Intervention Review

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Beta2-agonists for exercise-induced asthma

  1. Matteo Bonini1,2,3,*,
  2. Corrado Di Mambro4,
  3. Moises A Calderon3,
  4. Enrico Compalati5,
  5. Holger Schünemann6,
  6. Stephen Durham3,
  7. Giorgio W Canonica5

Editorial Group: Cochrane Airways Group

Published Online: 2 OCT 2013

Assessed as up-to-date: 13 SEP 2013

DOI: 10.1002/14651858.CD003564.pub3


How to Cite

Bonini M, Di Mambro C, Calderon MA, Compalati E, Schünemann H, Durham S, Canonica GW. Beta2-agonists for exercise-induced asthma. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003564. DOI: 10.1002/14651858.CD003564.pub3.

Author Information

  1. 1

    "Sapienza" University, Department of Public Health and Infectious Diseases, Rome, Italy

  2. 2

    Institute of Translational Pharmacology (IFT), CNR, Rome, Italy

  3. 3

    National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, Section of Allergy and Clinical Immunology, London, UK

  4. 4

    Children's Hospital "Bambino Gesù", Department of Medical and Surgical Pediatric Cardiology - UOC Arrhythmology, Rome, Italy

  5. 5

    University of Genoa, Allergy and Respiratory Diseases Clinic, Department of Internal Medicine (DIMI), Genoa, Italy

  6. 6

    McMaster University, Departments of Clinical Epidemiology and Biostatistics and of Medicine, Hamilton, Ontario, Canada

*Matteo Bonini, matte.bonini@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 2 OCT 2013

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Characteristics of included studies [ordered by study ID]
Anderson 2001 Salb Disk

MethodsStudy design: Randomized, double blind, cross over

Study location: 2 centres, Australia

Wash-out: 1-14 days

Exercise challenge: Cycle-ergometer for 8 min up to 50-60% of MVV

Criteria for EIB diagnosis: Positive history, FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 29

% of males: 40%

Age range: 18-40 years

Ethnicity: Not reported

Withdrawal or drop out: 2


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min.

Intervention: Salbutamol MDI 200 mcg; Salbutamol diskus 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed on the study day


OutcomesPrimary available: max FEV1 % fall, % protection

Secondary available: Number of patients with a max FEV1 % fall <10%, <15%, <20%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Anderson 2001 Salb MDI

Methods


Participants


Interventions


Outcomes


NotesSee: Anderson 2001 Salb Disk


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Blake 1999 Salb 180

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 3-14 days

Exercise challenge: Treadmill for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 26

% of males: 65%

Age range: 4-11 years

Ethnicity: 81% Caucasians, 15% Blacks, 4% Hispanic

Withdrawal or drop out: 3


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min, 5:30 hours, 11:30 hours

Intervention: Albuterol 180 mcg, Salmeterol 25 mcg Diskus, Salmeterol 50 mcg Diskus

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: max FEV1 % fall, % protection, FEV1 fall AUC

Secondary available: Side effects


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Blake 1999 Salm 25

Methods


Participants


Interventions


Outcomes


NotesSee: Blake 1999 Salb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Blake 1999 Salm 50

Methods


Participants


Interventions


Outcomes


NotesSee: Blake 1999 Salb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Boner 1994 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: 2-10 days

Exercise challenge: Treadmill for 6 min at 90±4% of max HR

Criteria for EIB diagnosis: Positive history, asthma according to ATS, FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 16

% of males: 68%

Age range: 6-12 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 3 hours, 12 hours

Intervention: Salbutamol 200 mcg, Formoterol 12 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: max FEV1 % fall, % protection, FEV1 fall AUC

Secondary available: Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Boner 1994 Salb 200

Methods


Participants


Interventions


Outcomes


NotesSee: Boner 1994 Form


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Boulet 1989 Salb

MethodsStudy design: Randomized, double blind, cross over

Study location: Canada

Wash-out: >2 days

Exercise challenge: Ergometer for 6 min at 80% of VO2 max

Criteria for EIB diagnosis: Positive history, asthma according to ATS, FEV1 fall >10% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 36%

Age range: 19-49 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min.

Intervention: Salbutamol 200 mcg

Control: Placebo

Other drug arms: Ipratroprium bromide, Sodium cromoglycate

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: % protection

Secondary available: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
High riskData on primary and secondary outcomes are reported incompletely

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 1995 Salb MDI

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 2-7 days

Exercise challenge: Treadmill for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 46

% of males: 59%

Age range: 4-11 years

Ethnicity: 87% Caucasians, 13% Others

Withdrawal or drop out: 2


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min.

Intervention: Albuterol MDI 180 mcg, Albuterol rotacaps 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: max FEV1 % fall, % protection

Secondary available: Side effects, Number of patients with a max FEV1 % fall <20%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 1995 Salb Pwd

Methods


Participants


Interventions


Outcomes


NotesSee: Bronski 1995 Salb MDI


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 1999 Salm Disk

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 2-14 days

Exercise challenge: Treadmill for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 24

% of males: 58%

Age range: 4-11 years

Ethnicity: 91% Caucasians, 9% Blacks

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min, 5:30 hours, 11:30 hours

Intervention: Salmeterol 50 mcg Diskus, Salmeterol 50 mcg Diskhaler

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: max FEV1 % fall, % protection, FEV1 fall AUC

Secondary available: Side effects, Number of patients with a max FEV1 % fall <15%, <20%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 1999 Salm Diskhal

Methods


Participants


Interventions


Outcomes


NotesSee: Bronski 1999 Salm Disk


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 2002 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 3-7 days

Exercise challenge: Treadmill for 6 min at 90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 18

% of males: 78%

Age range: 13-36 years

Ethnicity: 88% Caucasians, 12% Others

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min, 4 hours, 8 hours, 12 hours

Intervention: Albuterol 180 mcg, Formoterol 12 mcg, Formoterol 24 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: max FEV1 % fall; % protection; FEV1 fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%; Max PEF % fall


