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Oral zinc for treating diarrhoea in children

  1. Marzia Lazzerini1,*,
  2. Luca Ronfani2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 31 JAN 2013

Assessed as up-to-date: 20 FEB 2012

DOI: 10.1002/14651858.CD005436.pub4


How to Cite

Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD005436. DOI: 10.1002/14651858.CD005436.pub4.

Author Information

  1. 1

    WHO Collaborating Centre for Maternal and Child Health, Institute for Maternal and Child Health, Unit for Health Services Research and International Health, Trieste, Italy

  2. 2

    Institute for Maternal and Child Health, Unit of Epidemiology and Biostatistics, Trieste, Italy

*Marzia Lazzerini, Unit for Health Services Research and International Health, WHO Collaborating Centre for Maternal and Child Health, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, 8232, Italy. lazzerini@burlo.trieste.it.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 31 JAN 2013

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Characteristics of included studies [ordered by study ID]
Al-Sonboli 2003

MethodsRCT


ParticipantsNumber: 81

Inclusion criteria: age 3 to 60 months; diarrhoea < 7 days or 1 or more loose stool containing blood in the previous 24 h and at least mild dehydration

Exclusion criteria: suspected or confirmed severe systemic infections; antimicrobial or antidiarrhoeal treatment within 72 h before admission; severe malnutrition (< 60% median for weight for age of the NCHC standards)


Interventions1. Zinc sulphate: 22.5 mg (3 to 6 months) or 45 mg (7 to 60 months)
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Stool frequency


NotesLocation: Brazil

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Unclear riskNo details

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk8.6% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Bahl 2002

MethodsRCT


ParticipantsNumber: 1219

Inclusion criteria: age 6 to 35 months; acute diarrhoea (less than 4 days duration)

Exclusion criteria: visible blood in stools; likely to emigrate in the next 4 weeks; required hospitalization; previously enrolled; sibling  concurrently enrolled; refusal of consent


Interventions1. Zinc gluconate 30 mg (>12 months) or 15 mg (<12 months)  

2. Placebo


Outcomes1. Average duration of diarrhoea

2. Diarrhoea at day 3

3. Diarrhoea at day 5

4. Diarrhoea at day 7

5. Stool frequency

6. Adverse events (vomiting)


NotesLocation: India

Setting: Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated randomization lists

Allocation concealment (selection bias)Low riskThe glass bottles containing the products were labelled with the patient’s number corresponding to the randomization list by an independent individual who was not involved in patient enrolment. Randomization codes were secured until the completion of data collection and initial analysis.There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.

Blinding (performance bias and detection bias)
All outcomes
Low riskFour-blinded

Incomplete outcome data (attrition bias)
All outcomes
Low risk2% lost to follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Bhatnagar 2004a

MethodsRCT


ParticipantsNumber: 287

Inclusion criteria: male; 3 to 36 months; acute diarrhoea (< 72 h) with mild dehydration

Exclusion criteria: severe malnutrition (weight/height < 65% of NCHS median); visible blood in stool; severe systemic illness


Interventions1. Zinc sulphate: 15 mg (< 12 months) or 30 mg (> 12 months) syrup
2. Placebo

Both groups: multivitamin


Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 5
3. Diarrhoea at day 7
4. Stool output
5. Adverse events (vomiting)
6. Adverse events (copper levels)


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskCentral randomization performed at a site remote from trial location (World Health Organization, Geneva)

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Bhutta 1999b

MethodsRCT


ParticipantsNumber: 87

Inclusion criteria: 6 to 36 months; persistent diarrhoea (> 4 unformed stools/day for at least 14 days); malnutrition (weight-for-age z score < -2.0)

Exclusion criteria: kwashiorkor; clinical signs of vitamin A or zinc deficiency; needing intravenous fluids or unable to tolerate oral feeds after a 24-h period of stabilization


Interventions1. Zinc sulphate: 3 mg/kg/day
2. Placebo

Both groups: multivitamins


Outcomes1. Average duration of diarrhoea
2. Stool output
3. Adverse events (copper levels)


NotesLocation: Pakistan

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskCentral randomization by independent pharmacy; table block randomization maintained in the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
High risk11% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Brooks 2005a

MethodsRCT


ParticipantsNumber: 275

Inclusion criteria: male, 1 to 6 months; onset < 72 h; some dehydration or > 100 mL of watery stool within a 4-observation period

Exclusion criteria: clinical signs of zinc deficiency; kwashiorkor, weight/age < 60% NCHS; grossly bloody stool comorbidity; cholera


Interventions1. Zinc acetate: 20 mg
2. Zinc acetate: 5 mg
3. Placebo


Outcomes1. Death
2. Average duration of diarrhoea
3. Stool output
4. Stool frequency
5. Adverse events (vomiting)


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Unclear riskBottles labelled with randomization numbers; no other details

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk5% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Brooks 2005a (20 mg)

MethodsSee Brooks 2005a


ParticipantsNumber: 91 (5% lost at follow up)


Interventions1. Zinc acetate: 20 mg
2. Placebo


OutcomesSee Brooks 2005a


NotesSee Brooks 2005a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions

Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions

Incomplete outcome data (attrition bias)
All outcomes
Low risk5% lost at follow up

Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions

Other biasUnclear riskSee Brooks 2005a for all descriptions

Brooks 2005a (5 mg)

MethodsSee Brooks 2005a


ParticipantsNumber: 91 (7% lost at follow up)


Interventions1. Zinc acetate: 5 mg
2. Placebo


OutcomesSee Brooks 2005a


NotesSee Brooks 2005a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions

Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions

Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow up

Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions

Other biasUnclear riskSee Brooks 2005a for all descriptions

Dalgic 2011

MethodsRCT


ParticipantsNumber: 120

Inclusion criteria: 1 to 28 months and, on admission, stool positive for rotavirus antigen.  

Exclusion criteria: severe malnutrition (weight for height< -3SD as for WHO standards): duration of diarrhoea > 96 h; severe dehydration; exclusively breast-feeding; toxic clinical appearance; immunosuppression; any known allergies to any drugs or foods.


