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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2013 Oct 2;2013(10):CD003564. doi: 10.1002/14651858.CD003564.pub3

Beta2‐agonists for exercise‐induced asthma

Matteo Bonini 1,2,3,, Corrado Di Mambro 4, Moises A Calderon 3, Enrico Compalati 5, Holger Schünemann 6, Stephen Durham 3, Giorgio W Canonica 5
Editor: Cochrane Airways Group
PMCID: PMC11348701  PMID: 24089311

Abstract

Background

It is well known that physical exercise can trigger asthma symptoms and can induce bronchial obstruction in people without clinical asthma. International guidelines on asthma management recommend the use of beta2‐agonists at any stage of the disease. At present, however, no consensus has been reached about the efficacy and safety of beta2‐agonists in the pretreatment of exercise‐induced asthma and exercise‐induced bronchoconstriction. For the purpose of the present review, both of these conditions are referred to by the acronymous EIA, independently from the presence of an underlying chronic clinical disease.

Objectives

To assess the effects of inhaled short‐ and long‐acting beta2‐agonists, compared with placebo, in the pretreatment of children and adults with exercise‐induced asthma (or exercise‐induced bronchoconstriction).

Search methods

Trials were identified by electronic searching of the Cochrane Airways Group Specialised Register of Trials and by handsearching of respiratory journals and meetings. Searches are current as of August 2013.

Selection criteria

We included randomised, double‐blind, placebo‐controlled trials of any study design, published in full text, that assessed the effects of inhaled beta2‐agonists on EIA in adults and children. We excluded studies that did not clearly state diagnostic criteria for EIA.

Data collection and analysis

We used standard methodological procedures as expected by The Cochrane Collaboration.

Main results

We included 53 trials consisting of 1139 participants. Forty‐eight studies used a cross‐over design, and five were performed in accordance with a parallel‐group design. Forty‐five studies addressed the effect of a single beta2‐agonist administration, and eight focused on long‐term treatment. We addressed these two different intervention regimens as different comparisons.

Among primary outcomes for short‐term administration, data on maximum fall in forced expiratory volume in 1 second (FEV1) showed a significant protective effect for both short‐acting beta‐agonists (SABA) and long‐acting beta‐agonists (LABA) compared with placebo, with a mean difference of ‐17.67% (95% confidence interval (CI) ‐19.51% to ‐15.84%, P = 0.00001, 799 participants from 72 studies). The subgroup analysis of studies performed in adults compared with those performed in children showed high heterogeneity confined to children, despite the comparable mean bronchoprotective effect.

Secondary outcomes on other pulmonary function parameters confirmed a more positive and protective effect of beta2‐agonists on EIA compared with placebo. Occurrence of side effects was not significantly different between beta2‐agonists and placebo.

Overall evaluation of the included long‐term studies suggests a beta2‐agonist bronchoprotective effect for the first dose of treatment. However, long‐term use of both SABA and LABA induced the onset of tolerance and decreased the duration of drug effect, even after a short treatment period.

Authors' conclusions

Evidence of low to moderate quality shows that beta2‐agonists, both SABA and LABA, when administered in a single dose, are effective and safe in preventing EIA.

Long‐term regular administration of inhaled beta2‐agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for prolonged regular use of beta2‐agonists as monotherapy in the pretreatment of EIA, despite the warnings of drug agencies (FDA, EMA) regarding LABA.

Keywords: Adult; Child; Humans; Administration, Inhalation; Adrenergic beta‐2 Receptor Antagonists; Adrenergic beta‐2 Receptor Antagonists/administration & dosage; Asthma, Exercise‐Induced; Asthma, Exercise‐Induced/drug therapy; Bronchoconstriction; Bronchodilator Agents; Bronchodilator Agents/administration & dosage; Forced Expiratory Volume; Forced Expiratory Volume/drug effects; Randomized Controlled Trials as Topic

Plain language summary

Asthma reliever inhalers (beta2‐agonists) used for exercise‐induced asthma and exercise‐induced bronchoconstriction

Review question

Physical exercise may trigger symptoms such as cough, chest tightness and shortness of breath in people with asthma that is not adequately treated (exercise‐induced asthma). Sometimes people who do not have asthma still experience asthma‐like symptoms during exercise; this is called exercise‐induced bronchoconstriction. We looked at both types of people in this review. The treatments we were interested in are called beta2‐agonists. These are drugs that are known to open up the airways (small tubes in the lungs), making it easier for people to breathe. Two kinds of beta2‐agonists are available: short‐acting (SABA, e.g. salbutamol and terbutaline) and long‐acting (LABA, e.g. formoterol and salmeterol).

What evidence did we find?

