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Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children

  1. Benedict Griffiths1,*,
  2. Francine M Ducharme2,3

Editorial Group: Cochrane Airways Group

Published Online: 21 AUG 2013

Assessed as up-to-date: 18 APR 2012

DOI: 10.1002/14651858.CD000060.pub2


How to Cite

Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD000060. DOI: 10.1002/14651858.CD000060.pub2.

Author Information

  1. 1

    St Thomas' Hospital, Evelina Children's Hospital, London, UK

  2. 2

    University of Montreal, Department of Paediatrics, Montreal, Québec, Canada

  3. 3

    CHU Sainte-Justine, Research Centre, Montreal, Canada

*Benedict Griffiths, Evelina Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK. bgriffiths@doctors.org.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 AUG 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Beck 1985

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital for sick children, Toronto, Canada

DURATION OF STUDY: 7 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 28

N COMPLETED: 25

M = not available

F = not available

AGE: 6-17.5 years

BASELINE DETAILS: FEV1 < 50% predicted

INCLUSION CRITERIA: acute attack, FEV1 < 50% predicted, able to perform spirometry consistently

EXCLUSION CRITERIA: not available


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 150 minutes total
  • Single-dose protocol


INTERVENTION GROUP

  • Salbutamol 150 mcg/kg ((0.03 mL/kg) max 5 mg = 1 mL) then 50 mcg/kg (max 1.7 mg) q20 minutes x 6


  • IB 250 mcg at 60 minutes (with fourth salbutamol)


CONTROL GROUP

  • Salbutamol 150 mcg/kg ((0.03 mL/kg) max 5 mg = 1 mL) then 50 mcg/kg (max 1.7 mg) q20 minutes x 6 + placebo


CO-INTERVENTION (other medications during study)

  • Systemic corticosteroids: not described
  • Theophylline: 6 in each group on regular theophylline; no mention if continued during study


FOLLOW-UP PERIOD

  • Follow-up undertaken but duration not recorded


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: % change in FEV1

VITAL SIGNS: pulse, blood pressure, respiratory rate

ADVERSE EFFECTS: tremor, vomiting

ADMISSION: rate recorded but data not reported

RELAPSE: within ? time

CRITERIA FOR ADMISSION: not reported


NotesAuthor (HL) contacted

Confirmation by HL of methodology and data extraction: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; other information not available

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo used

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk3 children withdrawn due to protocol errors

Selective reporting (reporting bias)High riskHospital admission data recorded but only reported as "not significantly different"

Other biasLow risk

Benito Fernandez 2000

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital de Cruces, Vizcaya Spain

DURATION OF STUDY: 1 year


ParticipantsN SCREENED: not reported

N RANDOMIZED: 102

N COMPLETED: 102

M = 67

F = 35

AGE: 5 months to 16 years (mean age 5.7 years)

BASELINE DETAILS: both groups showed similar oxygen saturation and clinical scores at inclusion (oxygen saturations 93.5%, 4.45 and 4.35) (note: clinical score measured 0-5) (described as moderate to severe group)

INCLUSION CRITERIA: age 5 months to 16 years, severe acute asthma, previous recurrent wheezing episodes and previous asthma diagnosis

EXCLUSION CRITERIA: acute or chronic pulmonary disease other than asthma, and children with their first wheezing episode


InterventionsPROTOCOL

  • Fixed 60 minutes
  • Observation period 120 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • IB 250 mcg x 2 with salbutamol (2 doses of 0.2 mg/kg, 6 mg max, 30 minutes apart)


CONTROL GROUP

  • Placebo (normal saline solution) x 2 with salbutamol (2 doses of 0.2 mg/kg, 6 mg max, 30 minutes apart)


CO-INTERVENTIONS

  • Both groups received methylprednisolone 1 mg/kg, 40 mg max (oral administration)


FOLLOW-UP PERIOD

  • 2 weeks


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: PEFR

CLINICAL SCORE

VITAL SIGNS: oxygen saturation

NEED FOR ADDITIONAL SALBUTAMOL

NEED TO SEEK MEDICAL ATTENTION IN 2 WEEKS

HOSPITALIZATION

CRITERIA FOR ADMISSION: not reported


NotesTranslated by Carlos Rodriguez

Author not contacted


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlock randomisation

Allocation concealment (selection bias)Low riskThe department of pharmacy provided identical packages

Blinding (performance bias and detection bias)
All outcomes
Low riskBoth solutions had an identical smell and physical appearance

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in analysis (no withdrawals)

Selective reporting (reporting bias)Unclear riskUnable to ascertain

Other biasLow risk

BI [pers comm]

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Philippines (multicenter)

DURATION OF STUDY: 2002-2003


ParticipantsN SCREENED: not available

N RANDOMIZED: 500

N COMPLETED: 500

M = not available

F = not available

AGE: 2-10 years

BASELINE DETAILS: not available

INCLUSION CRITERIA: asthma exacerbation presenting to hospital

EXCLUSION CRITERIA: children: with known or suspected hypersensitivity to study drugs, with medical condition that would contraindicate the use of beta2-adrenergic or anticholinergic medications, with first wheezing episode only, with prior intubation for asthma for more than 24 hours, who used ipratropium in 6 hours prior to consultation, with concurrent stridor or possible presence of intrathoracic foreign body, with disease known to have chronic effect on respiratory function (e.g. CF or cardiac disease), requiring immediate resuscitation or airway intervention, with psychiatric disease or psychosocial problems, on other investigational drugs or have used any other investigational drugs within the past month


InterventionsPROTOCOL:

  • Fixed: 60 minutes
  • Observation period: 100 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Combivent UDV (ipratropium 500 mcg and salbutamol 2.5 mg), 1 UDV every 20 minutes for 3 doses


CONTROL GROUP

  • Salbutamol 2.5 mg UDV, 1 UDV every 20 minutes for 3 doses


DEVICE

  • Inhalation


OutcomesASTHMA SEVERITY SCORE

NUMBER OF CHILDREN ASSESSED TO BE NEEDING HOSPITALIZATION

AMOUNT OF ADDITIONAL RESCUE MEDICATION

O2 SATURATION

NUMBER OF DISCHARGED CHILDREN REVISITING THE EMERGENCY DEPARTMENT OR DOCTOR'S CLINIC WITHIN 24 HOURS

CRITERIA FOR ADMISSION: not reported


NotesUnpublished trial data supplied by Boehringer Ingelheim (Phil.) Inc


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; other information not available

Allocation concealment (selection bias)Unclear riskInformation not available; other information not available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double blind; other information not available

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 withdrawals due to adverse events (1 in each group)

Selective reporting (reporting bias)Unclear riskCannot ascertain this

Other biasUnclear riskCannot ascertain this

Calvo 1998

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Valdivia City, Chile

DURATION OF STUDY: fall and winter


ParticipantsN SCREENED: not available

N RANDOMIZED: 40

N COMPLETED: 40

M = 47

F = 33

AGE: 5-14 years

BASELINE DETAILS: PEF < 80% predicted and Tal Score > 5

INCLUSION CRITERIA: perform spirometry

EXCLUSION CRITERIA: cardiac failure, lung disease, needed to be hospitalised, experienced a first acute bronchial obstruction, had hypersensitivity to the medications used, were treated 8 hours before the onset of this study


InterventionsPROTOCOL

  • Titrated to child until symptoms controlled
  • Observation period: 120 minutes
  • Multiple flexible-dose protocol


INTERVENTION GROUP

  • Salbutamol 200 mcg + IB 40 mcg q15 minutes x 4 then q20 minutes x 3


CONTROL GROUP

  • Salbutamol 200 mcg q15 minutes x 4 then q20 minutes x 3


CO-INTERVENTION (other medications used during study)