Interventions1. Zinc 20 mg/day
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Hospitalization


NotesLocation: Turkey

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated

Allocation concealment (selection bias)Unclear riskNot specified

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDefined as "single blind", but not further specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll children completed the study

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Dutta 2000

MethodsRCT


ParticipantsNumber: 80

Inclusion criteria: male, 3 to 24 months; malnourished (< 80% Harvard Standard weight for age); clinical signs of dehydration

Exclusion criteria: antibiotics; systemic infections; chronic diseases; need for intensive care; exclusively breastfed


Interventions1. Zinc sulphate: 40 mg/day
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 5
3. Stool output


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskCode numbers kept in a sealed envelope; zinc and placebo bottles identical

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe number of lost at follow up is not specified

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Dutta 2011

MethodsRCT


ParticipantsNumber: 84

Inclusion criteria: age 6 to 24 months, history of acute watery diarrhoea, moderate dehydration.

Exclusion criteria: severe malnutrition (weight on height < -3SD WHO reference); systemic illness; chronic underlying disease (eg, tuberculosis, liver diseases) or needing intensive care; exclusively breastfed; antibiotics before enrolment or vitamin A within the previous 6 months.


Interventions1. Zinc 20 mg/day
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 5
3. Stool output


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskCode numbers kept in a sealed envelope; zinc and placebo bottles identical

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber of lost at follow up < 10%

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Fajolu 2008

MethodsRCT


ParticipantsNumber: 60

Inclusion criteria: age 6 to 24 months; acute diarrhoea (less than 14 days duration)

Exclusion criteria: refusal of consent; Protein Energy Malnutrition; use of stool hardeners, anti-motility drugs ant antibiotics; other medical condition requiring hospitalization


Interventions1. zinc sulphate 20 mg (>12 months) or 10 mg (<12 months)  

2. Placebo


Outcomes1. Average duration of diarrhoea

2. Stool frequency


NotesLocation: Nigeria

Setting: hospital (follow up in the community)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot detailed

Allocation concealment (selection bias)Unclear riskNot detailed

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot detailed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of lost at follow up not specified

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Faruque 1999

MethodsRCT


ParticipantsNumber: 684

Inclusion criteria: children 6 to 24 months with acute diarrhoea, some dehydration and no severe dehydration; underweight or stunted children were not excluded

Exclusion criteria: marasmus; kwashiorkor; systemic illnesses


Interventions1. Zinc acetate: 14.2 mg (first 417 children) or 40 mg (other 273 children randomized)

2. Placebo

Both groups: vitamin A


Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 7


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskBottles serially numbered according to the randomization schedule to correspond to the serial number of the participant; supplements prepared by pharmaceutical company and provided in dark-coloured bottles

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk4% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Fischer Walker 2006

MethodsRCT


ParticipantsNumber: 1110

Inclusion criteria: infants 1 to 5 months of age with acute diarrhoea (< 72 h)

Exclusion criteria: severe malnutrition (< -3 z score weight for age); signs of pneumonia if < 2 months (cough and difficult or fast breathing with a respiratory rate of > 60 breaths/min); signs severe pneumonia if 2 to 5 months of age (cough or difficult fast breathing and chest indrawing, nasal flaring, or grunting); required hospitalization (overnight stay at a healthcare facility) for any reason; known major congenital malformation; any other serious pre-existing medical condition; lived out of or planned to move out of study area within following 3 months; previously enrolled in the study


Interventions1. Zinc sulphate: 10 mg
2. Placebo


Outcomes1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
4. Stool frequency
5. Hospitalisation
6. Adverse events (vomiting)


NotesLocation: Ethiopia, India, and Pakistan

Setting: community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskRandomization scheme assigned in Geneva and kept secure until completion of data collection and initial analysis; upon enrolment, infants assigned chronological study identifiers corresponding to a pre-labelled blister pack of either zinc or placebo tablets

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk3% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Fischer Walker 2006 ETH

MethodsSee Fischer Walker 2006


ParticipantsNumber: 177 (8% lost at follow up)


InterventionsSee Fischer Walker 2006


OutcomesSee Fischer Walker 2006


NotesLocation: Ethiopia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Fischer Walker 2006

Allocation concealment (selection bias)Low riskSee Fischer Walker 2006

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006

Incomplete outcome data (attrition bias)
All outcomes
Low risk8% lost at follow up

Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006

Other biasUnclear riskSee Fischer Walker 2006

Fischer Walker 2006 IND

MethodsSee Fischer Walker 2006


ParticipantsNumber: 373 (1% lost at follow up)


InterventionsSee Fischer Walker 2006


OutcomesSee Fischer Walker 2006


NotesLocation: India


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Fischer Walker 2006

Allocation concealment (selection bias)Low riskSee Fischer Walker 2006

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006

Incomplete outcome data (attrition bias)
All outcomes
Low risk1% lost at follow up

Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006

Other biasUnclear riskSee Fischer Walker 2006

Fischer Walker 2006 PAK

MethodsSee Fischer Walker 2006


ParticipantsNumber: 560 (3% lost at follow up)


InterventionsSee Fischer Walker 2006


OutcomesSee Fischer Walker 2006


NotesLocation: Pakistan


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Fischer Walker 2006

Allocation concealment (selection bias)Low riskSee Fischer Walker 2006

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006

Incomplete outcome data (attrition bias)
All outcomes
Low risk3% lost at follow up

Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006

Other biasUnclear riskSee Fischer Walker 2006

Khatun 2001

MethodsRCT


ParticipantsNumber: 100

Inclusion criteria: 6 to 36 months; moderately malnourished (61% to 75% of the median NCHS median weight for age); persistent diarrhoea

Exclusion criteria: systemic infection; clinical signs of vitamin A deficiency; received vitamin A supplementation within 3 months; received prior antibiotics therapy; bloody mucoid diarrhoea; kwashiorkor; no longer received breast milk


Interventions1. Zinc acetate: 20 mg
2. Placebo

Both groups: multivitamins


Outcomes1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
4. Stool output
5. Adverse events (vomiting)


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNo details

Allocation concealment (selection bias)High riskNo details

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details

Incomplete outcome data (attrition bias)
All outcomes
Low risk4% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Larson 2005

MethodsRCT


ParticipantsNumber: 1067

Inclusion criteria: child aged 3 to 59 months; acute diarrhoea; having taken oral rehydration solution as instructed; no vomiting in the past 2 h for the short-stay ward or 30 minutes in the outpatient clinic, and no longer dehydrated

Exclusion criteria: returning to the hospital with diarrhoea; receiving zinc


Interventions1. Zinc sulphate: 20 mg
2. Placebo


Outcomes1. Adverse events (vomiting)


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskOpaque envelopes numbered in which the assigned zinc tablet, placebo tablet, or a similar-sized button was placed; randomization schedule kept in a locked cabinet

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Patel 2009

MethodsRCT


ParticipantsNumber: 808

Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 h); ability to accept oral fluids or feeds  

