Cao 1997.

Methods	Study design: A 3‐arm open label randomized controlled trial Study dates: Aug 1992 to Mar 1995
Participants	Number: 72 enrolled Inclusion criteria: children < 15 yr with severe malaria (asexual P. falciparum parasitaemia plus at least 1 of the following: coma (Blantyre Coma Scale less than or equal to 3), severe anaemia (capillary haematocrit < 15%) with parasitaemia (> 10,000/µL); hyperparasitaemia (> 10% parasitized red blood cells or parasitaemia > 500,000/µL); jaundice (obvious clinically or serum bilirubin > 48 µmol/L); hypoglycaemia (blood glucose < 2.2 mmol/L); spontaneous bleeding (eg gastrointestinal haemorrhage); shock (systolic blood pressure < 50 mmHg if aged < 6 yr, or < 70 mmHg if aged 6 to 14 yr); repeated generalized convulsions (3 or more in 24 h despite cooling); renal impairment (serum creatinine > 177 µmol/L, or urine output < 12 mL/kg/24 h that fails to improve despite rehydration) Exclusion criteria: severe diarrhoea, mixed infection with P. vivax, prior treatment with quinine > 60 mg/kg, artemisinin > 20 mg/kg, or artesunate > 2 mg/kg during the illness episode, or any antimalarial treatment continuing for > 48 h
Interventions	1. Artesunate: 3 mg/kg intramuscular (IM) at 0 h then 2 mg/kg IM at 12, 24, 48, and 72 h 2. Quinine: 20 mg/kg intravenous (IV) loading dose over 4 h (omitted if pretreatment with quinine) then 10 mg/kg IV every 8 h up to day 7 3. [Not relevant to review: rectal artemisinin] Additional antimalarials given: artesunate treatment arm received one dose of mefloquine by mouth 15 mg/kg at 96 h; quinine treatment arm given one dose of sulfadoxine‐pyrimethamine 500 mg/25 mg on day 7
Outcomes	1. Death 2. Number survived with neurological sequelae 3. Fever clearance time (all patients, excluding superinfections) 4. Coma resolution 5. Parasite clearance time of 50% 6. Parasite clearance time of 90% 7. Parasite clearance time of 100% 8. Period in hospital 9. Hypoglycaemia 10. Adverse effects Not included in this review: 11. Number survived well 12. Time to death from admission 13. Number with acute renal failure 14. Shock 15. Convulsions 16. Deterioration of coma score 17. Gastrointestinal bleeding 18. Anaemia 19. Chest infection 20. Urinary tract infection 21. Other infection 22. Reticulocyte count at admission, on day 5, at discharge 23. Haematocrit at admission, on day 5, at discharge
Notes	Location: Vietnamese hospital Transmission: not specified Funding: Wellcome Trust of Great Britain
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Personal communication with author: Computer generated
Allocation concealment (selection bias)	Low risk	Quote: 'Randomization slips were kept in sealed, consecutively numbered envelopes and opened only after a decision to include the patient in the study had been made'
Blinding (performance bias and detection bias) Objective outcomes: Death	Low risk	Comment: An open‐label trial is unlikely to bias an objective outcome like death
Blinding (performance bias and detection bias) Subjective outcomes: Others	High risk	Comment: An open label trial. No attempt was made to blind participants, providers or outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	Personal communication from author: 100% analysed, no losses to follow‐up.
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting
Other bias	Low risk	No other bias identified