Table 1   Antimalarial chemotherapy of severe falciparum malaria

Quinine (adults): 20 mg dihydrochloride salt/kg of body weight (loading dose)¹ diluted in 10 ml isotonic fluid/kg by IV infusion over 4 hours; then 8 hours after the start of the loading dose, give a maintenance dose of quinine, 10 mg salt/kg, over 4 hours. This maintenance dose should be repeated every 8 hours, calculated from the beginning of the previous infusion, until the patient can swallow, then quinine tablets, 10 mg salt/kg, 8-hourly to complete a 7-day course of treatment, or a single dose of 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine (maximum 1500 mg sulfadoxine–75 mg pyrimethamine).

Quinine (children): 20 mg dihydrochloride salt/kg (loading dose)¹ diluted in 10 ml isotonic fluid/kg by IV infusion over 4 hours; then 12 hours after the start of the loading dose, give a maintenance dose of quinine, 10 mg salt/kg, over 2 hours. This maintenance dose should be repeated every 12 hours, calculated from the beginning of the previous infusion, until the patient can swallow, then quinine tablets, 10 mg salt/kg, 8-hourly to complete a 7-day course of treatment, or a single dose of 25 mg /kg sulfadoxine and 1.25 mg/kg pyrimethamine.

N.B.   If IV infusion is not possible, quinine can be given IM (see important points, opposite); alternatively, consider artemisinin/artesunate suppositories.
or
Artesunate² : 2.4 mg/kg (loading dose) IV, followed by 1.2 mg/kg at 12 and 24 hours, then 1.2 mg/kg daily for 6 days. If the patient is able to swallow, the daily dose can be given orally.
or
Artemether: 3.2 mg/kg (loading dose) IM, followed by 1.6 mg/kg daily for 6 days. If the patient is able to swallow, the daily dose can be given orally.

N.B.   If parenteral administration is not possible, artemisinin or artesunate suppositories may be given.

Artemisinin suppositories: 40 mg/kg (loading dose) intrarectally, then 20 mg/kg 24, 48 and 72 hours later, followed by an oral antimalarial drug.³
or
Artesunate suppositories: 200 mg intrarectally at 0, 12, 24, 36, 48 and 60 hours may prove to be highly effective and is in trial. A loading dose of 4 mg/kg intrarectally, followed by 2 mg/kg at 4, 12, 48 and 72 hours has been used in Viet Nam. This treatment should be followed by an oral antimalarial drug.³

As a last resort, if parenteral quinine, artemisinin, or artesunate is not available:
Quinidine: 15 mg base/kg (loading dose) by IV infusion over 4 hours, then 8 hours after the start of the loading dose, give 7.5 mg base/kg over 4 hours, 8-hourly, until the patient can swallow, then quinine tablets (dosage as above for adults and children) to complete a 7-day course of treatment, or a single dose of 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine.

Chloroquine: 10 mg base/kg in isotonic fluid by constant-rate IV infusion over 8 hours, followed by 15 mg/kg given over the next 24 hours.
or
Chloroquine: 5 mg base/kg in isotonic fluid by constant-rate IV infusion over 6 hours, every 6 hours, for a total of 5 doses (i.e. 25 mg base/kg continuously over 30 hours).
or
(If IV infusion is not possible) chloroquine, 3.5 mg base/kg, every 6 hours IM or SC.⁴
or
Quinine or artemisinin derivative (see opposite).

¹   Alternatively, the loading dose can be administered as 7 mg salt/kg by IV infusion (or pump) over 30 minutes, followed immediately by 10 mg salt/kg diluted in 10 ml isotonic fluid/kg by IV infusion over 4 hours.
²   Artesunic acid, 60 mg per ampoule, is dissolved in 0.6 ml of 5% sodium bicarbonate diluted to 3–5 ml with 5% dextrose and given immediately by IV bolus ("push") injection.
³   For example, mefloquine, 25 mg/kg in two divided doses 8–24 hours apart.
⁴   Total dose 25 mg base/kg; change to oral therapy when the patient can swallow.

In areas where a 7-day course of quinine is not curative (e.g. Thailand), add an oral course of tetracycline 4 mg/kg four times daily or doxycycline 3 mg/kg once daily, for 3–7 days, as soon as the patient can swallow (NOT in children under 8 years and pregnant women); or clindamycin 10 mg/kg twice a day, for 3–7 days, as soon as the patient can swallow.