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 2002 Form 24

Methods


Participants


Interventions


Outcomes


NotesSee: Bronski 2002 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Bronski 2002 Salb

Methods


Participants


Interventions


Outcomes


NotesSee: Bronski 2002 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Carlsen 1995 Salm 25

MethodsStudy design: Randomized, double blind, cross over

Study location: Norway

Wash-out: 2-14 days

Exercise challenge: Treadmill for 6 min up to 170-180 bpm

Criteria for EIB diagnosis: Positive history, FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 23

% of males: 47%

Age range: 8-16 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: between 10-12 hours

Intervention: Salmeterol diskhaler 25 mcg, Salmeterol diskhaler 50 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Number of patients with a max FEV1 % fall <15%; Max MEF25-50 % fall


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Carlsen 1995 Salm 50

Methods


Participants


Interventions


Outcomes


NotesSee: Carlsen Salm 25


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Cavagni 1993 Salb Jet

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: Not reported

Exercise challenge: Treadmill for 6 min up to 170-180 bpm

Criteria for EIB diagnosis: Positive history, FEV1 fall >15% after exercise challenge, FEV1 >15% after bronchodilator


ParticipantsNumber of subjects: 9

% of males: 66%

Age range: 5-9 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min.

Intervention: Salbutamol MDI 200 mcg, Salbutamol jet disposable 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Side effects; Max PEF % fall; Max FEF25-75 % fall


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Cavagni 1993 Salb MDI

Methods


Participants


Interventions


Outcomes


NotesSee: Cavagni 1993 Salb Jet


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Clarke 1990 Fen

MethodsStudy design: Randomized, double blind, cross over

Study location: Australia

Wash-out: <14 days

Exercise challenge: Treadmill at 15° inclination for 6 min. up to 150 bpm

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 20

% of males: 70%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min.

Intervention: Fenoterol 100 mcg

Control: Placebo

Other drug arms: Sodim cromoglycate 20 mg; Sodium cromoglycate 20 mg + Fenoterol 100 mcg

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: None


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Daugbjerg 1996 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: Denmark

Wash-out: Not reported

Exercise challenge: Treadmill for 6 min. up to 150 bpm

Criteria for EIB diagnosis: FEV1 fall >22% after exercise challenge


ParticipantsNumber of subjects: 16

% of males: 81%

Age range: 10-14 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 3 hours, 12 hours

Intervention: Salbutamol 400 mcg, Formoterol 12 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Daugbjerg 1996 Salb

Methods


Participants


Interventions


Outcomes


NotesSee: Daugbjerg 1996 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Debelic 1988 Reproterol

MethodsStudy design: Randomized, double blind, cross over

Study location: Germany

Wash-out: Not reported

Exercise challenge: Free running for 6 min up to 160-180 bpm

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 16

% of males: Not reported

Age range: 8-20 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min.

Intervention: Reproterol 1 mg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Any drug suspended 12 hours before exercise challenge


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

DeBenedictis 1996 Salm 25

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: 2-10 days

Exercise challenge: Treadmill for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 83%

Age range: 7-14 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 1 hour, 12 hours

Intervention: Salmeterol 25 mcg, Salmeterol 50 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

DeBenedictis 1996 Salm 50

Methods


Participants


Interventions


Outcomes


NotesSee: De Benedictis 1996 Salm 25


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

DeBenedictis 1998 Salb

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: <10 days

Exercise challenge: Treadmill for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 66%

Age range: 7-13 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 20 min.

Intervention: Salbutamol 200 mcg

Control: Placebo

Other drug arms: Salbutamol 200 mcg + Nedocromil 4 mg

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Del Col 1993 Salb Jet

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: 2-6 days

Exercise challenge: Treadmill for 6 min at 90±4% of max HR

Criteria for EIB diagnosis: Positive history


ParticipantsNumber of subjects: 15

% of males: 60%

Age range: 9-13 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min.

Intervention: Salbutamol MDI 200 mcg, Salbutamol Jet device 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Max PEF % fall


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Del Col 1993 Salb MDI

Methods


Participants


Interventions


Outcomes


NotesSee: Del Col 1993 Salb Jet


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Dinh Xuan 1989 Terb

MethodsStudy design: Randomized, double blind, cross over

Study location: France

Wash-out: Not reported

Exercise challenge: Cycle-ergometer for 5 min at 90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 10

% of males: 70%

Age range: 6-16 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min.

Intervention: Terbutaline 500 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Number of patients with a max FEV1 % fall <10%, <15% and <20%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Egglestone 1981 Terb 250

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: ≧2 days

Exercise challenge: Treadmill for 5 min at 90% of max HR

Criteria for EIB diagnosis: Positive history; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 17

% of males: Not reported

Age range: 18-32 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 1 hour

Intervention: Terbutaline 250 mcg

Control: Placebo

Other drug arms: Isoproterenol 100 mcg

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Max FEF25-75 % fall;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Ferrari 2000 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: ≧2 days

Exercise challenge: Cycle-ergometer for 7 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 14

% of males: 92%

Age range: 12-28 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min, 4 hours

Intervention: Formoterol 12 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)High riskStatistical analysis and manuscript writing made by drug industry staff

Other biasUnclear riskInsufficient information

Garcia 2001 Form 12

MethodsStudy design: Randomized, double blind, parallel groups

Study location: Spain

Wash-out: Not applicable

Exercise challenge: Cycle-ergometer for 6 min at 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 19

% of males: 42%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Chronic administration (4 weeks)

Time of exercise challenge after drug administration: 30 min, 12 hours at day 1, 14 and 28

Intervention: Formoterol 12 mcg twice daily

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Onset of tolerance; Number of patients with a max FEV1 % fall <10%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Green 1992 Salm 50

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: 4-10 days

Exercise challenge: Treadmill for 8 min up to 170 bpm

Criteria for EIB diagnosis: Positive history, FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 13

% of males: 61%

Age range: 8-15 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 1 hour, 5 hours, 9 hours

Intervention: Salmeterol 50 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <15%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Gronnerod 2000 Form 4.5