  • Some children received systemic corticosteroids (prednisone 1 mg/kg/dose: max = 40 mg) at 60 minutes after beginning treatment if "no clinical or laboratory improvement"


FOLLOW-UP

  • 120 minutes


DEVICE

  • Inhalation


OutcomesPULMONARY FUNCTION TESTS: peak flow
CLINICAL SCORE: Tal score
VITAL SIGNS: pulse, respiratory rate
ADVERSE EFFECTS: tremor, mydriatic reaction, dryness of the oral membrane, pharyngeal irritation, nausea, vomiting
NUMBER OF CHILDREN NEEDING CORTICOSTEROIDS
ADMISSION

CRITERIA FOR ADMISSION: not reported


NotesAuthor (GMC) contacted

Confirmation by GMC of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskConsecutive assignment

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed

Selective reporting (reporting bias)Low riskNone noted

Other biasLow riskNone identified

Chakraborti 2006

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: paediatric chest clinic in Tertiary Hospital, North India

DURATION OF STUDY: 1 year 6 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 60

N COMPLETED: 60

M = 36

F = 24

AGE: 5-15 years

BASELINE DETAILS: mild to moderate acute exacerbation of asthma (FEV1 < 80% predicted)

INCLUSION CRITERIA: able to perform spirometry  

EXCLUSION CRITERIA: severe acute exacerbation, co-existing cardiac or renal disease, intolerance to study medication, glaucoma, urinary retention, use of oral bronchodilator in last 12 hours


InterventionsPROTOCOL

  • Fixed 0 minutes
  • Observation period: 30 minutes
  • Single-dose protocol


INTERVENTION GROUP

  • 4 x salbutamol 100 mcg via MDI and spacer + 4 x IB 20 mcg


CONTROL

  • 4 x salbutamol 100 mcg via MDI and spacer + 4 x placebo


TREATMENT PERIOD

CO-INTERVENTIONS

  • None


FOLLOW-UP PERIOD

  • 30 minutes


DEVICE

  • MDI


OutcomesHOSPITALIZATION

PULMONARY FUNCTION TESTS: FEV1 , FEV1%, FVC, FVC%, FEF25-75 , FEF%, FEV1/FVC, PEFR, PEFR%

VITAL SIGNS: heart rate

CLINICAL SCORE: wheeze score, accessory muscle score, clinical asthma score

CRITERIA FOR ADMISSION: not reported


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated blocks of 6

Allocation concealment (selection bias)Low risk"A person not involved in the study evaluation did the labelling"

Blinding (performance bias and detection bias)
All outcomes
Low risk"...similar looking MDIs..."

"...10 resident doctors were asked to identify labelled MDIs as to which contained drug and placebo. Only 1 resident could identify the MDIs (placebo or ipratropium) correctly. 90% cases failed to identify"

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data available for 60 children randomised

Selective reporting (reporting bias)Low riskAll data relevant to outcomes in this review were reported in full

Other biasHigh riskData only available for 30 minutes post-treatment

Cook 1985

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Christchurch Hospital, Christchurch, New Zealand

DURATION OF STUDY: not available


ParticipantsN SCREENED: not available

N RANDOMIZED: 48

N COMPLETED: 45

M = 26

F = 22

AGE: 18 months to 12 years

BASELINE DETAILS: "moderately severe"

INCLUSION CRITERIA: moderately severe asthma exacerbation

EXCLUSION CRITERIA: children deemed to require intravenous therapy


InterventionsPROTOCOL

  • Fixed
  • Observation period: 120 minutes
  • Single-dose protocol (with additional doses determined by clinical need)


INTERVENTION GROUP

  • Fenoterol 0.125 mL (1-4 y.o.)/0.25 mL (5-8 y.o.)/0.5 mL (9-12 y.o.) + IB 1 mL (1-4 y.o.)/1.5 mL (5-8 y.o.)/2.0 mL (9-12 y.o.)


CONTROL GROUP

  • Fenoterol 0.125 mL (1-4 y.o.)/0.25 mL (5-8 y.o.)/0.5 mL (9-12 y.o.) + placebo


CO-INTERVENTION (other medications used during study)

  • None


FOLLOW-UP:

  • None


DEVICE

  • Nebulizer


OutcomesCHANGE IN CLINICAL SCORE: overall score of wheeze, air entry and respiratory distress
VITAL SIGNS: pulse, respiratory rate
NEED FOR REPEAT TREATMENTS AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION


NotesCo-author (KPD) contacted

Confirmation by KPD of methodology: obtained

Confirmation of data extraction: pending

For change in clinical score, no values for t = 0 minutes, therefore used t = 5 minutes as baseline


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; other information not available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low risk"Three patients (1 in each group) required intravenous therapy and did not complete the trial. The results from these patients were excluded from the analysis"

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Ducharme 1998

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Montreal Children's Hospital, Canada

DURATION OF STUDY: 30 months


ParticipantsN SCREENED: 858

N RANDOMIZED: 298

N COMPLETED: 298

M = 182

F = 116

AGE: 3-17 years

BASELINE DETAILS: "mild to moderate" asthma attack

INCLUSION CRITERIA: exacerbation of mild or moderate severity requiring more than 1 nebulization of salbutamol. Ability to perform respiratory resistance consistently

EXCLUSION CRITERIA: children with severe asthma, in whom short delay for documenting baseline respiratory resistance appeared unacceptable or in whom continuous nebulizations of salbutamol were prescribed


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 210 minutes
  • Single-dose protocol


INTERVENTION GROUP - combination of:

  • Salbutamol 0.15 mg/kg q1 hour + IB 250 mcg (single dose) OR
  • Salbutamol 0.075 mg/kg q30 minutes + IB 250 mcg


CONTROL GROUP - combination of:

  • Salbutamol 0.15 mg/kg q1 hour + placebo OR
  • Salbutamol 0.075 mg/kg q30 minutes + placebo


CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: at discretion of treating physician


FOLLOW-UP

  • 10 days


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS:
% change in RFo
CHANGE IN CLINICAL SCORE:
Wheezing score
O2 SATURATION
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
VITAL SIGNS: pulse
ADVERSE EFFECTS: tremor, vomiting, nausea
NEED FOR CORTICOSTEROIDS PRIOR TO DISCHARGE
ADMISSION
RELAPSE: within 72 hours
RELAPSE
ADVERSE EFFECTS: not described

CRITERIA FOR ADMISSION: not reported


NotesAuthor (FMD)
contacted

Confirmation by FMD of methodology and data extraction obtained

Factorial design - tested 2 interventions simultaneously (frequent low doses of salbutamol + combination therapy with IB); no interaction observed between the 2 interventions


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskCoded solutions

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskNo evidence of unreported outcomes

Other biasLow riskNo other bias identified

Guill 1987

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Medical College of Georgia, USA

DURATION OF STUDY: not available


ParticipantsN SCREENED: not available

N RANDOMIZED: 44

N COMPLETED: 44

M = 26

F = 18

AGE: 13 months to 13 years

BASELINE DETAILS: not available

INCLUSION CRITERIA: bronchospasm for which bronchodilator treatment was considered necessary

EXCLUSION CRITERIA: not available


InterventionsPROTOCOL

  • Titrated to child until symptoms controlled or child admitted


TEST GROUP

  • Metaproterenol 0.2 mL (< 12 y.o.)/0.3 mL (≥ 12 y.o.) + atropine sulfate 0.05-0.1 mg/kg (max 2 mg)


CONTROL GROUP

  • Metaproterenol 0.2 mL (< 12 y.o.)/0.3 mL (≥ 12 y.o.)


CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: not mentioned


FOLLOW-UP

  • 48 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS:
change in % predicted PEF
CLINICAL SCORE:
pulmonary index
NUMBER OF REPEAT TREATMENTS REQUIRED PRIOR TO DISPOSITION
ADVERSE EFFECTS: no details in study given but data confirmed
ADMISSION: data not available
RELAPSE: data not available


NotesAuthor (MFG) contacted

Confirmation by MFG of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskOpaque consecutive numbered envelopes containing assignment

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebos used

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the trial and were included in the analysis

Selective reporting (reporting bias)Low riskNo evidence of unreported outcomes

Other biasLow riskNo other bias identified

Iramain 2011

MethodsSTUDY DESIGN: parallel randomised double-blind trial

LOCATION, NUMBER OF CENTERS: emergency department, location not reported

DURATION OF STUDY: not available


ParticipantsN SCREENED: not available

N RANDOMIZED: 106

N COMPLETED: 97 (49 salbutamol + ipratropium; 48 salbutamol + placebo)

M = 49%

F = 51%

AGE: 2-18 years

BASELINE DETAILS: moderate to severe asthma

INCLUSION CRITERIA: children presenting with moderate to severe asthma crises (episode of respiratory difficulty and wheezing associated with the use of intercostal muscles or subcostal retraction and fall in PEF and FEV1).

EXCLUSION CRITERIA: mild asthma crisis, administration of corticosteroids in the previous 24 hours, presence of severe respiratory failure requiring admission to ICU or mechanical ventilation, history of respiratory failure requiring admission to ICU, cardiac or pulmonary malfunction, chronic lung disease (pulmonary bronchodysplasia, CF), stridor, foreign body aspiration, neurologic alterations or contraindications for the use of SABAs or anticholinergic medications


InterventionsPROTOCOL:

  • Multiple fixed-dose: 6 nebulizations of salbutamol + placebo or 6 nebulizations if salbutamol + IB


  • Observation period: 30, 60, 90, 120 and 240 minutes at which point it was decide whether to admit


INTERVENTION GROUP

  • Salbutamol 5 mg + IB (40 drops 500 mcg) in 5 mL saline. 2.5 mL solution given to children weighing less than 20 kg and 5 mL in heavier children


CONTROL GROUP

  • Salbutamol 5 mg in 5 mL saline. 2.5 mL solution given to children weighing less than 20 kg and 5 mL in heavier children


RUN-IN PERIOD

  • None


CO-INTERVENTIONS

  • None


FOLLOW-UP

  • 30, 60, 90, 120 and 240 minutes


CRITERIA FOR ADMISSION

  • Asthma score < 7 and oxygen saturation < 94% or PEF or FEV1 < 60% predicted


DEVICE

  • Jet-type nebulizer


OutcomesFEV1 at 30, 60, 90, 120 and 240 minutes

Hospital admission


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"After obtaining informed consent from parents, patients were randomised using a computer generated sequence"

Allocation concealment (selection bias)Low riskNumbered bottles protect allocation

Blinding (performance bias and detection bias)
All outcomes
Low risk"The hospital pharmacy department prepared two types of numbered plastic bottles.... The two solutions have the same smell, colour and fluid level in order to prevent differentiation. Neither the investigators nor the patients knew which solution the bottles contained"

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 dropouts (2 from salbutamol + ipratropium due to tachycardia and 1 ICU admission; 1 from salbutamol due to tachycardia)

Selective reporting (reporting bias)Unclear riskNo trial protocol found

Other biasUnclear riskNone identified

Peterson 1996

MethodsRANDOMIZATION
METHOD: computer generated random numbers
MEANS: number-coded solutions supplied by the pharmacy
BLINDING: triple-blinding, identical placebo
WITHDRAWAL/DROPOUT: described

LOCATION: Canada


ParticipantsN = 163 (IB + salbutamol N = 82, salbutamol only N = 81)
AGE: 5-12 years
BASELINE SEVERITY: < 70% predicted FEV1
OTHER: ability to perform spirometry consistently


InterventionsPROTOCOL

  • Fixed: 90 minutes


  • Observation period: 120 minutes total


  • Multiple flexible-dose protocol


INTERVENTION GROUP

  • Salbutamol 3 mg + IB 250 mcg q45 minutes x 2 doses


CONTROL GROUP

  • Salbutamol 3 mg q45 minutes x 2 doses


CO-INTERVENTION (other medications used during study)

  • Additional inhalation of salbutamol + placebo/ipratropium at 90 minutes if FEV1 < 85% of predicted


  • Systemic corticosteroids: at discretion of treating physician


  • Other medications: documented


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: change in % predicted FEV1, change in predicted PEF
O2 SATURATION
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
VITAL SIGNS: blood pressure, pulse, respiratory rate
ADVERSE EFFECTS: rash, dizziness, hyperkinesia, hypertonia, tremor, conjunctivitis, taste perversion, vomiting, abdominal pain, nausea, coughing, epistaxis, pneumonia, pneumothorax, asthma exacerbation, headache, chest pain, fever, pain, sinusitis, stridor, bacterial infection
NEED FOR CORTICOSTEROIDS PRIOR TO DISPOSITION
ADMISSION

CRITERIA FOR ADMISSION: not reported
RELAPSE: within 72 hours


NotesUnpublished multicenter trial

Co-investigator (TK) contacted and granted permission to use unpublished data

Confirmation by TK of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCannot be ascertained

Selective reporting (reporting bias)Unclear riskCannot be ascertained

Other biasUnclear riskInsufficient details provided (unpublished data)

Phanichyakam 1990

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Ramathibodi Hospital, Bangkok, Thailand

DURATION OF STUDY: not available


ParticipantsN SCREENED: not available

N RANDOMIZED: 20

N COMPLETED: 20

M = 14

F = 6

AGE: 4 months to 15 years

BASELINE DETAILS: not available

INCLUSION CRITERIA: not available

EXCLUSION CRITERIA: not available


InterventionsPROTOCOL

  • Fixed: 15 minutes


  • Observation period: 360 minutes total


  • Single dose


INTERVENTION GROUP

  • Terbutaline 0.5 mg + IB 0.04 mg (15 minutes after terbutaline) x 1 dose


CONTROL GROUP

  • Terbutaline 0.5 mg x 1 dose


CO-INTERVENTION (other medications used during study)

  • Not mentioned


FOLLOW-UP

  • 360 minutes


DEVICE

  • MDI with 750 cc volumetric spacer


OutcomesPULMONARY FUNCTION TESTS: % change in FEV1, % change in PEF
VITAL SIGNS: blood pressure, heart rate, respiratory rate
ADVERSE EFFECTS: 'ocular', 'secretion-drying', 'facial-flushing'


NotesContact of 3 authors attempted but unsuccessful

Confirmation of methodology and data extraction not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
High risk"Each child received either 0.5 mg (2 puffs) of inhaled terbutaline or inhaled terbutaline 0.5 mg + inhaled IB 0.04mg (2 puffs) 15 minutes later"

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

Selective reporting (reporting bias)Low riskNo unreported outcomes identified

Other biasLow riskNo other bias identified

Qureshi 1997

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital of The King's Daughters, Virginia, USA

DURATION OF STUDY: 11 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 90

N COMPLETED: 90

M = 55

F = 35

AGE: 6-18 years

BASELINE DETAILS: < 50% predicted PEFR

INCLUSION CRITERIA: asthma exacerbation: difficulty breathing, wheezing and worsening of the child's usual symptoms or deterioration of pulmonary functions. The ability to perform reliable pulmonary function testing

EXCLUSION CRITERIA: evidence of an intrathoracic foreign body, high clinical suspicion of pneumonia, concurrent stridor, any disease process known to chronically affect respiratory function


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 120 minutes total
  • Multiple doses


INTERVENTION GROUP

  • Albuterol 0.15 mg/kg/dose q30 minutes + ipratropium 500 mcg at 0 and 60 minutes


