Adjunctive treatment Various adjunctive treatments for the complications of malaria may be needed to reduce the unacceptably high

mortality of severe malaria.[2,3] Patients with severe malaria often require care in an intensive care unit. Aggressive supportive care, including mechanical ventilation and hemofiltration or hemodialysis, can be instrumental in successful management of severe malaria. In technologically limited settings, high-quality nursing care, management of fluid balance, and control of seizures are helpful, although anticonvulsant agents that are respiratory depressants should be used with caution if mechanical ventilation is unavailable. Aggressive fluid resuscitation, blood transfusion for moderate anemia, exchange transfusion, and specific treatment for acidosis are of uncertain value. Bacterial infections can coexist with severe malaria, so blood cultures should be obtained from patients with shock or other signs of sepsis despite appropriate antimalarial therapy, and these patients should receive broadspectrum antibiotic therapy. Although hypoglycemia is less common when artesunate is used rather than quinine or quinidine, it is important to monitor the patient's blood glucose level and provide supplementary glucose as needed.[3] Immediate clinical management of severe manifestations and complications of falciparum malaria (WHO, 2006)2 Manifestation/complication Immediate management (in addition to antimalarial treatment) 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 treatment such as corticosteroids, heparin and adrenaline; intubate if necessary Hyperpyrexia Administer tepid sponging, fanning, cooling blanket and antipyretic drugs Convulsions Maintain airways; treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde Hypoglycaemia (blood glucose Check blood glucose, correct hypoglycaemia and maintain concentration of<2.2 mmol/l; with glucose-containing infusion <40 mg/100ml) Severe anaemia (haemoglobin Transfuse with screened fresh whole blood <5 g/100ml or packed cell volume <15%) Acute pulmonary oedema Over-enthusiastic rehydration should be avoided so as to prevent pulmonary oedema. Prop patient up at an angle of 45o, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/continuous positive airway pressure in lifethreatening hypoxaemia Acute renal failure Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. The benefits of diuretics/dopamine in acute renal failure are not proven Spontaneous bleeding and Transfuse with screened fresh whole blood coagulopathy (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

Hyperparasitaemia

parenteral antimicrobials, correct haemodynamic disturbances Treat with artemisinins, intravenously or orally (See below)

Supportive care:[1,2] Vital signs, with an accurate assessment of respiratory rate and pattern, coma score, and urine output should be recorded as frequently as possible. Blood glucose should be checked, using rapid stick tests every 4 h if possible, particularly in unconscious patients. Comatose patients should be placed in a semirecumbent position to reduce the risk for aspiration. Serum sodium concentration, arterial carbon dioxide tension, blood glucose, and arterial lactate concentration should be monitored frequently. The efficacy of hypertonic mannitol in treatment of cerebral edema is not proven.[1] Seizures are common in cerebral malaria, particularly in children. Convulsions should be treated promptly with intravenous or rectal diazepam or intramuscular paraldehyde. In a large double-blind placebo-controlled evaluation of a single intramuscular injection of 20 mg/kg bw of phenobarbital (phenobarbitone) in children with cerebral malaria there was a reduction in seizures but a significant increase in mortality in phenobarbital recipients, resulting from respiratory arrest. Prophylactic anticonvulsants are not recommended.[2] Fluid requirements should be assessed individually. Adults with severe malaria are very vulnerable to fluid overload and there is a thin dividing line between underhydration, and thus worsening renal impairment, and overhydration, with the risk of precipitating pulmonary oedema.[2] The intravascular volume should be maintained at the lowest level sufficient for adequate systemic perfusion.[1] If the patient becomes oliguric (<0.4 ml of urine/kg bw per hour) despite adequate rehydration, and the blood urea or creatinine are rising or already high, then fluids should be restricted to replace insensible losses only. Children, on the other hand, are more likely to be dehydrated and may respond well to a bolus of fluid. The fluid regimen must also be tailored around infusion of the antimalarial drugs. Central venous pressure should be maintained at 05 cm. If the venous pressure is elevated (usually because of excessive fluid administration), the patient should be nursed with the head raised at an angle of 45o and, if necessary, intravenous furosemide should be given. If available, heamofiltration should be started early for acute renal failure or severe metabolic acidosis unresponsive to rehydration.[2] In hypotension early use of inotropic support is indicated rather than overhydration. Negative fluid balance is critical to avoid exacerbating acute lung injury, but is balanced against the risk for precipitating acute renal failure[1] Early institution of renal replacement therapy may avoid the development of ARDS. Patients with hypotension tolerate continuous renal replacement therapy better than conventional intermittent hemodialysis. In addition, a continuous regulation of body fluid avoids periods of volume overload and depletion.[1] If blood glucose is <2.2 mmol/l (<40mg/dL), then hypoglycaemia should be treated immediately (0.30.5 g/kg bw of glucose). Hypoglycaemia should be suspected in any patient who deteriorates suddenly. Stick tests may overestimate the frequency of hypoglycaemia, so laboratory confirmation may be necessary. Patients with acute pulmonary oedema should be nursed in an upright position and given oxygen, and filling pressures on the right side of the heart should be reduced with whichever treatments are available (loop diuretics, opiates, venodilators, venesection, haemofiltration, dialysis). The right-sided pressure should be reduced to the lowest level compatible with an adequate cardiac output.[2] The patient may need to be intubated

