria. Placebo or no-treatment controlled trials of antimalarial treatment in people with severe malaria would be considered unethical.Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for malaria: severe, life-threatening

Important outcomes	Mortality, parasite clearance time, fever clearance time, coma recovery time, neurological sequelae, time to walking and drinking, convulsions, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of antimalarial treatments for complicated falciparum malaria in non-pregnant people?
at least 12 (at least 2247)[8] [9] [10] [11]	Mortality	Intramuscular artemether v quinine	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
at least 2 (unclear)[8] [10] [11]	Parasite clearance	Intramuscular artemether v quinine	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for no direct statistical analysis between groups in 1 review
at least 2 (unclear)[8] [10] [11]	Fever clearance time	Intramuscular artemether v quinine	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for no direct statistical analysis between groups in 1 review
at least 2 (unclear)[8] [10] [11]	Coma recovery time	Intramuscular artemether v quinine	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for no direct statistical analysis between groups in 1 review
at least 2 (at least 1677)[8] [9] [10] [11]	Neurological sequelae	Intramuscular artemether v quinine	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for no direct statistical analysis between groups in 1 review
4 (1637)[15] [16] [17]	Mortality	Intravenous artesunate v quinine	4	–1	0	0	0	Moderate	Quality point deducted for weak methods (2 small RCTs quasi-randomised, co-intervention in 1 small RCT)
3 (186)[15] [16] [17]	Parasite clearance time	Intravenous artesunate v quinine	4	–2	0	0	0	Low	Quality points deducted for sparse data and weak methods (2 RCTs quasi-randomised, co-intervention in 1 small RCT)
3 (186)[15] [16] [17]	Fever clearance time	Intravenous artesunate v quinine	4	–2	0	0	0	Low	Quality points deducted for sparse data and weak methods (2 RCTs quasi-randomised, co-intervention in 1 small RCT)
1 (80)[16]	Coma recovery time	Intravenous artesunate v quinine	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and RCT quasi-randomised. Directness point deducted for small number of comparators (RCT only in children in India) affecting generalisability
1 (1190)[15]	Neurological sequelae	Intravenous artesunate v quinine	4	0	0	–1	0	Moderate	Directness point deducted for small number of events (10 in total)
3 (144)[21]	Mortality	High initial dose quinine v standard regimens	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for small number of events (11 in total)
2 (67)[21]	Parasite clearance time	High initial dose quinine v standard regimens	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (68)[21]	Fever clearance time	High initial dose quinine v standard regimens	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (99)[21]	Coma recovery time	High initial dose quinine v standard regimens	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for narrow population (children only)
1 (38)[23]	Mortality	Intramuscular quinine v intravenous quinine	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only <12 years), one site (Kenya), restricted comparators (one high-dose regimen v another high-dose regimen), and small number of events (4 in total)
1 (unclear, less than 60)[23]	Parasite clearance time	Intramuscular quinine v intravenous quinine	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only <12 years), one site (Kenya), restricted comparators (one high-dose regimen v another high-dose regimen)
1 (unclear, less than 60)[23]	Time to walking and drinking	Intramuscular quinine v intravenous quinine	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only <12 years), one site (Kenya), restricted comparators (one high-dose regimen v another high-dose regimen), and subjective outcome
6 (499)[9] [26] [27] [28]	Mortality	Rectal artemisinin derivatives v quinine	4	0	0	–2	0	Low	Directness points deducted for small number of events (41 events in 4 RCTs; no events in 2 RCTs) and inclusion of people with moderately severe malaria
5 (446)[9] [26] [27] [19] [28]	Parasite clearance time	Rectal artemisinin derivatives v quinine	4	0	0	–2	0	Low	Directness points deducted for inclusion of people with moderately severe malaria and inconsistent results (depending on agents used, population analysed [children and adults in 1 RCT], and significance dependent on type of analysis [1 RCT])
at least 3 (at least 314)[9] [26] [27] [28]	Fever clearance time	Rectal artemisinin derivatives v quinine	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of people with moderately severe malaria
3 (162)[26] [9]	Coma recovery time	Rectal artemisinin derivatives v quinine	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for small number of comparators (rectal artemether and rectal artemisinin only)
1 (109)[27]	Time to walking and drinking	Rectal artemisinin derivatives v quinine	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for subjective outcome
1 (49)[9]	Mortality	Rectal artemisinin derivatives v intravenous artemisinin derivatives	4	–3	0	0	0	Very low	Quality points deducted for sparse data, unclear methods (randomisation, exclusion, loss to follow-up), and for intervention becoming unavailable during trial
1 (unclear, less than 79)[9]	Coma recovery time	Rectal artemisinin derivatives v intravenous artemisinin derivatives	4	–3	0	0	0	Very low	Quality points deducted for sparse data, unclear methods (randomisation, exclusion, loss to follow-up), incomplete reporting of results, and for intervention becoming unavailable during trial
1 (79)[31]	Parasite clearance time	Rectal artemisinin derivative v intramuscular artemisinin derivative	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only), one site (Papua New Guinea), and small number of comparators (rectal artesunate v im artemether only)
1 (79)[31]	Fever clearance time	Rectal artemisinin derivative v intramuscular artemisinin derivative	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only), one site (Papua New Guinea), and small number of comparators (rectal artesunate v im artemether only)
1 (79)[31]	Coma recovery time	Rectal artemisinin derivative v intramuscular artemisinin derivative	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only), one site (Papua New Guinea), and small number of comparators (rectal artesunate v im artemether only)
1 (22)[31]	Time to walking and drinking	Rectal artemisinin derivative v intramuscular artemisinin derivative	4	–1	0	–2	0	Very low	Quality point deducted for sparse data. Directness points deducted for restricted population (children only), one site (Papua New Guinea), and small number of comparators (rectal artesunate v im artemether only)
What are the effects of adjunctive treatment for complicated falciparum malaria in non-pregnant people?
1 (230)[34]	Mortality	Initial blood transfusion v conservative treatment/iron supplements	4	–1	0	–2	0	Very low	Quality point deducted for methods (loss to follow-up; subsequent cross-over between groups). Directness points deducted for small number of events (4 in total) and restricted population (children only; exclusion of clinically unstable children)
3 (573)[35]	Mortality	Anticonvulsants v no anticonvulsants	4	0	0	–2	0	Low	Directness point deducted for significance dependent on specific analysis undertaken, and for limited number of comparators (phenobarbitone only)
3 (573)[35]	Convulsions	Anticonvulsants v no anticonvulsants	4	0	0	–1	+1	High	Directness point deducted for limited number of comparators (phenobarbitone only). Effect size point added for RR <0.5
2 (143)[36]	Mortality	Dexamethasone v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (143)[36]	Coma recovery time	Dexamethasone v placebo	4	–1	–1	0	0	Low	Quality point deducted for sparse data. Consistency point deducted for conflicting results
2 (103)[36]	Adverse effects	Dexamethasone v placebo	4	–1	0	0	+1	High	Quality point deducted for sparse data. Effect size point added for RR >2

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Type of evidence: 4 = RCT. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.