CONTROL GROUP

  • Albuterol 0.15 mg/kg/dose q30 minutes + saline at 0 and 60 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids: all received oral corticosteroids at 60 minutes


FOLLOW-UP

  • 48 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS:
Change in predicted FEV1,
Change in predicted PEF
O2 SATURATION
VITAL SIGNS: blood pressure, heart rate, respiratory rate
ADVERSE EFFECTS: increasing breathlessness, dry mouth, palpitations, blurred vision, dilation of pupils, nausea, vomiting, mental confusion, dizziness, headache, back and chest pain
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
ADMISSION

CRITERIA FOR ADMISSION: oxygen saturations < 94%
RELAPSE: within 48 hours


NotesAuthor (FQ)
contacted

Confirmation by FQ of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskNo unreported outcomes identified

Other biasLow riskNo other sources of bias identified

Qureshi 1998

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital of The King's Daughters, Virginia, USA

DURATION OF STUDY: 8 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 480

N COMPLETED: 434

M = 248

F = 186

AGE: 2-18 years

(163 moderate group)

BASELINE DETAILS: < 70% predicted PEFR

INCLUSION CRITERIA: asthma exacerbation: increased difficulty breathing, wheezing and worsening of the child's usual symptoms or deterioration of PEFR

EXCLUSION CRITERIA: treatment with ipratropium within 6 hours before the visit, a disease known to have a chronic effect on respiratory function, concurrent stridor, possible presence of an intrathoracic foreign body, a medical condition that would contraindicate the use of beta2 adrenergic or anticholinergic medications, or need for immediate resuscitation or airway intervention


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 248 minutes
  • Multiple doses


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids - all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: % change in PEFR

CHANGE IN CLINICAL SCORE
O2 SATURATION
# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
VITAL SIGNS: pulse, respiratory rate
ADMISSION

CRITERIA FOR ADMISSION: "objective changes in clinical and pulmonary function and oxygen saturations in air" (saturations > 94% in air were accepted)

RELAPSE


NotesAuthor (FQ) contacted

Confirmation by FQ of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIn 46 children, symptoms resolved before the second dose of the study medication. 18 received a single dose of albuterol and improved. Of the remaining 26 children who had a moderate exacerbation, the split between treatment groups was even (14 and 12). This does not affect the results for outcome: hospital admission, but it may introduce bias in clinical scores since data would be collected on those children more likely to experience a change in their scores over the course of the trial protocol

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Qureshi 1998 (moderate)

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital of The King's Daughters, Virginia, USA

DURATION OF STUDY: 8 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 480

N COMPLETED: 434

M = 248

F = 186

AGE: 2-18 years

(163 moderate group)

BASELINE DETAILS: < 70% predicted PEFR

INCLUSION CRITERIA: asthma exacerbation: increased difficulty breathing, wheezing and worsening of the child's usual symptoms or deterioration of PEFR

EXCLUSION CRITERIA: treatment with ipratropium within 6 hours before the visit, a disease known to have a chronic effect on respiratory function, concurrent stridor, possible presence of an intrathoracic foreign body, a medical condition that would contraindicate the use of beta2 adrenergic or anticholinergic medications, or need for immediate resuscitation or airway intervention


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 248 minutes
  • Multiple doses


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids - all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: % change in PEFR

CHANGE IN CLINICAL SCORE
O2 SATURATION
# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
VITAL SIGNS: pulse, respiratory rate
ADMISSION

CRITERIA FOR ADMISSION: "objective changes in clinical and pulmonary function and oxygen saturations in air" (saturations > 94% in air were accepted)

RELAPSE


NotesAuthor (FQ) contacted

Confirmation by FQ of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskIn 46 children symptoms resolved before the second dose of the study medication. 18 received a single dose of albuterol and improved. Of the remaining 26 children who had a moderate exacerbation, the split between treatment groups was even (14 and 12). This does not affect the results for outcome: hospital admission, but it may introduce bias in clinical scores since data would be collected on those children more likely to experience a change in their scores over the course of the trial protocol

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Qureshi 1998 (severe)

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital of The King's Daughters, Virginia, USA

DURATION OF STUDY: 8 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 480

N COMPLETED: 434

M = 248

F = 186

AGE: 2-18 years

(271 severe group)

BASELINE DETAILS: < 50% predicted PEFR

INCLUSION CRITERIA: asthma exacerbation: increased difficulty breathing, wheezing and worsening of the child's usual symptoms or deterioration of PEFR

EXCLUSION CRITERIA: treatment with ipratropium within 6 hours before the visit, a disease known to have a chronic effect on respiratory function, concurrent stridor, possible presence of an intrathoracic foreign body, a medical condition that would contraindicate the use of beta2 adrenergic or anticholinergic medications, or need for immediate resuscitation or airway intervention


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 248 minutes
  • Multiple doses


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids - all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: % change in PEFR

CHANGE IN CLINICAL SCORE
O2 SATURATION
# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
VITAL SIGNS: pulse, respiratory rate
ADMISSION

CRITERIA FOR ADMISSION: "objective changes in clinical and pulmonary function and oxygen saturations in air" (saturations > 94% in air were accepted)

RELAPSE


NotesAuthor (FQ)
contacted

Confirmation by FQ of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskIn 46 children symptoms resolved before the second dose of the study medication. 18 received a single dose of albuterol and improved. Of the remaining 26 children who had a moderate exacerbation, the split between treatment groups was even (14 and 12). This does not affect the results for outcome: hospital admission, but it may introduce bias in clinical scores since data would be collected on those children more likely to experience a change in their scores over the course of the trial protocol

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Reisman 1988

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Hospital for Sick Children, Toronto, Canada

DURATION OF STUDY: 12 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 25

N COMPLETED: 24

M = not available

F = not available

AGE: 5-15 years

BASELINE DETAILS: < 55% predicted FEV1

INCLUSION CRITERIA: children who could perform spirometry and  < 55% predicted FEV1

EXCLUSION CRITERIA: not available


InterventionsPROTOCOL

  • Fixed: 80 minutes
  • Observation period: 150 minutes total
  • Multiple doses


INTERVENTION GROUP

  • Salbutamol 150 mcg/kg ((0.03 mL/kg) max 5 mg = 1 mL)) then 50 mcg/kg q20 minutes x 6 + IB 250 mcg at 0, 40 and 80 minutes


CONTROL GROUP

  • Salbutamol 150 mcg/kg ((0.03 mL/kg) max 5 mg = 1 mL)) then 50 mcg/kg q20 minutes x 6


CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: none
  • Theophylline: none


FOLLOW-UP

  • 150 minutes


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: change in % predicted FEV1
CHANGE IN WHEEZING SCORE
ADMISSION
CRITERIA FOR ADMISSION: not reported

RELAPSE: not reported
ADVERSE EFFECTS: tremor, vomiting


NotesAuthor (HL) contacted

Confirmation of methodology and data extraction not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 subject not completing the study was too tired to co-operate with the spirometry

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Schuh 1995

MethodsSTUDY DESIGN (parallel, cross-over): Parallel

LOCATION, NUMBER OF CENTERS: Hospital for Sick Children, Toronto, Canada

DURATION OF STUDY: 2 years 2 months


ParticipantsN SCREENED: 1586

N RANDOMIZED: 79

N COMPLETED: unclear

M = not available

F = not available

AGE: 5-17 years

BASELINE DETAILS: FEV1 < 50% predicted

INCLUSION CRITERIA: acute asthma attack, were able to perform the pulmonary function testing reliably, FEV1 < 50% predicted

EXCLUSION CRITERIA: children with 1st wheezing episode, used IB in last 4 hours prior to study start, previous PICU admission, concurrent cardiopulmonary disease, near death and requiring immediate intervention, known hypersensitivity to study drugs.