Exclusion criteria: severe dehydration and unable to drink,chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study


Interventions1. zinc sulcates 2 mg/kg/die

2. zinc sulphate 2 mg/kg/die + copper 0.2 mg/kg/die

3. Placebo


Outcomes1. Death

2. Average duration of diarrhoea

3. Diarrhoea at day 3

4. Diarrhoea at day 5

5. Diarrhoea at day 7


NotesLocation: India

Setting: hospital (follow up in the community)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSingle-site, blocked randomization procedure with blocks of sizes three, six and nine in equal proportions

Allocation concealment (selection bias)Low riskRandomization list generated off site by an investigator not directly involved in the data collection. The code list of the placebo and the treatment groups was secured and held only by the pharmacist at the Universal Medicaments Pvt. Ltd, Nagpur, until initial data analysis was completed

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: bottle packs sequentially labelled according to the treatment allocation list and assigned to patients by the research physician

Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow up

Selective reporting (reporting bias)Low riskProtocol available. Trial registered in metaRegister of Controlled Trials (ISRCTN85071383)

Other biasUnclear riskNo information available

Patel 2009a (zinc)

MethodsRCT


ParticipantsNumber: 808

Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 h); ability to accept oral fluids or feeds  

Exclusion criteria: severe dehydration and unable to drink,chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study


Interventions1. zinc sulphate 2 mg/kg/die

2. zinc sulphate 2 mg/kg/die + copper 0.2 mg/kg/die

3. Placebo


Outcomes1. Death

2. Average duration of diarrhoea

3. Diarrhoea at day 3

4. Diarrhoea at day 5

5. Diarrhoea at day 7


NotesLocation: India

Setting: hospital (follow up in the community)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Patel 2009

Allocation concealment (selection bias)Low riskSee Patel 2009

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009

Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009

Selective reporting (reporting bias)Low riskSee Patel 2009

Other biasUnclear riskSee Patel 2009

Patel 2009b (zinc+copper)

MethodsSee Patel 2009a


ParticipantsSee Patel 2009a


InterventionsSee Patel 2009a


OutcomesSee Patel 2009a


NotesSee Patel 2009a


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Patel 2009

Allocation concealment (selection bias)Low riskSee Patel 2009

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009

Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009

Selective reporting (reporting bias)Low riskSee Patel 2009

Other biasUnclear riskSee Patel 2009

Patro 2010

MethodsRCT


ParticipantsNumber: 160

Inclusion criteria: age 3 to 48 months diagnosed with acute diarrhoea lasting less than 5 days, with at least some degree of dehydration.

Exclusion criteria: diarrhoea lasting <1 day or >5 days, recent history of diarrhoea (last 2 weeks before enrolment day), chronic gastrointestinal disease with diarrhoea manifestation, (eg, food allergy, celiac disease), weight-to-height ratio <5th percentile, severe dehydration, coexistence of serious systemic disease(s), coadministration of antibiotics, exclusive or >50% breastfeeding, immunodeficiency, immunosuppressive therapy.


Interventions1. Zinc sulphate (20 mg in children >6 months or 10 mg in children <6 months)  

2. Placebo


Outcomes1. Average duration of diarrhoea

2. Diarrhoea at day 7


NotesLocation:Poland

Setting: hospital (90% of children) and outpatient (10%)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTwo different randomization lists for each centre were computer-generated by an investigator at the Medical University of Warsaw.  

Allocation concealment (selection bias)Low riskThe glass bottles containing the products were labelled with the patient’s number corresponding to the randomization list by an independent individual who was not involved in patient enrolment. Randomization codes were secured until the completion of data collection and initial analysis. The placebo was identically supplied and formulated. There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.

Blinding (performance bias and detection bias)
All outcomes
Low riskInvestigators, participants, outcome assessors, and data analysts

Incomplete outcome data (attrition bias)
All outcomes
High risk11.8% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNote: source of funding: Nutricia.

Penny 1999

MethodsRCT


ParticipantsNumber: 413

Inclusion criteria: 6 to 36 months, persistent diarrhoea

Exclusion criteria: vitamins or minerals within 6 weeks; major congenital malformation affecting growth; severe dehydration; requiring hospitalization


Interventions1. Zinc gluconate: 20 mg
2. Placebo


Outcomes1. Death
2. Hospitalization
3. Diarrhoea at day 3
4. Diarrhoea at day 5
5. Diarrhoea at day 7
6. Adverse events (vomiting)


NotesLocation: Peru

Setting: community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers

Allocation concealment (selection bias)Low riskRandomization numbers linked to letter codes, each indicating 1 treatment group; codes kept secret; supplements provided by independent laboratories

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Polat 2003

MethodsRCT


ParticipantsNumber: 200

Inclusion criteria: 2 to 29 months; malnourished children (weight for age scale, score < 76% according to NCHS standards); acute non-bacterial diarrhoea

Exclusion criteria: concomitant illness or oedema


Interventions1. Zinc sulphate: 20 mg
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Diarrhoea at day 3
3. Diarrhoea at day 7
4. Adverse events (vomiting)


NotesLocation: Turkey

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskBottles labelled with randomization numbers, no other details

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk9% lost to follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Polat 2003 low Zn

MethodsSee Polat 2003


ParticipantsNumber: 76

Children with low zinc serum levels


InterventionsSee Polat 2003


OutcomesSee Polat 2003


NotesSee Polat 2003


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Polat 2003

Allocation concealment (selection bias)Low riskSee Polat 2003

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003

Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003

Selective reporting (reporting bias)Unclear riskSee Polat 2003

Other biasUnclear riskSee Polat 2003

Polat 2003 normal Zn

MethodsSee Polat 2003


ParticipantsNumber: 106

Children with normal zinc serum levels


InterventionsSee Polat 2003


OutcomesSee Polat 2003


NotesSee Polat 2003


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSee Polat 2003

Allocation concealment (selection bias)Low riskSee Polat 2003

Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003

Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003

Selective reporting (reporting bias)Unclear riskSee Polat 2003

Other biasUnclear riskSee Polat 2003

Roy 1997

MethodsRCT


ParticipantsNumber: 111
Inclusion criteria: 2 to 24 months; weight below the 76th centile of weight-for-age according to the NCHS standard 18 (by Gomez classification, protein energy malnutrition grades II and III included)

Exclusion criteria: systemic infection or oedema


Interventions1. Zinc acetate: 20 mg
2. Placebo

Both groups: multivitamin


Outcomes1. Average duration of diarrhoea
2. Stool output


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskBottles labelled with randomization numbers

