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Table 1 List of randomized controlled trials of adjunctive therapy in severe malaria

From: Adjunctive therapy for severe malaria: a review and critical appraisal

Author, year, country, references Antimalarial Adjuvant therapy Dosage and route Study design Type of malaria Ages Sample size Outcome
Immunomodulation
 Warrell et al. 1982, Thailand, [31] IV quinine Dexamethasone IV; children 0.6 mg/kg at the start followed by 7 doses of 0.2 mg/kg at 6-h intervals; adults 0.5 mg/kg at the start followed by 7 doses of 10 mg each (total duration of treatment 48 h) RCT, DB, PC CM 6–70 years 100 Failed to decrease mortality. Increased risk of adverse events (prolonged coma, pneumonia and gastrointestinal bleeding)
 Hoffman et al. 1988, Indonesia, [32] IV quinine Dexamethasone IV; initial dose, 3 mg/kg; total, 11.4 mg/kg per 48 h RCT, DB, PC CM 1.5–42 years 38 No differences in mortality, parasite and fever clearance times or incidence of complications
 Taylor et al. 1992, Malawi, [34] IV quinine Immunoglobulin (IFAT antimalarial Ab) IV; 400 mg/kg over 3 h RCT, DB, PC Coma 1–12 years 31 Increased mortality but not statistically significant. No differences in parasite and fever clearance times or incidence of complications
 Havlik et al. 2005, Thailand, [36] IV artesunate Curdlan sulphate IV; 4 mg/kg over 30 min/8 h (adjusted dose according to APTT) RCT, DB, PC SM but not CM (Phase IIB); SM and CM (Phase IIC) 12–60 years Phase IIB: 44; Phase IIC: 26 No differences in mortality or parasite clearance times. Trend to improve duration of coma and fever clearance time
 van Hensbroek et al. 1996, The Gambia, [37] IM quinine and IM artemether ± oral pyrimethaminesulfadoxine anti-TNF mAb IV; 5 mg/kg over 15 min RCT, DB, PC CM 1–9 years 624 No differences in mortality, coma recovery or complications. Lower fever clearance time. Trend towards faster parasite clearance time. Higher rate of neurological sequelae
 Di Perri et al. 1995, Burundi, [38] IV quinine Pentoxifyline IV; 10 mg/kg/24, 72 h RCT CM < 14 years 56 Lower mortality not statistically significant. Significant reduction in coma recovery
 Das et al. 2003, India, [39] IV quinine Pentoxifylline IV; 10 mg/kg/24, 72 h RCT CM > 18 years 52 Improved mortality, not statistically significant. Significant reduction in coma recovery time
 Hemmer et al. 1997, Germany, [40] 1. IV quinine + doxycycline; 2. oral mefloquine or halofantrine Pentoxifylline IV; 5 mg/kg/24 h for 5 days RCT, DB, PC UM and CM 22–69 years 51 No differences in mortality, clinical outcomes or laboratory parameters. More side effects
 Looareesewam et al. 1998, Thailand, [41] IV artesunate Pentoxifylline IV; low (0.83 mg/kg/h) or high (1.67 mg/kg/h) over 72 h RCT, DB, PC SM 16–60 years 45 No significant differences in fever and parasite clearance time or in clinical outcomes
 Lell et al. 2005, Kenya, [42] IV quinine Pentoxifylline IV; 10 mg/kg/24 h for 72 h RCT, DB, PC CM 9 month–8 years 15 Higher mortality. No difference in coma recovery, incidence of complications or neurological sequelae. Trend to faster fever and parasite clearance times
Decreasing procoagulant effects
 Hemmer et al. 1991, Germany, [52] 1. IV quinine + oral doxycycline or oral mefloquine; 2. IV quinine + oral doxycycline Heparin or acetylsalicylic acid (ASA) IV: Heparin 70 U/kg/day SC. for 5 days; ASA 500 mg on days 0, 2, 4 RCT SM > 14 years 97 No difference in fever, parasite clearance, or time to discharge
Decreasing cytoadherence and sequestration
 Maude et al. 2014, Bangladesh, [57] IV artesunate Levamisole Oral, 150 mg, single dose RCT, OL SM 21–45 years 56 No differences in mortality, parasite clearance time, ‘sequestration ratio’ or normalization of plasma lactate
Improving liver function
 Treeprasertsuk et al. 2009, Thailand, [80] IV artesunate Ursodeoxycholic acid IV; 750 mg/day, 2 weeks RCT, DB, PC SM with jaundice > 15 years 80 Safe, but no differences between liver test, fever and parasite clearance times
Restricting iron availability
 Gordeauk et al. 1992, Zambia, [81] IV quinine +oral pyrimethaminesulfadoxine Deferoxamine IV; 100 mg/kg/day over 72 h RCT, DB, PC CM 20–54 months 83 Lower mortality, not statistically significant. Faster coma recovery time and parasite clearance time
 Thuma et al. 1998, Zambia, [82] IV quinine Deferoxamine IV; 100 mg/kg/day over 72 h RCT, PC CM < 6 years 352 Non-significant trend to faster recovery from coma. No statistical differences in mortality