We found 53 trials consisting of 1139 participants. Forty‐eight studies used a cross‐over design, which meant that each person in the trial received two or more treatments-one or more active treatments, the beta‐agonist and a placebo in random order. The rest were parallel‐group trials, meaning that people received either the active treatment or a placebo. Most of the studies addressed the effect of a giving a single beta2‐agonist treatment before exercise and recorded the effect on lung function following exercise. Only eight focused on longer treatment-longer treatments would be needed to assess whether these treatments were harmful over the longer term.

Results

Studies in which people received a single administration of a beta‐agonist showed that FEV1 (a measure of lung function) fell significantly less for people taking SABA or LABA compared with placebo (mean difference (MD) ‐17.67%; 95% confidence interval (CI) ‐19.51% to ‐15.84%). Other lung function measures confirmed that beta2‐agonists were more beneficial compared with placebo. No significant difference in the number of side effects was noted in people taking SABA or LABA compared with people taking placebo. However, it is unlikely that people would be prescribed an inhaler for a single treatment, so we must consider longer‐term studies to get a true measure of the side effects that inhalers can cause.

We found that included longer‐term studies showed that beta2‐agonists were helpful in terms of lung function for the first dose of treatment. However, studies that provided longer‐term treatment with SABA or LABA showed that over time, people built up a tolerance to the effects of treatments, and the beneficial effects lasted for shorter periods of time.

Quality of the evidence

Overall, we believe that the evidence was of low to moderate quality.

Conclusions

This review shows that beta2‐agonists-both SABA and LABA-when administered in a single dose, are effective and safe in preventing the symptoms of EIA. Longer‐term administration of inhaled beta2‐agonists induces tolerance and lacks sufficient safety data. It is important to note that taking LABA without background inhaled steroids is considered unsafe and is not currently recommended in most of the clinical guidelines for asthma. We recommend that more studies are needed to determine whether it is safe to administer inhaled beta2‐agonists alone to people who experience asthma symptoms when exercising.

This review is current as of August 2013.

Summary of findings

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)
Outcomes Illustrative comparative risks* (95% CI) Relative effect
 (95% CI) No. of participants
 (studies) Quality of the evidence
 (GRADE) Comments
Assumed risk Corresponding risk
Placebo (single administration) Beta2‐agonists
Maximal percentage fall in FEV1 The mean fall in FEV1 in the intervention group was MD 17.67 lower (19.51 lower to 15.84 lower)a 799
 (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 PEF The mean maximal percentage fall in PEF in the intervention group was MD 24.61 lower (37.57 lower to 11.65 lower)1 92
 (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)1 106
 (8 studies)b ⊕⊕⊝⊝
 lowd,e,g  
Side effects 50 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.

Background

Exercise‐induced asthma (EIA) is the term commonly used to describe the transient increase in airway resistance that follows vigorous exercise (Anderson 1997). However a recent position paper suggested a preferred definition of exercise‐induced bronchoconstriction (EIB) with or without asthma, depending on the presence of underlying clinical asthma (Weiler 2010). Despite this new nomenclature, most of the relevant studies were published before these terms were proposed and often do not provide sufficient information to distinguish between the two conditions. We therefore decided to adopt the term exercise‐induced asthma (EIA) throughout the review for the sake of better consistency and clarity.

The prevalence of EIA ranges from 5% to 20% in the general population, to even 100% in people with uncontrolled asthma. This huge variability depends not only on the criteria used for diagnosis, but also on the population samples studied. EIA is, in fact, reported to be particularly frequent in children (Randolph 2008), in people with rhinitis (Brozek 2010) and in athletes, with percentages varying according to different sport disciplines (Carlsen 2008).

The diagnosis of EIA is usually made by exercise testing, either in the field or in the laboratory; this second option allows more standardised procedures (Rundell 2000). An individual's response to exercise is generally expressed by the maximal percent fall in forced expiratory volume in one second (FEV1). The maximal percent fall is considered an expression of severity of EIA and is calculated by subtracting the lowest FEV1 value from the pre‐exercise value and expressing it as a percentage of the pre‐exercise value. Both European Respiratory Society (ERS) and American Respiratory Society (ATS) recommendations set a fall threshold of 10% as a diagnostic criterion for EIA and a value greater than 30% as a marker of severe bronchial hyperreactivity, particularly if the person is treated with inhaled steroids (Sterk 1993). Other indirect tests such as eucapnic voluntary hyperpnoea (EVH) and mannitol challenge are usually considered surrogate tests for the diagnosis of EIA because they induce similar pathophysiological changes in the airways (Anderson 2003).