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
High risk32.4% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Roy 1998

MethodsRCT


ParticipantsNumber: 190

Inclusion criteria: 3 to 24 months; persistent diarrhoea; underweight (low weight-for-age) using a cut-off of 70% weight/age of the 50th centile of the NCHS standard; wasted (low weight/height) using a cut-off of 80%; short (low height/age) using a cut-off of less than 95% of the height/age standard

Exclusion criteria: none stated


Interventions1. Zinc acetate: 20 mg
2. Placebo

Both groups: multivitamin


Outcomes1. Death
2. Average duration of diarrhoea
3. Adverse events


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Unclear riskNo details

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if any lost to follow up; 11% discontinued intervention

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Roy 2008

MethodsRCT


ParticipantsNumber: 56

Inclusion criteria: aged 12 to 59 months; moderately malnourished (weight/age 61% to 75% of NCHS median); history suggestive of dysentery (eg bloody-mucoid diarrhoea or febrile diarrhoea less than 5-days' duration); with culture-proven shigellosis

Exclusion criteria: severe malnutrition; receiving zinc supplementation; measles in the last 6 months; living beyond 2 h of travel time; complications such as haemolytic uraemic syndrome or other systemic illness, including pneumonia, meningitis, and septicaemia


Interventions1. Zinc acetate: 10 mg
2. Placebo

Both groups: multivitamins


Outcomes1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7


NotesLocation: Bangladesh

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskBottles identical labelled with sequential numbers that had earlier been allocated to either intervention or control according to the randomization

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
High risk11% lost at follow up

Selective reporting (reporting bias)Low riskTrial registered in ClinicalTrial.gov (NCT00321126)

Other biasUnclear riskNo information available

Sachdev 1988

MethodsRCT


ParticipantsNumber: 50

Inclusion criteria: children 6 to 18 months; dehydration secondary to acute diarrhoea of < 4 days' duration

Exclusion criteria: antibiotics; severe malnutrition (grades III and IV); concomitant features (meningitis, pneumonia, liver disease, otitis media, fever > 39 °C)


Interventions1. Zinc sulphate: 20 mg
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Stool frequency
3. Adverse events (vomiting)


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Sachdev 1990

MethodsRCT


ParticipantsNumber: 40

Inclusion criteria: 6 to 18 months; persistent diarrhoea

Exclusion criteria: another diarrhoeal episode 1 month prior; critically ill; obvious parenteral infections; severe malnutrition (grade III and IV)


Interventions1. Zinc sulphate: 20 mg
2. Placebo


Outcomes1. Average duration of diarrhoea
2. Stool frequency
3. Adverse events (vomiting)


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Sazawal 1995

MethodsRCT


ParticipantsNumber: 947

Inclusion criteria: 6 to 35 months; diarrhoea for 7 days; permanent resident in study area; stunted defined (length for age less than -2 standard deviation)

Exclusion criteria: second visit; malnutrition requiring hospitalization; not provide consent


Interventions1. Zinc gluconate: 20 mg
2. Placebo

Both groups: multivitamin


Outcomes1. Diarrhoea at day 7
2. Stool frequency
3. Adverse events (vomiting)


NotesLocation: India

Setting: hospital


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskChildren allocated to sequential numbers indicating zinc or placebo; code kept by World Health Organization, not available for investigators

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk2% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

Strand 2002

MethodsRCT


ParticipantsNumber: 899

Inclusion criteria: 6 to 35 months; diarrhoea < 96 h

Exclusion criteria: massive dose of vitamin A; requiring hospitalization; family intended to leave Bhaktapur within 2 months


Interventions1. Zinc gluconate: 15 mg for infants; 30 mg for older children
2. Placebo


Outcomes1. Diarrhoea at day 3
2. Diarrhoea at day 7
3. Adverse events (vomiting)
4. Adverse events (copper levels)


NotesLocation: Nepal

Setting: community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers

Allocation concealment (selection bias)Low riskPacking with serial number; list kept in Copenhagen; capsule identical in appearance; syrup identical in appearance and taste

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk1% lost at follow up

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskNo information available

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adu Afarwuah 2007Not concerning the intervention of interest (3 types of micronutrients for food fortification)

Adu-Afarwuah 2008Not concerning the intervention of interest (zinc fortification)

Aggarwal 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Agustina 2007Not concerning the intervention of interest (probiotic, prebiotic, fibre, and micronutrients mixture)

Alam 2010Prevention study

Alarcon 2004RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Awasthi 2006Not concerning the intervention of interest (zinc in oral rehydration solution)

Baqui 2002Community RCT without a placebo group

Baqui 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Baqui 2006Not concerning any outcome of interest (serum zinc)

Baum 2010Not concerning the population of interest (adults, HIV positive)

Behrens 1990Not concerning any outcome of interest (nutritional status)

Bhandari 2002RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Bhandari 2005Not a RCT

Bhandari 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Bhandari 2008RCT without a placebo group

Bhatnagar 2004bNot a RCT

Bhutta 2000aNot concerning any outcome of interest (appetite)

Bilenko 2010Not concerning the intervention of interest (multiple micronutrients in sprinkles)

Black 2001Not a RCT

Bobat 2005Not concerning the population of interest (only children with HIV enrolled)

Borges 2007Not a RCT

Brooks 2005bRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Brown 2007Not concerning the Intervention of interest (food fortification)

Brown 2007aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Carbajal 2000Not a placebo-controlled RCT

Carcamo 2006Not concerning the population of interest (adults with HIV)

Chandyo 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Chang 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Chen 2010Not concerning the intervention of interest (food fortification with multiple micronutrients)

Chhagan 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Chhagan 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Christian 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, on a different population (pregnant women)

CIGNIS 2010Not concerning the intervention of interest (food fortification with multiple micronutrients)

Cross 2009Not RCT

Dhingra 2009Not RCT

Doherty 1998Not a placebo-controlled RCT, and criteria for inclusion of children was malnutrition, not diarrhoea

Ebrahimi 2006Not concerning any outcome of interest (growth)

Ellis 2007Not a RCT

Ferraz 2007Not RCT

Ferrufino 2007Not RCT

Fischer Walker 2008Secondary analysis of a previously excluded study (Baqui 2002)

Gardner 2005Not a RCT

Garenne 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Gregorio 2007Not concerning the intervention of interest (zinc-fortified oral rehydration solution)

Gupta 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Gupta 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Habib 2010Longituidinal cohort study

Heinig 2006Not concerning any outcome of interest (growth, morbidity, and motor development)

Hettiarachchi 2008Not concerning the population of interest (children 12-16 years), nor the outcomes

Hidayat 1998Community RCT, but results could not be compared with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea)

Hoque 2006Not RCT (review)

Hyder 2007Not concerning the population of interest (adolescent girl), the intervention (multiple micronutrients), nor the outcomes.

