Treating severe malaria
Treat adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women) with intravenous or intramuscular artesunate for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT.
Strong recommendation, high-quality evidence
Revised dose recommendation for parenteral artesunate in young children
Children weighing < 20 kg should receive a higher dose of artesunate (3 mg/kg bw per dose) than larger children and adults (2.4 mg/kg bw per dose) to ensure equivalent exposure to the drug.
Strong recommendation based on pharmacokinetic modelling
Parenteral alternatives when artesunate is not available
If parenteral artesunate is not available, use artemether in preference to quinine for treating children and adults with severe malaria.
Conditional recommendation, low-quality evidence
Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
Pre-referral treatment options
Where complete treatment of severe malaria is not possible but injections are available, give adults and children a single intramuscular dose of artesunate, and refer to an appropriate facility for further care. Where intramuscular artesunate is not available use intramuscular artemether or, if that is not available, use intramuscular quinine.
Strong recommendation, moderate-quality evidence
Where intramuscular injections of artesunate are not available, treat children < 6 years with a single rectal dose (10 mg/kg bw) of artesunate, and refer immediately to an appropriate facility for further care. Do not use rectal artesunate in older children and adults.
Strong recommendation, moderate-quality evidence
Mortality from untreated severe malaria (particularly cerebral malaria) approaches 100%. With prompt, effective antimalarial treatment and supportive care, the rate falls to 10–20% overall. Within the broad definition of severe malaria some syndromes are associated with lower mortality rates (e.g. severe anaemia) and others with higher mortality rates (e.g. acidosis). The risk for death increases in the presence of multiple complications.
Any patient with malaria who is unable to take oral medications reliably, shows any evidence of vital organ dysfunction or has a high parasite count is at increased risk for dying. The exact risk depends on the species of infecting malaria parasite, the number of systems affected, the degree of vital organ dysfunction, age, background immunity, pre-morbid, and concomitant diseases, and access to appropriate treatment. Tests such as a parasite count, haematocrit and blood glucose may all be performed immediately at the point of care, but the results of other laboratory measures, if any, may be available only after hours or days. As severe malaria is potentially fatal, any patient considered to be at increased risk should be given the benefit of the highest level of care available. The attending clinician should not worry unduly about definitions: the severely ill patient requires immediate supportive care, and, if severe malaria is a possibility, parenteral antimalarial drug treatment should be started without delay
7.1. DEFINITIONS
7.1.1. SEVERE FALCIPARUM MALARIA
For epidemiological purposes, severe falciparum malaria is defined as one or more of the following, occurring in the absence of an identified alternative cause and in the presence of P. falciparum asexual parasitaemia.
Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma score < 3 in children
Prostration: Generalized weakness so that the person is unable to sit, stand or walk without assistance
Multiple convulsions: More than two episodes within 24 h
Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ⩾ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured breathing).
Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)
Severe malarial anaemia: Haemoglobin concentration ⩽ 5 g/dL or a haematocrit of ⩽ 15% in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite count > 10 000/μL
Renal impairment: Plasma or serum creatinine > 265 μmol/L (3 mg/dL) or blood urea > 20 mmol/L
Jaundice: Plasma or serum bilirubin > 50 μmol/L (3 mg/dL) with a parasite count > 100 000/ μL
Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate > 30/min, often with chest indrawing and crepitations on auscultation
Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or venepuncture sites; haematemesis or melaena
Shock: Compensated shock is defined as capillary refill ⩾ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm Hg in children or < 80 mm Hg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
7.1.2. SEVERE VIVAX AND KNOWLESI MALARIA
Severe vivax malaria is defined as for falciparum malaria but with no parasite density thresholds.
Severe knowlesi malaria is defined as for falciparum malaria but with two differences:
7.2. THERAPEUTIC OBJECTIVES
The main objective of the treatment of severe malaria is to prevent the patient from dying. Secondary objectives are prevention of disabilities and prevention of recrudescent infection.
Death from severe malaria often occurs within hours of admission to a hospital or clinic, so it is essential that therapeutic concentrations of a highly effective antimalarial drug be achieved as soon as possible. Management of severe malaria comprises mainly clinical assessment of the patient, specific antimalarial treatment, additional treatment and supportive care
7.3. CLINICAL ASSESSMENT
Severe malaria is a medical emergency. An open airway should be secured in unconscious patients and breathing and circulation assessed. The patient should be weighed or body weight estimated, so that medicines, including antimalarial drugs and fluids, can be given appropriately. An intravenous cannula should be inserted, and blood glucose (rapid test), haematocrit or haemoglobin, parasitaemia and, in adults, renal function should be measured immediately. A detailed clinical examination should be conducted, including a record of the coma score. Several coma scores have been advocated: the Glasgow coma scale is suitable for adults, and the simple Blantyre modification is easily performed in children. Unconscious patients should undergo a lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis.