The main principle of treating EIA involves reversing the bronchial obstruction induced by exercise with bronchodilators or preventing it with daily use of either controller drugs in people with asthma (Koh 2007; Bateman 2008) or drugs that inhibit symptoms and improve pulmonary function immediately before exercise. Pretreatment before exercise includes mast cell stabilisers (Kelly 2000; Spooner 2003), leukotriene antagonists (Peroni 2011), short‐acting beta2‐agonists (SABA) and, more recently, long‐acting beta2‐agonists (LABA), especially in endurance athletes (Shapiro 2002).

Both SABA and LABA, administered at standard doses immediately before exercise, have been shown to reduce the fall in FEV1 by 70% to 80% in most people with EIA (Anderson 2006). The mechanism of this protection is believed to be related to beta2‐receptor-induced relaxation of bronchial smooth muscle, which opposes the contractile effects of the various mediators of bronchoconstriction. Protection from EIA is also afforded by beta2‐receptor-induced inhibition of mediator release from mast cells.

At present, however, no consensus has been reached about the efficacy and safety of beta2‐agonists in the pretreatment of EIA. The role of these molecules in preventing EIA was questioned when patients taking beta2‐agonists daily reported breakthrough EIA within a dosing period. Several negative findings have been reported regarding the efficacy of daily treatment with beta2‐agonists in controlling the severity of bronchoconstriction and recovery from EIA. In fact, in a significant minority of people, EIA is not prevented by beta2‐agonists administered at the recommended dose (Anderson 1991; Weiler 2005). Furthermore, it has been reported how daily treatment with beta2‐agonists can enhance the severity of EIA (Hancox 2002) and decrease the duration of their protective effect, especially for LABA (Ramage 1994). In addition, recovery from EIA after a standard dose of beta2‐agonists is slower, and additional doses are often required when SABA or LABA are used daily (Hancox 2002).

On the other hand, the reported association between administration of LABA, not in combination with inhaled corticosteroids, and increased numbers of severe cardiovascular side effects and sudden deaths (Nelson 2006; Salpeter 2010) induced the U.S. Food and Drug Administration (FDA) to set a "black box" on these drugs, highlighting the urgent need to promote clear studies of pharmacovigilance (Martinez 2005).

Objectives

To assess the effects of inhaled short‐ and long‐acting beta2‐agonists, compared with placebo, in the pretreatment of children and adults with exercise‐induced asthma (or exercise‐induced bronchoconstriction).

Methods

Criteria for considering studies for this review

Types of studies

We included double‐blind, randomised controlled trials (RCTs) of any study design. Data published in abstract form only were excluded. At least one primary outcome of this systematic review had to be reported for a study to be considered eligible.

Types of participants

We included children and adults (aged 18 years or older) with a clear history of exercise‐induced asthma and/or a positive response to a standardised exercise challenge, defined according to ERS and ATS guidelines as a fall in FEV1 ≥ 10%. Studies that did not clearly state criteria for EIA diagnosis were excluded.

Types of interventions

Eligible interventions included inhaled beta2‐agonists administered, at any dose, as short‐term or long‐term prophylactic treatment before participants underwent a standardised exercise challenge. SABA and LABA had to be administered within a time period before exercise challenge that did not exceed their pharmacological half‐life (arbitrarily set at 1 hour for SABA, and at 12 hours for LABA). For studies with more than one drug arm, only the comparison with placebo was considered. Studies with more than one drug arm that evaluated different beta2‐agonist molecules were considered as separate trials.

Types of outcome measures

Primary outcomes
  • Mean max % fall in FEV1 (100 × (baseline pre‐exercise value - lowest postexercise value)/baseline pre‐exercise value) in people treated with a beta2‐agonist versus mean max % fall in FEV1 in people treated with placebo

  • Mean % protection afforded by beta2‐agonists (% protection = 100 × (max % fall FEV1 placebo - max % fall FEV1 beta2‐agonist)/max % fall FEV1 placebo)

  • Mean area under the curve (AUC) of time course changes in FEV1 after exercise in people treated with a beta2‐agonist versus mean AUC of time course changes in FEV1 after exercise in people treated with placebo

Secondary outcomes
  • Number of people with a max % fall in FEV1 < 10% (complete protection), < 15% and < 20%

  • Changes from baseline in symptom and sign scores

  • Mean max % fall in other pulmonary function parameters (peak expiratory flow (PEF), forced expiratory flow 25–75% (FEF), maximal expiratory flow at 50% (MEF) etc.)

  • Onset of tolerance (considered for long‐term administration studies and in relation to concomitant treatment with inhaled corticosteroids)

  • Outcomes of physical performance

  • Side/adverse effects

Search methods for identification of studies

Electronic searches

Trials were identified using the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, as well as handsearching of respiratory journals and meeting abstracts (see Appendix 1 for additional details). The Register was searched using the terms in Appendix 2 from the date of inception up to August 2013. No restriction was placed on language of publication.