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 120 minutes total
  • Single and multiple doses


TEST GROUPS

  • Albuterol 0.15 mg/kg q20 minutes x 3 + IB 250 mcg x 1 OR
  • Albuterol 0.15 mg/kg q20 minutes x 3 + IB 250 mcg q20 minutes x 3


CONTROL GROUP

  • Albuterol 0.15 mg/kg q20 minutes x 3


RUN-IN PERIOD: none

CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: none
  • Other medications: no bronchodilators


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS
- change in % predicted FEV1
OXYGEN SATURATION
CHANGE IN CLINICAL SCORE: accessory muscle, wheeze, dyspnoea and overall
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
VITAL SIGNS: heart rate, respiratory rate
ADVERSE EFFECTS: nausea, tremor, conjunctivitis, coughing spasm with syncope
ADMISSION: described 'children with respiratory distress'
RELAPSE: within 72 hours


NotesAuthor (SS) contacted

Confirmation of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 parent changed his mind and demanded withdrawal before the start of experimental therapy. "Seven patients had to stop the trial prematurely at either 60 or 80 minutes; three children (one each in groups 1, 2 and 3) stopped cooperating before the 120 minute measurement, and three children in group 2 and one child in group 3 were too ill to continue. Two patients had missing data at 80 minutes (because of vomiting) but both had recovered by 120 minutes"

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Schuh 1995 (multiple)

MethodsSee table Schuh 1995


ParticipantsN SCREENED: 1586

N RANDOMIZED: 81

N COMPLETED: unclear

M = not available

F = not available

AGE: 5-17 years

BASELINE DETAILS: FEV1 < 50% predicted


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 120 minutes total
  • Multiple doses


TEST GROUPS

  • Albuterol 0.15 mg/kg q20 minutes x 3 + IB 250 mcg q20 minutes x 3


CONTROL GROUP

  • Albuterol 0.15 mg/kg q20 minutes x 3


RUN-IN PERIOD

  • None


CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: none
  • Other medications: no bronchodilators


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS
- change in % predicted FEV1
OXYGEN SATURATION
CHANGE IN CLINICAL SCORE: accessory muscle, wheeze, dyspnoea and overall
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
VITAL SIGNS: heart rate, respiratory rate
ADVERSE EFFECTS: nausea, tremor, conjunctivitis, coughing spasm with syncope
ADMISSION: described 'children with respiratory distress'
RELAPSE: within 72 hours


NotesAuthor (SS) contacted

Confirmation of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 parent changed his mind and demanded withdrawal before the start of experimental therapy. "Seven patients had to stop the trial prematurely at either 60 or 80 minutes; three children (one each in groups 1, 2 and 3) stopped cooperating before the 120 minute measurement, and three children in group 2 and one child in group 3 were too ill to continue. Two patients had missing data at 80 minutes (because of vomiting) but both had recovered by 120 minutes"

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Schuh 1995 (single)

MethodsSee table Schuh 1995


ParticipantsN SCREENED: 1586

N RANDOMIZED: 79

N COMPLETED: unclear

M = not available

F = not available

AGE: 5-17 years

BASELINE DETAILS: FEV1 < 50% predicted

INCLUSION CRITERIA: acute asthma attack, were able to perform the pulmonary function testing reliably, FEV1 < 50% predicted

EXCLUSION CRITERIA: children with first wheezing episode, used IB in last 4 hours prior to study start, previous PICU admission, concurrent cardiopulmonary disease, near death and requiring immediate intervention, known hypersensitivity to study drugs


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 120 minutes total
  • Single dose


TEST GROUPS

  • Albuterol 0.15 mg/kg q20 minutes x 3 + IB 250 mcg x 1


CONTROL GROUP

  • Albuterol 0.15 mg/kg q20 minutes x 3


RUN-IN PERIOD

  • None


CO-INTERVENTION (other medications used during study)

  • Systemic corticosteroids: none
  • Other medications: no bronchodilators


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS
- Change in % predicted FEV1
OXYGEN SATURATION
CHANGE IN CLINICAL SCORE: accessory muscle, wheeze, dyspnoea and overall
# REPEAT TREATMENTS REQUIRED AFTER STANDARD PROTOCOL PRIOR TO DISPOSITION
VITAL SIGNS: heart rate, respiratory rate
ADVERSE EFFECTS: nausea, tremor, conjunctivitis, coughing spasm with syncope
ADMISSION: described 'children with respiratory distress'
RELAPSE: within 72 hours


NotesAuthor (SS) contacted

Confirmation of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Allocation concealment (selection bias)Low riskIdentical placebo

Blinding (performance bias and detection bias)
All outcomes
Low risk1 parent changed his mind and demanded withdrawal before the start of experimental therapy. "Seven patients had to stop the trial prematurely at either 60 or 80 minutes; three children (one each in groups 1, 2 and 3) stopped cooperating before the 120 minute measurement, and three children in group 2 and one child in group 3 were too ill to continue. Two patients had missing data at 80 minutes (because of vomiting) but both had recovered by 120 minutes"

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone identified

Selective reporting (reporting bias)Low riskNone identified

Other biasLow risk

Sharma 2004

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: India, 1 center


ParticipantsN SCREENED: not available

N RANDOMIZED: 50

N COMPLETED: 50

M = not available

F = not available

AGE: 6-14 years

BASELINE DETAILS: % PEFR 34% (mean baseline of study population)

INCLUSION CRITERIA: acute exacerbation of bronchial asthma defined as increasing cough, inability to speak in sentences and drink, wheezing and chest recession

EXCLUSION CRITERIA: children with life-threatening or severe attack characterized by cyanosis, silent chest or poor air entry, marked dyspnoea so that a child was unable to speak even 3 or 4 words, PEFR < 30% for height, received bronchodilator 6 hours prior to admission, previous ITU admission


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 240 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Salbutamol 0.03 mL/kg/dose (150 mcg/kg/dose) with 250 mcg IB q20 x 3


CONTROL GROUP

  • Salbutamol 0.03 mL/kg/dose (150 mcg/kg/dose) q20 x 3


RUN-IN PERIOD

  • None


CO-INTERVENTIONS

  • Corticosteroids used in those who failed to respond


FOLLOW-UP

  • 240 minutes


DEVICE

  • Nebulizer


OutcomesIMPROVEMENT IN % PREDICTED PEFR

RESPIRATORY RATE

WHEEZE SCORE

USE OF ACCESSORY MUSCLES SCORES

HOSPITAL ADMISSION RATE: reported

ADMISSION RATE: not reported

ADVERSE EVENTS


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
High risk"The study was not blinded..."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Sienra Monge 2000

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: Children's Hospital of Mexico, Mexico

DURATION OF STUDY: not available


ParticipantsN SCREENED: 40

N RANDOMIZED: 30

N COMPLETED: 30

M = 18

F = 12

AGE: 8-15 years

BASELINE DETAILS: not available

INCLUSION CRITERIA: acute asthma presenting to the emergency department (mild to severe according to the Woodran Scale)

EXCLUSION CRITERIA: not available


InterventionsPROTOCOL

  • Fixed: 30 minutes
  • Observation period: 480 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Salbutamol 200 mcg + IB 120 mcg q10 minutes x 3


CONTROL GROUP

  • Salbutamol 200 mcg q10 minutes x 3


CO-INTERVENTION

  • Unclear


FOLLOW-UP

  • 480 minutes


DEVICE

  • MDI


OutcomesCHANGE IN FEV1

HOSPITALIZATION RATE

ADMISSION CRITERIA: not reported


NotesTranslated by Luis Nannini


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInformation not available

Allocation concealment (selection bias)Unclear riskInformation not available

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

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk40 children referred to in the abstract but results are given for a study population of 30

