Intrarectal quinine versus intravenous or intramuscular quinine for treating Plasmodium falciparum malaria

doi:10.1002/14651858.CD004009.pub3

Intervention Review

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Intrarectal quinine versus intravenous or intramuscular quinine for treating Plasmodium falciparum malaria

Michael Eisenhut^1,*,
Aika AA Omari²

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 27 AUG 2008

DOI: 10.1002/14651858.CD004009.pub3

Database Title

The Cochrane Library

Additional Information

How to Cite

Eisenhut M, Omari AAA. Intrarectal quinine versus intravenous or intramuscular quinine for treating Plasmodium falciparum malaria. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004009. DOI: 10.1002/14651858.CD004009.pub3.

Author Information

¹
Luton & Dunstable Hospital NHS Foundation Trust, Paediatric Department, Luton, UK
²
Alder Hey Children's Hospital, Liverpool, UK

^*Michael Eisenhut, Paediatric Department, Luton & Dunstable Hospital NHS Foundation Trust, Lewsey Road, Luton, LU4 0DZ, UK. michael.eisenhut@talk21.com.

Publication History

Publication Status: New search for studies and content updated (no change to conclusions)
Published Online: 21 JAN 2009

ARTICLE TOOLS

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Characteristics of included studies [ordered by study ID]

Achan 2007

Methods	Design: randomized controlled trial Generation of allocation sequence: computer randomization Allocation concealment: assignments sealed in opaque numbered envelopes; preparation of drugs and placebos in a separate room by separate treatment nurses Blinding: double blind Inclusion of all randomized participants in the final analysis: 100% (110/110)

Participants	Number: 110 children aged 6 months to 5 years Inclusion criteria: children aged 6 months to 5 years with cerebral malaria (as defined by the World Health Organization) Exclusion criteria: Blantyre coma score ≥ 3; diarrhoea; anal pathology; quinine given in the previous 48 hours

Interventions	1. Intravenous quinine base (8 mg/kg of quinine base) given as Quinimax 8 hourly until oral treatment possible 2. Intrarectal quinine base 20 mg/kg as the buffered proprietary preparation Quinimax as initial dose followed by 15 mg/kg of quinine base 8 hourly until oral treatment possible

Outcomes	1. Parasite clearance time 2. Coma recovery time 3. Fever clearance time 4. Time to begin oral intake 5. Time to sit unsupported 6. Adverse events

Notes	Location: Uganda Date: September 2003 to January 2004 Source of funding: Sanofi-Synthelabo, Gentilly, France

Assimadi 2002

Methods	Design: randomized controlled trial Generation of allocation sequence: not described Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: not reported

Participants	Number: 64 children aged 0 to 15 years Inclusion criteria: positive thick film; uncomplicated malaria with vomiting; single seizure with post-ictal loss of consciousness < 30 minutes; clinical prostration without neurological signs Exclusion criteria: diarrhoea; quinine in preceding week; any rectal-anal anomaly

Interventions	1. Intramuscular quinine base (12.5 mg/kg 12 hourly for 72 hours) 2. Intrarectal quinine (15 mg/kg 12 hourly for 72 hours); Quinimax, the buffered proprietary preparation was diluted with water and injected with a syringe

Outcomes	1. Death 2. Parasite clearance by 48 hours 3. Adverse events

Notes	Location: Togo Date: November 1998 to August 1999 Source of funding:

Barennes 1995

Methods	Design: quasi-randomized controlled trial Generation of allocation sequence: alternate allocation Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: parasite clearance time only analysed for 30% (20/66) trial participants with no reason for the missing participants

Participants	Number: 66 children aged 2 to 15 years Inclusion criteria: > 1000 asexual Plasmodium falciparum parasites/µL; acute malaria with vomiting; slight coma and restlessness of convulsions warranting parenteral therapy; consent Exclusion criteria: deep coma; diarrhoea; other documented causes of fever; other antimalarial in preceding week

Interventions	1. Intrarectal quinine (11.8 mg/kg base 12 hourly for 3 days); given as the buffered proprietary preparation Quinimax diluted with 2 mL of water and administered with a 5 mL syringe 2. Intravenous quinine (7.4 mg/kg base 12 hourly for 3 days) 3. Intramuscular quinine (7.4 mg/kg base 12 hourly for 3 days)