Searching other resources

We screened reference lists of included studies, recent reviews and textbooks for relevant citations. We contacted authors of unpublished or 'in‐progress' studies and selected manufacturers of beta2‐agonists to identify additional studies. Furthermore, we searched national and international clinical trial websites (www.clinicalstudyresults.org; www.clinicaltrials.gov; www.fda.gov) for additional trials. Personal contacts with colleagues, collaborators and other trialists working in the field of asthma were at last made to identify further potentially relevant studies. No language or publication restrictions were applied to these searches.

Data collection and analysis

Selection of studies

Titles and abstracts of papers identified in the search were reviewed independently by two review authors (MB, CDM), and articles that appeared to fulfil the inclusion criteria were retrieved. From the full text of these papers, two review authors (MB, EC) independently established whether studies met the inclusion criteria. Studies that did not fulfil all of the inclusion criteria were excluded, and reasons for exclusion were reported. The percentage of agreement was recorded, and any disagreement was solved by consensus. If the two review authors did not reach an agreement, a third review author adjudication (MC) was used to resolve disagreements. In case of further uncertainty, study authors were contacted. Review authors were not blinded to authors, journals, results, etc.

Data extraction and management

Data extraction was performed independently by two review authors (MB, EC). Full texts were screened, and bibliographic details, as well as data regarding study design, participants, disease severity, intervention and outcomes, were recorded in predefined forms and entered into RevMan 5.2. All data, numerical calculations and graphic extrapolations were independently confirmed. We did not deal with missing data.

Assessment of risk of bias in included studies

We assessed the risk of bias in included studies as high, low or unclear using The Cochrane Collaboration’s 'Risk of bias' tool (Higgins 2011) and the following headings.

  • Random sequence generation (selection bias).

  • Allocation concealment (selection bias).

  • Blinding of participants and personnel (performance bias).

  • Blinding of outcome assessment (detection bias).

  • Incomplete outcome data (attrition bias).

  • Selective reporting (reporting bias).

  • Other bias.

Discussion or third party adjudication was used to resolve disagreements when necessary.

Measures of treatment effect

Treatment effects were measured as mean differences (MDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes.

Unit of analysis issues

Many included studies were of cross‐over design, but many did not report the results of paired t‐tests for continuous outcomes in this review. Some studies provided raw data that allowed a calculation of the correlation between treatment periods on beta2‐agonists and placebo on maximum percentage fall in FEV1 (see Appendix 3 for the raw data). We used the average correlation from these studies (0.36) to impute an appropriate standard error for within‐‐participant differences (as described in Section 16.4.6.4 of the Cochrane Handbook for Systematic Reviews of Interventions; Higgins 2011). We carried out a meta‐analysis of the mean differences and their standard errors for this outcome using the Generic Inverse Variance method in RevMan 5.2.

Dealing with missing data

Missing data on the correlation between results from participants in the cross‐over studies were imputed using the average correlation from studies that reported appropriate raw data. Cross‐over studies provided information on the number of participants in each arm who experienced a given drop in FEV1, but not the number of participants whose FEV1 dropped on both interventions (active treatment and placebo). We were able to calculate marginal odds ratios for these outcomes but could not adjust the standard error to take advantage of the cross‐over design.

Assessment of heterogeneity

To assess the level of heterogeneity, the Chi2 test and the I2 statistic were used. In establishing the level of heterogeneity, we considered the following rules for interpretation of results (Higgins 2011).

  • 0 to 30% as low heterogeneity.

  • 30% to 60% as moderate heterogeneity worthy of investigation.

  • 60% to 90% as severe heterogeneity worthy of understanding.

  • 90% to 100% as allowing aggregation only with major caution.

Assessment of reporting biases

Funnel plots were used to investigate the possibility of publication bias.

Data synthesis

Data were entered into RevMan 5.2. For continuous measures, individual and pooled statistics were reported as mean difference (MD) of treatment effect with 95% confidence intervals (95% CIs) using the fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

Heterogeneity worthy of investigation was examined using the following predefined subgroup analyses.

  • Type of beta2‐agonist (SABA vs LABA).

  • Molecule of beta2‐agonist (formoterol vs salmeterol).

  • Age of participants (children vs adults).

  • Concomitant treatments (beta2‐agonist monotherapy vs concomitant inhaled corticosteroid treatment).

Results

Description of studies

See:Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The search identified 2400 articles, and from these, 289 papers were independently selected by two review authors (k = 0.95) as being of potential interest on the basis of titles and abstracts. After non‐ interventional studies (n = 27) and articles published as abstract only (n = 52) were removed, we retrieved the remaining articles in full text and from these identified 51 studies for inclusion in the meta‐analysis (Figure 1). Two further articles were added through the cross‐checking reference process. We excluded 158 studies with reasons provided in Characteristics of excluded studies; one study is listed under Studies awaiting classification to be considered for inclusion when the review is next updated.