Selective reporting (reporting bias)Unclear riskUnable to ascertain this

Other biasLow riskNone identified

Watanasomsiri 2006

MethodsSTUDY DESIGN: parallel  

LOCATION, NUMBER OF CENTERS: Thammasat University Hospital, Thailand

DURATION OF STUDY: 2 years 5 months


ParticipantsN SCREENED: not available

N RANDOMIZED: 74

N COMPLETED: 71

M = not available

F = not available

AGE: 3-15 years

BASELINE DETAILS: % PEFR 29.2 (baseline characteristics of study group)

INCLUSION CRITERIA: clinical diagnosis of asthma, moderate to severe asthma attack (children younger than 5 years were required to have 3 or more episodes of wheezing before the presenting illness)

EXCLUSION CRITERIA: first-time episode of wheeze; co-existent cardiac, renal or other chronic pulmonary disease; bronchopulmonary dysplasia; intolerance to study drugs; glaucoma or urinary retention. Children who had used IP within 24 hours, used oral corticosteroids within 3 days and required immediate resuscitation or airway intervention were also excluded from the study


InterventionsPROTOCOL

  • Fixed 60 minutes
  • Observation period 120 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Salbutamol (1.2 mg for body weight < 10 kg and 2.5 mg for body weight > 10 kg) + 250 mcg of IB q20 minutes x 3


CONTROL GROUP

  • Salbutamol (1.2 mg for body weight < 10 kg and 2.5 mg for body weight > 10 kg) + isotonic sodium chloride solution q20 minutes x 3


CO-INTERVENTIONS

  • Oral corticosteroid 0.5 mg/kg with the second dose of the nebulized solution. After the third dose of the randomised medication, children received additional doses of nebulized salbutamol if indicated by incomplete clinical response at 70, 100 and 120 minutes


FOLLOW-UP PERIOD

  • 3 days


DEVICE

  • Nebulizer


OutcomesCHANGE IN CLINICAL SCORE

PULMONARY FUNCTION TESTS: % change in actual PEFR from baseline, changes in % predicted PEFR

VITAL SIGNS: respiratory rate, heart rate, oxygen saturation

NEED FOR ADDITIONAL SALBUTAMOL DOSES

HOSPITALIZATION

ADMISSION CRITERIA: not reported

RELAPSE: within 3 days


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInformation not available

Allocation concealment (selection bias)Low risk"Solutions supplied by pharmacy", "Solutions drawn up an independent nurse..."

Blinding (performance bias and detection bias)
All outcomes
Low risk"...parents and physicians were unaware of vial contents"

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 children withdrawn for technical reasons (errors in protocol) 1 child withdrawn by parents

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskNone identified

Watson 1988

MethodsRANDOMIZATION: method and means not described

BLINDING: double-blind, not described

WITHDRAWAL/DROPOUT: none

JADAD's QUALITY SCORE: 3


ParticipantsN: 31
AGE: 6-17 years
BASELINE SEVERITY: 30-70% predicted FEV1
COUNTRY: Canada
OTHER: ability to perform spirometry consistently


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: 120 minutes total
  • Multiple fixed-dose protocol


TEST GROUP

  • Fenoterol 625 mcg + IB 250 mcg combined q60 minutes x 2


CONTROL GROUP

  • Fenoterol 625 mcg q60 minutes x 2


CO-INTERVENTION

  • None


FOLLOW-UP

  • 120 minutes


DEVICE

  • Nebulizer


OutcomesPULMONARY FUNCTION TESTS: change in % predicted FEV1, % change in FEV1
OXYGEN SATURATION: no details given
CHANGE IN CLINICAL SCORE: pulmonary Index, no details given
ADVERSE EFFECTS: tremor, "no adverse effects" but none other specified
ADMISSION: described
RELAPSE: not mentioned


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskInformation not available

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Unclear riskUnable to ascertain this reliably

Other biasLow riskNone identified

Zorc 1999

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: John Hopkins Hospital, Baltimore, USA

DURATION OF STUDY: 1 year


ParticipantsN SCREENED: 1215

N RANDOMIZED: 427

N COMPLETED: 427

M = 298

F = 129

AGE: 1-17 years

BASELINE DETAILS: initial severity score of 1-3, excluded children if required initial therapy in addition to the critical pathway - initial severity score was incomplete/missing for 14% of the total 427 children of the full study

INCLUSION CRITERIA: children who were to be treated according to a standardized emergency department protocol for acute asthma

EXCLUSION CRITERIA: mild illness; decision not to treat on critical pathway; severe presentation requiring additional therapy; pretreatment with corticosteroids or IB; a history of glaucoma, CF or sickle cell disease


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 295 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids: all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


Outcomes# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
ADMISSION: to ward, to ICU

ADMISSION CRITERIA: not reported
RELAPSE


NotesAuthor (MP) contacted

Confirmation by MP of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskTrial protocol not reviewed

Other biasLow riskNone identified

Zorc 1999 (mild)

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: John Hopkins Hospital, Baltimore, USA

DURATION OF STUDY: 1 year


ParticipantsN SCREENED: 1215

N RANDOMIZED: 427

N COMPLETED: 427

M = 298

F = 129

AGE: 1-17 years

MILD GROUP N = 117

BASELINE DETAILS: initial severity score of 1-3, excluded children if required initial therapy in addition to the critical pathway - initial severity score was incomplete/missing for 14% of the total 427 children of the full study

INCLUSION CRITERIA: children who were to be treated according to a standardized emergency department protocol for acute asthma

EXCLUSION CRITERIA: mild illness; decision not to treat on critical pathway; severe presentation requiring additional therapy; pretreatment with corticosteroids or IB; a history of glaucoma, CF or sickle cell disease


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 295 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (͗≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids: all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


Outcomes# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
ADMISSION: to ward, to ICU

ADMISSION CRITERIA: not reported
RELAPSE


NotesAuthor (MP) - contacted

Confirmation by MP of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskTrial protocol not reviewed

Other biasLow riskNone identified

Zorc 1999 (moderate)

MethodsSTUDY DESIGN: parallel

LOCATION, NUMBER OF CENTERS: John Hopkins Hospital, Baltimore, USA

DURATION OF STUDY: 1 year


ParticipantsN SCREENED: 1215

N RANDOMIZED: 427

N COMPLETED: 427

M = 298

F = 129

AGE: 1-17 years

MODERATE GROUP: N = 194  

BASELINE DETAILS: initial severity score of 4-6, excluded if required initial therapy in addition to the critical pathway - initial severity score was incomplete/missing for 14% of the total 427 children of the full study

INCLUSION CRITERIA: children who were to be treated according to a standardized emergency department protocol for acute asthma

EXCLUSION CRITERIA: mild illness; decision not to treat on critical pathway; severe presentation requiring additional therapy; pretreatment with corticosteroids or IB; a history of glaucoma, CF or sickle cell disease


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 295 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids : all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


Outcomes# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
ADMISSION: to ward, to ICU

ADMISSION CRITERIA: not reported
RELAPSE


NotesAuthor (MP) contacted

Confirmation by MP of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskTrial protocol not reviewed

Other biasLow riskNone identified

Zorc 1999 (severe)

MethodsSTUDY DESIGN: Parallel

LOCATION, NUMBER OF CENTERS: John Hopkins Hospital, Baltimore, USA

DURATION OF STUDY: 1 year


ParticipantsN SCREENED: 1215

N RANDOMIZED: 427

N COMPLETED: 427

M = 298

F = 129

AGE: 1-17 years

SEVERE GROUP: N = 51

BASELINE DETAILS: initial severity score of 7-9, excluded children if respiratory failure or required initial therapy in addition to the critical pathway - initial severity score was incomplete/missing for 14% of the total 427 children of the full study

INCLUSION CRITERIA: children who were to be treated according to a standardized emergency department protocol for acute asthma