The degree of acidosis is an important determinant of outcome; the plasma bicarbonate or venous lactate concentration should be measured, if possible. If facilities are available, arterial or capillary blood pH and gases should be measured in patients who are unconscious, hyperventilating or in shock. Blood should be taken for cross-matching, a full blood count, a platelet count, clotting studies, blood culture and full biochemistry (if possible). Careful attention should be paid to the patient's fluid balance in severe malaria in order to avoid over- or under-hydration. Individual requirements vary widely and depend on fluid losses before admission.
The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may be due to meningoencephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia or Kernig's sign), but the patient may be opisthotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria, and these conditions may coexist. When possible, blood should always be taken on admission for bacterial culture. In malaria-endemic areas, particularly where parasitaemia is common in young age groups, it is difficult to rule out septicaemia immediately in a shocked or severely ill obtunded child. In all such cases, empirical parenteral broad-spectrum antibiotics should be started immediately, together with antimalarial treatment.
7.4. TREATMENT OF SEVERE MALARIA
It is essential that full doses of effective parenteral (or rectal) antimalarial treatment be given promptly in the initial treatment of severe malaria. This should be followed by a full dose of effective ACT orally. Two classes of medicine are available for parenteral treatment of severe malaria: artemisinin derivatives (artesunate or artemether) and the cinchona alkaloids (quinine and quinidine). Parenteral artesunate is the treatment of choice for all severe malaria. The largest randomized clinical trials ever conducted on severe falciparum malaria showed a substantial reduction in mortality with intravenous or intramuscular artesunate as compared with parenteral quinine. The reduction in mortality was not associated with an increase in neurological sequelae in artesunate-treated survivors. Furthermore, artesunate is simpler and safer to use
7.4.1. ARTESUNATE
Treating severe malaria
Treat adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women) with intravenous or intramuscular artesunate for at least 24 h. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT.
Strong recommendation, high-quality evidence
In a systematic review of artesunate for severe malaria, eight randomized controlled trials with a total of 1664 adults and 5765 children, directly compared parenteral artesunate with parenteral quinine. The trials were conducted in various African and Asian countries between 1989 and 2010. In comparison with quinine, parenteral artesunate:
reduced mortality from severe malaria by about 40% in adults (RR, 0.61; 95% CI, 0.50–0.75, five trials, 1664 participants, high-quality evidence);
reduced mortality from severe malaria by about 25% in children (RR, 0.76; 95% CI, 0.65–0.90, four trials, 5765 participants, high-quality evidence); and
was associated with a small increase in neurological sequelae in children at the time of hospital discharge (RR, 1.36; 95% CI, 1.01–1.83, three trials, 5163 participants, moderate-quality evidence), most of which, however, slowly resolved, with little or no difference between artesunate and quinine 28 days later (moderate-quality evidence).
Other considerations
The guideline development group considered that the small increase in neurological sequelae at discharge after treatment with artesunate was due to the delayed recovery of the severely ill patients, who would have died had they received quinine. This should not be interpreted as a sign of neurotoxicity. Although the safety of artesunate given in the first trimester of pregnancy has not been firmly established, the guideline development group considered that the proven benefits to the mother outweigh any potential harm to the developing fetus.
Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Systemat Rev. 2012;6 CD005967. [PMC free article: PMC6532684] [PubMed: 22696354] [CrossRef].
Dosing of artesunate injection in severe malaria
Revised dose recommendation for parenteral artesunate in young children with severe malaria
Children weighing less than 20 kg should receive a higher parenteral dose of artesunate (3 mg/kg/dose) than larger children and adults (2.4 mg/kg/dose) to ensure equivalent drug exposure.
Strong recommendation based on pharmacokinetic modelling
The dosing subgroup reviewed all available pharmacokinetic data on artesunate and the main biologically active metabolite dihydroartemisinin following administration of artesunate in severe malaria (published pharmacokinetic studies from 71 adults and 265 children). Simulations of artesunate and dihydroartemisinin exposures were conducted for each age group. These showed underexposure in younger children. The revised parenteral dose regimens are predicted to provide equivalent artesunate and dihydroartemisinin exposures across all age groups.
