Background
Treatment for children aged < 5 years with a diagnosis of severe malaria | GoK 2005 Basic Paediatric Protocols* | GoK 2010 Malaria Case Management Guidelines | WHO 2010 Malaria Case Management Guidelines |
---|---|---|---|
Pre-referral quinine loading dose | 15 mg/kg IM injection | 20 mg/kg IM injection | 20 mg/kg IM injection |
First-line treatment with quinine dose | 15 mg/kg loading dose then 10 mg/kg every 12 hours by IV infusion or divided IM injection | 20 mg/kg loading dose then 10 mg/kg every 8 hours by IV infusion or divided IM injection | 20 mg/kg loading dose then 10 mg/kg every 8 hours by IV infusion or divided IM injection |
Methods
Inclusion criteria | Exclusion criteria |
---|---|
P. falciparum malaria | Uncomplicated malaria |
Randomized Controlled Trials (observational studies to be considered if no RCT evidence) | IR administration |
Children < 5 years old (older children and adult data to be considered if no studies in children) | |
Diagnosis of severe or complicated malaria, confirmed with microscopy or rapid diagnostic test or cerebral malaria | |
African setting | |
IM or IV administration |
Evidence Quality | Level of confidence in estimate |
---|---|
High | Further research is very unlikely to change our confidence in the estimate of effect |
Moderate | Further research is likely to change our confidence in the estimate of effect, and may change the estimate |
Low | Further research is very likely to change the estimate of effect, and is likely to change the estimate |
Very low | The estimate of effect is very uncertain |
Results
Systematic review 1: Is there a value in administration of a loading dose of quinine in African children with severe malaria?
Test quinine sulphate dose (IV) | Comparator quinine sulphate dose (IV) | ||||
---|---|---|---|---|---|
Study | Age range | Country | Loading dose | Maintenance dose | Uniform dose |
Assimadi 2002* (N = 72) | 8 months to 15 years | Benin | 21 mg/kg | 10.5 mg/kg every 12 hours | 15.9 mg/kg every 12 hours |
Fargier 1991* (N = 20) | 15 years and above | Cameroon | 19 mg/kg | 9.7 mg/kg every 8 hours | 9.7 mg/kg every 8 hours |
Pasvol 1991
#
(N = 59) | up to 12 years | Kenya | 20 mg/kg | 10 mg/kg every 12 hours | 5 to 10 mg/kg every 12 hours |
Tombe 1992 (N = 33) | 14 years and above | Kenya | 20 mg/kg | 10 mg/kg every 8 hours | 10 mg/kg every 8 hours |
Systematic review 2: Should Kenya change its recommendation for treatment of severe malaria in children under 5 of 15 mg/kg loading dose followed by 10 mg/kg every 12 hours and replace it with the WHO recommended regimen of 20 mg/kg loading dose followed by 10 mg/kg every 8 hours?
Systematic review 3: What are the pharmacokinetics and effectiveness of IV-administered quinine compared to IM-administered quinine in African children with severe malaria?
Study ID | Age range | Country | IV Quinine Dose | IM Quinine Dose |
---|---|---|---|---|
Waller 1990 (N = 21) | 19 months to 8 years | Gambia | N/A | 20 mg/kg loading dose, then 10 mg/kg every 12 hours |
Pasvol 1991
‡
(N = 59) | up to 12 years | Kenya | 20 mg/kg loading dose, then 10 mg/kg every 12 hours | 20 mg/kg loading dose, then 10 mg/kg every 12 hours |
Krishna 1991 (N = 120) | 1 to 10 years | Ghana | N/A | 20 mg/kg loading dose, then 10 mg/kg every 12 hours |
Schapira 1993 (N = 104) | 6 months to 7 years | Mozambique | 20 mg/kg loading dose, then 10 mg/kg every 8 hours | 20 mg/kg loading dose, then 10 mg/kg every 8 hours |
Winstanley 1993 (N = 22) | 7 months to 6.8 years | Kenya | 14 mg/kg loading dose, then 10 mg/kg every 12 hours | 20 mg/kg loading dose, then 10 mg/kg every 12 hours |
Winstanley 1994 (N = 9) | 1 to 3 years | Kenya | 15 mg/kg loading dose, then 10 mg/kg every 12 hours | N/A |
van Hensbroek 1996 (N = 16) | 5 to 23 months | The Gambia | 20 mg/kg loading dose, then 10 mg/kg every 12 hours | 20 mg/kg loading dose, then 10 mg/kg every 12 hours |
Study ID
|
Age
|
Country
|
IR Quinine Dose
|
IV Quinine Dose
|
Achan 2007† (N = 110) | 6 months to 5 years | Uganda | 20 mg/kg base loading dose, then 10 mg/kg every 8 hours, until oral treatment possible | 8 mg/kg base every 8 hours, until oral treatment possible |
Bareness 1998† (N = 77) | 2 to 15 years | Niger | 11.8 mg/kg base loading dose, then 8.8 mg/kg every 8 hours for 2 days, then oral treatment with chloroquine | 4.7 mg/kg base every 8 hours for 2 days, then oral treatment with chloroquine |
Study ID
|
Age range
|
Country
|
IR Quinine Dose
|
IM Quinine Dose
|
Bareness 2001† (N = 58) | 2 to 15 years | Niger | 17.9 mg/kg base loading dose, then 11.75 mg/kg base every 12 hours | 7.5 mg/kg base every 12 hours |
Systematic review 3a: What is the effectiveness of IV-administered quinine compared to IM-administered quinine in African children with severe malaria?