Iannotti 2010Not concerning the population of interest (pregnant women)

Islam 2010Not concerning the population of interest (preterm infants), nor any outcome of interest (growth)

Jimenez 2000Not concerning any outcome of interest (growth)

Kelly 1999Intervention and the population (micronutrient supplementation in AIDS diarrhoea-wasting syndrome) considered in this RCT not relevant

Kelly 2010Not concerning any outcome of interest (intestinal function)

Larson 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Lin 2008Not placebo controlled, not outcomes of interest (weight)

Lind 2004RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Lind 2008Secondary analysis of a previously excluded study (Lind 2004)

Lira 1998Not concerning the population of interest (low birthweight infants)

Long 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Long 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)

Lopez 2005Not concerning the intervention of interest (multiple micronutrient), nor the outcomes (anaemia, micronutrient status, growth, and morbidity)

Luabeya 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Lukacik 2008Not RCT (meta-analysis)

Makonnen 2003aNot concerning any outcome of interest

Makonnen 2003bNot concerning any outcome of interest

Manger 2008No placebo controlled, different intervention (multiple micronutrients), prevention study

Mazariegos 2010Not concerning any outcome of interest (linear growth)

Mazumder 2010Secondary analysis of a previously excluded study (Bhandari 2008)

Mda 2010Not concerning population of interest (only children with HIV), different intervention (multiple micronutrient)

Meeks 1998RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Müller 2001RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Naheed 2009Secondary analysis of a previously excluded study (Baqui 2002)

Nasrin 2005Not a RCT

Nga 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Osendarp 2002RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Ouedraogo 2008RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Passariello 2010Not concerning the intervention of interest (zinc in oral rehydration solution)

Patel 2005Not concerning the intervention of interest (zinc and copper in oral rehydration solution)

Patel 2010Secondary analysis of an included study (Patel 2009), with no outcome of interest (by isolated micro-organism)

Patel 2010aNot a RCT (review)

Patro 2008Not RCT (meta-analysis)

Penny 2004aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Penny 2004bNot a RCT

Polat 2006Not a placebo-controlled RCT

Rahman 2001RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Rahman 2005Not concerning any outcome of interest

Raqib 2004Not concerning any outcome of interest (immune and inflammatory responses)

Richard 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Rollins 2007Not concerning the population of interest (only HIV infected children), and different outcomes (growth, immunity)

Rosado 1997RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Rosado 1998Not a RCT

Rosado 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)

Roy 1992Not concerning any outcome of interest (intestinal permeability)

Roy 1999RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Roy 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Roy 2008aNot concerning the population of interest (children aged between 3 and 14 years)

Ruel 1997RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Sabatier 1997Not a placebo-controlled RCT

Samuel 1995Not a RCT

Sancho Martinez 2007Not RCT (review)

Sazawal 1996RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Sazawal 1997aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Sazawal 2004aRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Sazawal 2007aNot concerning the intervention of interest (milk fortification)

Sazawal 2007bNot concerning any outcome of interest (plasma retinol)

Sazawal 2007cRCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Shamir 2005Not concerning the interventions (zinc and probiotics) considered in this RCT not relevant

Shankar 1998Not RCT (Review)

Sharieff 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Sheikh 2010Not a RCT

Sur 2003RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Taneja 2009RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, in a different population (low birth weight infants)

Taneja 2010RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (growth)

Tielsch 2006RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Tielsch 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Umeta 2000RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Untoro 2005Not concerning the intervention of interest (multiple micronutrient), nor any outcome(anaemia, micronutrient status, growth, and morbidity)

Valery 2005Not concerning the population of interest (all children aged under 11 years)

Veenemans 2011Prevention study

Wadhwa 2011Study on zinc enriched ORS

Walden 2004Not a RCT

Walker 2007RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Wieringa 2010Not concerning the population of interest (pregnant women)

Winch 2006Not a RCT

Winch 2008Not a RCT

Wuehler 2008RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

 
Characteristics of ongoing studies [ordered by study ID]
NCT01140074

Trial name or titleEfficacy of Zinc Sulfate With Probiotics for the Treatment of Acute diarrhoea in Children

MethodsRCT

ParticipantsInclusion Criteria: Age 1-36 months

Acute diarrhoea defined as 3 or more watery stools per day Informed consent (parents)

Exclusion Criteria: Severe dehydration (> 10%) Coexisting severe infection (e.g. sepsis, pneumonia, meningitis) Immune deficiency Chronic digestive tract disease (e.g. celiac diseases, food allergy) Antibiotic therapy

Interventions1. Zinc sulphate 10-20 mg per day orally plus probiotics

2. Zinc sulphate 10-20 mg per day orally

3.Placebo

Outcomes1. Period of diarrhoea in hours [ Time Frame: 15 days ] [ Designated as safety issue: No ]

2. Number of stools in consequent days [ Time Frame: 15 days ]

3. Hospitalization

4. Tolerability

5. Adherence to the therapy

Starting dateJuly 2010 (not yet recruiting in December 2010)

Contact informationContact: Leszek Szenborn, Prof szenborn@zak.am.wroc.pl (principal investigator)

Contact: Ernest P. Kuchar, MD kuchar@zak.am.wroc.pl

NotesLocation: Poland

Registration number: NCT01140074

Source of funding: unclear

Sponsor: University Hospital No 1 Wroclaw

NCT01198587

Trial name or titleA Double Blind Randomized Placebo Controlled Trial of Oral Zinc for Children With Acute diarrhoea in a Developed Nation.

MethodsRCT

 

ParticipantsInclusion Criteria:

  • Healthy Children with non-bloody diarrhoea illness defined as loose or watery stools
  • Symptoms must be present for greater than 24 hours but less than 72 hours.
  • Comorbid conditions including; Asthma, Gastroesophageal reflux (unless followed by a Gastroenterologist), Mild speech, language, motor delays, Benign heart murmurs, Isolated atrial septal defect (ASD) or ventricular septal defect VSD, Epilepsy (unless developmentally delayed), Children born Prematurely between 33-37 weeks without long term sequelae, Repaired tetralogy of Fallot (no cardiac issues for >6 months), Diabetes may be enrolled in the study.