Glossary

Coma recovery time: The time between commencing treatment and regaining consciousness.
Fever clearance time: The time between commencing treatment and the temperature returning to normal.
High-quality evidence: Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Parasite clearance time (PCT): The time between commencing treatment and the first negative blood test. PCT 50 is the time taken for parasites to be reduced to 50% of the first test value, and PCT 90 is the time taken for parasites to be reduced to 10% of the first test value.
Very low-quality evidence: Any estimate of effect is very uncertain.

Malaria: prevention in travellers

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Susanne Helena Hodgson, The Jenner Institute, University of Oxford, Oxford, UK.

Brian John Angus, University of Oxford, Oxford, UK.

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BMJ Clin Evid. 2011 Mar 7;2011:0913.

Artemether (intramuscular) versus quinine

Summary

MORTALITY Intramuscular artemether compared with quinine: Intramuscular artemether seems to be as effective as quinine at reducing mortality in people with severe malaria ( moderate-quality evidence ). PARASITE CLEARANCE TIME Intramuscular artemether compared with quinine: We don't know whether intramuscular artemether is more effective than quinine at reducing parasite clearance time in people with severe malaria ( low-quality evidence ). FEVER CLEARANCE TIME Intramuscular artemether compared with quinine: We don't know whether intramuscular artemether is more effective than quinine at reducing fever clearance time in people with severe malaria (low-quality evidence). COMA RECOVERY TIME Intramuscular artemether compared with quinine: We don't know whether intramuscular artemether is more effective than quinine at improving coma recovery time in people with severe malaria (low-quality evidence). NEUROLOGICAL SEQUELAE Intramuscular artemether compared with quinine: We don't know whether intramuscular artemether is more effective than quinine at preventing neurological sequelae in people with severe malaria (low-quality evidence).

Benefits

We found three systematic reviews[8] [9] [10] and one additional RCT.[11] The three reviews had different inclusion criteria and reported slightly different analyses so we report them all here.

The first review (search date not reported, 7 RCTs, 1919 adults and children) analysed individual participant data.[8] It found no significant difference in mortality between intramuscular artemether and either intravenous or intramuscular quinine (im quinine in 1 RCT only) in severe falciparum malaria (mortality: 136/961 [14%] with artemether v 164/958 [17%] with quinine; OR 0.80, 95% CI 0.62 to 1.02). Parasite clearance was faster with artemether than with quinine (HR 0.62, 95% CI 0.56 to 0.69). The review found no significant difference in the speed of coma recovery, fever clearance time, or neurological sequelae between artemether and quinine (coma recovery time with quinine: HR 1.09, 95% CI 0.97 to 1.22; fever clearance time with quinine: HR 1.01, 95% CI 0.90 to 1.15; neurological sequelae: 81/807 [10%] with artemether v 91/765 [12%] with quinine; OR 0.82, 95% CI 0.59 to 1.15). It found that rates for the combined outcome of death or neurological sequelae were significantly lower for artemether than for quinine (OR 0.77, 95% CI 0.62 to 0.96; P = 0.02).

The second review (search date 1999, 11 RCTs, 2142 people) found a small significant reduction in mortality for intramuscular artemether compared with intravenous quinine (OR 0.72, 95% CI 0.57 to 0.91).[9] However, more rigorous analysis, excluding three poorer quality RCTs, found no significant difference in mortality (OR 0.79, 95% CI 0.59 to 1.05). The review found no significant difference in neurological sequelae at recovery between artemether and quinine (OR 0.8, 95% CI 0.52 to 1.25).

The third review (search date 2008) included children only, and pooled data for all parenteral artemisinin derivatives (including im artemether, im artesunate, and im B-artemether) versus parenteral quinine.[10] We have only reported data relating to intramuscular artemether alone here. The review found no significant difference in mortality between intramuscular artemether and quinine (9 RCTs [8 RCTs iv quinine; 1 RCT im quinine]; RR 0.94, 95% CI 0.74 to 1.19; absolute numbers not reported). The review reported that intramuscular artemether did not shorten parasite or fever clearance time or reduce neurological sequelae compared with quinine (statistical analysis for intramuscular artemether alone v quinine for these outcomes not reported, absolute numbers not reported). The review reported that intramuscular artemether resolved coma faster than did quinine (statistical analysis between groups not reported, absolute numbers not reported).[10] However, of the 9 RCTs comparing intramuscular artemether versus quinine, the review reported that allocation concealment was unclear in three RCTs, and the procedures were described as open in three RCTs.

The additional RCT (105 people, aged 15–40 years, with cerebral malaria in Bangladesh) compared intramuscular artemether (160 mg initially, then 80 mg/kg once daily) versus intravenous quinine (loading dose 20 mg/kg, then 10 mg/kg 8-hourly).[11] It found no significant difference in mortality or neurological sequelae between artemether and quinine (death: 9/51 [18%] with artemether v 10/54 [19%] with quinine; OR 0.94, 95% CI 0.35 to 2.55; neurological sequelae: 3/51 [6%] with artemether v 1/54 [2%] with quinine; RR 3.18, 95% CI 0.34 to 29.56). Mean fever clearance time and coma recovery time were significantly longer for artemether than for quinine (fever clearance time: 58 hours with artemether v 47 hours with quinine; WMD 11.0 hours, 95% CI 1.6 hours to 20.4 hours; coma recovery time: 74 hours with artemether v 53 hours with quinine; WMD 20.8 hours, 95% CI 3.6 hours to 38.0 hours). There was no significant difference in mean parasite clearance time between artemether and quinine (52 hours with artemether v 61 hours with quinine; WMD –8.6 hours, 95% CI –22.5 hours to +5.3 hours).

Harms

The second review stated that not all RCTs reported on adverse effects.[9] Among those that did, the proportion affected was small and similar between groups. The adverse effects reported included nausea, vomiting, diarrhoea, abdominal pain, pruritus, urticaria, rash and injection site pain, and abscess. The third review reported that included RCTs were not designed to evaluate differences in adverse effects between groups, and noted that reporting on adverse effects was poor.[10] One included RCT found that significant prolongation of the QTc interval occurred significantly more frequently with artemether compared with quinine (20/82 [24%] people with im artemether v 5/80 [6%] people with iv quinine; reported as significant difference between groups; P value not reported). However, another included RCT found no significant difference in QTc intervals between groups (further details not reported). One included RCT found that local reactions at the site of injection were more common with quinine (5.9%) compared with artemether (0.7%), with abscess formation requiring drainage in 5/288 (2%) people with quinine and 1/288 (0.3%) people with artemether (statistical analysis between groups not reported).[10]

Comment

One RCT included in the third review did not use loading doses of either artemether or quinine at the beginning of treatment.[12] Treatment allocation in another included RCT was quasi-randomised by date of admission.[13] We found a second additional RCT (52 people).[14] However, it was not clear whether participants had severe malaria, and outcomes were poorly reported.