Outcomes	1. Parasite clearance by day 7 2. Parasite clearance time 3. Fever clearance time 4. Death 5. Adverse events

Notes	Location: Niger Date: 1992 to 1994 Source of funding: Sanofi-Synthelabo, Gentilly, France

Barennes 1996a

Methods	Design: randomized controlled trial Generation of allocation sequence: not described Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: not reported

Participants	Number: 21 children aged 2 to 14 years Inclusion criteria: > 1000 asexual Plasmodium falciparum/µL; acute malaria with vomiting; slight coma; no neurological symptoms of cerebral malaria Exclusion criteria: coma score < 12 on Glasgow coma scale; other documented causes of fever; diarrhoea; other antimalarial in preceding week

Interventions	1. Intrarectal quinine (8 mg/kg base 8 hourly for 3 days); administered as quinine gluconate as quinine cream, a buffered proprietary preparation 2. Intramuscular quinine (4.7 mg/kg base 8 hourly for 3 days) 3. Intravenous quinine (4.7 mg/kg base 8 hourly for 3 days)

Outcomes	1. Death 2. Parasite clearance by day 7 3. Adverse events

Notes	Location: Niger Date: July to December 1993 Source of funding:

Barennes 1998

Methods	Design: randomized controlled trial Generation of allocation sequence: random-numbers tables Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: 98.7% (76/77); 1 participant excluded

Participants	Number: 77 children aged 2 to 15 years Inclusion criteria: > 1000 asexual Plasmodium falciparum/µL; unrousable coma Exclusion criteria: other cases of coma; severe anaemia; diarrhoea; antimalarials within preceding 48 hours

Interventions	1. Intrarectal quinine (11.8 mg/kg quinine base once, then 8.8 mg/kg 8 hourly for 2 days); quinine base was given as Quinimax solution as buffered proprietary solution diluted in water via a 5 mL syringe 2. Intravenous quinine (4.7 mg/kg base 8 hourly for 2 days) Both groups received oral chloroquine for 3 days after this

Outcomes	1. Death 2. Parasite clearance time 3. Fever clearance time 4. Days in hospital 5. Coma recovery time 6. Time to drinking 8. Adverse events

Notes	Location: Niger Date: July to December 1995 Source of funding: Sanofi-Synthelabo, Gentilly, France

Barennes 1999

Methods	Design: randomized controlled trial Generation of allocation sequence: random-numbers tables Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: not reported

Participants	Number: 15 children aged 2 to 14 years Inclusion criteria: > 1000 asexual Plasmodium falciparum/µL Exclusion criteria: severe malaria; diarrhoea; other causes of fever; other antimalarial within preceding 48 hours

Interventions	1. Intravenous quinine (4.74 mg/kg quinine base immediately) 2. Intramuscular quinine (4.74 mg/kg quinine base immediately) 3. Intrarectal quinine as buffered proprietary solution (11.85 mg/kg base immediately) All groups given oral Quinimax (8 mg/kg 8 hourly for 3 days)

Outcomes	1. Death 2. Parasite clearance by day 7 3. Adverse events

Notes	Location: Niger Date: 1996 Source of funding:

Barennes 2001

Methods	Design: randomized controlled trial Generation of allocation sequence: random-numbers tables Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: not reported

Participants	Number: 58 children aged 2 to 15 years Inclusion criteria: clinically severe malaria as defined by the World Health Organization Exclusion criteria: any rectal-anal pathology; diarrhoea; pre-existing major illness apart from malaria; immediate life-threatening condition (eg decompensating anaemia or shock)

Interventions	1. Intrarectal quinine base (17.9 mg/kg immediately, then 11.75 mg/kg 12 hourly); given as Quinimax as buffered, proprietary solution diluted with 2 to 4 mL of water through a syringe 2. Intramuscular quinine base (7.5 mg/kg 12 hourly)

Outcomes	1. Death 2. Fever clearance time 3. Duration of hospitalization 4. Coma recovery time

