High first dose quinine regimen for treating severe malaria

 

Characteristics of included studies [ordered by study ID]

Assimadi 2002

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Methods	Randomized controlled trial
Participants	Number of participants: 72 Inclusion criteria: children between 8 months to 15 years with cerebral malaria
Interventions	1. Loading dose: 17.5 mg/kg intravenous quinine base followed 8 h later by 8.7 mg/kg and then every 12 h 2. Uniform dose: 13.1 mg/kg intravenous quinine base every 12 h
Outcomes	1. Death 2. Duration of coma 3. Parasite clearance time 4. Adverse events
Notes	Study location: Lome, Republic of Benin Parasite counts and clinical assessments done every 6 h

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Fargier 1991

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Methods	Randomized controlled trial
Participants	Number of participants: 20 Inclusion criteria: 15 years and above with cerebral malaria
Interventions	1. Loading dose: 16 mg/kg intravenous quinine base followed by 8 mg/kg every 8 h 2. Uniform dose: 8 mg/kg intravenous quinine base every 8 h
Outcomes	1. Duration of coma 2. Parasite clearance time
Notes	Study location: Yaounde, Cameroon (Central Africa)

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Pasvol 1991

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Methods	Randomized controlled trial
Participants	Number of participants: 59; 20 not included in the final analysis as they had been randomized to a group that received intramuscular quinine Inclusion criteria: children with severe malaria
Interventions	1. High initial dose: 20 mg/kg intravenous or intramuscular quinine salt followed by 10 mg/kg every 12 h 2. Uniform dose: 5 to 10 mg/kg intravenous quinine salt every 12 h
Outcomes	1. Death 2. Convulsion 3. Fever clearance time 4. Parasite clearance time 5. Coma recovery time 6. Adverse events
Notes	Study location: Kilifi, Kenya Parasite counts and clinical parameters every 6 h

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Tombe 1992

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Methods	Randomized controlled trial
Participants	Number of participants: 33 Inclusion criteria: aged 14 years and above with severe malaria
Interventions	1. Loading dose: 20 mg/kg intravenous quinine salt followed by 10 mg/kg every 8 h 2. Uniform dose: 10 mg/kg quinine salt every 8 h
Outcomes	1. Death 2. Fever clearance time 3. Parasite clearance time 4. Adverse events
Notes	Study location: Nairobi, Kenya Parasite counts every 6 h

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Davis 1988	Clinical trial; not a randomized controlled trial
Davis 1990	Clinical trial; not a randomized controlled trial
Mehta 1994	Case control study; participants matched for age and sex; not a randomized controlled trial
van der Torn 1998	Not a randomized controlled trial
White 1983	Some participants did not have severe malaria
Winstanley 1994	Clinical trial; not a randomized controlled trial

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Comparison 1. High first (loading) dose compared with no loading dose

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Death

3

144

Risk Ratio (M-H, Fixed, 95% CI)

0.62 [0.19, 2.04]

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 2 Coma recovery time

2

99

Mean Difference (IV, Fixed, 95% CI)

5.17 [-1.14, 11.47]

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 3 Convulsions

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

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 4 Fever clearance time

2

68

Mean Difference (IV, Fixed, 95% CI)

-11.11 [-20.04, -2.18]

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 5 Parasite clearance time

2

67

Mean Difference (IV, Fixed, 95% CI)

-7.44 [-13.24, -1.64]

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 6 Number with asexual parasitaemia at 24 hours

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

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 7 Number with asexual parasitaemia at 48 hours

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

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 8 Neurological sequelae

2

111

Risk Ratio (M-H, Fixed, 95% CI)

0.56 [0.11, 2.90]

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 9 Adverse events

3

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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9.1 Hypoglycaemia

2

72

Risk Ratio (M-H, Fixed, 95% CI)

1.39 [0.32, 6.00]

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9.2 Tinnitus

1

33

Risk Ratio (M-H, Fixed, 95% CI)

2.82 [0.33, 24.43]

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9.3 Hearing loss

1

33

Risk Ratio (M-H, Fixed, 95% CI)

3.14 [1.05, 9.38]

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9.4 Cinchonism

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

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9.5 Hypotension (diastolic blood pressure < 60 mm mercury)

1

33

Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.84, 1.19]

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9.6 Arrhythmia (prolonged QT interval)

1

72

Risk Ratio (M-H, Fixed, 95% CI)

3.17 [0.13, 75.24]

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Table 1. Search strategies for databases

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Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b
1	quinine	quinine	QUININE	quinine	quinine
2	malaria	loading dose	quinine	quinimax	malaria
3	—	high dose	1 or 2	1 or 2	1 and 2
4	—	malaria	loading dose	loading dose	—
5	—	2 or 3	high dose	high dose	—
6	—	1 and 4 and 5	load*	4 or 5	—
7	—	—	4 or 5 or 6	3 and 6	—
8	—	—	3 and 7	exp MALARIA	—
9	—	—	exp MALARIA	malaria	—
10	—	—	malaria	8 or 9	—
11	—	—	9 or 10	7 and 10	—
12	—	—	8 and 11	limit 11 to human	—
13	—	—	limit 12 to human	—	—

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 ^aCochrane Infectious Diseases Group Specialized Register.
^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Alderson 2004); upper case: MeSH or EMTREE heading; lower case: textword.

 

Table 2. Comparison of treatment groups given intravenous quinine (Fargier 1991)^a

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Outcome	Loading dose	No loading dose	P value
Mean age (years)	24.2	22.1	Not statistically significant
Glasgow coma score on admission	8.6 (6 to 11)	8.8 (8 to 11)	Not statistically significant
Duration of coma before admission (h)	10.0	10.2	Not statistically significant
Duration of coma after start of treatment (h)	6.8 (3 to 14)	13.0 (8 to 24)	0.003
Parasite clearance time (h)	40.8	52.2	0.05

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 ^aNon-parametric Mann-Whitney U test corrected for ties; figures presented are median (range) except where otherwise stated.

 

Table 3. Risk of bias assessment

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Trial	Sequence	Concealment	Blinding	Loss to follow up
Assimadi 2002	Unclear	Unclear	None	Unclear^a
Fargier 1991	Adequate (using random-number tables)	Unclear	None	Unclear^a
Pasvol 1991	Adequate (using computers)	Adequate (sealed envelopes)	None	Inadequate (loading dose group: 21 randomized, 1 excluded, 2 had another severe diagnosis (meningitis), 18 analysed; uniform dose group: 22 randomized, 1 excluded, 1 withdrew, 20 analysed)
Tombe 1992	Adequate (using random-number tables)	Unclear	None	Unclear^a

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 ^aNo information in the published trial, and the trial authors did not respond to our request for clarification.