Substantive changes

Artemether (intramuscular) versus quinine New evidence added.[10] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Artesunate (intravenous) versus quinine

Summary

MORTALITY Intravenous artesunate compared with quinine: Intravenous artesunate seems more effective than intravenous quinine at reducing mortality in people (mainly adults in analysis) with severe malaria in Asia ( moderate-quality evidence ). PARASITE CLEARANCE TIME Intravenous artesunate compared with quinine: Intravenous artesunate may be more effective than intravenous quinine at reducing parasite clearance time in people with severe malaria in Vietnam or India ( low-quality evidence ). FEVER CLEARANCE TIME Intravenous artesunate compared with quinine: Intravenous artesunate may be more effective than intravenous quinine at reducing fever clearance time in people with severe malaria in Vietnam or India (low-quality evidence). COMA RECOVERY TIME Intravenous artesunate compared with quinine: Intravenous artesunate may be more effective than intravenous quinine at reducing coma recovery time in children with severe malaria in India, but we don't know about adults or at other different locations ( very low-quality evidence ). NEUROLOGICAL SEQUELAE Intravenous artesunate compared with quinine: Intravenous artesunate and intravenous quinine seem to be equally effective at reducing neurological sequelae at discharge in people (mainly adults in analysis) with severe malaria in Asia (moderate-quality evidence).

Benefits

We found one systematic review (search date 2007, 6 RCTs, 1938 people), which compared artesunate versus quinine for the treatment of severe malaria[15] and two additional RCTs.[16] [17]

The systematic review included 6 RCTs comparing artesunate versus intravenous quinine. However, three RCTs were open label, and one RCT compared intramuscular artesunate versus intravenous quinine, so we have not reported these further. We have therefore separately reported the two remaining RCTs of sufficient quality (see comment). The first large multicentre RCT (1461 people [1259 adults, 202 children] with severe malaria, in 11 centres in Bangladesh, Myanmar, India, and Indonesia) compared intravenous artesunate (2.4 mg/kg iv stat, then at 12 hours and 24 hours, then daily until able to swallow) versus quinine (20 mg/kg iv loading dose then 10 mg/kg every 8 hours until able to swallow). It found that intravenous artesunate significantly reduced mortality compared with intravenous quinine (107/730 [15%] with artesunate v 164/731 [22%] with quinine; RR 0.65, 95% CI 0.52 to 0.81).[15] It found no significant difference between groups in neurological sequelae at discharge (7/623 [1.1%] with artesunate v 3/567 [0.5%] with quinine; RR 2.12, 95% CI 0.55 to 8.17).[15]

The second RCT (61 adults, cerebral malaria, intensive treatment unit in Vietnam) compared intravenous artesunate (60 mg at 0 hours and 4 hours, then 60 mg at 24 hours and 48 hours) versus intravenous quinine (500 mg iv over 4 hours then 500 mg iv every 8 hours until able to swallow then 500 mg by mouth every 8 hours until day 14). It found no significant difference between groups in mortality, although rates were lower with artesunate (5/31 [16%] with artesunate v 8/30 [27%] with quinine; RR 0.60, 95% CI 0.22 to 1.64).[15] The RCT may have been underpowered to detect a clinically important difference. The RCT found that parasite and fever clearance times were significantly faster with intravenous artesunate compared with intravenous quinine (parasite clearance time of 50%; mean: 5.4 with artesunate v 16.6 with quinine; mean difference –11.20, 95% CI –15.19 to –7.21; fever clearance time; mean: 39 with artesunate v 78 with quinine; mean difference –39.00, 95% CI –77.00 to –1.00).[15]

The two additional RCTs were excluded from the review as they were quasi-randomised. The first quasi-randomised RCT (80 children with complicated malaria in India; allocation by odd and even numbers) compared intravenous artesunate (2.4 mg/kg iv stat, followed by 1.2 mg/kg after 6 hours, then once daily for 5 days) versus intravenous quinine (20 mg/kg loading dose, followed by 10 mg/kg iv 8 hourly).[16] It found that artesunate significantly reduced parasite clearance time, fever clearance time, and coma recovery time compared with quinine, with no significant difference in mortality between treatment groups (parasite clearance time: 52.2 hours with quinine v 41.7 with artesunate; P <0.05; fever clearance time: 62.2 hours with quinine v 43.6 hours with artesunate; P <0.05; coma recovery time: 70.2 hours with quinine v 50.4 hours with artesunate; P <0.05; mortality: 8/40 [20%] with quinine v 5/40 [13%] with artesunate; P >0.05).[16] The RCT may have been underpowered to detect a clinically important difference in mortality.

The second small quasi-randomised RCT (35 adults with severe malaria in India; allocation by alternate allocation) compared intravenous artesunate (2.4 mg/kg iv stat, followed by 1.2 mg/kg iv or 2 mg/kg orally for 6 days) versus intravenous quinine (20 mg/kg loading dose, then 10 mg/kg 8 hourly).[17] It found no significant difference between treatments in mortality (1/17 [5.9%] with artesunate v 1/18 [5.6%] with quinine; P = 0.96). The RCT may have been underpowered to detect a clinically important difference. It found that artesunate significantly reduced the median fever clearance time compared with quinine (32 hours with artesunate v 58 hours with quinine; P = 0.023). The interquartile range for the time taken to clear 50% and 90% of the parasites suggested that the parasite clearance time was shorter with artesunate than with quinine (for 50% clearance: interquartile range 14–24 hours for quinine v 8–16 hours for artesunate; P = 0.01). In this RCT, all participants received at least 24 hours of intravenous therapy and completed a 7-day course of treatment.[17]

Harms

The systematic review concluded that all adverse events with the exception of hypoglycaemia could be attributable to malaria.[15] The review found that artesunate was associated with significantly less hypoglycaemia than quinine after admission in one open-label RCT that measured blood glucose routinely (1 RCT; 6/59 [10%] with iv artesunate v 15/54 [28%] with iv quinine; RR 0.37, 95% CI 0.15 to 0.88). The second large included RCT, which measured this outcome solely in participants with clinical signs of hypoglycaemia, also found that rates of hypoglycaemia were significantly lower with artesunate (6/730 [1%] with iv artesunate v 19/731 [3%] with iv quinine; RR 0.32, 95% CI 0.13 to 0.79).[15]

The first additional RCT found no adverse effects associated with artesunate, but found that people in the quinine group experienced nausea (20/40 [50%]), headache (16/40 [40%]), vomiting (12/40 [30%]), tinnitus (8/40 [20%]), vertigo (4/40 [10%]), circulatory failure (2/50 [4%]), and sudden blindness (1/40 [3%]) at 28 days.[16] The second additional RCT reported no significant adverse effects.[17]

Comment

The systematic review pooling data from two blinded RCTs and three open-label RCTs found that intravenous artesunate significantly reduced mortality compared with intravenous quinine (5 RCTs; 129/938 [14%] with artesunate v 209/928 [23%] with quinine; RR 0.61, 95% CI 0.50 to 0.75; P <0.00001).[15] Including open-label data, it found that intravenous artesunate significantly reduced parasite clearance time of 50% compared with intravenous quinine, but found no significant difference between groups in coma recovery time.

The review noted that included trials were conducted mainly in adults in Asia, which might affect the generalisability of the results beyond this group, particularly to children who tend to present with a more severe spectrum of disease, and to children in Africa.[15] Since the search date of this Clinical Evidence review, one large multicentre RCT (5425 children in Africa) has been published, which compared parenteral artesunate (65% given iv; 35% given im) versus quinine.[18] The RCT found that either parenteral or intravenous artesunate significantly reduced mortality compared with quinine (parenteral artesunate v quinine, 5425 children; OR 0.75, 95% CI 0.62 to 0.90; intravenous artesunate v quinine, 3503 children; OR 0.75, 95% CI 0.59 to 0.95).[18] This RCT was published after the search date of this Clinical Evidence review so has not been included in this review, but will be reported fully in the next update.