MethodsStudy design: Randomized, double blind, cross over

Study location: Germany and Norway

Wash-out: ≧3 days

Exercise challenge: Treadmill for 4-8 min up to 180 bpm

Criteria for EIB diagnosis: Asthma according ATS; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 27

% of males: 55%

Age range: 8-17 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min, 4 hours, 8 hours, 12 hours

Intervention: Terbutaline 500 mcg; Formoterol 9 mcg; Formoterol 4.5 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Gronnerod 2000 Form 9

Methods


Participants


Interventions


Outcomes


NotesSee: Gronnerod 2000 Form 4.5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Gronnerod 2000 Terb 500

Methods


Participants


Interventions


Outcomes


NotesSee: Gronnerod 2000 Form 4.5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Hancox 2002

MethodsStudy design: Randomized, double blind, cross over

Study location: Canada

Wash-out: No

Exercise challenge: Cycle ergometer for 7 min at 80% of max work rate

Criteria for EIB diagnosis: Positive history; FEV1 fall >15% after exercise challenge which was sustained >10% for at least 5 minutes


ParticipantsNumber of subjects: 9

% of males: 11%

Age range: 18-44 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Chronic administration (1 week)

Time of exercise challenge after drug administration: 8 hours

Intervention: Salbutamol 800 mcg daily

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Tolerance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Hawksworth 2002 Salb HFA

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: 1-14 days

Exercise challenge: Treadmill for 6 min at >80% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 24

% of males: 75%

Age range: 18-45 years

Ethnicity: Caucasian 83%; Asian 17%

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min

Intervention: Salbutamol 180 HFA; Salbutamol 180 mcg MDI

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Hawksworth 2002 Salb MDI

Methods


Participants


Interventions


Outcomes


NotesSee: Hawksworth 2002 Salb HFA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Henricksen 1983 Terb

MethodsStudy design: Randomized, double blind, cross over

Study location: Denmark

Wash-out: No

Exercise challenge: Free running for 6 min at 80-85% of max work capacity

Criteria for EIB diagnosis: PEF fall >20% after exercise challenge


ParticipantsNumber of subjects: 14

% of males: Not reported

Age range: 8-15 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min

Intervention: Terbutaline 32.5 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Max PEF % fall; Side effects; Number of patients with a max FEV1 % fall <20%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Henricksen 1992 Salb

Methods


Participants


Interventions


Outcomes


NotesSee: Henricksen 1992 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Henriksen 1992 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: Denmark

Wash-out: Not reported

Exercise challenge: Treadmill for 6 min up to 180 bpm

Criteria for EIB diagnosis: PEF or FEV1 fall >25% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: Not reported

Age range: 8-15 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min, 3 hours, 5.30 hours, 8 hours

Intervention: Salbutamol 200 mcg; Formoterol 12 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Max PEF % fall; Side effects; Number of patients with a max FEV1 % fall <20%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Hills 1976 Salb

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: < 7 days

Exercise challenge: Free running for 8 min at max speed

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 19

% of males: 42%

Age range: 5-15 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 20 min

Intervention: Salbutamol 200 mcg; Salmefamol 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Hills 1976 Salmefamol

Methods


Participants


Interventions


Outcomes


NotesSee: Hills 1976 Salb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Inman 1996

MethodsStudy design: Randomized, double blind, cross over

Study location: Canada

Wash-out: 7-21 days

Exercise challenge: Cycle ergometer for 5 min at 80% of max work rate

Criteria for EIB diagnosis: Positive history


ParticipantsNumber of subjects: 10

% of males: 70%

Age range: 19-37 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Chronic administration 81 week)

Time of exercise challenge after drug administration: 24 hours

Intervention: Salbutamol 800 mcg daily

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Onset of tolerance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Kemp 1994 Salb

MethodsStudy design: Randomized, double blind, parallel groups

Study location: United States

Wash-out: Not applicable

Exercise challenge: Treadmill for 6 min at 80% of max HR

Criteria for EIB diagnosis: Asthma according to ATS; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 161

% of males: 42%

Age range: 12-35 years

Ethnicity: Not reported

Withdrawal or drop out: 8


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min, 5.30 hours, 11.30 hours

Intervention: Salbutamol 180 mcg; Salmeterol 42 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10% and 20%


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Kemp 1994 Salm 42

Methods


Participants


Interventions


Outcomes


NotesSee: Kemp 1994 Salb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Konig 1981 Metaprot

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: Not reported

Exercise challenge: Treadmill for 6 min at 90% of max HR

Criteria for EIB diagnosis: Asthma according to ATS; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 24

% of males: 67%

Age range: 17-34 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min, 1 hour

Intervention: Metaproterenol 130 mcg

Control: Placebo

Other drug arms: Oral metaproterenol

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Max FEF 25--75 % fall; Side effects; Number of patients with a max FEV1 % fall <10%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Konig 1984 Fen 0.4

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: Not reported

Exercise challenge: Treadmill up to 90% of max HR

Criteria for EIB diagnosis: Asthma according to ATS; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 100%

Age range: 17-29 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min, 2 hours, 4 hours

Intervention: Fenoterol 40 mcg; Fenoterol 80 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Max FEF 25--75 % fall; Side effects; Number of patients with a max FEV1 % fall <10%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
High riskData for max FEF 25--75 % fall not reported

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Konig 1984 Fen 0.8

Methods


Participants


Interventions


Outcomes


NotesSee: Konig 1984 Fen 0.4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
High riskData for max FEF 25--75 % fall not reported

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Larsson 1982 Fen

MethodsStudy design: Randomized, double blind, cross over

Study location: Sweden

Wash-out: Not reported

Exercise challenge: Cycle ergometer for 6-9 min till exhaustion

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 8

% of males: 69%

Age range: 29-64 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 10 min

Intervention: Fenoterol 400 mcg

Control: Placebo

Other drug arms: Oxitropium bromide; Ipratropium bromide

Concomitant inhaled corticosteroid (ICS) treatment: Any anti-asthmatic drug suspended 12 hours before the test