1.

1

Study flow diagram.

Included studies

Full details can be found in the Characteristics of included studies tables.

Study features and design

All 53 included studies were double‐blind, placebo‐controlled, randomised trials. Forty‐eight studies used a cross‐over design, and five were performed in a parallel ‐group design. In the cross‐over studies, washout periods ranged between 1 and 21 days. Nine studies did not mention duration of washout, and in two papers, no washout was performed. The exercise challenges involved treadmill (n = 35), cycle ergometer (n = 13) and free running (n = 5). All challenges were standardised and met recommended testing criteria. Trials were conducted between 1976 and 2010 in 12 different countries: Europe (N = 27), United States/Canada (N = 22) and Australia (N = 4). All articles except one (in Spanish) were written in English.

Population

Collectively, included studies reported data on 1139 participants. Population sample size ranged from 10 to 161 participants (55 in a single drug arm of parallel‐group studies and 46 in cross‐over studies-the highest number of enrolled participants). Studies included children and adults (age range 4 to 64 years). A total of 20 studies were performed in children, 18 in adults and 12 in both children and adults. Three papers did not provide sufficient information to allocate people according to age. Nine studies provided only information about ethnicity, and Caucasian was the most represented race.

Interventions

Of 53 included studies, 45 addressed beta2‐agonist short‐term administration, and eight focused on long‐term treatment. Articles were grouped on the basis of the type of beta2‐agonist drugs evaluated: SABA (N = 42; short‐term administration n = 40 and long‐term administration n = 2) and LABA (N = 27, short‐term administration n = 21 and long‐term administration n = 6). Among different beta2‐agonists, salbutamol (n = 27), salmeterol (n = 14), formoterol (n = 13) and terbutaline (n = 6) represented the molecules most frequently investigated. Beta2‐agonists were delivered through different devices (nebulisers, metered‐dose inhalers (MDIs) and inhalers).

Details on dosage and types of beta2‐agonist administration are summarised in Table 2, together with timing in relation to exercise.