because of impaired consciousness or because of acute lung injury. Mechanical ventilation with lower tidal volume improves the clinical outcome. A higher positive endexpiratory pressure may be needed to maintain optimal arterial oxygenation. In respiratory acidosis, the plateau pressure should be in excess of 25 cm H2O and the ventilator rate should be increased. Surfactant therapy, inhaled nitric oxide, and corticosteroids have no effect on survival or duration of ventilation in patients with ARDS.[1] Fewer than 5% of patients with severe malaria develop clinically significant disseminated intravascular coagulation. These patients should be given fresh blood transfusions and vitamin K. Patients with secondary pneumonia should be given empirical treatment with a thirdgeneration cephalosporin, unless admitted with clear evidence of aspiration, in which case penicillin or clindamycin is adequate. Unexplained deterioration may result from a supervening bacterial infection. Children with persistent fever despite parasite clearance may have a systematic Salmonella infection, although in the majority of cases of persistent fever no other pathogen is identified after parasite clearance. Urinary tract infections are common in catheterized patients. Antibiotic treatments should take account of likely local antibiotic sensitivity patterns. Other treatments:[2] Many other supportive strategies and interventions have been proposed in severe malaria, but very few are supported by evidence of benefit, and many have proved harmful. Heparin, prostacyclin, deferoxamine, pentoxifylline, low molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid, deferoxamine, anti-tumour necrosis factor antibody, cyclosporin, dichloroacetate, adrenaline and hyperimmune serum have all been suggested but none of these is recommended. One systematic review on the use of corticosteroids in severe malaria found no significant difference in mortality but increased risk of gastrointestinal bleeding; therefore, corticosteroids should not be used in severe malaria. Severe metabolic acidosis is common but apart from correction of hypovolaemia and anaemia, no specific treatment is of proven value. Significant electrolyte abnormalities are relatively unusual, and potassium supplementation is often not required in the acute phase. The optimum fluid resuscitation regimens, the thresholds for blood transfusion, the role of exchange transfusion, and the management of seizures remain areas of uncertainty. It is generally agreed that early ventilation for respiratory abnormalities and early management of renal failure or severe metabolic acidosis are beneficial. In acute renal failure, haemofiltration is associated with a lower mortality, and more rapid correction of biochemical abnormalities compared with peritoneal dialysis. Blood transfusion:[2] In high transmission settings, blood transfusion is 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/100ml) is recommended. These general recommendations still need to be tailored to the individual, as the pathological consequences of rapid development of anaemia are worse than those of acute on chronic anaemia, where there has been adaptation and a compensatory right shift in the oxygen dissociation curve. Exchange blood transfusion (EBT)[2]