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Number of patients with a max FEV1 % fall <15%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

McAlpine 1990 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: 1-7 days

Exercise challenge: Treadmill for 5-8 min up to 90% of max HR

Criteria for EIB diagnosis: Documented exercise-induced bronchoconstriction


ParticipantsNumber of subjects: 12

% of males: 41%

Age range: 19-41 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 2 hours, 4 hours

Intervention: Salbutamol 200 mcg; Formoterol 12 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

McAlpine 1990 Salb

Methods


Participants


Interventions


Outcomes


NotesSee: McAlpine 1990 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

McFadden 1986 Salb (I)

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 1-15 days

Exercise challenge: Cycle ergometer for 4-5 min till exhaustion

Criteria for EIB diagnosis: Positive screening exercise challenge


ParticipantsNumber of subjects: 20

% of males: 60%

Age range: 21-42 years

Ethnicity: Not reported

Withdrawal or drop out: 5


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min

Intervention: Salbutamol 200 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Max FEF 25--75 % fall; Side effects; Number of patients with a max FEV1 % fall <20%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

McFadden 1986 Salb (II)

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 1-10 days

Exercise challenge: Cycle ergometer for 4-5 min till exhaustion

Criteria for EIB diagnosis: Positive screening exercise challenge


ParticipantsNumber of subjects: 20

% of males: 60%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min

Intervention: Salbutamol 180 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Max FEF 25--75 % fall; Side effects; Number of patients with a max FEV1 % fall <20%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Morton 1989 Rimet

MethodsStudy design: Randomized, double blind, cross over

Study location: Australia

Wash-out: 2-7 days

Exercise challenge: Treadmill for 8 min at 80% of anaerobic threshold

Criteria for EIB diagnosis: Asthma according to ATS; FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 10

% of males: 70%

Age range: 15-30 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 2 min

Intervention: Rimeterol 400 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Side effects; Number of patients with a max FEV1 % fall <15%;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Nelson 1998

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 7 days

Exercise challenge: Cycle ergometer for 4 min at exhausting work

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 20

% of males: 45%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Chronic administration (29 days)

Time of exercise challenge after drug administration: 30 min, 9 hours

Intervention: Salmeterol 84 mcg daily

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Onset of tolerance; Number of patients with a max FEV1 % fall <10%;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Newnham 1993 Salb 200

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: ≥2 days

Exercise challenge: Treadmill for 6 min up to 90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 50%

Age range: 21-33 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 1 hour, 6 hours, 12 hours

Intervention: Salbutamol 200 mcg; Salmeterol 50 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Newnham 1993 Salm 50

Methods


Participants


Interventions


Outcomes


NotesSee: Newnham 1993 Salb 200


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Patel 1986 Salb 200

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: Not reported

Exercise challenge: Treadmill for 6-8 min

Criteria for EIB diagnosis: Diagnosis of exercise-induced bronchoconstriction


ParticipantsNumber of subjects: 9

% of males: Not reported

Age range: 19-46 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 20 min

Intervention: Salbutamol 200 mcg; Tolobuterol 200 mcg; Tolobuterol 400 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Patel 1986 Tulob 200

Methods


Participants


Interventions


Outcomes


NotesSee: Patel 1986 Salb 200


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Patel 1986 Tulob 400

Methods


Participants


Interventions


Outcomes


NotesSee: Patel 1986 Salb 200


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Patessio 1991 Form 24

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: 1 day

Exercise challenge: Treadmill for 7 min up to 90% of max HR

Criteria for EIB diagnosis: Asthma according to ATS; FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects:12

% of males: 16%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 2 hours, 8 hours

Intervention: Salbutamol 200 mcg; Formoterol 24 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <15%;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Patessio 1991 Salb 200

Methods


Participants


Interventions


Outcomes


NotesSee: Patessio 1991 Form 24


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Pearlman 2006 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: ≥3 days

Exercise challenge: Treadmill for 6 min up to 80-90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects:23

% of males: 30%

Age range: 4-11 years

Ethnicity: Not reported

Withdrawal or drop out: 2


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min, 4 hours, 8 hours, 12 hours

Intervention: Salbutamol 180 mcg; Formoterol 12 mcg; Formoterol 24 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10% and <20%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Pearlman 2006 Form 24

Methods


Participants


Interventions


Outcomes


NotesSee: Pearlman 2006 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Pearlman 2006 Salb 180

Methods


Participants


Interventions


Outcomes


NotesSee: Pearlman 2006 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Pearlman 2007 Salb 90

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 3-7 days

Exercise challenge: Treadmill for at least 4 min at 85% of max HR

Criteria for EIB diagnosis: Exercise-induced bronchoconstriction for at least 6 months; FEV1 fall >20% and <50% after exercise challenge


ParticipantsNumber of subjects:15

% of males: 86%

Age range: Not reported

Ethnicity: 100% Caucasian

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 20 min

Intervention: Salbutamol 90 mcg

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%, <15% and <20%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Philip 2007 Salm 50

MethodsStudy design: Randomized, double blind, cross over

Study location: South America

Wash-out: 3-7 days

Exercise challenge: Treadmill for 6 min up to 80-90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% and <40% after exercise challenge


ParticipantsNumber of subjects:47

% of males: 49%

Age range: 15-45 years

Ethnicity: 55% Caucasian; 45% Others

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 2 hours, 8.30 hours, 24 hours

Intervention: Salmeterol 50 mcg

Control: Placebo

Other drug arms: Oral Montelukast 10 mg

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: Side effects


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Ramage 1994

MethodsStudy design: Randomized, double blind, cross over

Study location: United Kingdom

Wash-out: 7 days

Exercise challenge: Treadmill for 6 min up to 80-90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% and <40% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 66%

Age range: 19-36 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Chronic administration (28 days)

Time of exercise challenge after drug administration: 6 hours, 12 hours

Intervention: Salmeterol 100 mcg daily

Control: Placebo

Other drug arms: No

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Onset of tolerance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Richter 2002 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: Germany