EXCLUSION CRITERIA: mild illness; decision not to treat on critical pathway; severe presentation requiring additional therapy; pretreatment with corticosteroids or IB; a history of glaucoma, CF or sickle cell disease


InterventionsPROTOCOL

  • Fixed: 60 minutes
  • Observation period: up to 295 minutes
  • Multiple fixed-dose protocol


INTERVENTION GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + IB 500 mcg at 20 and 40 minutes


CONTROL GROUP

  • Albuterol 2.5 mg (< 20 kg)/5.0 mg (≥ 20 kg) q20 minutes x 3 + saline at 20 and 40 minutes


CO-INTERVENTION (other medications used during the study)

  • Systemic corticosteroids: all received oral corticosteroids at 20 minutes


FOLLOW-UP

  • 72 hours


DEVICE

  • Nebulizer


Outcomes# NEBULIZER TREATMENTS UNTIL DISPOSITION
TIME TO DISPOSITION
ADMISSION: to ward, to ICU

ADMISSION CRITERIA: not reported
RELAPSE


NotesAuthor (MP) contacted

Confirmation by MP of methodology and data extraction obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskNumber-coded solutions supplied by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals

Selective reporting (reporting bias)Low riskTrial protocol not reviewed

Other biasLow riskNone identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Anthracopoulos 2005Study compared anticholinergic agents and salbutamol versus higher dose of salbutamol alone

Boner 1987Study on people with stable asthma

Bratteby 1986Study on people with chronic asthma

Browne 2002Hospitalized participants treated with IV salbutamol and placebo versus IV salbutamol and anticholinergics

Caubet 1989Study on people with chronic asthma

Craven 2001Acute inpatient setting

Davis 1984Study on people with stable asthma

Delacourt 1994The study was not a randomised controlled trial

DeStefano 1989Study on people with chronic asthma

Ekwo 1978The study was not a randomised controlled trial

Freeman 1989The study pertained to participants who were already admitted

Friberg 1989Study on people with chronic asthma

Goggin 2001Hospitalized children

Greenough 1986Study on people with chronic asthma

Groggins 1981Study on people with stable asthma

Hodges 1981The study pertained to infants

Kumaratne 2003Significant number of participants under 18 months (mean: 19-27 months, SD 20-23)

Lenney 1986Study on people with chronic asthma

Mann 1982Study on people with chronic asthma

O'Driscoll 1989Age range: 17-81 years

Paredes 1994Conference abstract - incomplete data given

Ralston 2005Different SABAs used in each treatment arm

Rayner 1987The study pertained to people who were already admitted

Stokes 1983The study did not combine anticholinergic inhalations and SABAs inhalations

Storr 1986The study pertained to people who were already admitted

Timsit 2002Different doses of SABA in treatment groups

Vichyanond 1990Study on people with chronic asthma

Ward 1981Age range: 15-79 year olds

Ward 1985Age range: 14-75 years

Wilson 1984Study on people with chronic asthma

 
Comparison 1. Anticholinergic and beta2-agonists versus beta2-agonists alone (all protocols)

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

 1 Primary outcome: hospital admissions192497Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.85]

 2 Primary outcome: hospital admissions subgrouped by trial protocol192497Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.85]

    2.1 Single-dose protocol
3419Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.56, 1.26]

    2.2 Multiple fixed-dose protocol
151998Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.61, 0.84]

    2.3 Multiple flexible-dose protocol
180Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Primary outcome: hospital admissions subgrouped by review authors' judgment of trial report182497Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.85]

    3.1 Severe
81188Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.61, 0.87]

    3.2 Moderate-severe
4371Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.41, 0.89]

    3.3 Moderate
3463Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.49, 1.22]

    3.4 Mild-moderate
2358Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.52, 1.47]

    3.5 Mild
1117Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.42, 4.79]

 4 Primary outcome: hospital admissions subgrouped by control group event rate (tertiles)182417Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.85]

    4.1 High control group event rate (upper tertile)
6669Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.56, 0.82]

    4.2 Medium control group event rate (middle tertile)
6780Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.57, 0.99]

    4.3 Low control group event rate (lower tertile)
6968Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.59, 1.42]

 5 Primary outcome: hospital admissions subgrouped by co-intervention of corticosteroid172407Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.84]

    5.1 Background corticosteroids
81043Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.59, 0.86]

    5.2 No background corticosteroids
6353Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.47, 0.94]

    5.3 Variable (at physicians discretion)
3511Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.54, 1.10]

    5.4 Not reported
1500Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.48, 1.53]

 6 Change from baseline in % predicted FEV1, 60 minutes after the last of IB5402Mean Difference (IV, Fixed, 95% CI)10.08 [6.24, 13.92]

 7 Change from baseline in % predicted FEV1, 120 minutes after last IB2117Mean Difference (IV, Fixed, 95% CI)6.87 [1.17, 12.56]

 8 % Change in FEV1 or PEFR at 60 minutes after last IB (± 15 minutes)4166Std. Mean Difference (IV, Fixed, 95% CI)0.57 [0.25, 0.88]

 9 % Change in FEV1 or PEFR at 120 minutes after last IB (± 30 minutes)4219Std. Mean Difference (IV, Fixed, 95% CI)0.12 [-0.15, 0.39]

 10 % Change in respiratory resistance at 60 minutes after IB (± 15 minutes)1294Mean Difference (IV, Fixed, 95% CI)0.02 [-0.02, 0.07]

    10.1 Co-intervention: corticosteroids during the previous 60 minutes
170Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.13, 0.09]

    10.2 Co-intervention: no corticosteroids
1224Mean Difference (IV, Fixed, 95% CI)0.03 [-0.02, 0.08]

 11 % Change in respiratory resistance at 120 minutes after IB (± 30 minutes)1108Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.09, 0.07]

    11.1 Co-intervention: corticosteroids during the previous 120 minutes
147Mean Difference (IV, Fixed, 95% CI)0.02 [-0.12, 0.16]

    11.2 Co-intervention: no corticosteroids
161Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.12, 0.08]

 12 Change in clinical score at 120 minutes (± 30 minutes)3934Std. Mean Difference (IV, Fixed, 95% CI)-0.23 [-0.42, -0.04]

 13 Need for repeat bronchodilator treatment after standard protocol prior to disposition91074Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.79, 0.97]

 14 O2 saturation < 95% at 60 minutes (± 15 minutes)2416Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.55, 0.97]

 15 O2 saturation < 95% at 120 minutes (± 30 minutes)2185Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.76, 1.59]

 16 Need for corticosteroids in emergency department prior to disposition2378Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.73, 1.08]

 17 Tremor9524Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.51, 0.93]

 18 Vomiting81230Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.49, 1.56]

 19 Nausea7757Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.38, 0.95]

 20 Relapse101389Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.68, 1.68]

 
Summary of findings for the main comparison. Anticholinergic and short-acting beta2-agonists versus beta2-agonists alone (all protocols) for initial treatment of acute asthma in children

Anticholinergic and shorth-acting beta2-agonists (SABA) versus SABA alone (all protocols) for initial treatment of acute asthma in children

Patient or population: children with initial treatment of acute asthma
Settings: emergency department
Intervention: anticholinergic and SABA versus SABA alone (all protocols)

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

Assumed riskCorresponding risk

ControlAnticholinergic and SABA versus SABA alone (all protocols)

Primary outcome: hospital admissions
hospital admissions
23 per 10017 per 100
(15 to 20)
RR 0.73
(0.63 to 0.85)
2497
(19 studies)
⊕⊕⊕⊕
high
3 studies had no admissions so did not contribute to the RR.

*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) 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; SABA: short-acting beta-agonists.

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.