Other considerations
Individual parenteral artesunate doses between 1.75 and 4 mg/kg have been studied and no toxicity has been observed. The GRC concluded that the predicted benefits of improved antimalarial exposure in children are not at the expense of increased risk.
Hendriksen IC, Mtove G, Kent A, Gesase S, Reyburn H, Lemnge MM, et al. Population pharmacokinetics of intramuscular artesunate in African children with severe malaria: implications for a practical dosing regimen. Clin Pharmacol Ther. 2013;93:443–50. [PMC free article: PMC3630454] [PubMed: 23511715].
Zaloumis SG, Tarning J, Krishna S, Price RN, White NJ, Davis TM, McCaw JM, Olliaro P, Maude RJ, Kremsner P, Dondorp A, Gomes M, Barnes K, Simpson JA. Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria. CPT Pharmacometrics Syst Pharmacol. 2014;3:e145. [PMC free article: PMC4259998] [PubMed: 25372510].
Artesunate is dispensed as a powder of artesunic acid, which is dissolved in sodium bicarbonate (5%) to form sodium artesunate. The solution is then diluted in approximately 5 mL of 5% dextrose and given by intravenous injection or by intramuscular injection into the anterior thigh.
The solution should be prepared freshly for each administration and should not be stored. Artesunate is rapidly hydrolysed in-vivo to dihydroartemisinin, which provides the main antimalarial effect. Studies of the pharmacokinetics of parenteral artesunate in children with severe malaria suggest that they have less exposure than older children and adults to both artesunate and the biologically active metabolite dihydroartemisinin. Body weight has been identified as a significant covariate in studies of the pharmacokinetics of orally and rectally administered artesunate, which suggests that young children have a larger apparent volume of distribution for both compounds and should therefore receive a slightly higher dose of parenteral artesunate to achieve exposure comparable to that of older children and adults.
Artesunate and post-treatment haemolysis
Delayed haemolysis starting >1 week after artesunate treatment of severe malaria has been reported in hyperparasitaemic non-immune travellers. Between 2010 and 2012, there were six reports involving a total of 19 European travellers with severe malaria who were treated with artesunate injection and developed delayed haemolysis. All except one were adults (median age, 50 years; range, 5–71 years). In a prospective study involving African children, the same phenomenon was reported in 5 (7%) of the 72 hyperparasitaemic children studied. Artesunate rapidly kills ring-stage parasites, which are then taken out of the red cells by the spleen; these infected erythrocytes are then returned to the circulation but with a shortened life span, resulting in the observed haemolysis. Thus, post-treatment haemolysis is a predictable event related to the life-saving effect of artesunate. Hyperparasitaemic patients must be followed up carefully to identify late-onset anaemia.
7.4.2. PARENTERAL ALTERNATIVES WHEN ARTESUNATE IS NOT AVAILABLE
Parenteral alternatives when artesunate is not available
If parenteral artesunate is not available, use intramuscular artemether in preference to quinine for treating children and adults with severe malaria.
Strong recommendation, high-quality evidence
A systematic review of intramuscular artemether for severe malaria comprised two randomized controlled trials in Viet Nam in which artemether was compared with artesunate in 494 adults, and 16 trials in Africa and Asia in which artemether was compared with quinine in 716 adults and 1447 children. The trials were conducted between 1991 and 2009.
In comparison with artesunate, intramuscular artemether was not as effective at preventing deaths in adults in Asia (RR, 1.80; 95% CI, 1.09–2.97; two trials, 494 participants, moderate-quality evidence).
Artemether and artesunate have not been directly compared in randomized trials in African children.
In comparison with quinine:
Intramuscular artemether prevented a similar number of deaths in children in Africa (RR, 0.96; 95% CI, 0.76–1.20; 12 trials, 1447 participants, moderate-quality evidence).
Intramuscular artemether prevented more deaths in adults in Asia (RR, 0.59; 95% CI, 0.42–0.83; four trials, 716 participants, moderate-quality evidence).
Other considerations
Indirect comparisons of parenteral artesunate and quinine and of artemether and quinine were considered by the guideline development group with what is known about the pharmacokinetics of the two drugs. They judged the accumulated indirect evidence to be sufficient to recommend parenteral artesunate rather than intramuscular artemether for use in all age groups.