 Mohanty et al. 2002, India, [83] IV quinine and oral doxycycline Deferiprone Oral; 75 mg/kg/day in 12 hourly divided doses over 10 days RCT, DB, PC SM 13–84 years 45 Faster fever, parasite clearance and coma recovery time. No differences in mortality
Prevention of seizures
 White et al. 1988, Thailand, [85] IV quinine Phenobarbital IM; 3.5 mg/kg, single dose RCT, DB, PC CM 6–78 years 48 Fewer convulsions
 Crawley et al. 2000, Kenya, [86] IV quinine Phenobarbital IM; 20 mg/kg, single dose RCT, DB, PC CM 19–65 months 340 Fewer convulsions. Higher mortality
Decreasing intracranial pressure
 Namutangula et al. 2007, Uganda, [91] IV quinine Mannitol IV; 1 g/kg RCT, DBO, PC CM 6–60 months 156 Did not significantly reduce time taken to regain consciousness, sit unsupported, or mortality
 Mohanty et al. 2011, India, [92]   Mannitol IV; 1.5 g/kg over 15 min, followed by 0.5 g/kg every 8 h until the patient regained consciousness or for a maximum period of 72 h RCT, OL, PC CM with brain swelling 25–31 years 61 Trend towards higher mortality in mannitol group. Mannitol prolonged coma recovery
Fluid resuscitation
 Maitland et al. 2005, Kenya, [97] IV quinine Human albumin/saline IV; 20 mL/kg of either 4.5% human albumin solution or 0.9% saline vs control (fluids maintenance group) RCT, OL SM with either moderate and severe acidosis > 1 years 150 Safe and resulted in significantly lower mortality. Acidosis did not improve
Akech et al. 2006, Kenya, [98] IV quinine Human albumin/gelofusine IV; 20–40 mL/kg of either 4.5% human albumin solution or gelofusine RCT, OL SM > 3 years 88 Trend to lower mortality, not statistically significant with albumin. No difference between shock and acidosis recovery. Higher neurological sequelae with albumin group
Fluid resuscitation
 Maitland et al. 2011, Uganda, Kenya, Tanzania, [99] IV quinine Human albumin/saline 20 mL/kg of either 4.5% human albumin solution or 0.9% saline vs (fluids maintenance group) RCT, OL SM 2 month–12 years 1793 SM cases out of 3123 total sample size Higher mortality in children treated with bolus
Decreasing oxidative stress
 Watt et al. 2002, Thailand, [105] IV artesunate N-Acetylcysteine IV; 300 mg/kg over 20 h RCT, DB, PC SM > 18 years 30 Faster normalization of lactate levels and Glasgow Coma Score
 Treeprasertsuk et al. 2003, Thailand, [106] IV artesunate N-Acetylcysteine IV, oral: 3 different regimes RCT, PC SM 14–16 years 108 No differences in mortality, fever and parasite clearance time. No differences in adverse events between groups
Charunwatthana et al. 2009, Bangladesh, Thailand, [107] IV artesunate N-Acetylcysteine IV; 300 mg/kg over 20 h RCT, DB, PC SM 30–39 years 108 No differences in clearance of elevated plasma lactate levels, coma recovery times, mortality, fever clearance time, and complications or adverse events
Correcting lactic acidosis
 Khrisna et al. 1994, Thailand, [112] IV quinine Dichloroacetate IV; 46 mg/kg, single dose not stated SM > 14 years 45 Decreased lactate concentrations. No evidence of toxicity. Mortality, incidence of complications and clinical/parasitological measures of recovery did not differ
Correcting lactic acidosis
 Khrisna et al. 1995, Ghana, [113] IM quinine Dichloroacetate IV; 50 mg/kg, single dose RCT, OL, PC SM 1.5–12 years 18 Decreased lactate concentrations. No differences in mortality, fever or parasite clearance times
 Khrisna et al. 1996, Thailand, [114] IV quinine Dichloroacetate IV; 46 mg/kg single dose RCT, OL, PC SM > 14 years 20 No differences in mortality, greater decrease in lactate concentrations
 Agbenyega et al. 2003, Ghana, [115] IV quinine Dichloroacetate IV; 50 mg/kg, single dose RCT, DB, PC SM 1–12 years 124 Significantly reduced the concentration of blood lactate
Increasing NO availability
 Hawkes et al. 2015, Uganda, [119] IV artesunate Nitric Oxide inhaled, 80 ppm RCT, B, PC SM 1–10 years 180 No differences in levels of Ang-2. No differences in mortality, recovery rates or parasite clearance time
 Mwanga-Amumpaire et al. 2015, Uganda, [120] IV artesunate Nitric Oxide inhaled, 80 ppm RCT, OL, PC CM 2 month–2 years 92 Did not increase Ang-1, did not reduce mortality rate. Similar clinical outcomes and neurological sequelae between groups
  1. Ab antibody, Ang angiopoeitin, APPT activated partial thromboplastin time, CM cerebral malaria, IM intramuscular, IV intravenous, mAb monoclonal antibody, MO: months, NO nitric oxide, OL open-label, PC placebo-controled, PPM parts per million, SC subcutaneous, SM severe malaria, UM uncomplicated malaria, YR years