The two RCTs we have reported included in the first systematic review gave an additional oral antimalarial drug to at least one of the treatment arms. In the large multicentre RCT, people in both arms were given doxycycline when able to swallow except in India and Bangladesh, whereas in the other small RCT people in the artesunate arm had mefloquine once able to swallow. There was also wide variation in trial design between RCTs.[15]

Substantive changes

Artesunate (intravenous) versus quinine New evidence added.[15] [18] Categorisation changed from Likely to be beneficial to Beneficial.

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Quinine

Summary

MORTALITY Compared with intramuscular artemether: Quinine seems to be as effective as intramuscular artemether at reducing mortality in people with severe malaria ( moderate-quality evidence ). Compared with intravenous artesunate: Intravenous quinine seems less effective than intravenous artesunate at reducing mortality in people (mainly adults in analysis) with severe malaria in Asia (moderate-quality evidence). Compared with rectal artemisinin derivatives: We don't know whether quinine and rectal artemisinin derivatives (artemether, artemisinin, artesunate, dihydroartemisinin) differ in effectiveness at reducing mortality in people with severe malaria ( low-quality evidence ). PARASITE CLEARANCE TIME Compared with intramuscular artemether: We don't know whether quinine is more effective than intramuscular artemether at reducing parasite clearance time in people with severe malaria (low-quality evidence). Compared with intravenous artesunate: Intravenous quinine may be less effective than intravenous artesunate at reducing parasite clearance time in people with severe malaria in Vietnam or India (low-quality evidence). Compared with rectal artemisinin derivatives: Quinine may be less effective than some rectal artemisinin derivatives at reducing parasite clearance times in people with severe malaria. However, results varied by the artemisinin derivative studied and the population included, and the significance varied by the exact analysis undertaken (low-quality evidence). FEVER CLEARANCE TIME Compared with intramuscular artemether: We don't know whether quinine is more effective than intramuscular artemether at reducing fever clearance time in people with severe malaria (low-quality evidence). Compared with intravenous artesunate: Intravenous quinine may be less effective than intravenous artesunate at reducing fever clearance time in people with severe malaria in Vietnam or India (low-quality evidence). Compared with rectal artemisinin derivatives: We don't know whether quinine and rectal artemisinin derivatives (artemether, artemisinin, artesunate, dihydroartemisinin) differ in effectiveness at reducing fever clearance time in people with severe malaria (low-quality evidence). COMA RECOVERY TIME Compared with intramuscular artemether: We don't know whether quinine is more effective than intramuscular artemether at improving coma recovery time in people with severe malaria (low-quality evidence). Compared with intravenous artesunate: Intravenous quinine may be less effective than intravenous artesunate at reducing coma recovery time in children with severe malaria in India, but we don't know about in adults or at other different locations ( very low-quality evidence ). Compared with rectal artemisinin derivatives: We don't know whether quinine and rectal artemether or artemisinin differ in effectiveness at improving coma recovery time in people with severe malaria (low-quality evidence). NEUROLOGICAL SEQUELAE Compared with intramuscular artemether: We don't know whether quinine is more effective than intramuscular artemether at preventing neurological sequelae in people with severe malaria (low-quality evidence). Compared with intravenous artesunate: Intravenous quinine and intravenous artesunate seem to be equally effective at reducing neurological sequelae at discharge in people with severe malaria in Asia (moderate-quality evidence). TIME TO WALKING AND DRINKING Compared with rectal artemisinin derivatives: We don't know whether quinine and rectal artesunate differ in effectiveness at increasing the proportion of children with severe malaria able to drink at 24 hours (low-quality evidence). NOTE We found no direct information about whether quinine is better than no active treatment in people with severe malaria. Placebo or no-treatment controlled trials of antimalarial treatment in people with severe malaria would be considered unethical. International consensus has historically recommended quinine for the treatment of severe falciparum malaria. Controlled trials will generally compare new treatments against this standard.

Benefits

Quinine versus placebo:

We found no systematic review or RCTs comparing quinine with placebo in people with severe, life-threatening malaria. Placebo or no-treatment controlled trials of antimalarial treatment in people with severe malaria would be considered unethical.

Quinine versus intramuscular artemether:

See benefits of intramuscular artemether.

Quinine versus intravenous artesunate:

See benefits of intravenous artesunate.

Quinine versus rectal artemisinin derivatives:

See benefits of rectal artemisinin derivatives.

Harms

We found no systematic review or RCTs comparing quinine with placebo in people with severe, life-threatening malaria.

Quinine versus intramuscular artemether:

See harms of intramuscular artemether.

Quinine versus intravenous artesunate:

See harms of intravenous artesunate.

Quinine versus rectal artemisinin derivatives:

See harms of artemisinin derivatives.

Comment

Clinical guide:

International consensus has historically recommended quinine for the treatment of severe falciparum malaria. Controlled trials will generally compare new treatments against this standard.

Substantive changes

Quinine New evidence added.[10] [15] [19] [18] [20] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Mar 7;2011:0913.

High initial dose quinine compared with standard regimens

Summary

MORTALITY High initial dose compared with standard regimens: Giving a high initial dose of quinine followed by standard-dose quinine may be no more effective than no loading dose followed by standard-dose quinine at reducing mortality in people with severe malaria ( low-quality evidence ). PARASITE CLEARANCE TIME High initial dose compared with standard regimens: Giving a high initial dose of quinine followed by standard-dose quinine seems more effective than no loading dose followed by standard-dose quinine at reducing parasite clearance time in people with severe malaria ( moderate-quality evidence ). FEVER CLEARANCE TIME High initial dose compared with standard regimens: Giving a high initial dose of quinine followed by standard-dose quinine seems more effective than no loading dose followed by standard-dose quinine at reducing fever clearance time in people with severe malaria (moderate-quality evidence). COMA RECOVERY TIME High initial dose compared with standard regimens: Giving a high initial dose of quinine followed by standard-dose quinine may be no more effective than no loading dose followed by standard-dose quinine at reducing the mean time to recover consciousness in children with severe malaria (low-quality evidence).

Benefits

We found one systematic review (search date 2009, 4 RCTs, 144 people).[21] The systematic review found no significant difference in mortality between high initial dose of quinine (20 mg salt/kg or 16 mg base/kg given im or iv) and no loading dose, followed in both groups by standard-dose quinine (3 RCTs; 4/70 [6%] died with high initial dose v 7/74 [9%] died with no loading dose; RR 0.62, 95% CI 0.19 to 2.04). Two RCTs (99 children) found no significant difference between high initial dose and no loading dose in mean time to recover consciousness (WMD +5.17 hours, 95% CI –1.14 hours to + 11.47 hours). Parasite clearance time and fever clearance time were shorter for the high initial dose quinine group than for the group with no loading dose (parasite clearance time: 2 RCTs, 67 people; WMD –7.4 hours, 95% CI –13.2 hours to –1.6 hours; fever clearance time: 2 RCTs, 68 people; WMD –11.1 hours, 95% CI –20.0 hours to –2.2 hours).