Esu E, Effa EE, Opie ON, Uwaoma A, Meremikwu MM. Artemether for severe malaria. Cochrane Database Systemat Rev. 2014;9 CD010678. [PMC free article: PMC4455227] [PubMed: 25209020] [CrossRef].
Artemether
Artemether is two to three times less active than its main metabolite dihydroartemisinin. Artemether can be given as an oil-based intramuscular injection or orally. In severe falciparum malaria, the concentration of the parent compound predominates after intramuscular injection, whereas parenteral artesunate is hydrolysed rapidly and almost completely to dihydroartemisinin. Given intramuscularly, artemether may be absorbed more slowly and more erratically than water-soluble artesunate, which is absorbed rapidly and reliably after intramuscular injection. These pharmacological advantages may explain the clinical superiority of parenteral artesunate over artemether in severe malaria.
Artemether is dispensed dissolved in oil (groundnut, sesame seed) and given by intramuscular injection into the anterior thigh.
Therapeutic dose: The initial dose of artemether is 3.2 mg/kg bw intramuscularly (to the anterior thigh). The maintenance dose is 1.6 mg/kg bw intramuscularly daily.
Quinine
Quinine treatment for severe malaria was established before the methods for modern clinical trials were developed. Several salts of quinine have been formulated for parenteral use, but the dihydrochloride is the most widely used. The peak concentrations after intramuscular quinine in severe malaria are similar to those after intravenous infusion. Studies of pharmacokinetics show that a loading dose of quinine (20 mg salt/kg bw, twice the maintenance dose) provides therapeutic plasma concentrations within 4 h. The maintenance dose of quinine (10 mg salt/kg bw) is administered at 8-h intervals, starting 8 h after the first dose. If there is no improvement in the patient's condition within 48 h, the dose should be reduced by one third, i.e. to 10 mg salt/kg bw every 12 h.
Rapid intravenous administration of quinine is dangerous. Each dose of parenteral quinine must be administered as a slow, rate-controlled infusion (usually diluted in 5% dextrose and infused over 4 h). The infusion rate should not exceed 5 mg salt/kg bw per h.
Whereas many antimalarial drugs are prescribed in terms of base, for historical reasons quinine doses are usually recommended in terms of salt (usually sulphate for oral use and dihydrochloride for parenteral use). Recommendations for the doses of this and other antimalarial agents should state clearly whether the salt or the base is being referred to; doses with different salts must have the same base equivalents. Quinine must never be given by intravenous bolus injection, as lethal hypotension may result.
Quinine dihydrochloride should be given by rate-controlled infusion in saline or dextrose solution. If this is not possible, it should be given by intramuscular injection to the anterior thigh; quinine should not be injected into the buttock in order to avoid sciatic nerve injury. The first dose should be split, with 10 mg/kg bw into each thigh. Undiluted quinine dihydrochloride at a concentration of 300 mg/mL is acidic (pH 2) and painful when given by intramuscular injection, so it is best to administer it either in a buffered formulation or diluted to a concentration of 60–100 mg/mL for intramuscular injection. Gluconate salts are less acidic and better tolerated than the dihydrochloride salt when given by the intramuscular and rectal routes.
As the first (loading) dose is the most important in the treatment of severe malaria, it should be reduced only if there is clear evidence of adequate pre-treatment before presentation. Although quinine can cause hypotension if administered rapidly, and overdose is associated with blindness and deafness, these adverse effects are rare in the treatment of severe malaria. The dangers of insufficient treatment (i.e. death from malaria) exceed those of excessive initial treatment.
7.5. PRE-REFERRAL TREATMENT OPTIONS
Treating cases of suspected severe malaria pending transfer to higher-level facilities (pre-referral treatment)
Where complete treatment of severe malaria is not possible but injections are available, give adults and children a single intramuscular dose of artesunate, and refer to an appropriate facility for further care. Where intramuscular artesunate is not available use intramuscular artemether or, if that is not available, use intramuscular quinine.
Strong recommendation, moderate-quality evidence
Where intramuscular injections of artesunate are not available, treat children < 6 years with a single rectal dose (10mg/kg bw) of artesunate, and refer immediately to an appropriate facility for further care. Do not use rectal artesunate in older children and adults.
Strong recommendation, moderate-quality evidence
In a systematic review of pre-referral treatment for suspected severe malaria, in a single large randomized controlled trial of 17 826 children and adults in Bangladesh, Ghana and the United Republic of Tanzania, pre-referral rectal artesunate was compared with placebo.