Notes	Location: Niger; paper reports two sites Dosso and Niamey (published as Barennes 1998) Date: 1995 to 1996 Source of funding: Sanofi-Synthelabo, Gentilly, France

Barennes 2003

Methods	Design: randomized controlled trial Generation of allocation sequence: not described Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: not reported

Participants	Number: 48 children aged 2 to 15 years Inclusion criteria: > 1000 asexual Plasmodium falciparum/µL; vomiting impeding any oral treatment Exclusion criteria: unconscious (Blantyre coma scale < 4); other forms of severe malaria; diarrhoea; other documented causes of fever; antimalarial treatment within preceding week

Interventions	1. Intravenous quinine bichlorhydrate 2. Intrarectal quinine bichlorhydrate (no data on buffering of solution) 3. Intravenous cinchona alkaloid 4. Intrarectal cinchona alkaloid (no data on buffering of solution); given diluted in a syringe Dose: 8 mg/kg quinine base 8 hourly Duration: 2 days All received oral quinine to complete 5 days of treatment

Outcomes	1. Parasite clearance by 48 hours 2. Parasite clearance by day 7

Notes	Location: Burkina Faso Date: not stated Source of funding:

Barennes 2006

Methods	Design: randomized controlled trial Generation of allocation sequence: computer randomization Allocation concealment: sealed envelope Blinding: not used Inclusion of all randomized participants in the final analysis: detailed analysis of drop outs given

Participants	Number: 898 children aged 1 to 15 years Inclusion criteria: < 15 years; non severe Plasmodium falciparum malaria with >1000 asexual parasites/µL in which antimalarials could not be administered by mouth Exclusion criteria: diarrhoea; anal lesion; traditional enema in the previous week

Interventions	1. Intrarectal quinine base (20 mg/kg 12 hourly for 3 days); Quinimax was given as buffered, proprietary gluconate solution diluted with water in a syringe 2. Intramuscular quinine base (12.5 mg/kg 12 hourly for 3 days)

Outcomes	1. Death 2. Fever clearance time 3. Time to oral intake 4. Adverse events

Notes	Location: Burkina Faso Date: 2000 and 2001 Source of funding: Sanofi-Synthelabo, Gentilly, France

Pussard 2004

Methods	Design: randomized controlled trial Generation of allocation sequence: unknown Allocation concealment: not used Blinding: not used Inclusion of all randomized participants in the final analysis: 100% (60/60)

Participants	Number: 60 children; aged 4 to 162 months Inclusion criteria: children with moderate malaria and > 1000 asexual Plasmodium falciparum parasites/µL and requiring parenteral treatment Exclusion criteria: severe malaria (cerebral malaria, severe hypoglycaemia, or anaemia); diarrhoea; anatomical abnormalities of the rectum and antimalarial treatment within the preceding week

Interventions	1. Intrarectal quinine base either 8 mg/kg or 16 mg/kg 8 hourly or 12 mg/kg or 20 mg/kg 12 hourly for 48 hours; preparation used was Quinimax (buffered proprietary solution of quinine as gluconate) 2. Intramuscular quinine 12 mg/kg 12 hourly for 48 hours 3. Intravenous quinine 8 mg/kg 8 hourly for 48 hours

Outcomes	1. Parasite clearance at 24, 48, and 72 hours 2. Parasite count (number of parasites/µL) at 24 hours 3. Body temperature at 24 and 48 hours

Notes	Location: Burkina Faso Date: unknown Source of funding: Sanofi-Synthelabo, Gentilly, France

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion

Barennes 1989	Not a randomized controlled trial

Barennes 1993	Not a randomized controlled trial

Barennes 1994	Letter not containing data on randomized controlled trials

Barennes 1996b	Comparison of different doses of intrarectal quinine only; no control group

Barennes 1999b	Summary of observations and narrative review of previous trial without data on a randomized controlled trial

Landais 2007	Not a randomized controlled trial

Ndiaye 2007	Not a randomized controlled trial

Pussard 1996	Not a randomized controlled trial; review of intrarectal administration of antimalarial drugs

Thera 2007	Not a randomized controlled trial