Harms

The systematic review found no significant difference between high initial dose of quinine and no loading dose in the rate of hypoglycaemia (2 RCTs; 4/35 [11%] with high initial dose v 3/37 [8%] with no loading dose; RR 1.39, 95% CI 0.32 to 6.00).[21] One RCT (33 people) included in the review found that high initial dose quinine significantly increased transient partial hearing loss compared with no loading dose (10/17 [59%] with high initial dose v 3/16 [19%] with no loading dose; RR 3.14, 95% CI 1.05 to 9.38).[22] Another RCT (3-arm RCT; 59 children) included in the review found no significant difference between high initial dose of quinine and no loading dose in neurological sequelae (1/18 [6%] with high initial dose v 2/21 [10%] with no loading dose; RR 0.58, 95% CI 0.06 to 5.91).[23]

Comment

The RCTs may have been too small to detect a clinically important difference.[22] [23] [24] [25]

Clinical guide:

International consensus has historically recommended quinine for the treatment of severe falciparum malaria. Controlled trials will generally compare new treatments against this standard.

Substantive changes

High initial dose quinine compared with standard regimens Search updated for an already included systematic review.[21] No new evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Quinine given intramuscularly versus quinine given intravenously

Summary

MORTALITY Intramuscular quinine compared with intravenous quinine: We don't know whether high loading dose intramuscular quinine and high loading dose intravenous quinine differ in effectiveness at reducing mortality in children <12 years old with severe malaria, as we found insufficient evidence from one small RCT ( very low-quality evidence ). PARASITE CLEARANCE TIME Intramuscular quinine compared with intravenous quinine: We don't know whether high loading dose intramuscular quinine and high loading dose intravenous quinine differ in effectiveness at reducing mean parasite clearance time in children <12 years old with severe malaria, as we found insufficient evidence from one small RCT (very low-quality evidence). TIME TO WALKING AND DRINKING Intramuscular quinine compared with intravenous quinine: We don't know whether high loading dose intramuscular quinine and high loading dose intravenous quinine differ in effectiveness at improving recovery time to walking and drinking in children <12 years old with severe malaria, as we found insufficient evidence from one small RCT (very low-quality evidence).

Benefits

We found no systematic review but found one RCT.[23] The RCT (59 Kenyan children <12 years old in 1989–1990) compared high loading dose intramuscular quinine (20 mg salt/kg initially followed by 10 mg salt/kg 12 hourly) versus high loading dose intravenous quinine (20 mg salt/kg initially followed by 10 mg salt/kg 12 hourly) versus standard-dose intravenous quinine (10 mg salt/kg 12 hourly) in severe falciparum malaria.[23] It found no significant difference in mortality, mean parasite clearance time, or recovery time to drinking or walking between high-dose intramuscular and high-dose intravenous quinine, but lacked power to detect a clinically important difference (mortality: 3/20 [15%] with im quinine v 1/18 [6%] with iv quinine; RR 2.7, 95% CI 0.3 to 23.7; mean parasite clearance time: 57 hours with im quinine v 58 hours with iv quinine; WMD –1.0 hours, 95% CI –12.2 hours to +10.2 hours; mean recovery times to drinking: 47 hours with im quinine v 32 hours with iv quinine; WMD +15 hours, 95% CI –5.6 hours to +35.6 hours; mean recovery times to walking: 98 hours with im quinine v 96 hours with iv quinine; WMD +2.0 hours, 95% CI –24.5 hours to +28.5 hours).

Harms

In the RCT, neurological sequelae were reported in two children in the intramuscular group, and one child in the intravenous group had transient neurological sequelae that were not specified (2/20 [10%] with im quinine v 1/18 [6%] with iv quinine; RR 1.8, 95% CI 0.2 to 18.2).[23]

Comment

Quinine concentration profiles were similar with both routes of administration, and peak concentrations were achieved soon after intramuscular injection. The sample size might have been insufficient to rule out clinically important differences.[23]

Clinical guide:

International consensus has historically recommended quinine for the treatment of severe falciparum malaria. Controlled trials will generally compare new treatments against this standard.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Artemisinin derivatives (artemether, artemisinin, artesunate, or dihydroartemisinin) given rectally versus quinine

Summary

MORTALITY Rectal artemisinin derivatives compared with quinine: We don't know whether rectal artemisinin derivatives (artemether, artemisinin, artesunate, dihydroartemisinin) and quinine differ in effectiveness at reducing mortality in people with severe malaria ( low-quality evidence ). PARASITE CLEARANCE TIME Rectal artemisinin derivatives compared with quinine: Some rectal artemisinin derivatives may be more effective than quinine at reducing parasite clearance times in people with severe malaria. However, results varied by the artemisinin derivative studied and the population included, and the significance varied by the exact analysis undertaken (low-quality evidence). FEVER CLEARANCE TIME Rectal artemisinin derivatives compared with quinine: We don't know whether rectal artemisinin derivatives (artemether, artemisinin, artesunate, dihydroartemisinin) and quinine differ in effectiveness at reducing fever clearance time in people with severe malaria (low-quality evidence). COMA RECOVERY TIME Rectal artemisinin derivatives compared with quinine: We don't know whether rectal artemether or artemisinin and quinine differ in effectiveness at improving coma recovery time in people with severe malaria (low-quality evidence). TIME TO WALKING AND DRINKING Rectal artemisinin derivatives compared with quinine: We don't know whether rectal artesunate and quinine differ in effectiveness at increasing the proportion of children with severe malaria able to drink at 24 hours (low-quality evidence). NOTE Rectal artemisinin derivatives may be associated with fewer adverse effects than quinine.

Benefits

Rectal artemisinin derivatives versus quinine:

We found three systematic reviews, which performed slightly different analyses.[20] [19] [9] The first and second reviews (search dates 2006[20] [19]) included studies involving rectal administration of artemisinin derivatives. Both reviews included data from a range of clinical trials; we have only reported data from RCTs of sufficient quality here. The second review also included individual patient data.[19] The third review (search date 1999) included only RCT data.[9]

Rectal artemether:

The first[20] and second[19] reviews included one RCT[26] conducted in Uganda comparing rectal artemether (children weighing up to 8.9 kg given 40 mg daily; children 9–18.9 kg given 80 mg dose immediately, then 40 mg daily; children 19–27.9 kg given 120 mg dose immediately, then 80 mg daily) versus intravenous quinine (20 mg/kg dose immediately, then 10 mg/kg 8 hourly) over 7 days. The RCT found no significant difference in mortality between rectal artemether and intravenous quinine treatment (103 children with cerebral malaria, aged 6 months to 5 years; mortality: 6/51 [12%] with artemether v 10/52 [19%] with quinine; RR 0.78, 95% CI 0.50 to 1.19).[26] It found no significant difference in parasite and fever clearance times (mean parasite clearance time: 54.2 hours with artemether v 55.0 hours with quinine; P = 0.48; mean fever clearance time: 33.2 hours with artemether v 24.1 hours with quinine; P = 0.08). There was no significant difference in the time taken to regain consciousness (mean time: 30.1 hours with artemether v 22.7 hours with quinine; P = 0.1).[26]