In comparison with placebo:
Rectal artesunate reduced mortality by about 25% in children < 6 years (RR, 0.74; 95% CI, 0.59–0.93; one trial, 8050 participants, moderate-quality evidence).
Rectal artesunate was associated with more deaths in older children and adults (RR, 2.21; 95% CI, 1.18–4.15; one trial 4018 participants, low-quality evidence).
Other considerations
The guideline development group could find no plausible explanation for the finding of increased mortality among older children and adults in Asia who received rectal artesunate, which may be due to chance. Further trials would provide clarification but are unlikely to be done. The group was therefore unable to recommend its use in older children and adults.
In the absence of direct evaluations of parenteral antimalarial drugs for pre-referral treatment, the guideline development group considered the known benefits of artesunate in hospitalized patients and downgraded the quality of evidence for pre-referral situations. When intramuscular injections can be given, the group recommends intramuscular artesunate in preference to rectal artesunate.
Okebe J, Eisenhut M. Pre-referral rectal artesunate for severe malaria. Cochrane Database Systemat Rev. 2014;5 CD009964. [PMC free article: PMC4463986] [PubMed: 24869943] [CrossRef].
The risk for death from severe malaria is greatest in the first 24 h, yet, in most malaria-endemic countries, the transit time between referral and arrival at a health facility where intravenous treatment can be administered is usually long, thus delaying the start of appropriate antimalarial treatment. During this time, the patient may deteriorate or die. It is therefore recommended that patients, particularly young children, be treated with a first dose of one of the recommended treatments before referral (unless the referral time is < 6 h).
The recommended pre-referral treatment options for children < 6 years, in descending order of preference, are intramuscular artesunate; rectal artesunate; intramuscular artemether; and intramuscular quinine. For older children and adults, the recommended pre-referral treatment options, in descending order of preference, are intramuscular injections of artesunate; artemether; and quinine.
Administration of an artemisinin derivative by the rectal route as pre-referral treatment is feasible and acceptable even at community level. The only trial of rectal artesunate as pre-referral treatment showed the expected reduction in mortality of young children but unexpectedly found increased mortality in older children and adults. As a consequence, rectal artesunate is recommended for use only in children aged < 6 years and only when intramuscular artesunate is not available.
When rectal artesunate is used, patients should be transported immediately to a higher-level facility where intramuscular or intravenous treatment is available. If referral is impossible, rectal treatment could be continued until the patient can tolerate oral medication. At this point, a full course of the recommended ACT for uncomplicated malaria should be administered.
The single dose of 10 mg/kg bw of artesunate when given as a suppository should be administered rectally as soon as a presumptive diagnosis of severe malaria is made. If the suppository is expelled from the rectum within 30 min of insertion, a second suppository should be inserted and the buttocks held together for 10 min to ensure retention of the dose.
7.6. ADJUSTMENT OF PARENTERAL DOSING IN RENAL FAILURE OR HEPATIC DYSFUNCTION
The dosage of artemisinin derivatives does not have to be adjusted for patients with vital organ dysfunction. However quinine accumulates in severe vital organ dysfunction. If a patient with severe malaria has persisting acute kidney injury or there is no clinical improvement by 48 h, the dose of quinine should be reduced by one third, to 10 mg salt/kg bw every 12 h. Dosage adjustments are not necessary if patients are receiving either haemodialysis or haemofiltration.
7.7. FOLLOW-ON TREATMENT
The current recommendation of experts is to give parenteral antimalarial drugs for the treatment of severe malaria for a minimum of 24 h once started (irrespective of the patient's ability to tolerate oral medication earlier) or until the patient can tolerate oral medication, before giving the oral follow-up treatment.
After initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial drug by giving a full course of effective ACT (artesunate + amodiaquine, artemether + lumefantrine or dihydroartemisinin + piperaquine). If the patient presented initially with impaired consciousness, ACTs containing mefloquine should be avoided because of an increased incidence of neuropsychiatric complications. When an ACT is not available, artesunate + clindamycin, artesunate + doxycycline, quinine + clindamycin or quinine + doxycycline can be used for follow-on treatment. Doxycycline is preferred to other tetracyclines because it can be given once daily and does not accumulate in cases of renal failure, but it should not be given to children < 8 years or pregnant women. As treatment with doxycycline is begun only when the patient has recovered sufficiently, the 7-day doxycycline course finishes after the artesunate, artemether or quinine course. When available, clindamycin may be substituted in children and pregnant women.