Wash-out: ≥2 days

Exercise challenge: Cycle-ergometer for 6 min up to 85% of max HR

Criteria for EIB diagnosis: Positive history; Positive methacholine test (PC20 <8mg/ml); Positive exercise challenge


ParticipantsNumber of subjects: 25

% of males: 66%

Age range: 19-36 years

Ethnicity: Not reported

Withdrawal or drop out: 1


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 5 min, 30 min, 1 hour

Intervention: Terbutaline 500 mcg; Formoterol 12 mcg; Salmeterol 50 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: None


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Richter 2002 Salm 50

Methods


Participants


Interventions


Outcomes


NotesSee: Richter Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Richter 2002 Terb 500

Methods


Participants


Interventions


Outcomes


NotesSee: Richter Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Shapiro 2002 Form 12

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: 3-7 days

Exercise challenge: Treadmill for 6 min at 90% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 20

% of males: 45%

Age range: 13-41 years

Ethnicity: Caucasians 90%; Others 10%

Withdrawal or drop out: 3


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min, 4 hours, 8 hours, 12 hours

Intervention: Salbutamol 180 mcg; Formoterol 12 mcg; Formoterol 24 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%; Max PEF % fall;


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Shapiro 2002 Form 24

Methods


Participants


Interventions


Outcomes


NotesSee: Shapiro 2002 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Shapiro 2002 Salb 180

Methods


Participants


Interventions


Outcomes


NotesSee: Shapiro 2002 Form 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Simons 1997

MethodsStudy design: Randomized, double blind, cross over

Study location: Canada

Wash-out: 14 days

Exercise challenge: Treadmill for 8 min up to 90% of max HR or 180 bpm

Criteria for EIB diagnosis: Asthma according to ATS; Positive exercise challenge


ParticipantsNumber of subjects: 16

% of males: 41%

Age range: 12-16 years

Ethnicity: Not reported

Withdrawal or drop out: 2


InterventionsDrug administration: Chronic administration (28 weeks)

Time of exercise challenge after drug administration: 1 hour, 9 hours

Intervention: Salmeterol 50 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: None


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Stelmach 2008

MethodsStudy design: Randomized, double blind, parallel groups

Study location: Poland

Wash-out: Not applicable

Exercise challenge: Treadmill for six min at 95% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 100

% of males: Not reported

Age range: 6-18 years

Ethnicity: Not reported

Withdrawal or drop out: 9


InterventionsDrug administration: Chronic administration (28 weeks)

Time of exercise challenge after drug administration: 1 hour, 9 hours

Intervention: Formoterol 9 mcg daily

Control: Placebo

Other drug arms: Oral Montelukast

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Onset of tolerance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomization described explicitly

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Storms 2004

MethodsStudy design: Randomized, double blind, parallel groups

Study location: United States

Wash-out: Not applicable

Exercise challenge: Treadmill for six min at 95% of max HR

Criteria for EIB diagnosis: FEV1 fall >20% (or >15% if on ICS) after an exercise challenge in the last year


ParticipantsNumber of subjects: 122

% of males: Not reported

Age range: 15-58 years

Ethnicity: Not reported

Withdrawal or drop out: 13


InterventionsDrug administration: Chronic administration (28 weeks)

Time of exercise challenge after drug administration: 1 hour, 9 hours

Intervention: Salmeterol 100 mcg daily

Control: Placebo

Other drug arms: Oral Montelukast 10 mg

Concomitant inhaled corticosteroid (ICS) treatment: Allowed


OutcomesPrimary available: Max FEV1 % fall; % protection; FEV1 % fall AUC

Secondary available: Onset of tolerance


NotesIndustry funded study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Sturani 1983 Fen 400

MethodsStudy design: Randomized, double blind, cross over

Study location: Italy

Wash-out: Not reported

Exercise challenge: Free running for 6 min up to 85% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 58%

Age range: 16-42 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 30 min.

Intervention: Fenoterol 400 mcg; Salbutamol 200 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection

Secondary available: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Sturani 1983 Salb 200

Methods


Participants


Interventions


Outcomes


NotesSee: Sturani 1983 Fen 400


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

VanHaitsma 2010 Salb

MethodsStudy design: Randomized, double blind, cross-over

Study location: United States

Wash-out: ≥2 days

Exercise challenge: Treadmill for at least 3 min at 85% of max HR

Criteria for EIB diagnosis: Physician diagnosed asthma; FEV1 fall >10% after exercise challenge


ParticipantsNumber of subjects: 10

% of males: 70%

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min.

Intervention: Salbutamol 180 mcg

Control: Placebo

Other drug arms: None

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Max Pef % fall; Max FEF 25--75 % fall


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk Insufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Vasquez 1984 Salb 400

MethodsStudy design: Randomized, double blind, parallel groups

Study location: Spain

Wash-out: Not applicable

Exercise challenge: Free running 5-8 min at max speed (around 170 bpm)

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 25

% of males: Not reported

Age range: Not reported

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 15 min.

Intervention: Salbutamol 400 mcg

Control: Placebo

Other drug arms: Disodium cromoglycate 200 mcg; Ipratropium bromide 40 mcg;

Concomitant inhaled corticosteroid (ICS) treatment: Not reported


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Number of patients with a max FEV1 % fall <15%; Max MEF50 % fall;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Walker 1986 Bitolterol

MethodsStudy design: Randomized, double blind, cross over

Study location: United States

Wash-out: Not reported

Exercise challenge: Cycle-ergometer for 6 min at 80% of max HR

Criteria for EIB diagnosis: FEV1 fall >15% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 58%

Age range: 14-25 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 45 min.