1. Summary of study interventions.
Study Intervention (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 dose 30 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 dose 30 min, 5 h 30, 11 h 30
Boner 1994 Salb 200
Boner 1994 Form 12
Salbutamol 200 mcg
Formoterol 12 mcg
Single dose 3 h, 12 h
Boulet 1989 Salb Salbutamol 200 mcg Single dose 30 min
Bronski 1995 Salb MDI
Bronski 1995 Salb Pwd
Albuterol MDI 180 mcg
Albuterol rotacaps 200 mcg
Single dose 15 min
Bronski 1999 Salm Disk
Bronski 1999 Salm Diskhal
Salmetrol discus 50 mcg
Salmeterol diskhaler 50 mcg
Single dose 30 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 dose 15 min, 4 h, 8 h, 12 h
Carlsen 1995 Salm 25
Carlsen 1995 Salm 50
Salmeterol diskhaler 25 mcg
Salmeterol diskhaler 50 mcg
Single dose 10‐12 h
Cavagni 1993 Salb MDI
Cavagni 1993 Salb Jet
Salbutamol MDI 200 mcg
Salbutamol jet disposable 200 mcg
Single dose 10 min
Clarke 1990 Fen Fenoterol 100 mcg Single dose 10 min
Daugbjerg 1996 Salb
Daugbjerg 1996 Form 12
Salbutamol 400 mcg
Formoterol 12 mcg
Single dose 3 h, 12 h
Debelic 1988 Reproterol Reproterol 1 mg Single dose 15 min
DeBenedictis 1996 Salm 25
DeBenedictis 1996 Salm 50
Salmeterol 25 mcg
Salmeterol 50 mcg
Single dose 1 h, 2 h
DeBenedictis 1998 Salb Salbutamol 200 mcg Single dose 20 min
Del Col 1993 Salb MDI
Del Col 1993 Salb Jet
Salbutamol MDI 200 mcg
Salbutamol jet device 200 mcg
Single dose 10 min
Dinh Xuan 1989 Terb Terbutaline 500 mcg Single dose 15 min
Egglestone 1981 Terb 250 Terbutaline 250 mcg Single dose 1 h
Ferrari 2000 Form 12 Formoterol 12 mcg Single dose 15 min, 4 h
Garcia 2001 Form 12 Formoterol 12 mcg twice daily Long‐term (4 weeks) 30 min, 12 h at days 1, 14 and 28
Green 1992 Salm 50 Salmeterol 50 mcg Single dose 1 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 dose 15 min, 4 h, 8 h
Hancox 2002 Salbutamol 800 mcg daily Long‐term (1 week) 8 h
Hawksworth 2002 Salb HFA
Hawksworth 2002 Salb MDI
Salbutamol 180 HFA
Salbutamol 180 mcg MDI
Single dose 30 min
Henricksen 1983 Terb Terbutaline 32.5 mcg Single dose 15 min
Henricksen 1992 Salb
Henriksen 1992 Form 12
Salbutamol 200 mcg
Formoterol 12 mcg
Single dose 30 min, 3 h, 5 h 30, 8 h
Hills 1976 Salb
Hills 1976 Salmefamol
Salbutamol 200 mcg
Salmefamol 200 mcg
Single dose 20 min
Inman 1996 Salbutamol 800 mcg daily Long‐term (81 weeks) 24 h
Kemp 1994 Salb
Kemp 1994 Salm 42
Salbutamol 180 mcg
Salmeterol 42 mcg
Single dose 30 min, 5 h 30, 11 h 30
Konig 1981 Metaprot Metaproterenol 130 mcg Single dose 10 min, 1 h
Larsson 1982 Fen Fenoterol 400 mcg Single dose 10 min
McAlpine 1990 Salb
McAlpine 1990 Form 12
Salbutamol 200 mcg
Formoterol 12 mcg
Single dose 2 h, 4 h
McFadden 1986 Salb (I) Salbutamol 200 mcg Single dose 15 min
McFadden 1986 Salb (II) Salbutamol 180 mcg Single dose 15 min
Morton 1989 Rimet Rimeterol 400 mcg Single dose 2 min
Nelson 1998 Salmeterol 84 mcg daily Long‐term (29 days) 30 min, 9 h
Newnham 1993 Salb 200
Newnham 1993 Salm 50
Salbutamol 200 mcg
Salmeterol 50 mcg
Single dose 1 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 dose 20 min
Patessio 1991 Salb 200
Patessio 1991 Form 24
Salbutamol 200 mcg
Formoterol 24 mcg
Single dose 2 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 dose 15 min, 4 h, 8 h, 12 h
Pearlman 2007 Salb 90 Salbutamol 90 mcg Single dose 20 min
Philip 2007 Salm 50 Salmeterol 50 mcg Single dose 2 h, 8 h 30, 24 h
Ramage 1994 Salmeterol 100 mcg daily Long‐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 dose 5 min, 30 min, 1 h
Shapiro 2002 Salbutamol 180 mcg
Formoterol 12 mcg
Formoterol 24 mcg
Single dose 15 min, 4 h, 8 h, 12 h
Simons 1997 Salmeterol 50 mcg Long‐term (28 weeks) 1 h, 9 h
Stelmach 2008 Formoterol 9 mcg daily Long‐term (28 weeks) 1 h, 9 h
Storms 2004 Salmeterol 100 mcg daily Long‐term (28 weeks) 1 h, 9 h
Sturani 1983 Fen 400
Sturani 1983 Salb 200
Fenoterol 400 mcg
Salbutamol 200 mcg
Single dose 30 min
VanHaitsma 2010 Salb Salbutamol 180 mcg Single dose 15 min
Vasquez 1984 Salb 400 Salbutamol 400 mcg Single dose 15 min
Walker 1986 Bitolterol Bitolterol 1050 mcg Single dose 45 min
Wolley 1990 Terb 500 Terbutaline 500 mcg Single dose 25 min, 2 h, 4 h, 6 h
Outcomes

As per inclusion criteria, all 53 included studies reported data on at least one primary outcome of this review.

Excluded studies

See Characteristics of excluded studies.

Risk of bias in included studies

An assessment of the risk of bias is presented in the Characteristics of included studies tables and is summarised in a risk of bias figure (Figure 2).

2.

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Most of the included studies were judged at unclear risk for selection bias. Lack of information provided on random sequence generation and on allocation concealment may be explained by the high number of papers (40/53) conducted before 2000, when reporting of these risk of bias criteria was less common.

Blinding

Risks of performance and detection bias were minimised by the narrow inclusion criteria adopted, which allow inclusion in the systematic review of only randomised, at least double‐blind, placebo‐controlled trials.

Incomplete outcome data

Three drug arms ( Konig 1984 Fen 0.4; Konig 1984 Fen 0.8; Boulet 1989 Salb) reported incomplete data on outcomes as specified in this systematic review and were therefore assigned a high risk of bias.

Selective reporting

All studies except one (Ferrari 2000 Form 12) were rated as having unclear risk for reporting bias.

Other potential sources of bias

The possibility of publication bias was investigated in the funnel plot shown in Figure 3. The presence of other potential sources of bias was rated as unclear risk because of the scarce information provided.

