Abstract
Introduction
Severe malaria mainly affects children aged under 5 years, 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 may lead to neurological sequelae in survivors. Severe malarial anaemia may have a mortality rate of over 13%. The role of fluid resuscitation in severe malaria is complex and controversial. Volume expansion could help to improve impaired organ perfusion and correct metabolic acidosis. However, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What is the optimal method of fluid resuscitation in patients with severe malaria? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, searching of electronic databases retrieved 187 studies. After deduplication and removal of conference abstracts, 93 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 82 studies and the further review of 11 full publications. Of the 11 full articles evaluated, two systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for seven PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of human albumin, intravenous fluids, and whole blood or plasma.
Key Points
Severe malaria mainly affects children aged under 5 years, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria.
The manifestations of severe malaria depend on age. Severe anaemia and hypoglycaemia are more common in children. Acute pulmonary oedema, acute kidney injury, and jaundice are more common in adults, while acidosis and coma (cerebral malaria) occur in all age groups.
Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and may lead to neurological sequelae in survivors.
Severe malarial anaemia may have a mortality rate of more than 13%.
The main aspect of malaria treatment is the use of appropriate antimalarial medications. However, for this update, we have decided to focus on fluid resuscitation in people with severe malaria, which is a complex and controversial issue.
Volume expansion could help to improve impaired organ perfusion and correct metabolic acidosis. However, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation.
For this overview, we evaluated evidence from RCTs and systematic reviews of RCTs on the following three intervention groups: intravenous fluids (such as normal saline, dextrose saline, dextrose, Hartmann's solution, Ringer's lactate, but not including human albumin or plasma substitutes such as gelatin); human albumin; and whole blood or plasma.
We compared these interventions with usual standard treatment and with each other. We also included within-option comparisons (e.g., different volumes and regimen protocols).
We don't know whether a routine blood transfusion is more effective than no blood transfusion with regards to mortality in children with severe anaemia and confirmed malaria parasitaemia, but who are otherwise not in distress or severely unwell.
Much of the data for human albumin and intravenous fluid therapy come from a subgroup analysis of one large multicentre RCT, the FEAST trial.
Overall, the FEAST trial found a significant increase in 48-hour mortality in children with severe febrile illness and impaired perfusion (including children with severe malaria) receiving fluid bolus (combined results for saline or albumin) compared with usual care (no fluid bolus, maintenance fluids only). It found that the excess mortality with fluid bolus compared with no fluid bolus also occurred in the subgroup of children with severe malaria.
Data from a subgroup analysis of the FEAST trial (human albumin and intravenous saline considered as separate interventions) plus evidence from further RCTs found that a fluid bolus with human albumin may be associated with higher mortality than no bolus (maintenance intravenous fluids only) in children with severe malaria.
We don’t know whether a bolus of saline has a greater effect on mortality in children with severe malaria compared with maintenance fluids alone. There was a non-significant trend towards higher mortality with intravenous saline bolus compared with no bolus reported in the subgroup analysis of the FEAST trial.
All the RCTs we found were in children, so may not be directly relevant to adult patients. While all these trials administered boluses of fluid determined by patient weight, the relative size of bolus varied between trials, meaning that 'bolus' is a heterogeneous intervention and care should be taken when interpreting collective findings. Quality of evidence may be reduced due to lack of blinding to the interventions administered in many of the RCTs, although blinding may be very difficult to achieve when comparing different fluid resuscitation regimens.
Clinical context
General background
Severe malaria mainly affects children aged under 5 years, 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 may lead to neurological sequelae in survivors. Severe malarial anaemia may have a mortality rate of over 13%.
Focus of the review
The main aspect of malaria treatment is the use of appropriate antimalarial medications. Please see previous versions of this overview. For this update, we have focused on fluid resuscitation in people with severe malaria.