If there is no clinical improvement after 48 hours of parenteral therapy, the maintenance dose of quinine or quinidine should be reduced by one-third to one-half (i.e. 5–7 mg quinine dihydrochloride/kg or 3.75–5 mg quinidine base/kg, 8-hourly).

Total daily doses of IV quinine in those patients who are not improving after 48 hours of parenteral therapy are as follows:

day 0 (first day of treatment): 30–40 mg salt/kg of body weight
day 1: 30 mg salt/kg of body weight
day 2 and subsequent days: 15–21 mg salt/kg of body weight

day 0 (first day of treatment): 30–40 mg salt/kg of body weight
day 1: 20 mg salt/kg of body weight
day 2 and subsequent days: 10–14 mg salt/kg of body weight

It is unusual to have to continue IV infusions of quinine for more than 4–5 days. If it is more convenient, quinine may be given by continuous infusion. (Infusion rates should not exceed 5 mg salt/kg of body weight per hour.)

A loading dose of quinine should not be used if the patient has received quinine, quinidine or mefloquine within the preceding 12 hours.

If for some reason quinine cannot be administered by infusion, quinine dihydrochloride can be given in the same dosages by IM injection in the anterior thigh ( not in the buttock). The dose of quinine should be divided between two sites – half the dose in each anterior thigh. If possible, for IM use, quinine should be diluted in normal saline to a concentration of 60–100 mg salt/ml.

Global status of chloroquine resistance

Among the countries where falciparum malaria is endemic, only those of Central America have not reported resistance of Plasmodium falciparum to chloroquine. Chloroquine resistance of various levels is now common in practically all endemic countries of Africa and, especially in eastern Africa, poses increasing problems for the provision of adequate treatment. In western and middle South Asia, as well as in Malaysia, the Philippines and Oceania, levels of chloroquine resistance are variable.

In view of the global distribution of chloroquine resistance, except for countries of Central America, chloroquine should not be used to treat severe falciparum malaria.

Summary of the management of severe falciparum malaria

In all cases an appropriate antimalarial drug should be started immediately and complications managed appropriately as below.

1.   Coma (cerebral malaria)
Maintain airway; nurse on side; exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningoencephalitis). Avoid harmful adjuvant treatments such as corticosteroids, heparin and epinephrine (adrenaline).

2.   Convulsions
Maintain airway; treat with diazepam given intravenously (0.15 mg/kg of body weight) or intrarectally (0.5 mg/kg of body weight), or intramuscular paraldehyde injection (0.1 ml/kg of body weight). Paraldehyde should, if possible, be given from a glass syringe. A disposable plastic syringe may be used, provided that the injection is given immediately the paraldehyde is drawn up and that the syringe is never reused.

3.   Severe anaemia
Transfuse screened fresh whole blood or packed cells.

4.   Acute renal failure
Exclude dehydration; maintain strict fluid balance; carry out dialysis if indicated.

5.   Hypoglycaemia
Measure blood glucose, give 50% dextrose injection 50 ml (1 ml/kg of body weight for children) followed by 5% or 10% dextrose infusion.

6.   Metabolic acidosis
Exclude or treat hypoglycaemia, hypovolaemia and Gram-negative septicaemia. Give isotonic saline 20 ml/kg of body weight rapidly or screened whole blood 10 ml/kg of body weight over 30 minutes if haemoglobin is <5g/dl.

7.   Acute pulmonary oedema
Prevent by avoiding excessive rehydration. Prop patient up; give oxygen. If pulmonary oedema is due to over-hydration, stop intravenous fluids, give a diuretic (furosemide (frusemide) 40 mg intravenously) and withdraw 3 ml/kg of blood by venesection into a donor bag.

8.   Shock,algid malaria
Suspect Gram-negative septicaemia; take blood samples for culture. Give parenteral antimicrobials; correct haemodynamic disturbances.

9.   Spontaneous bleeding and coagulopathy
Transfuse screened fresh whole blood or clotting factors; give vitamin K, 10 mg intravenously.

10.  Hyperpyrexia
Give antipyretic (paracetamol 15 mg/kg of body weight) and use tepid sponging and fanning.

11.  Hyperparasitaemia
Give initial dose of parenteral antimalarial therapy; consider exchange transfusion if there are other signs of severity.

12.  Malarial haemoglobinuria
Continue antimalarial treatment; transfuse screened fresh blood if needed.

13.  Aspiration pneumonia
Give parenteral antimicrobials; change position of patient; give physiotherapy; give oxygen.