Intervention: Bitolterol 1050 mcg

Control: Placebo

Other drug arms: Isoproterenol 255 mcg

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%; Max PEF % fall; Max FEF25-75 % fall;


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

Wolley 1990 Terb 500

MethodsStudy design: Randomized, double blind, cross over

Study location: Australia

Wash-out: Not reported

Exercise challenge: Treadmill for 8 min at 60% of MVV

Criteria for EIB diagnosis: Positive history, FEV1 fall >20% after exercise challenge


ParticipantsNumber of subjects: 12

% of males: 58%

Age range: 18-28 years

Ethnicity: Not reported

Withdrawal or drop out: 0


InterventionsDrug administration: Single dose

Time of exercise challenge after drug administration: 25 min, 2 hours, 4 hours, 6 hours

Intervention: Terbutaline 500 mcg

Control: Placebo

Other drug arms: Cromolyn sodium 2 mg; Cromolyn sodium 2 mg + Terbutaline 500 mcg

Concomitant inhaled corticosteroid (ICS) treatment: Not allowed


OutcomesPrimary available: Max FEV1 % fall; % protection;

Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information

Allocation concealment (selection bias)Unclear riskInsufficient information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information

Other biasUnclear riskInsufficient information

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aebischer 1984No beta-2 agonist pretreatment

Agostini 1983 IDuplicate

Agostini 1983 IINo systematic review primary outcomes

Allegra 1976No clear diagnosi of exercise-induced bronchoconstriction

Anderson 1975No double blind

Anderson 1976No randomization

Anderson 1991No randomization

Aranda 1992No double blind

Bakran 1980No placebo control

Battistini 1980No inhaled beta-2 agonist administration

Baur 1979No systematic review primary outcomes

Berkowitz 1986No double blind

Boner 1984No double blind

Boner 1987No placebo control

Boner 1988No inhaled beta-2 agonist administration

Bratteby 1986No placebo control

Bundgaard 1980No systematic review primary outcomes

Bundgaard 1983 INo randomization

Bundgaard 1983 IINo systematic review primary outcomes

Bundgaard 1983 IIINo systematic review primary outcomes

Bye 1980No randomization

Ceugniet 1997No placebo control

Colice 1999No double blind

Coreno 2000No double blind

Corrias 1989No placebo control

Dal Col 1995No double blind

Del Bono 1979No double blind

Di Gioacchino 1987No inhaled beta-2 agonist administration

Dockhorn 1997No double blind

Edelman 2000No placebo control

Eggleston 1981No inhaled beta-2 agonist administration

Ferrari 2002No placebo control

Fogel 2010No placebo control

Francis 1980No clear diagnosi of exercise-induced bronchoconstriction

Freeman 1989No clear diagnosi of exercise-induced bronchoconstriction

Gibson 1978No randomization

Gimeno 1985No clear diagnosi of exercise-induced bronchoconstriction

GlaxoSmithKline 2006 INo placebo control

GlaxoSmithKline 2006 IIDuplicate

Godfrey 1975Duplicate

Godfrey 1976No inhaled beta-2 agonist administration

Guerin 1992No placebo control

Gunawardena 2005No placebo control

Hermansen 2006No beta-2 agonist pretreatment

Higgs 1983No placebo control

Ienna 1997No systematic review primary outcomes

Iikura 1988No randomization

Ioli 1986No double blind

Johnson 1986No clear diagnosi of exercise-induced bronchoconstriction

Koch 1972No randomization

Kumar 1988No randomization

Lopes Dos Santos 1991No beta-2 agonist pretreatment

Machado 2012No placebo control

Macucci 2004No randomization

Magnussen 1984No double blind

Makela 2012No placebo control

Martinsson 1985No inhaled beta-2 agonist administration

Merck 2005 IDuplicate

Merck 2005 IINo placebo control

Mickleborough 2007No placebo control

Millqvist 2000No randomization

Morandini 1982No randomization

Morooka 1987No clear diagnosi of exercise-induced bronchoconstriction

Morse 1976No inhaled beta-2 agonist administration

Morton 1992No double blind

Murray 2011No placebo control

Pearlman 2009No placebo control

Pfleger 2002No exercise challenge

Pichaipat 1995No randomization

Pichon 2005No clear diagnosi of exercise-induced bronchoconstriction

Poppius 1973No placebo control

Rabe 1993No systematic review primary outcomes

Raissy 2006No placebo control

Raissy 2008No placebo control

Revill 1998No placebo control

Robertson 1994No clear diagnosi of exercise-induced bronchoconstriction

Rohr 1987No placebo control

Sanguinetti 1986Exercise challenge beyond beta-2 agonist pharmacological half-life

Schaanning 1996No systematic review primary outcomes

Shah 1983No clear diagnosi of exercise-induced bronchoconstriction

Shapiro 1981No inhaled beta-2 agonist administration

Shapiro 1990No double blind

Sichletidis 1993No placebo control

Silverman 1973No randomization

Singh 1992No randomization

Sly 1968No double blind

Sly 1975No systematic review primary outcomes

Sly 1982No inhaled beta-2 agonist administration

Spada 1985No placebo control

Stark 1981No clear diagnosi of exercise-induced bronchoconstriction

Steinshamn 2004No placebo control

Svenonius 1983No randomization

Svenonius 1988No double blind

Svenonius 1994No beta-2 agonist pretreatment

Tabas 1985No inhaled beta-2 agonist administration

Tammivaara 1979No randomization

Unnithan 1994No clear diagnosi of exercise-induced bronchoconstriction

Verini 1983No placebo control

Verini 1985No inhaled beta-2 agonist administration

Verini 1999No placebo control

Villaran 1999No placebo control

Vilsvik 1991No beta-2 agonist pretreatment

Vilsvik 2001No placebo control

Von Berg 2002No placebo control

Weiler 2005No placebo control

Weinberg 1982No double blind

Yeung 1980No placebo control

Zanconato 1990No placebo control

Zimmermann 2003No placebo control

 
Comparison 1. Beta2-agonists versus placebo (single administration)