Comments on evidence
All the RCTs we found were in children rather than adults, so may not be directly relevant to all patients. Some of the trials assessed 'bolus' administration of fluid. While all these trials administered boluses of fluid determined by patient weight, the relative size of bolus varied between trials, meaning that 'bolus' is a heterogeneous intervention and care should be taken when interpreting collective findings. Quality of evidence may be reduced due to lack of blinding to the interventions administered, although blinding may be very difficult to achieve when comparing different fluid resuscitation regimens. In some trials, the population included was broader than people with severe malaria and included people with severe febrile illness and impaired perfusion due to causes other than severe malaria.
Search and appraisal summary
The literature search was carried out in December 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 187 studies. After deduplication and removal of conference abstracts, 93 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 82 studies and the further review of 11 full publications. Of the 11 full articles evaluated, two systematic reviews and three RCTs were included.
About this condition
Definition
Plasmodium falciparum malaria is caused by protozoan infection of red blood cells and comprises a variety of syndromes. This overview deals with 'severe' or clinically complicated malaria as defined by clinical or laboratory evidence of vital organ dysfunction.[1] This includes coma, severe anaemia, renal failure, respiratory distress syndrome, hypoglycaemia, shock, spontaneous haemorrhage, and convulsions. Cerebral malaria is defined as unrousable coma in the absence of any other cause of encephalopathy, and in the presence of P falciparum infection.[2] This overview does not currently cover the treatment of malaria in pregnancy. Fluid resuscitation in severe malaria The main aspect of malaria treatment is the use of appropriate antimalarial medications.[3] However, mortality remains high, even in the case of rapid administration of appropriate antimalarial chemotherapy.[4] There is, therefore, much interest in identifying supportive measures (such as fluid resuscitation) that could reduce malaria mortality. Metabolic acidosis is an important predictor of fatal outcome in severe malaria.[5] Hypoperfusion is thought to contribute to poor tissue perfusion and an increased rate of anaerobic glycolysis that results in metabolic acidosis.[6] [7] [5] It is postulated that treatment of hypovolaemia with intravenous fluid resuscitation could, therefore, correct acidosis, and possibly improve outcomes.[5] However, in malaria, acidosis is likely to be multifactorial, and not simply explained by hypovolaemia. In addition, there are real risks that fluid resuscitation, in the context of severe malaria, could be associated with important deleterious effects. For example, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation.[8] In addition, in the context of acute respiratory distress syndrome rapid infusion of intravenous fluid can be lethal.[3] [9]The role of fluid resuscitation in severe malaria is, therefore, complex and controversial. This overview sets out to analyse the evidence base for the use of intravenous fluid resuscitation in the context of severe malaria.
Incidence/ Prevalence
Malaria is a major health problem in the tropics, with an estimated 198 million clinical cases and 584,000 deaths worldwide in 2013.[10] More than 85% of malaria cases and 90% of malaria deaths occur in sub-Saharan Africa, mainly in young children (i.e., those aged younger than 5 years),[3] [11] mainly from cerebral malaria and anaemia.[3] Depending on the intensity of transmission, children in malaria-endemic regions become resistant to severe malaria by the age of 5 years; however, they remain susceptible to uncomplicated episodes of febrile infection until late childhood or early adolescence.[12] Non-immune travellers and individuals spending time away from malaria-endemic regions are also at risk of infection and severe malaria.[3] [13]
Aetiology/ Risk factors
Malaria is a protozoan parasite transmitted by the bite of infected female Anopheles mosquitoes.[3] There are five parasite strains responsible for malaria (Plasmodium falciparum, P vivax, P ovale, P malariae, and P knowseli); however, P falciparum, which causes 'severe' malaria, is the most important cause of mortality. Susceptibility to clinical disease is determined by the degree of prior exposure to P falciparum.[13] Genetic mutations that affect the ability of P falciparum to infect and/or replicate in RBCs, such as haemoglobin S (HbS)[14] and HbC,[15] ovalocytosis,[16] thalassaemias,[17] and glucose-6-phosphate dehydrogenase deficiency,[18] have also been shown to confer a survival advantage in the presence of malaria. For example, in the case of HbS, heterozygotes are protected against P falciparum (due to reduced cyto-adherence and parasite growth at low oxygen tensions).[3] (See also our BMJ Clinical Evidence overview on Sickle cell disease.)