Rectal artemisinin:

The third systematic review (search date 1999, 3 RCTs) compared rectal artemisinin versus quinine in severe malaria.[9] In the review, meta-analysis found lower mortality with artemisinin and quicker coma recovery time, but the differences were not significant (mortality: 3 RCTs; 9/87 [10%] with artemisinin v 16/98 [16%] with quinine; RR 0.73, 95% CI 0.35 to 1.50; coma recovery time: 2 RCTs, 59 people; WMD –9.0 hours, 95% CI –19.7 hours to +1.7 hours). Fever clearance time was not significantly different, and although the review reported that all studies reported that artemisinin reduced parasitaemia significantly faster, the analysis reported by the review found no significant difference between groups in parasite clearance (parasite clearance at day 7: 2 RCTs, 132 people; OR 2.04, 95% CI 0.18 to 23.75; parasite clearance at day 28: 1 RCT, 57 people; OR 0.46, 95% CI 0.04 to 5.43).[9] The first review also reported that two of the RCTs found significantly faster parasite clearance (times to 50% and 90% reduction in parasitaemia and total parasite clearance time) with artemisinin compared with quinine (further numerical details not reported).[20]

Rectal artesunate:

The first[20] and second[19] systematic reviews included one RCT (144 people with moderately severe malaria: 109 children in Malawi and 35 adults in South Africa)[27] comparing rectal artesunate (single dose 10 mg/kg) and intravenous quinine (10 mg/kg at 0, 4, and 10 hours, then every 12 hours until oral treatment was tolerated). The RCT found no deaths in either treatment group.[27] It found that in children, artesunate significantly reduced fever clearance time and parasite clearance time compared with quinine (median fever clearance time: 20 hours with artesunate v 44 hours with quinine; P <0.0001; mean parasite clearance time: 36 hours with artesunate v 45 hours with quinine; P = 0.0003).[27] There was no significant difference in the proportion of children able to drink at 24 hours (AR 77/87 [89%] with artesunate v 21/22 [95%] with quinine; P = 0.3). In adults, there was no significant difference in fever clearance time and parasite clearance time (mean parasite clearance time: 49 hours with artesunate v 63 hours with quinine; P = 0.10; median fever clearance time: 36 hours with artesunate v 23 hours with quinine; P = 0.116).[27] The RCT may have been too small to detect a clinically important difference. The second systematic review performed a further analysis on the data from this RCT, and found that a single dose of rectal artesunate significantly improved the parasite reduction ratio compared with quinine at 24 hours (WMD 0.6, 95% CI 0.32 to 0.89; absolute numbers not reported; based on log transformation).[19]

Rectal dihydroartemisinin:

The first review[20] included one RCT (67 people aged 2–60 years with severe malaria in Kenya in 1998),[28] which compared rectal dihydroartemisinin (160 mg initially, then 80 mg for 2 days for people aged >16 years; variable dosage depending on age in people <16 years) versus intravenous quinine (20 mg/kg initially, then 10 mg/kg 8 hourly). It found no deaths with either treatment.[28] The RCT found that dihydroartemisinin significantly improved parasite clearance time compared with quinine, but found no significant difference in fever clearance time (mean parasite clearance time: 38 hours with dihydroartemisinin v 49 hours with quinine; P = 0.04; mean fever clearance time: 27.9 hours with dihydroartemisinin v 22.0 hours with quinine; P = 0.25).

Harms

Rectal artemisinin derivatives versus quinine:

Rectal artemether:

The RCT found no significant difference in the number of children vomiting (2/51 with artemether v 5/52 with quinine; P = 0.235).[26]

Rectal artemisinin:

One RCT found that artemisinin significantly reduced the risk of hypoglycaemia compared with quinine (3/30 [10%] with artemisinin v 19/30 [63%] with quinine; RR 0.16, 95% CI 0.05 to 0.48).[29]

Rectal artesunate:

The RCT found no significant difference in adverse effects between treatment groups (data not reported) at 28 days, but found local reactions at quinine injection sites in three adults.[27] No adverse neurological events were reported with artesunate, and 1/8 (13%) adults treated with quinine developed transient dysdiadochokinesis.

Rectal dihydroartemisinin:

The RCT found that dihydroartemisinin significantly reduced tinnitus compared with quinine (1/30 [3%] with dihydroartemisinin v 10/37 [27%] with quinine; OR 0.09, 95% CI 0.01 to 0.78).[28]

General harms:

The first review included published and unpublished studies involving rectal administration of artemisinin derivatives to healthy volunteers or patients, and both single arm and comparative trials were included.[20] The review reported that minor adverse effects for all artemisinin derivatives administered intrarectally included dizziness, transient fever occurring approximately 24 hours after parasite clearance, and gastrointestinal symptoms (nausea, vomiting, abdominal pain, constipation or diarrhoea).[20] The review reported that it was is unclear whether these adverse effects were related to the artemisinin drugs, co-interventions, or malaria itself. No symptoms suggestive of neurotoxicity were described in any study evaluating artemisinin derivatives in the review, including those using rectal artesunate at doses up to 20 mg/kg and artemisinin derivatives up to 40 mg/kg. This is reassuring given brain-stem lesions observed in laboratory animals receiving prolonged supratherapeutic doses of lipid-soluble artemisinin derivatives. No studies described rectal bleeding or anal irritation. Some included studies reported tenesmus and a burning sensation post rectal administration, but there was no evidence of proctitis of the type associated with rectal quinine.[20]

The second review included data from 15 clinical trials, both published and unpublished, including comparative and non-comparative trials and individual patient observations.[19] Overall, 21/786 (3%) rectal artemisinin-treated patients were thought to have had a potentially drug-related adverse event, whereas 54/786 (6%) had an adverse event of uncertain causality. By comparison, 27/123 (22%) quinine-treated patients experienced a potentially drug-related adverse event. Approximately 11/37 (30%) suspected drug-related adverse events with rectal artemisinin were systemic including fever, headache, and unspecified pain (1 related to the nervous system [dizziness]; 3 included hearing impairment; 18 related to the gastrointestinal system). For those with quinine, 7/27 (26%) adverse events were related to the nervous system, 8/27 (30%) to the digestive system, 5/27 (19%) affected special senses/hearing, and 4/27 (15%) the haemopoetic system. These data were from people treated with either artesunate (591 people) or artemisinin (144 people) suppositories. The total incidence of adverse events ranged between 2.7% and 9% of all artemisinin-treated patients, compared with 22% of quinine-treated patients.[19]

MORTALITY Rectal artemisinin derivatives compared with intravenous artemisinin derivatives: We don't know whether rectal artemisinin and intravenous artesunate differ in effectiveness at reducing mortality in adults with cerebral malaria in Vietnam ( very low-quality evidence ). COMA RECOVERY TIME Rectal artemisinin derivatives compared with intravenous artemisinin derivatives: We don't know whether rectal artemisinin and intravenous artesunate differ in effectiveness at improving coma recovery time in adults with cerebral malaria in Vietnam (very low-quality evidence).