Exclusion Criteria:

  • Children with symptoms less than 24 hours
  • Children with symptoms greater than 24 hours
  • Failure to thrive
  • G or J tube
  • Major surgery within last 3 months
  • Minor surgery (tonsillectomy, ear tubes, skin lesion removals etc) within last 1 month
  • Followed by GI service for any reason (Crohn, ulcerative colitis, constipation
  • Developmental delay, patient >1 year behind milestones
  • Current brain tumour
  • Currently being treated for cancer or in remission < 6 months
  • Intussuception
  • Antibiotics in the last 14 days or currently taking antibiotics for any reason
  • Autism
  • Children born premature <33 weeks
  • Cystic Fibrosis
  • Major congenital Heart Disease (any disease where child's baseline oxygen saturations <93%)
  • Short Gut
  • Liver disease
  • History of bowel resection


Age minimum: 6 Months
Age maximum: 6 Years
Gender: both

Interventions1. Zinc Sulfate

For children ages 6month to 1 year, 12.5mg orally daily for 14 days mixed in 60 mL of fluid.

For children aged 1 year and above 25mg orally daily for 14 days mixed in 60 mL of fluid.

2. Placebo

Outcomes1. Duration of diarrhoea in acute diarrhoeal illnesses in a developed nation while taking zinc or placebo.[Time Frame: 14 days]

2. Length of hospitalization for children with diarrhoeal illness taking zinc or placebo.[Time Frame: 14 days of study medication]

Starting dateSeptember 2010

Contact informationMichelle L Niescierenko, MD

michelle.niescierenko@childrens.harvard.edu

Children's Hospital Boston

NotesLocation: USA

Registration number: NCT01198587

Source of funding: unclear

Sponsor: Children's Hospital Boston

 
Comparison 1. Zinc vs placebo for acute diarrhoea

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)194446Mean Difference (IV, Random, 95% CI)-12.63 [-21.05, -4.21]

    1.1 Age < 6 months
51334Mean Difference (IV, Random, 95% CI)5.23 [-2.00, 14.45]

    1.2 Age > 6 months
62175Mean Difference (IV, Random, 95% CI)-10.44 [-21.13, 0.25]

    1.3 Ages both < and > 6 months
8937Mean Difference (IV, Random, 95% CI)-22.53 [-34.77, -10.29]

 2 Diarrhoea on day 341568Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.67, 0.89]

    2.1 Age > 6 months
21386Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 0.99]

    2.2 Ages both < and > 6 months
2182Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.42, 0.72]

 3 Diarrhoea on day 551730Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.51, 0.89]

    3.1 Age > 6 months
31384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.52, 1.01]

    3.2 Ages both < and > 6 months
2346Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.32, 0.95]

 4 Diarrhoea on day 7135528Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.94]

    4.1 Age < 6 months
31074Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.99, 1.54]

    4.2 Age > 6 months
63865Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.61, 0.88]

    4.3 Ages both < and > 6 months
4589Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.18, 0.52]

 5 Stool frequency (stools /day)92323Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.20, 0.10]

    5.1 Age < 6 months
51334Mean Difference (IV, Fixed, 95% CI)0.0 [-0.17, 0.17]

    5.2 Age > 6 months
3915Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.47, 0.15]

    5.3 Ages both < and > 6 months
174Mean Difference (IV, Fixed, 95% CI)-5.9 [-9.44, -2.36]

 6 Adverse events (vomiting)125189Risk Ratio (M-H, Random, 95% CI)1.59 [1.27, 1.99]

    6.1 Age < 6 months
31334Risk Ratio (M-H, Random, 95% CI)1.54 [1.05, 2.24]

    6.2 Age > 6 months
52340Risk Ratio (M-H, Random, 95% CI)1.56 [1.32, 1.85]

    6.3 Ages both < and > 6 months
41515Risk Ratio (M-H, Random, 95% CI)2.01 [1.06, 3.81]

 
Comparison 2. Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)15Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Nutritional status: only well-nourished
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.2 Nutritional status: well-nourished plus moderately malnourished
92635Mean Difference (IV, Random, 95% CI)-16.77 [-27.59, -5.94]

    1.3 Nutritional status: malnourished
4336Mean Difference (IV, Random, 95% CI)-26.98 [-39.34, -14.62]

    1.4 Sex: male
3430Mean Difference (IV, Random, 95% CI)-22.35 [-36.40, -8.31]

    1.5 Sex: male and female
112682Mean Difference (IV, Random, 95% CI)-16.04 [-26.97, -5.11]

    1.6 Region: Africa
160Mean Difference (IV, Random, 95% CI)-2.40 [-33.25, 28.45]

    1.7 Region: Asia
112837Mean Difference (IV, Random, 95% CI)-18.88 [-29.33, -8.43]

    1.8 Region: South America
174Mean Difference (IV, Random, 95% CI)-31.20 [-46.43, -15.97]

    1.9 Region: Europe
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.10 Region: countries ranked as high risk of zinc deficiency
82535Mean Difference (IV, Random, 95% CI)-14.97 [-26.21, -3.72]

    1.11 Region: countries ranked as medium risk of zinc deficiency
5436Mean Difference (IV, Random, 95% CI)-25.92 [-44.80, -7.04]

    1.12 Region: countries ranked as low risk of zinc deficiency
1141Mean Difference (IV, Random, 95% CI)1.80 [-13.55, 17.15]

    1.13 Zinc dose:≤ 20 mg
8711Mean Difference (IV, Random, 95% CI)-18.72 [-32.02, -5.43]

    1.14 Zinc dose: > 20 mg
3959Mean Difference (IV, Random, 95% CI)-23.52 [-42.09, -4.94]

    1.15 Zinc type: zinc acetate
3875Mean Difference (IV, Random, 95% CI)-30.55 [-49.29, -11.82]

    1.16 Zinc type: gluconate
1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]

    1.17 Zinc type: zinc sulphate
91348Mean Difference (IV, Random, 95% CI)-14.04 [-26.76, -1.32]

    1.18 Study setting: hospital
132307Mean Difference (IV, Random, 95% CI)-18.46 [-28.61, -8.30]

    1.19 Study setting:community
1805Mean Difference (IV, Random, 95% CI)-7.20 [-15.33, 0.93]

    1.20 Concomitant treatment: zinc alone
142988Mean Difference (IV, Random, 95% CI)-17.58 [-26.64, -8.52]

    1.21 Concomitant treatment: zinc plus copper
1383Mean Difference (IV, Random, 95% CI)2.20 [-5.08, 9.48]

 
Comparison 3. Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea on day 711Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Nutritional status: only well nourished
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.2 Nutritional status: well nourished plus moderately malnourished
64075Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]