 
Table 1. Study treatments

ProtocolStudyAge range (years)Delivery deviceDose of ipratropium bromideNumber of dosesTotal dose delivered

Single doseBeck 19856-17.5Nebulized250 mcg1250 mcg

Chakraborti 20065-15MDI and spacer80 mcg180 mcg

Cook 198512-18Nebulized1-2 mL of 0.025% solution11-2 mL of 0.025% solution

Ducharme 19983-17Nebulized250 mcg1250 mcg

Phanichyakam 19904-14MDI and spacer40 mcg140 mcg

Schuh 1995 (single) (single dose)5-17Nebulized250 mcg1250 mcg

Multiple fixed-dose protocolBenito Fernandez 20005 months to 16 yearsNebulized250 mcg2500 mcg

BI [pers comm]2-10Nebulized500 mcg31500 mcg

Iramain 20112-18Nebulized500 mcg children over 20 kg

250 mcg children under 20 kg
63000 mcg or 1500 mcg

Peterson 19965-12Nebulized250 mcg2500 mcg

Qureshi 19976-18Nebulized500 mcg21000 mcg

Qureshi 1998 (moderate)2-18Nebulized500 mcg21000 mcg

Qureshi 1998 (severe)2-18Nebulized500 mcg21000 mcg

Reisman 19885-15Nebulized250 mcg3750 mcg

Schuh 1995 (multiple dose)5-17Nebulized250 mcg3750 mcg

Sharma 20046-14Nebulized250 mcg3750 mcg

Sienra Monge 20008-15MDI and spacer120 mcg2240 mcg

Watanasomsiri 20063-15Nebulized250 mcg3750 mcg

Watson 19886-17Nebulized250 mcg2500 mcg

Zorc 1999 (mild)1-17Nebulized500 mcg21000 mcg

Zorc 1999 (moderate)1-17Nebulized500 mcg21000 mcg

Zorc 1999 (severe)1-17Nebulized500 mcg21000 mcg

Multiple flexible-dose protocolCalvo 19985-14MDI and spacer20 mcgMax 7140 mcg (max)

Guill 198713 months to 13 yearsNebulized0.05-0.1 mg/kgMax 30.15-0.3 mg/kg (max)

 Max: maximum; MDI: metered-dose inhaler.
 
Table 2. Severity based on review author assessment of trial report

StudyMEAN FEV1/PEFR (inclusion criteria)MEAN scoreTrial report description of severityReview authors severity classificationAge

Beck 1995FEV 30-31% (eligibility: FEV1 < 50% pred)Not reportedSevereSevere6 years-upper range not reported

Benito-Fernandez 2000Mean PEF: 45% predicted4.5 on a 5-point scoreModerate to severeSevere5 months to 16 years

BI (pers comm)Unclear if measuredseverity score of 13 (unknown scale)SevereSevere2-10 years

Calvo (1998)PEF = 69-71% (excluded if PEF > 80% pred.)12-point TAL score: 5.6-6 (moderate)Moderate Moderate5-14 years

Chakraborti (2006)FEV1 69-71 ± 37% (S+IB) and 57 ± 21% (S alone)10-point clinical asthma score 1.83 (S+IB) vs. 2.07 (S alone)Mild and moderate  Mild and moderate5-15 years

Ducharme (1998)Children requiring continuous nebulizations of salbutamol were excludedMild and moderateMild and moderate3-7 years

Iramain (2011)FEV1 60-64%/PEF 62-60%15-point pulmonary score: 12.3Moderate and severeModerate and severe2-18 years

Pederson (1996)Mean not reported (eligibility FEV1 < 70% pred.)Not reportedNot reportedModerate and severe5-12 years

Qureshi (1997)Mean FEV1 and PEF at baseline 37% and 34% (eligibility FEV1 < 50% pred.)Not reportedSevereSevere6-18 years

Qureshi (1998) (sev)Subgroup data provided by author:

FEV1 34% (eligibility FEV1 < 50% pred.)
12-15 on 15-point asthma score)SevereSevere2-18 years

Qureshi (1998) (mod)Subgroup data provided by author:

FEV1 55% (eligibility: 50% < FEV1 < 70% pred.)
8-11 on a 15-point Clinical scoreModerateModerate2-18 years

Reisman (1998)FEV1 33-40% (eligibility; FEV1 < 55% pred.)-SevereSevere5-15 years

Schuh (1995)mean FEV1-34% (eligibility; FEV1 < 50% pred.)wheezing score 2.2-2.5 on max of 3SevereSevere5-17 years

Sharma (2004)PEF 35% pred. (excluded PEF < 30% pred. and signs of impending respiratory diseaseWheezing score 2.5 to 2.6 (max = 3)ModerateSevere6-14 years

Sienra monge (2000)FEV1: 1 Lnot reportedModerate to severeUnrated8-15 years

Watson (1988)Mean FEV1 not reported (eligibility FEV1: 30-70% pred.)5.7-6 on a scale of 0 to 12Moderate and severeModerate and severe6-17 years

Watanasomsiri (2006)Mean % pred. PEFR at baseline 27-30% in the subset of people cooperating with the forced expiratory technique)(PEFR was not an inclusion criteria) no exclusion or inclusion based on severity6.42 on a scale of 0 to 12Proportion of moderate asthma: 73% and of severe asthma: 27%Moderate and severe3-15 years

Zorc (1999)Subgroups data obtained from authorsNot reported-3 strata (mild, moderate and severe)1-17 years

 FEV1: forced expiratory volume in one second; IB: ipratropium bromide; max: maximum; PEF: peak expiratory flow; PEFR: peak expiratory flow rate; pred.: predicted; S: salbutamol; y.o.: years old.
 
Table 3. Studies grouped by control group event rate as a proxy for severity

ProtocolStudyAdmission rate

(control group)
Baseline population spirometry characteristics

(where available)
Admission rate - ranking

Multiple fixed-dose protocol Benito Fernandez 20000.53PEFR (%) mean 44.8High

Qureshi 1998 (severe)0.52PEFR < 50% predictedHigh

Schuh 1995 (multiple)0.46FEV1 < 50% predictedHigh

Qureshi 19970.45PEFR < 50% predictedHigh

Iramain 20110.43PEF or FEV1 < 60% predictedHigh

Zorc 1999 (severe)0.41Not reportedMedium

Peterson 19960.30FEV1 < 70% predictedMedium

Zorc 1999 (moderate)0.26Not reportedMedium

Reisman 19880.23FEV1 < 55% predictedMedium

Sharma 20040.16% predicted PEFR 34.4% (mean)Medium

Qureshi 1998 (moderate)0.09PEFR < 70% predictedLow

Watanasomsiri 20060.09% PEFR 29.2Low

BI [pers comm]0.09Not reportedLow

Zorc 1999 (mild)0.07Not reportedLow

Watson 19880.00Not reportedLow

Single-dose protocolSchuh 1995 (single)0.46FEV1 < 50% predictedHigh

Ducharme 19980.17Respiratory resistanceMedium

Chakraborti 20060.00FEV1 < 80%Low

 FEV1: forced expiratory volume in one second; PEF: peak expiratory flow; PEFR: peak expiratory flow rate.
 
Table 4. Number needed to treat for hospital admissions grouped by severity tertile

Risk tertileWeighted control group riskRisk ratio (95% CI)Corresponding treatment group risk (95% CI)NNTB (95% CI)

Low8.0%0.91 (0.59 to 1.42)7% (4 to 11)139 (not significant)

Medium24.1%0.75 (0.57 to 0.99)18% (14 to 24)17 (10 to 415)

High48.7%0.68 (0.56 to 0.82)33% (27 to 40)7 (5 to 12)

 Comparing the control group weighted risk against the treatment group's risk it can be seen that the NNTB in the high risk group was 7 versus 13 in the medium-risk group and 131 in the low-risk group.
CI: confidence interval; NNTB: number need to treat for an additional beneficial effect.