Benefits

Rectal artemisinin derivatives versus intravenous artemisinin derivatives:

We found three systematic reviews (search dates 1999,[9] 2006[19] [20]), which included one RCT[9] of sufficient quality. The three-armed RCT (79 Vietnamese adults with cerebral malaria) compared rectal artemisinin versus intravenous artesunate versus intravenous quinine.[9] We have only reported the artemisinin and artesunate arms here. No exclusion or loss to follow-up was reported in the RCT, and the randomisation method was not specified. The RCT found no significant difference between groups in mortality (5/18 [28%] with rectal artemisinin v 5/31 [16%] with iv artesunate; RR 2.00, 95% CI 0.49 to 8.17).[9] The review reported that the RCT found no difference between groups in time to recover consciousness, but the number of people evaluated was not explicit (further data and statistical analysis not reported).[9] One review noted that artemisinin suppositories became unavailable during the trial.[20] We found no subsequent RCTs.

Harms

Rectal artemisinin derivatives versus intravenous artemisinin derivatives:

No adverse effects were reported in the RCT.[9]

Comment

Clinical guide:

Rectal formulations have been developed for pre-referral use and current World Health Organization guidelines suggest rectally administered artemisinins should only be used for complete treatment when parenteral antimalarial treatment is not possible.[30] There are insufficient data to substantiate the use of rectal treatment for full management of severe malaria, but no evidence to suggest that early treatment in rural areas with suppositories is inappropriate while patients are being transferred to a higher grade facility.[9]

Substantive changes

Artemisinin derivatives given rectally (artemether, artemisinin, artesunate, or dihydroartemisinin) versus artemisinin derivatives given intravenously (artemether, artemisinin, artesunate, or dihydroartemisinin) New option added.[9] [20] [19] Categorised as Unknown effectiveness as we found insufficient evidence to assess effects.

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Artemisinin derivatives given rectally (artemether, artemisinin, artesunate, or dihydroartemisinin) versus artemisinin derivatives given intramuscularly (artemether, artemisinin, artesunate, or dihydroartemisinin)

Summary

PARASITE CLEARANCE TIME Rectal artemisinin derivatives compared with intramuscular artemisinin derivatives: We don't know whether rectal artesunate and intramuscular artemether differ in effectiveness at reducing parasite clearance time in children with severe malaria in Papua New Guinea. Rectal artesunate may be more effective than intramuscular artemether at shortening the time to 50% and 90% reduction in parasitaemia ( very low-quality evidence ). FEVER CLEARANCE TIME Rectal artemisinin derivatives compared with intramuscular artemisinin derivatives: We don't know whether rectal artesunate and intramuscular artemether differ in effectiveness at reducing fever clearance time in children with severe malaria in Papua New Guinea (very low-quality evidence). COMA RECOVERY TIME Rectal artemisinin derivatives compared with intramuscular artemisinin derivatives: We don't know whether rectal artesunate and intramuscular artemether differ in effectiveness at reducing coma recovery time in children with severe malaria with impaired consciousness in Papua New Guinea (very low-quality evidence). TIME TO WALKING AND DRINKING Rectal artemisinin derivatives compared with intramuscular artemisinin derivatives: We don't know whether rectal artesunate and intramuscular artemether differ in effectiveness at reducing time to return to oral medication in children with severe malaria in Papua New Guinea (very low-quality evidence).

Benefits

Rectal artemisinin derivatives versus intramuscular artemisinin derivatives:

We found three systematic reviews (search date 1999,[9] 2006[19] [20]), which included one RCT[31] of sufficient quality. The RCT (79 children with severe malaria in Papua New Guinea) compared artesunate suppositories versus intramuscular artemether. The method of randomisation was not described. The primary endpoint was time for parasite density to fall, and assessment was blinded. The RCT found that rectal artesunate significantly reduced times to 50% and 90% reduction in parasitaemia compared with intramuscular artemether (50%: difference –4.3 hours, 95% CI –7.5 hours to –1.2 hours; P <0.01; 90%: difference –4.8 hours, 95% CI –8.5 hours to –1.1 hours; P <0.02).[31] However, the RCT found no significant difference between groups in parasite clearance time, fever clearance time, or time to return to oral medication (difference in parasite clearance time –2.5 hours, 95% CI –8.8 hours to +3.8 hours; difference in fever clearance time +2.8 hours, 95% CI –1.9 hours to +3.8 hours; difference in time to return to oral medication –0.25 days, 95% CI –0.62 days to +0.11 days). In 22 children with impaired consciousness, there was no significant difference between groups in time to recovery (Blantyre score <5: 15 hours with artesunate suppositories v 20 hours with im artemether; P >0.2).[31] We found no subsequent RCTs.

Harms

Rectal artemisinin derivatives versus intramuscular artemisinin derivatives:

The RCT reported that 5 children (2 with artesunate and 3 with artemether) developed constipation, abdominal distension, or both during convalescence.[31] One child in the artesunate suppository group died during the course of the trial.

Comment

None.

Substantive changes

Artemisinin derivatives given rectally (artemether, artemisinin, artesunate, or dihydroartemisinin) versus artemisinin derivatives given intramuscularly (artemether, artemisinin, artesunate, or dihydroartemisinin) New option added.[9] [20] [19] [31] Categorised as Unknown effectiveness as we found insufficient evidence to assess effects.

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Exchange blood transfusion

Summary

We found no clinically important results from RCTs about exchange blood transfusion in people with severe malaria.

Benefits

We found one systematic review (search date 2001).[32] It found no suitable RCTs in people with malaria. We found no additional RCTs that met our inclusion criteria (see comment below).

Harms

We found no RCTs.

Comment

We found one systematic review of case-control studies[32] and one small RCT.[33] The review (search date 2001, 8 studies, 279 people) found no significant difference in mortality between exchange transfusion plus antimalarial drugs and antimalarial drugs alone (8 studies; OR for death 1.2, 95% CI 0.7 to 2.1).[32] Admission criteria for exchange transfusion varied in the included studies, but generally, parasitaemia was greater than 10%, and most people had failed to improve after 24 hours of antimalarial treatment. The methods and volumes used for exchange transfusion also varied. Those who received exchange blood transfusions had higher mean levels of parasitaemia before treatment began and fulfilled more World Health Organization criteria for the diagnosis of severe malaria (parasitaemia level: 26% with exchange transfusion v 11% with no exchange transfusion; P <0.05; mean World Health Organization criteria: 3.6 with exchange transfusion v 2.8 with no exchange transfusion; P = 0.03). The RCT compared exchange transfusion plus antimalarial drugs versus antimalarial drugs alone, but it included only 8 people.[33]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Initial blood transfusion for treating malarial anaemia

Summary

MORTALITY Initial blood transfusion compared with no transfusion: We don't know whether initial blood transfusion is more effective than conservative treatment or iron supplements in reducing mortality in clinically stable children (clinically unstable children with respiratory distress or heart failure excluded from trials) with severe malaria in Tanzania or The Gambia ( very low-quality evidence ). NOTE Transfusion may be clinically essential in some circumstances.