Systematic review 3b: What is the pharmacokinetics of IV-administered quinine compared to IM-administered quinine in African children with severe malaria?
Study ID (sample size) | Evidence Quality | Route of admn | Sample size per arm | Quinine loading dose | Quinine maintenance dose | Infusion time | Cmax (mg/l) | tmax (h) | t1/2 (h) | Cl (ml/min/kg) | Vd (l/kg) | AUC (mg/l/h) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Pasvol 1991 (N = 43) | Low | IV | n = 21 | 10 mg/kg | 5 mg/kg | 2 h | 9.7 ± 5.3 | 2.7 ± 1.3 | 8.9 ± 4.0 | 1.36 ± 0.58 | 0.87 ± 0.27 | 145 ± 61 |
Winstanley 1993
(N = 22)
|
Very
Low
|
IV
|
n = 12
|
14 mg/kg
|
10 mg/kg bd
|
2 h
|
13.8 ± 3.1
|
-
|
16.4 ± 8.8
|
0.45 ± 0.13
|
0.45 ± 0.10
| |
Winstanley 1994 (N = 9)
|
Very
Low
|
IV
|
n = 9
|
15 mg/kg
|
10 mg/kg bd
|
2 h
|
17.9 ± 2.9
|
-
|
12.6 ± 3.1
|
0.81 ± 0.24
|
0.75 ± 0.11
| |
Pasvol 1991 (N = 43) | Low | IV | n = 18 | 20 mg/kg | 10 mg/kg bd | 2 h | 15.3 ± 5.5 | 2.4 ± 1.5 | 12.5 ± 3.2 | 1.19 ± 0.29 | 1.22 ± 0.16 | 254 ± 86 |
van Hensbroek 1996 (N = 16) | Very Low | IV | n = 6 | 20 mg/kg | 10 mg/kg bd | 4 h | 17.48 ± 2.43 | - | 13.16 ± 6.43 | 0.51 ± 0.16 | 1.04 ± 0.21 | 354 ± 143 |
Waller 1990 (N = 21)
|
Very
Low
|
IM
|
n = 21
|
20 mg/kg
|
10 mg/kg bd
|
N/A
|
15.4 ± 4.5
|
3.23 ± 1.63
|
18.8 ± 8.0
|
0.89 ± 0.81
|
-
|
449 ± 243
|
Pasvol 1991 (N = 43)
|
Low
|
IM
|
n = 20
|
20 mg/kg
|
10 mg/kg bd
|
N/A
|
15.3 ± 7.6
|
2.4 ± 1.7
|
15.7 ± 8.2
|
1.12 ± 0.56
|
1.22 ± 0.32
|
332 ± 254
|
Winstanley 1993 (N = 22)
|
Very
Low
|
IM
|
n = 10
|
20 mg/kg
|
10 mg/kg bd
|
N/A
|
15.7 ± 3.1
|
1.6 ± 1.7
|
-
|
-
|
-
|
-
|
van Hensbroek 1996 (N = 16)
|
Very
Low
|
IM
|
n = 10
|
20 mg/kg
|
10 mg/kg bd
|
N/A
|
16.36 ± 3.67
|
1.08 ± 0.37
|
15.31 ± 7.16
|
0.59 ± 0.25
|
1.32 ± 0.49
|
358 ± 164
|
Krishna 2001 (N = 120)
|
Very
Low
|
IM
|
n = 120
|
20 mg/kg
|
10 mg/kg bd
|
N/A
|
-
|
-
|
19.9 ± 4.4
|
0.05
|
-
|
-
|
Systematic review 4: Is there a link between IV-administered quinine and risk of hypoglycaemia in African children with severe malaria?