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

 1 Maximal percentage fall in FEV172799Mean Difference (Random, 95% CI)-17.67 [-19.51, -15.84]

 2 Number of participants with an FEV1 fall > 10%19773Odds Ratio (M-H, Random, 95% CI)0.08 [0.06, 0.13]

 3 Number of participants with an FEV1 fall > 15%13457Odds Ratio (M-H, Random, 95% CI)0.06 [0.03, 0.15]

 4 Number of participants with an FEV1 fall > 20%251021Odds Ratio (M-H, Random, 95% CI)0.09 [0.06, 0.14]

 5 Maximal percentage fall in PEF1492Mean Difference (Random, 95% CI)-24.61 [-37.57, -11.65]

 6 Maximal percentage fall in FEF 25-758106Mean Difference (Fixed, 95% CI)-20.75 [-27.17, -14.32]

 7 Side effects552165Odds Ratio (M-H, Random, 95% CI)0.83 [0.43, 1.59]

 8 Subgroup analysis: maximal percentage fall in FEV1 SABA vs LABA72Mean Difference (Random, 95% CI)-17.67 [-19.51, -15.84]

    8.1 SABA
44Mean Difference (Random, 95% CI)-18.99 [-21.38, -16.60]

    8.2 LABA
28Mean Difference (Random, 95% CI)-15.60 [-18.29, -12.92]

 9 Subgroup analysis: maximal percentage fall in FEV1: salmeterol versus formoterol28Mean Difference (Random, 95% CI)-15.60 [-18.29, -12.92]

    9.1 Salmeterol
13Mean Difference (Random, 95% CI)-12.73 [-16.10, -9.37]

    9.2 Formoterol
15Mean Difference (Random, 95% CI)-18.24 [-22.15, -14.34]

 10 Subgroup analysis: maximal percentage fall in FEV1: adults versus children51Mean Difference (Random, 95% CI)-16.75 [-19.12, -14.39]

    10.1 Adults
19Mean Difference (Random, 95% CI)-18.77 [-20.78, -16.76]

    10.2 Children
32Mean Difference (Random, 95% CI)-15.32 [-18.88, -11.75]

 
Summary of findings for the main comparison. Beta2-agonists compared with placebo (single administration) for exercise-induced asthma

Beta2-agonists compared with placebo (single administration) for exercise-induced asthma

Patient or population: exercise-induced asthma
Intervention: beta2-agonists
Comparison: placebo (single administration)

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

Assumed riskCorresponding risk

Placebo (single administration)Beta2-agonists

Maximal percentage fall in FEV1The mean fall in FEV1 in the intervention group was MD 17.67 lower (19.51 lower to 15.84 lower)a799
(72 studies)a,b,c
⊕⊕⊕⊝
moderated,e,f
The results in the subgroup of LABA and SABA were similar: MD 15.6 lower (18.29 lower to 12.92 lower) and MD 18.99 lower (21.38 lower to 16.6 lower) in 44 and 28 studies, respectively






Number of participants with an FEV1 fall > 10%843 per 1000 (84.3)%300 per 1000
(243 to 410)
OR 0.08 (0.06 to 0.13)773
(19 studies)
⊕⊕⊕⊝
moderated,e

Maximal percentage fall in PEFThe mean maximal percentage fall in PEF in the intervention group was MD 24.61 lower (37.57 lower to 11.65 lower)192
(14 studies)b
⊕⊕⊝⊝
lowd,e,g






Maximal percentage fall in FEF25-75%The mean maximal percentage fall in FEF25-75% in the intervention group was MD 20.75 lower (27.17 lower to 14.32 lower)1106
(8 studies)b
⊕⊕⊝⊝
lowd,e,g






Side effects50 per 1000 (5.0)%42 per 1000
(22 to 77)
OR 0.83 (0.43 to 1.59)2165
(55 studies)h
⊕⊕⊝⊝
lowe,g,I

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; FEF25-75%: forced expiratory flow 25–75%; FEV1: forced expiratory volume in 1 minute; LABA: long-acting beta2-agonist; MD: mean difference; OR: odds ratio; peak expiratory flow (PEF); SABA: short-acting beta2-agonist.

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.

 aLower indicates that beta2-agonists are better than placebo.
bIn 51 studies that provided data for subgroup analysis, no difference was observed in the maximal percentage fall in FEV1, but the heterogeneity of the effect was seen primarily in the paediatric population.
cThese represent 72 study arms from 53 studies.
dIt is unclear how directly pulmonary function measures relate to what participants feel.
eThere was concern about lack of concealment, loss to follow-up and reporting bias.
fInconsistency was moderate to high and was explained in part by subgroup analyses of adults and children.
gSmall numbers of participants were included with resulting wide confidence intervals.
hThese represent 55 study arms rather than studies.
iThis represents a mix of outcomes, and not all of them are of equal importance to patients.
 
Table 1. Summary of study interventions

StudyIntervention (single dose)Study type (single-dose test or chronic [duration])When administered before challenge/exercise (min, h)

Anderson 2001 Salb Disk;