Prognosis
When treated promptly with effective antimalarial drugs, uncomplicated falciparum malaria has a mortality of roughly 0.1%. Mortality rises when the proportion of infected erythrocytes (parasitaemia) exceeds 2%, although the relationship between parasite density and prognosis in falciparum malaria is very variable.[3] The manifestations of severe malaria depend on age. Severe anaemia and hypoglycaemia are more common in children, and acute pulmonary oedema, acute kidney injury and jaundice more common in adults, while acidosis and coma (cerebral malaria) occur in all age groups.[3] In children aged under 5 years with cerebral malaria, the estimated case fatality of treated malaria is 19%, although reported hospital case fatality may be as high as 40%.[2] [19] 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%.[19] In adults, mortality of cerebral malaria is 20%; this rises to 50% in pregnancy.[20]
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; neurological sequelae at follow-up; hypotensive shock; coma recovery time; adverse effects (pulmonary oedema, intracranial hypertension or severe allergic reaction in those receiving albumin).
Methods
Search strategy BMJ Clinical Evidence search and appraisal date December 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to December 2014, Embase 1980 to December 2014, The Cochrane Database of Systematic Reviews 2014, issue 12 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 individuals or more, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions from this overview: What are the effects of antimalarial treatments for complicated falciparum malaria in non-pregnant people? What are the effects of adjunctive treatment for complicated falciparum malaria in non-pregnant people? We have added the following question: What is the optimal method of fluid resuscitation in patients with severe malaria? Data and quality To aid readability of the numerical data in our overviews, 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). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. 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 (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.
GRADE Evaluation of interventions for Malaria: fluid therapy in severe disease.
| Important outcomes | Coma recovery time, Hypotensive shock, Mortality, Neurological sequelae at follow-up | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What is the optimal method of fluid resuscitation in patients with severe malaria? | |||||||||
| 3 (1288) | Mortality | Human albumin (bolus) versus usual care (no bolus) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological flaws (open-label nature of studies and subgroup analysis in largest RCT); directness point deducted for uncertainty about generalisability of population (evidence in children only) |
| 1 (63) | Neurological sequelae at follow-up | Human albumin (bolus) versus usual care (no bolus) | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data, methodological flaws (open-label nature of study), and incomplete reporting of results (lack of statistical assessment); directness points deducted for uncertainty about generalisability of population (includes moderate acidosis only) and evidence in children only |
| 3 (1372) | Mortality | Human albumin (bolus) versus intravenous saline (bolus) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological flaws (open-label nature of studies and subgroup analysis in largest RCT); directness point deducted for uncertainty about generalisability of population evidence (in children only) |
| 1 (63) | Neurological sequelae at follow-up | Human albumin (bolus) versus intravenous saline (bolus) | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, methodological flaws (open-label nature of study), and incomplete reporting of results (lack of statistical assessment); directness point deducted for uncertainty about generalisability of population evidence (in children only) |
| 3 (1309) | Mortality | Intravenous fluids (bolus) versus usual care (no bolus, maintenance fluids only) | 4 | –1 | 0 | –1 | 0 | Low | Quality points deducted for methodological flaws (open-label nature of studies and subgroup analysis in largest RCT); directness point deducted for uncertainty about generalisability of population (evidence in children only) |
| 1 (68) | Neurological sequelae at follow-up | Intravenous fluids (bolus) versus usual care (no bolus, maintenance fluids only) | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data, methodological flaws (open-label nature of study), and incomplete reporting of results (lack of statistical assessment); directness points deducted for uncertainty about generalisability of population (includes moderate acidosis only) and evidence in children only |
| 2 (230) | Mortality | Blood transfusion versus usual care (no blood transfusion) | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for methodological flaws (open-label nature of studies) and for uncertainty about result due to low event rate; directness point deducted for uncertainty about generalisability of population (evidence in children only) |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- 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.
- 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, University of Oxford, Oxford, UK.
Brian John Angus, University of Oxford, Oxford, UK.
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