3.

3

Funnel plot of comparison: 1 Beta2‐agonists versus placebo (single administration), outcome: 1.1 Maximal percentage fall in FEV1.

Several papers reported data derived from industry‐funded studies.

Effects of interventions

See: Table 1

Effects of intervention were separately assessed for short‐term (single administration) and long‐term beta2‐agonist administration.

Short‐term administration

The 45 studies evaluating short‐term beta2‐agonist administration included 77 arms of active treatment (49 SABA and 28 LABA) in comparison with placebo.

Primary outcomes

Data on max % fall in FEV1 were provided by 77 arms. Effects of SABA short‐term administration were evaluated beyond the pharmacological half‐life (1 hour) in five studies, which were therefore excluded. Analysis of the remaining 72 arms, including 799 participants (Figure 4), showed a significant protective effect of beta2‐agonists compared with placebo (MD ‐17.67%, 95% CI ‐19.51% to ‐15.84%; P = 0.00001). In particular, 58 study arms favoured the active treatment, and 14 trial arms reported no significant difference. Heterogeneity was, however, high (I2 = 71%).

4.

4

Forest plot of comparison: 1 beta2‐agonists versus placebo (single administration), outcome: 1.1 Maximal percentage fall in FEV1.

Mean % protection was 66% (range 29% to 91%). In seven studies, beta2‐agonist administration not only completely protected participants from EIA but also induced a bronchodilator effect compared with baseline values. In only one case (Bronski 1995 Salb Pwd), placebo offered greater protection compared with the active treatment.

Seventeen studies evaluating LABA short‐term administration at different time points showed an FEV1 % fall AUC that favoured the active treatment. Different study designs prevented merging of the data in a unique comprehensive analysis.

Secondary outcomes

Secondary outcomes on pulmonary function parameters confirmed a positive protective effect of beta2‐agonists on EIA compared with placebo. Complete protection from EIA as assessed by numbers of participants with an FEV1 % fall < 10% was evaluated in 19 studies (Analysis 1.2). A significant difference was noted in the number of participants completely protected (OR 0.08, 95% CI 0.06 to 0.13; P = 0.00001). Similar results were obtained for thresholds of FEV1 fall set at 15% (OR 0.06, 95% CI 0.03 to 0.15) and 20% (OR 0.09, 95% CI 0.06 to 0.14) (Analysis 1.3; Analysis 1.4). Max PEF and FEF25‐75 % fall were assessed, respectively, in 14 and in 8 studies (Analysis 1.5; Analysis 1.6). However, statistical analysis for these two outcomes was based on a limited number of trials because dispersion data were lacking in most of the studies considered. Only three arms (Vasquez 1984 Salb 400; Carlsen 1995 Salm 25; Carlsen 1995 Salm 50) reported data on max MEF25‐50 % fall. No study provided information on changes in symptoms and sign scores and effects on physical performance.

1.2. Analysis.

1.2

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 2 Number of participants with an FEV1 fall > 10%.

1.3. Analysis.

1.3

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 3 Number of participants with an FEV1 fall > 15%.

1.4. Analysis.

1.4

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 4 Number of participants with an FEV1 fall > 20%.

1.5. Analysis.

1.5

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 5 Maximal percentage fall in PEF.

1.6. Analysis.

1.6

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 6 Maximal percentage fall in FEF 25‐75.

As far as they concern secondary outcomes related to safety, side effects were assessed in 55 trials (Figure 5). Among these, 42 arms reported no adverse event for either active or placebo treatment. Analysis of the remaining 13 trials showed no significant difference between beta2‐agonists and placebo.

5.

5

Forest plot of comparison: 1 Beta2‐agonists versus placebo (single administration), outcome: 1.1 Side effects.

Subgroup analysis

The high heterogeneity (I2 = 71%) found for the primary outcome max FEV1 % fall was investigated through the preplanned subgroup analysis.

We performed a subgroup analysis according to types of beta2‐agonists (SABA vs LABA; Figure 6). Although subgroup analysis confirmed a significant bronchoprotective effect against EIA for both classes compared with placebo, it was not able to explain the marked heterogeneity observed in the entire population sample: SABA (I2 = 71%) and LABA (I2 = 67%). Accordingly, non‐significant differences emerged from the analysis of the different beta2‐agonist molecules administered (Figure 7). This evaluation was plotted only for the comparison between formoterol and salmeterol, because the number of studies evaluating different SABA molecules, apart from salbutamol, appeared to be too small for a reliable investigation. It is interesting to note that analysis of studies performed only in adults (n = 19) compared with those performed only in children (n = 32) showed that high heterogeneity was largely confined to studies in children (I2 = 11% and 80%, respectively), despite the comparable mean bronchoprotective effect (Figure 8). Furthermore all studies that failed to show a positive protective effect against EIA of beta2‐agonists compared with placebo dealt with the paediatric population.