    1.3 Nutritional status: malnourished
3238Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.22, 0.61]

    1.4 Sex: male
1266Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 0.88]

    1.5 Sex: male and female
94188Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.58, 0.81]

    1.6 Region: Asia
94313Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.56, 0.79]

    1.7 Region: Europe
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.8 Region: countries ranked as high risk of zinc deficiency
63240Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]

    1.9 Region: countries ranked as medium risk of zinc deficiency
31073Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.35, 0.68]

    1.10 Region: countries ranked as low risk of zinc deficiency
1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]

    1.11 Zinc dose: 20 mg
83154Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.74]

    1.12 Zinc dose: >20mg
1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]

    1.13 Zinc type: zinc acetate
31628Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.45, 0.79]

    1.14 Zinc type:gluconate
1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]

    1.15 Zinc type: zinc sulphate
62021Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.57, 0.90]

    1.16 Study setting: hospital
82758Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.56, 0.84]

    1.17 Study setting: community
21696Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.44, 0.85]

    1.18 Concomitant treatment: zinc alone
104330Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.55, 0.78]

    1.19 Concomitant treatment: zinc plus copper
1383Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.45]

 
Comparison 4. Zinc vs placebo for persistent diarrhoea

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea duration (h)5529Mean Difference (IV, Fixed, 95% CI)-15.84 [-25.43, -6.24]

    1.1 Age > 6 months
4388Mean Difference (IV, Fixed, 95% CI)-16.01 [-26.16, -5.86]

    1.2 Ages both < and > 6 months
1141Mean Difference (IV, Fixed, 95% CI)-14.40 [-43.77, 14.97]

 2 Diarrhoea on day 31Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Age > 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Diarrhoea on day 51Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Age > 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Diarrhoea on day 72221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]

    4.1 Age > 6 months
2221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]

 5 Stool frequency (stools/day)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 Age > 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Adverse events (vomiting)4505Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]

    6.1 Age > 6 months
3364Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]

    6.2 Ages both < and > 6 months
1141Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Summary of findings table 1

Zinc compared to placebo for children aged > 6 months with acute diarrhoea

Patient or population: children with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placeboZinc

Death---864
(2 studies)
⊕⊝⊝⊝
very low1,2

Hospitalization---891
(1 study)
⊕⊝⊝⊝
very low3,4

Duration of diarrhoea

 
all trials

The mean duration of diarrhoea ranged from 41 to 170 hoursZinc reduced the mean duration of diarrhoea by 10.44 hours
(21.13 hours shorter to 0.25 hours longer)
 2175
(6 studies)
⊕⊕⊝⊝
low5,6

trials limited to children with signs of moderate malnutrition

The mean duration of diarrhoea ranged from 103 to 147 hoursZinc reduced the mean duration of diarrhoea by 26.98 hours
(39.34 to 14.62 hours shorter)
 336
(3 studies)
⊕⊕⊕⊕

high7,8

Diarrhoea on day 7128 per 100093 per 1000
(78 to 113)
RR 0.73
(0.61 to 0.88)
3865
(6 studies)
⊕⊕⊕⊝

moderate9

Adverse events (vomiting)131 per 1000204 per 1000
(173 to 242)
RR 1.56
(1.32 to 1.85)
2340
(5 studies)
⊕⊕⊕⊕

high8

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for indirectness: Only two trials specifically stated that deaths occurred; one was conducted in hospital and so likely to underestimate death, and the effect of zinc if given at community level.
2 Downgraded by 2 for imprecision: Only three deaths occurred in these two studies, consequently the trials are significantly underpowered to detect or exclude an effect.
3 Downgraded by 1 for indirectness: Only one community based trial reports on hospitalisation rates. No statistically significant effect was seen but this result is not easily generalised to other settings.
4 Downgraded by 2 for imprecision: The trials reports that no statistically significant difference in hospitalisation was seen but did not present the data.
5 Downgraded by 1 for indirectness: The majority of data is from Asia. In the single trial from Africa (Nigeria) no effect was seen. The data may therefore be poorly generalised globally.
6 Downgraded by 1 for inconsistency: There remains moderate unexplained heterogeneity between trials. Some trials show a statistically significant benefit and some do not.
7 The effect of zinc appears to be largest in malnourished children, and with no effect seen in the one trial which only included well nourished children. The three trials were conducted in India, Bangladesh, and Turkey but it seems likely that this effect is still present in malnourished children elsewhere.
8 There was no reason to downgrade for risk of bias, inconsistency, indirectness or imprecision.
9 Downgraded by 1 for indirectness: These trials were all conducted in Asia in countries at high risk of zinc deficiency.
 
Summary of findings 2. Summary of findings table 2

Zinc compared to placebo for children aged < 6 months with acute diarrhoea

Patient or population: children aged < 6 months with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placeboZinc

Death---1334
(2 studies)
⊕⊝⊝⊝
very low1,2

Hospitalization---1074
(1 study)
⊕⊝⊝⊝
very low1,3

Duration of diarrhoeaThe mean duration of diarrhoea ranged from
98 to 133 hours
Zinc reduced the mean duration of diarrhoea 5.23 hours
(4 less to 14.45 more )
 1334
(2 studies)
⊕⊕⊝⊝
low1,4

Diarrhoea on day 7203 per 1000252 per 1000
(201 to 313)
RR 1.24
(0.99 to 1.54)
1074
(1 study)
⊕⊕⊕⊝

moderate5

Adverse events (vomiting)64 per 100099 per 1000
(67 to 143)
RR 1.54
(1.05 to 2.24)
1334
(2 studies)
⊕⊕⊕⊕

high6

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for indirectness: The majority of this data is from Asia and may not be applicable elsewhere.
2 Downgraded by 2 for imprecision: In these two studies deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
3 Downgraded by 2 for imprecision: Only one being hospitalization was recorded in 1074 patients. Much larger trials would be necessary to prove or exclude an effect.
4 Downgraded by 1 for imprecision: the result is not statistically significant.
5 This multi-centre study from India, Pakistan and Ethiopia found that Zinc increased the number of infants with diarrhoea persisting until day 7. The result was consistent across the trial settings and approaches statistical significance. Downgraded by 1 under directness as it is not yet possible to generalise this to all settings.
6 There was no reason to downgrade under study limitations, consistency, directness or precision.
 