7.8. CONTINUING SUPPORTIVE CARE
Patients with severe malaria require intensive nursing care, preferably in an intensive care unit where possible. Clinical observations should be made as frequently as possible and should include monitoring of vital signs, coma score and urine output. Blood glucose should be monitored every 4 h, if possible, particularly in unconscious patients.
7.9. MANAGEMENT OF COMPLICATIONS
Severe malaria is associated with a variety of manifestations and complications, which must be recognized promptly and treated as shown below.
Immediate clinical management of severe manifestations and complications of P. falciparum malaria
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| Manifestation or complication | Immediate managementa |
|---|
| Coma (cerebral malaria) | Maintain airway, place patient on his or her side, exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis); avoid harmful ancillary treatments, intubate if necessary. |
| Hyperpyrexia | Administer tepid sponging, fanning, a cooling blanket and paracetamol. |
| Convulsions | Maintain airways; treat promptly with intravenous or rectal diazepam, lorazepam, midazolam or intramuscular paraldehyde. Check blood glucose. |
| Hypoglycaemia | Check blood glucose, correct hypoglycaemia and maintain with glucose-containing infusion. Although hypoglycaemia is defined as glucose < 2.2 mmol/L, the threshold for intervention is < 3 mmol/L for children < 5 years and < 2.2 mmol/L for older children and adults. |
| Severe anaemia | Transfuse with screened fresh whole blood. |
| Acute pulmonary oedemab | Prop patient up at an angle of 45°, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure or continuous positive airway pressure in life-threatening hypoxaemia. |
| Acute kidney injury | Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure, add haemofiltration or haemodialysis, or, if not available, peritoneal dialysis. |
| Spontaneous bleeding and coagulopathy | Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets, if available); give vitamin K injection. |
| Metabolic acidosis | Exclude or treat hypoglycaemia, hypovolaemia and septicaemia. If severe, add haemofiltration or haemodialysis. |
| Shock | Suspect septicaemia, take blood for cultures; give parenteral broad-spectrum antimicrobials, correct haemodynamic disturbances. |
- a
It is assumed that appropriate antimalarial treatment will have been started in all cases.
- b
Prevent by avoiding excess hydration
7.10. ADDITIONAL ASPECTS OF MANAGEMENT
7.10.1. FLUID THERAPY
Fluid requirements should be assessed individually. Adults with severe malaria are very vulnerable to fluid overload, while children are more likely to be dehydrated. The fluid regimen must also be adapted to the infusion of antimalarial drugs. Rapid bolus infusion of colloid or crystalloids is contraindicated. If available, haemofiltration should be started early for acute kidney injury or severe metabolic acidosis, which do not respond to rehydration. As the degree of fluid depletion varies considerably in patients with severe malaria, it is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit. In high-transmission settings, children commonly present with severe anaemia and hyperventilation (sometimes termed “respiratory distress”) resulting from severe metabolic acidosis and anaemia; they should be treated by blood transfusion. In adults, there is a very thin dividing line between over-hydration, which may produce pulmonary oedema, and under-hydration, which contributes to shock, worsening acidosis and renal impairment. Careful, frequent evaluation of jugular venous pressure, peripheral perfusion, venous filling, skin turgor and urine output should be made.
7.10.2. BLOOD TRANSFUSION
Severe malaria is associated with rapid development of anaemia, as infected, once infected and uninfected erythrocytes are haemolysed and/or removed from the circulation by the spleen. Ideally, fresh, cross-matched blood should be transfused; however, in most settings, cross-matched virus-free blood is in short supply. As for fluid resuscitation, there are not enough studies to make strong evidence-based recommendations on the indications for transfusion; the recommendations given here are based on expert opinion. In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL (haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin, 7 g/100 mL) is recommended. These general recommendations must, however, be adapted to the individual, as the pathological consequences of rapid development of anaemia are worse than those of chronic or acute anaemia when there has been adaptation and a compensatory right shift in the oxygen dissociation curve.