Anderson 2001 Salb MDI
Salbutamol diskus 200 mcg

Salbutamol MDI
Single dose30 min

Blake 1999 Salb 180

Blake 1999 Salm 25

Blake 1999 Salm 50
Albuterol 180 mcg

Salmeterol diskus 25 mcg

Salmeterol diskus 50 mcg
Single dose30 min, 5 h 30, 11 h 30

Boner 1994 Salb 200

Boner 1994 Form 12
Salbutamol 200 mcg

Formoterol 12 mcg
Single dose3 h, 12 h

Boulet 1989 SalbSalbutamol 200 mcgSingle dose30 min

Bronski 1995 Salb MDI

Bronski 1995 Salb Pwd
Albuterol MDI 180 mcg

Albuterol rotacaps 200 mcg
Single dose15 min

Bronski 1999 Salm Disk

Bronski 1999 Salm Diskhal
Salmetrol discus 50 mcg

Salmeterol diskhaler 50 mcg
Single dose30 min, 5 h 30, 11 h 30

Bronski 2002 Salb

Bronski 2002 Form 12

Bronski 2002 Form 24
Albuterol 180 mcg

Formoterol 12 mcg

Formoterol 24 mcg
Single dose15 min, 4 h, 8 h, 12 h

Carlsen 1995 Salm 25

Carlsen 1995 Salm 50
Salmeterol diskhaler 25 mcg

Salmeterol diskhaler 50 mcg
Single dose10-12 h

Cavagni 1993 Salb MDI

Cavagni 1993 Salb Jet
Salbutamol MDI 200 mcg

Salbutamol jet disposable 200 mcg
Single dose10 min

Clarke 1990 FenFenoterol 100 mcgSingle dose10 min

Daugbjerg 1996 Salb

Daugbjerg 1996 Form 12
Salbutamol 400 mcg

Formoterol 12 mcg
Single dose3 h, 12 h

Debelic 1988 ReproterolReproterol 1 mgSingle dose15 min

DeBenedictis 1996 Salm 25

DeBenedictis 1996 Salm 50
Salmeterol 25 mcg

Salmeterol 50 mcg
Single dose1 h, 2 h

DeBenedictis 1998 SalbSalbutamol 200 mcgSingle dose20 min

Del Col 1993 Salb MDI

Del Col 1993 Salb Jet
Salbutamol MDI 200 mcg

Salbutamol jet device 200 mcg
Single dose10 min

Dinh Xuan 1989 TerbTerbutaline 500 mcgSingle dose15 min

Egglestone 1981 Terb 250Terbutaline 250 mcgSingle dose1 h

Ferrari 2000 Form 12Formoterol 12 mcgSingle dose15 min, 4 h

Garcia 2001 Form 12Formoterol 12 mcg twice dailyLong-term (4 weeks)30 min, 12 h at days 1, 14 and 28

Green 1992 Salm 50Salmeterol 50 mcgSingle dose1 h, 5 h, 9 h

Gronnerod 2000 Terb 500

Gronnerod 2000 Form 9

Gronnerod 2000 Form 4.5
Terbutaline 500 mcg

Formoterol 9 mcg

Formoterol 4.5 mcg
Single dose15 min, 4 h, 8 h

Hancox 2002Salbutamol 800 mcg dailyLong-term (1 week)8 h

Hawksworth 2002 Salb HFA

Hawksworth 2002 Salb MDI
Salbutamol 180 HFA

Salbutamol 180 mcg MDI
Single dose30 min

Henricksen 1983 TerbTerbutaline 32.5 mcgSingle dose15 min

Henricksen 1992 Salb

Henriksen 1992 Form 12
Salbutamol 200 mcg

Formoterol 12 mcg
Single dose30 min, 3 h, 5 h 30, 8 h

Hills 1976 Salb

Hills 1976 Salmefamol
Salbutamol 200 mcg

Salmefamol 200 mcg
Single dose20 min

Inman 1996Salbutamol 800 mcg dailyLong-term (81 weeks)24 h

Kemp 1994 Salb

Kemp 1994 Salm 42
Salbutamol 180 mcg

Salmeterol 42 mcg
Single dose30 min, 5 h 30, 11 h 30

Konig 1981 MetaprotMetaproterenol 130 mcgSingle dose10 min, 1 h

Larsson 1982 FenFenoterol 400 mcgSingle dose10 min

McAlpine 1990 Salb

McAlpine 1990 Form 12
Salbutamol 200 mcg

Formoterol 12 mcg
Single dose2 h, 4 h

McFadden 1986 Salb (I)Salbutamol 200 mcgSingle dose15 min

McFadden 1986 Salb (II)Salbutamol 180 mcgSingle dose15 min

Morton 1989 RimetRimeterol 400 mcgSingle dose2 min

Nelson 1998Salmeterol 84 mcg dailyLong-term (29 days)30 min, 9 h

Newnham 1993 Salb 200

Newnham 1993 Salm 50
Salbutamol 200 mcg

Salmeterol 50 mcg
Single dose1 h, 6 h, 12 h

Patel 1986 Salb 200

Patel 1986 Tulob 200

Patel 1986 Tulob 400
Salbutamol 200 mcg

Tolobuterol 200 mcg

Tolobuterol 400 mcg
Single dose20 min

Patessio 1991 Salb 200

Patessio 1991 Form 24
Salbutamol 200 mcg

Formoterol 24 mcg
Single dose2 h, 8 h

Pearlman 2006 Salb 180

Pearlman 2006 Form 12

Pearlman 2006 Form 24
Salbutamol 180 mcg

Formoterol 12 mcg

Formoterol 24 mcg
Single dose15 min, 4 h, 8 h, 12 h

Pearlman 2007 Salb 90Salbutamol 90 mcgSingle dose20 min

Philip 2007 Salm 50Salmeterol 50 mcgSingle dose2 h, 8 h 30, 24 h

Ramage 1994Salmeterol 100 mcg dailyLong-term (28 days)6 h, 12 h

Richter 2002 Terb 500

Richter 2002 Form 12

Richter 2002 Salm 50
Terbutaline 500 mcg

Formoterol 12 mcg

Salmeterol 50 mcg
Single dose5 min, 30 min, 1 h

Shapiro 2002Salbutamol 180 mcg

Formoterol 12 mcg

Formoterol 24 mcg
Single dose15 min, 4 h, 8 h, 12 h

Simons 1997Salmeterol 50 mcgLong-term (28 weeks)1 h, 9 h

Stelmach 2008Formoterol 9 mcg dailyLong-term (28 weeks)1 h, 9 h

Storms 2004Salmeterol 100 mcg dailyLong-term (28 weeks)1 h, 9 h

Sturani 1983 Fen 400

Sturani 1983 Salb 200
Fenoterol 400 mcg

Salbutamol 200 mcg
Single dose30 min

VanHaitsma 2010 SalbSalbutamol 180 mcgSingle dose15 min

Vasquez 1984 Salb 400Salbutamol 400 mcgSingle dose15 min

Walker 1986 BitolterolBitolterol 1050 mcgSingle dose45 min

Wolley 1990 Terb 500Terbutaline 500 mcgSingle dose25 min, 2 h, 4 h, 6 h