There have been many anecdotal reports and several series claiming benefit for EBT in severe malaria but no comparative trials, and there is no consensus on whether it reduces mortality or how it might work. It requires intensive nursing and a relatively large volume of blood, and 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. Therefore no recommendation regarding the use of EBT has been made by the WHO. Treatment during pregnancy Pregnant women, particularly in the second and third trimesters of pregnancy are more likely to develop severe malaria than other adults, 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. The role of early Caesarean section for the viable live fetus is unproven, but is recommended by many authorities. Obstetric advice should be sought at an early stage, the paediatricians alerted, and blood glucose checked frequently. Hypoglycaemia should be expected and is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately following delivery. Postpartum bacterial infection is a common complication in these cases. Falciparum malaria has also been associated with severe mid-trimester haemolytic anaemia in Nigeria. This often requires transfusion, in addition to antimalarial treatment and folate supplementation. Parenteral antimalarials should be given to pregnant women with severe malaria in full doses without delay. Artesunate or artemether are preferred over quinine in the second and third trimesters because quinine is associated with recurrent hypoglycaemia. Recent evidence shows that in non pregnant adults with severe malaria in areas of low transmission, artesunate was superior to quinine, reducing mortality by 35% compared to quinine, which makes artesunate the preferred option in the second and third trimesters. In the first trimester, the risk of hypoglycaemia associated with quinine is lower, and the uncertainties over the safety of the artemisinin derivatives are greater. However, weighing these risks against the above evidence in favour of the efficacy of artesunate, and until more evidence becomes available, both artesunate and quinine may be considered as options. Treatment must not be delayed, so if only one of the drugs artesunate, artemether or quinine is available, it should be started immediately. The National vector Borne Disease Programme in India recommends quinine for the treatment of severe malaria in pregnancy.[5] Management in epidemic situations:[2] In epidemic situations, staff shortages and high workloads make intensive care monitoring difficult. Drug treatment should therefore be as simple and safe as possible, with simple dosing schedules and a minimum need for monitoring. As reconstitution of artesunate is a two step procedure and the dosing is twice a day, and as parenteral quinine requires either intravenous infusions or a three times a day intramuscular regimen, plus monitoring of blood glucose, the simple once a day regimens of intramuscular artemether is a suitable alternative for severe malaria in most epidemic situations, including in pregnant women in all trimesters. Artesunate suppositories may be appropriate in severely ill patients who are unable to swallow oral medication when intramuscular artemether (or quinine by intravenous infusion) is unavailable and in such cases, the patients should be moved as soon as possible to a facility where intramuscular or intravenous therapy can be started. When the patient cannot be moved, continued treatment with rectal artesunate is appropriate until oral drugs can be taken. Hyperparasitaemia:[2]

Patients with high parasite counts are known to be at increased risk of dying, although the relationship between parasite counts and prognosis varies at different levels of malaria endemicity. Many hyperparasitaemic patients have evidence of vital organ dysfunction but there is a large subgroup in which no other manifestations of severe disease are present. These patients have symptoms and signs compatible with a diagnosis of uncomplicated malaria in association with a high parasite count (sometimes termed uncomplicated hyperparasitaemia). The relevance for treatment is firstly the increased risk of progressing to severe malaria, and secondly the generally higher treatment failure rates. This is of particular concern as resistance to antimalarials is most likely to arise in patients with heavy parasite burdens and little or no immunity. In a lowtransmission area in north-west Thailand, the overall mortality of uncomplicated falciparum malaria was 0.1%, but in patients with parasitaemia of >4% it was 3%. In areas of moderate or high transmission, much higher parasitaemias are often well tolerated, however. There is not enough evidence to provide a firm recommendation on the definition of hyperparasitaemia, although 5% parasitaemia in a low-transmission setting and 10% in a higher transmission setting are commonly used. The rapidity of action of the artemisinin derivatives makes them ideal drugs for the treatment of hyperparasitemia. Available evidence indicates that use of oral treatment under close supervision is effective in the treatment of patients with hyperparasitaemia who have no other features of severe malaria. Patients must be monitored closely for the first 48 h after the start of treatment and if there is concern or if the patient does not retain oral medication, parenteral treatment should be given without delay. Non-immune patients with parasitaemia of >20% should receive parenteral antimalarial treatment. Alternatively, the first dose of artemisinin derivative can be given parenterally or rectally to ensure adequate absorption, followed by a full course of ACT. Mefloquine, if used, should be given on days 2 and 3, rather than day 1, when it is better tolerated, with a lower incidence of early vomiting. The optimum duration of treatment for hyperparasitaemia is still unresolved. Data to support the suggestion that patients should be treated conservatively with 7 days of an artemisinin derivative, plus a full course of partner medicine (e.g. artesunate 7 days + mefloquine 25 mg/kg bw divided over 2 days) are lacking. Treatment of severe vivax malaria:[2] Although P. vivax malaria is considered to be a benign malaria, with a very low casefatality ratio, it may still cause a severe and debilitating febrile illness. It can also very occasionally result in severe disease as in falciparum malaria. Severe vivax malaria manifestations that have been reported are cerebral malaria, severe anaemia, severe thrombocytopenia and pancytopenia, jaundice, spleen rupture, acute renal failure and acute respiratory distress syndrome. Severe anaemia and acute pulmonary oedema are not uncommon. The underlying mechanisms of severe manifestations are not well understood. Prompt and effective treatment and case management should be the same as for severe and complicated falciparum malaria.