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