7.10.3. EXCHANGE BLOOD TRANSFUSION
Many anecdotal reports and several series have claimed the benefit of exchange blood transfusion in severe malaria, but there have been no comparative trials, and there is no consensus on whether it reduces mortality or how it might work. Various rationales have been proposed:
removing infected red blood cells from the circulation and therefore lowering the parasite burden (although only the circulating, relatively non-pathogenic stages are removed, and this is also achieved rapidly with artemisinin derivatives);
rapidly reducing both the antigen load and the burden of parasite-derived toxins, metabolites and toxic mediators produced by the host; and
replacing the rigid unparasitized red cells by more easily deformable cells, therefore alleviating microcirculatory obstruction.
Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.
7.10.4. CONCOMITANT USE OF ANTIBIOTICS
The threshold for administering antibiotic treatment should be low in severe malaria. Septicaemia and severe malaria are associated, and there is substantial diagnostic overlap, particularly in children in areas of moderate and high transmission. Thus broad-spectrum antibiotic treatment should
be given with antimalarial drugs to all children with suspected severe malaria in areas of moderate and high transmission until a bacterial infection is excluded. After the start of antimalarial treatment, unexplained deterioration may result from a supervening bacterial infection. Enteric bacteria (notably Salmonella) predominated in many trial series in Africa, but a variety of bacteria have been cultured from the blood of patients with a diagnosis of severe malaria.
Patients with secondary pneumonia or with clear evidence of aspiration should be given empirical treatment with an appropriate broad-spectrum antibiotic. In children with persistent fever despite parasite clearance, other possible causes of fever should be excluded, such as systemic Salmonella infections and urinary tract infections, especially in catheterized patients. In the majority of cases of persistent fever, however, no other pathogen is identified after parasite clearance. Antibiotic treatment should be based on culture and sensitivity results or, if not available, local antibiotic sensitivity patterns.
7.10.5. USE OF ANTICONVULSANTS
The treatment of convulsions in cerebral malaria with intravenous (or, if this is not possible, rectal) benzodiazepines or intramuscular paraldehyde is similar to that for repeated seizures from any cause. In a large, double-blind, placebo-controlled evaluation of a single prophylactic intramuscular injection of 20 mg/kg bw of phenobarbital to children with cerebral malaria, the frequency of seizures was reduced but the mortality rate was increased significantly. This resulted from respiratory arrest and was associated with additional use of benzodiazepine. A 20 mg/kg bw dose of phenobarbital should
not
be given without respiratory support. It is not known whether a lower dose would be effective and safer or whether mortality would not increase if ventilation were given. In the absence of further information, prophylactic anticonvulsants are not recommended.
7.10.6. TREATMENTS THAT ARE NOT RECOMMENDED
In an attempt to reduce the high mortality from severe malaria, various adjunctive treatments have been evaluated, but none has proved effective and many have been shown to be harmful. Heparin, prostacyclin, desferroxamine, pentoxifylline, low-molecular-mass dextran, urea, high-dose corticosteroids, aspirin anti-TNF antibody, cyclosporine A, dichloroacetate, adrenaline, hyperimmune serum, N-acetylcysteine and bolus administration of albumin are not recommended. In addition, use of corticosteroids increases the risk for gastrointestinal bleeding and seizures and has been associated with prolonged coma resolution times when compared with placebo.
7.11. TREATMENT OF SEVERE MALARIA DURING PREGNANCY
Women in the second and third trimesters of pregnancy are more likely to have severe malaria than other adults, and, in low-transmission settings, this is often complicated by pulmonary oedema and hypoglycaemia. Maternal mortality is approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature labour are common.
Parenteral antimalarial drugs should be given to pregnant women with severe malaria in full doses without delay. Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed. If artesunate is unavailable, intramuscular artemether should be given, and if this is unavailable then parenteral quinine should be started immediately until artesunate is obtained.
Obstetric advice should be sought at an early stage, a paediatrician alerted and blood glucose checked frequently. Hypoglycaemia should be expected, and it is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately after delivery. Postpartum bacterial infection is a common complication and should be managed appropriately.
7.12. TREATMENT OF SEVERE P. VIVAX MALARIA
Although P. vivax malaria is considered to be benign, with a low case-fatality rate, it may cause a debilitating febrile illness with progressive anaemia and can also occasionally cause severe disease, as in P. falciparum malaria. Reported manifestations of severe P. vivax malaria include severe anaemia, thrombocytopenia, acute pulmonary oedema and, less commonly, cerebral malaria, pancytopenia, jaundice, splenic rupture, haemoglobinuria, acute renal failure and shock.
Prompt effective treatment and case management should be the same as for severe P. falciparum malaria (see section 7.4). Following parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.