Benefits

We found one systematic review (search date 2007, 2 RCTs, 230 children with malarial anaemia; packed cell volume range 12–17%).[34] The first RCT (116 children) compared initial blood transfusion versus conservative treatment in children from Tanzania, and the second RCT (114 children) compared blood transfusion versus iron supplements in children from The Gambia. Both trials excluded children who were clinically unstable with respiratory distress or signs of cardiac failure. Meta-analysis found fewer deaths in the transfused children, but the difference was not significant (1/118 [1%] with transfusion v 3/112 [3%] with control; RR 0.41, 95% CI 0.06 to 2.70).[34] We found no RCTs examining the effects of transfusion in adults with malaria.

Harms

Coma and convulsions occurred significantly more often after transfusion (8/118 [7%] with transfusion v 0/112 [0%] without transfusion; RR 8.6, 95% CI 1.1 to 66.4).[34] Seven of the 8 adverse events occurred in one RCT. Meta-analysis combining deaths and severe adverse events found no significant difference between people who received transfusions and people who did not (8/118 [7%] with transfusion v 3/112 [3%] without transfusion; RR 2.5, 95% CI 0.7 to 9.3). Transmission of hepatitis B or HIV was not reported.

Comment

Studies were small and loss to follow-up was greater than 10%, both of which are potential sources of bias.[34] In the first RCT, one child in the transfusion group and one child in the conservative treatment group required an additional transfusion after clinical assessment. In the second RCT, 10 children allocated to receive iron supplements later required transfusion when packed cell volume fell below 12% or they showed signs of respiratory distress.

Clinical guide:

Transfusion may be clinically essential in some circumstances.

Substantive changes

Initial blood transfusion for treating malarial anaemia Search updated for an already included systematic review.[34] No new evidence added. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Anticonvulsants

Summary

MORTALITY Compared with no anticonvulsants: The routine use of phenobarbitone (particularly high doses) may be associated with an increase in mortality compared with no anticonvulsants in people with cerebral malaria. The significance of the result varied by the exact analysis undertaken ( low-quality evidence ). CONVULSIONS Compared with no anticonvulsants: The routine use of phenobarbitone is more effective than no anticonvulsants at reducing convulsions within 4 weeks of attending hospital in people with cerebral malaria ( high-quality evidence ).

Benefits

We found one systematic review comparing anticonvulsants versus control (placebo or no anticonvulsants) for treating cerebral malaria.[35] It examined the routine use of anticonvulsants for treating people with cerebral malaria. The review identified three RCTs, all of which assessed phenobarbitone. The review found that phenobarbitone significantly reduced convulsions within 4 weeks of attending hospital compared with control (search date 2004, 3 RCTs, 573 people; convulsions: 24/296 [8%] with phenobarbitone v 78/277 [28%] with control; RR 0.27, 95% CI 0.14 to 0.52). Overall, the review found no significant difference in mortality between phenobarbitone and control (AR of death: 67/296 [23%] with phenobarbitone v 52/277 [19%] with control; RR 1.30, 95% CI 0.58 to 2.88). However, meta-analysis of only the two trials with adequate allocation concealment found significantly higher mortality in people receiving phenobarbitone (2 RCTs, 388 people; AR of death: 38/194 [20%] with phenobarbitone v 19/194 [10%] with control; RR 1.98, 95% CI 1.19 to 3.28).[35]

Harms

The review found limited evidence that phenobarbitone can increase mortality (see benefits section above).

Comment

The RCTs included in the review used different doses of phenobarbitone (3.5 mg/kg, 10 mg/kg, and 20 mg/kg).[35] The highest dose of phenobarbitone (20 mg/kg) significantly increased mortality compared with placebo (AR: 30/170 [18%] with phenobarbitone v 14/170 [8%] with placebo; RR 2.14, 95% CI 1.18 to 3.90).

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 7;2011:0913.

Dexamethasone

Summary

MORTALITY Compared with placebo: Dexamethasone seems no more effective than placebo at reducing mortality in people with severe/cerebral malaria treated with quinine ( moderate-quality evidence ). COMA RECOVERY TIME Compared with placebo: Dexamethasone may be no more effective than placebo at improving coma recovery time in people with severe/cerebral malaria treated with quinine ( low-quality evidence ). ADVERSE EFFECTS Compared with placebo: Dexamethasone is associated with an increased proportion of people with gastrointestinal bleeding or seizures compared with placebo in people with severe/cerebral malaria treated with quinine ( high-quality evidence ).

Benefits

Dexamethasone versus placebo:

We found one systematic review (search date 2008, 2 RCTs, 143 people with severe/cerebral malaria treated with quinine), which compared dexamethasone versus placebo over 48 hours.[36] One RCT was conducted in Indonesia and the other in Thailand. The review found no significant difference in mortality (14/71 [20%] with dexamethasone v 16/72 [23%] with placebo; RR 0.89, 95% CI 0.48 to 1.68). One RCT found a longer mean time between start of treatment and coma recovery with dexamethasone (76 hours with dexamethasone v 57 hours with placebo; P <0.02),[37] but the other RCT found no significant difference (83.4 hours with dexamethasone v 80.0 hours with placebo; WMD +3.4 hours, 95% CI –31.3 hours to +38.1 hours).[38]

Harms

The review found that dexamethasone significantly increased gastrointestinal bleeding and seizures compared with placebo (gastrointestinal bleeding: 7/71 [10%] with dexamethasone v 0/72 [0%] with placebo; RR 8.17, 95% CI 1.05 to 63.6; seizures: 11/71 [15%] with dexamethasone v 3/72 [4%] with placebo; RR 3.32, 95% CI 1.05 to 10.47).[36]

Comment

No effect of steroids on mortality was shown, but the trials were small. The effect of steroids on disability was not reported.

Substantive changes

Dexamethasone Search updated for an already included systematic review.[36] No new evidence added. Categorisation unchanged (Likely to be ineffective or harmful).

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PERMALINK

Malaria: severe, life-threatening

Susanne Helena Hodgson

Brian John Angus

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

Clinical context

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table 1.

Glossary

Disclaimer

Contributor Information

References

Artemether (intramuscular) versus quinine

Summary

Benefits

Harms

Comment

Substantive changes

Artesunate (intravenous) versus quinine

Summary

Benefits

Harms

Comment

Substantive changes

Quinine

Summary

Benefits

Quinine versus placebo:

Quinine versus intramuscular artemether:

Quinine versus intravenous artesunate:

Quinine versus rectal artemisinin derivatives:

Harms

Quinine versus intramuscular artemether:

Quinine versus intravenous artesunate:

Quinine versus rectal artemisinin derivatives:

Comment

Clinical guide:

Substantive changes

High initial dose quinine compared with standard regimens

Summary

Benefits

Harms

Comment

Clinical guide:

Substantive changes

Quinine given intramuscularly versus quinine given intravenously

Summary

Benefits

Harms

Comment

Clinical guide:

Substantive changes

Artemisinin derivatives (artemether, artemisinin, artesunate, or dihydroartemisinin) given rectally versus quinine

Summary

Benefits

Rectal artemisinin derivatives versus quinine:

Rectal artemether:

Rectal artemisinin:

Rectal artesunate:

Rectal dihydroartemisinin:

Harms

Rectal artemisinin derivatives versus quinine:

Rectal artemether:

Rectal artemisinin:

Rectal artesunate:

Rectal dihydroartemisinin:

General harms:

Comment