Study ID | Evidence quality | Age range | Country | IV Quinine Dose and diluent | Infusion time | Infusion rate (ml/kg/24 h) | Glucose Threshold (mmol/l) |
---|---|---|---|---|---|---|---|
Molyneux 1989 (N = 29) | Very low | 2 to 9 years | Malawi | 10 mg/kg in 5% glucose in half strength Darrow's solution | 1 h | 80 | < 2.2 |
10 mg/kg in 5% glucose in half strength Darrow's solution | 3 h | 80 | < 2.2 | ||||
20 mg/kg in 5% glucose in half strength Darrow's solution | 3 h | 80 | < 2.2 | ||||
Okitolonda 1987 (N = 9)* | Very low | 6 to 10 years | Zaïre | 10 mg/kg in 30 ml saline supplemented with 2.5% glucose every 8 hours | 1 h | 105 | < 2.8 |
Kawo 1991 (N = 97) | Very low | Up to 7 years | Tanzania | 10 mg/kg in 10 ml/kg of 5% glucose every 8 hours | 4 h | Not reported | < 2.2 |
Ogetii 2010 (N = 1237) | Low | Up to 12 years | Kenya | 15 mg/kg loading dose in 5% dextrose then 10 mg/kg in 5% dextrose every 12 hours | 2 h | Not reported | < 3, < 2.8 and < 2.2 |
20 mg/kg loading dose in 5% dextrose then 10 mg/kg in 5% dextrose every 8 hours | 4 h | Not reported | < 3, < 2.8 and < 2.2 | ||||
Taylor 1988 (N = 95) | Very low | 7 months to 8 years | Malawi | 20 mg/kg loading dose then 10 mg/kg every 8 hours | Loading dose 4 h, then maintenance dose 2 to 8 h | 80 | < 2.2 |
Dondorp 2010 | High | Up to 15 years | Multi-centre trial in Mozambique, The Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda and Democratic Republic of Congo | ¥20 mg/kg loading dose in 5-10 ml/kg of 5% dextrose then 10 mg/kg in 5-10 ml/kg of 5% dextrose every 8 hours | Loading dose 4 h, then maintenance dose 2 to 8 h | Not reported | Not reported |
Discussion
Clinical Issue | Recommendation | Evidence quality/strength of recommendation | |
---|---|---|---|
Systematic review 1: Is there a value in administration of a loading dose of quinine in African children with severe malaria?
| Quinine loading dose [9] | Loading dose results in faster clearance of malaria parasites from the blood stream and thus faster clearance of fever and thus loading dose should be administered, with monitoring and patient/care giver support for episodes of partial hearing loss adverse event | Moderate |
Systematic review 3a: What is the effectiveness of IV-administered quinine compared to IM-administered quinine in African children with severe malaria
| The clinical outcome of IV-administered quinine vs. IM-administered quinine is equivocal in the treatment of African children with severe malaria. However, due to reported side effects with IM route, such as risk of abscess and pain, the IV route is preferred. | Low to very low | |
Systematic review 3b: What is the pharmacokinetics of IV-administered quinine compared to IM-administered quinine in African children with severe malaria
| Pharmacokinetic profile of the old and new Kenyan dosing regimen are similar | Low | |
Systematic review 4: Is there a link between IV-administered quinine and risk of hypoglycaemia in African children with severe malaria?
| The risk of hypoglycaemia with quinine treatment in African children with severe malaria may be countered by administering the quinine at a low infusion rate. Glucose levels should be monitored due to hypoglycaemic risk that occurs due to the disease and/or quinine treatment, and should be treated with glucose infusion | Low to high | |
AQUAMAT Findings
| Quinine vs artemisinin derivatives [2] | Artesunate is a superior treatment to quinine for African children with severe malaria and should be strongly considered for implementation as a first line treatment, taking contextual factors such as cost-effectiveness into account | High |