Summary of findings 3. Summary of findings table 3

Zinc compared to placebo for children with persistent diarrhoea

Patient or population: children with persistent diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placeboZinc

Death---402
(3 studies)
⊕⊝⊝⊝
very low1,2

Hospitalization---275
(1 study)
⊕⊝⊝⊝
very low1,3

Duration of diarrhoea

 
The mean diarrhoea duration (h) ranged from
84 to 168 hours
Zinc reduced the mean duration of diarrhoea of
15.84
(25.43 to 6.24 less )
529
(5 studies)
⊕⊕⊕⊝
moderate1

Diarrhoea on day 7191 per 100099 per 1000
(52 to 195)
RR 0.52
(0.27 to 1.02)
221
(2 studies)
⊕⊕⊝⊝
low1,4

Adverse events (vomiting)8 per 100016 per 1000
(3 to 85)
RR 1.97
(0.37 to 10.59)
505
(4 studies)
⊕⊝⊝⊝
very low1,5

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by 1 for indirectness: The majority of this data is from Asia and may not be applicable elsewhere.
2 Downgraded by 2 for imprecision: In these three studies deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
3 Downgraded by 2 for imprecision: No hospitalizations were recorded. Much larger trials would be necessary to prove or exclude an effect.
4 Downgraded by 1 for imprecision: The result does not reach statistically significance, and the number of recorded events is low.
5 Downgraded by 2 for imprecision: Vomiting was very uncommon in these trials.
 
Table 1. Detailed search strategies

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSbCINAHLCCT

1zinczinczinczinczinczinczinc

2diarrhoeadiarrhoeaZINCZINCdiarrhoeadiarrhoeadiarrhoea

3vomitingmorbidity1 or 21 or 2morbiditymorbidityvomiting

4adverse effects2 or 3diarrhoeadiarrhoea2 or 32 or 3adverse effects

51 and 4diarrhoeamorbidity1 and 41 and 4

6vomitingmorbidity4 or 5vomitingvomiting

7adverse effectsMORBIDITY3 and 6adverse effectsadverse effects

86 or 74 or 5 or 6 or 7Limit 7 to human6 or 76 or 7

91 and 2 and 83 and 8vomiting1 and 2 and 81 and 8

10Limit 9 to humanadverse effects

11vomiting9 or 10

12adverse effects3 and 4 and 11

1311 or 12

143 and (4 or 5) and 13

 aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.
 
Table 2. Results of the study selection

Studies identified through the search236

Excluded as clearly not concerning the topic of interest76 trials

Further evaluated and excluded a133

  • Not RCTs: 25 trials
  • Not placebo-controlled RCTs: 8 trials
  • RCTs on prevention of diarrhoea, not on treatment: 48 trials
  • Not concerning the population of interest (eg studies on low birthweight, HIV): 13 trials
  • Not concerning the interventions of interest (eg studies on zinc in oral rehydration solution, multiple micronutrients, probiotics, food fortification):17 trials
  • Concerning different outcomes (eg studies on serology, appetite, mental or motor development, malnutrition): 14 trials
  • Could not be compared with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea): 1 trial
  • Secondary analysis of other studies: 5

Duplicate of included studies5 trials

  • Folwaczny 1996; Darmon 1997 are review articles of the same trial (Sazawal 1995)


  • Roy 1991 is a duplication of Roy 1997 and Roy 1998


  • Roy 1998b is an abstract of Khatun 2001


  • Cuevas 2000 is an abstract of Al-Sonboli 2003

Independent trials included in the review24 RCTs (9128 participants)

 aSee 'Characteristics of excluded studies'
HIV: human immunodeficiency virus
RCT: randomized controlled trial
 
Table 3. Stool output

StudyOutcomeUnitsN zincValues zincN placeboValues placeboMean difference or rate ratioStatistical test

ACUTE DIARRHOEA

Age < 6 months

Brooks 2005a (5 mg)Total (mL)Mean (95% CI)85229 (180 to 256)45202 (180 to 246)27 (-23.3 to 77.3)aNot significant

Brooks 2005a (20 mg)Total (mL)Mean (95% CI)86240 (200 to 266)44202 (180 to 246)38 (-8.6 to 84.6)aNot significant

Age > 6 months

Patel 2009a (zinc)Total (g)Mean (SD)248972 (858 to 1087)247877 (728 to 1026)-95 (-283 to 92)Not significant

Dutta 2011Total (L)Mean (SD)411.2 (0.6)432.0 (0.7)P < 0.0001

Dutta 2011Per day (ml/kg/day)Mean (SD)4151.22 (23.83)4366.83 (4.42)P = 0.0001

Ages < and > 6 months

Bhatnagar 2004aTotal (g/kg)Geometric mean (95% CI)132111 (86 to 147)134148 (116 to 190)0.69 (0.48 to 0.99)bP < 0.05

Per day (g/kg/day)Geometric mean (95% CI)13262 (51 to 78)13478 (68 to 91)0.76 (0.59 to 0.98)bP < 0.05

Dutta 2000Total (kg)Mean (95% CI)441.5 (1.3 to 1.7)362.4 (2.2 to 2.6)-0.9 (-1.2 to -0.6)aP = 0.0001

Roy 1997Per day (g/kg/day)Median (range)37238 (35 to 2416)37329 (32 to 1464)P = 0.06

PERSISTENT DIARRHOEA

Age > 6 months

Bhutta 1999bPer day of diarrhoea, day 1 (g/kg/day)Mean (95% CI)43116.8 (85.8 to 147.8)44141.9 (91.2 to 192.6)-25.1 (-84.5 to 34.3)aNot significant

Per day of diarrhoea, day 7 (g/kg/day)Mean (95% CI)4366.7 (40.9 to 92.4)4443.9 (32.1 to 55.7)22.8 (-5.5 to 51.1)aNot significant

Per day of diarrhoea, day 14 (g/kg/day)Mean (95% CI)4324.9 (20.1 to 29.7)4427.8 (18.5 to 37.1)-2.9 (-13.4 to 7.6)aNot significant

Khatun 2001Cumulative day 1 (mg/kg)Mean (95% CI)24127 (113 to 141)24137 (121 to 153)-10 (-31.6 to 11.6)aNot significant

Cumulative day 7 (mg/kg)Mean (95% CI)24528 (472 to 584)24866 (815 to 917)-338 (-413.6 to -262.4)aP ≤ 0.001

 aArithmetic mean difference (95% CI) for means.
bGeometric mean ratio (95% CI) for geometric means, adjusted for confounders. (Stool output using zinc is 0.69 and 0.76 times that of participants using placebo, which means a 31% and 24% less stool output under zinc treatment.)
CI: confidence intervals.