6.

6

Forest plot of comparison: 1 Beta2‐agonists versus placebo (single administration), outcome: 1.8 Subgroup analysis: maximal percentage fall in FEV1 SABA versus LABA.

7.

7

Forest plot of comparison: 1 Beta2‐agonists versus placebo (single administration), outcome: 1.9 Subgroup analysis: maximal percentage fall in FEV1: salmeterol versus formoterol.

8.

8

Forest plot of comparison: 1 Beta2‐agonists versus placebo (single administration), outcome: 1.10 Subgroup analysis: maximal percentage fall in FEV1: adults versus children.

The different study designs used and the limited information provided prevented assessment of the potential role of concomitant treatment with inhaled corticosteroids.

Long‐term administration

Long‐term beta2‐agonist administration was addressed in only eight papers. Five trials were performed with a cross‐over design in a total of 64 people (50 adults and 14 children). Three studies adopted a parallel‐group design and included 69 people (49 adults and 20 children) in the active arms and 73 (53 adults and 20 children) placebo controls. Treatment periods range from 7 to 29 days. Effects of SABA were evaluated in two protocols, and LABA administration was assessed in six studies. The limited number of trials, the small population samples and the different study designs and drugs tested allow only a descriptive approach and prevent plotting of data in a meta‐analysis.

Garcia and coauthors (Garcia 2001 Form 12) evaluated the effects of 28‐day formoterol administration in a parallel‐group design (10 people in the beta2‐agonist arm and 9 people in the placebo arm). The protective effect of salmeterol 12 mcg twice daily was assessed on the 1st, 14th and 28th study days, and results were not significantly greater than those provided by placebo at any time point. Furthermore, tachyphylaxis to the beta2‐agonist effect was developed already after two weeks of treatment, although it was not progressive.

Hancox (Hancox 2002) studied the effect of 200 mcg once daily of salbutamol in eight adults treated for seven days in a cross‐over study. Results showed not only an increased max FEV1 % fall after the exercise challenge, but also a sub‐optimal bronchodilator response to further beta2‐agonist administration at the end of the treatment period in the active group.

Ten adults who inhaled 200 mcg of salbutamol or placebo four times a day for seven days were studied by Inman and O'Byrne (Inman 1996) in a cross‐over study. One week of regular inhaled salbutamol resulted in worsening of EIA.

A cross‐over design was also adopted by Nelson (Nelson 1998) in 20 adults treated for a month with inhaled salmeterol 42 mcg twice a day. Significant beta2‐agonist protection against EIA was maintained for the entire study period. However, the length of time that the drug remained active after a single dose significantly decreased. Furthermore, the number of participants for whom salmeterol did not offer complete protection against EIA (FEV1 % fall < 10%) increased from two on study day 1 to 11 on day 29 (P = 0.02)

Ramage and coworkers (Ramage 1994) studied 12 adults treated with inhaled salmeterol 50 mcg twice daily for 4 weeks in a cross‐over manner. The significant protection provided by the first dose of salmeterol against EIA at 6 and 12 hours was no longer present at the end of the treatment period.

Fourteen children were studied by Simons (Simons 1997) in a four‐week cross‐over study. The first dose of salmeterol had an excellent bronchoprotective effect against EIA at 1 and 9 hours. At the end of the study, however, the bronchoprotective effect was significantly greater than that of placebo only at 1 hour.

A parallel‐group study design was adopted by Stelmach (Stelmach 2008) to compare the effects of formoterol 9 mcg daily against placebo in two arms, each consisting of 20 children. Both groups of people were receiving concomitant inhaled corticosteroid (ICS) treatment with budesonide 100 mcg daily. At the end of the four‐week treatment period, bronchoconstriction induced by a standardised treadmill exercise challenge was significantly diminished in the active group compared with the placebo group,

At last, Storms (Storms 2004) in a four‐week parallel‐group study compared the protective effect of salmeterol 50 mcg twice daily against placebo. All enrolled people were receiving concomitant 100 mcg twice‐daily fluticasone treatment. The protective effect against EIA was evaluated at weeks 1 and 4 and was not different between the two groups.

Only one study (Simons 1997) took into consideration safety aspects of long‐term beta2‐adrenergic administration. Reported side effects were minor, were poorly related to study drug and anyway were not different between active and placebo groups.

The overall evaluation of presented studies seems to confirm the beta2‐agonist bronchoprotective effect for the first dose of treatment. However, long‐term use of both SABA and LABA induced the development of tolerance and decreased the duration of drug effect, even after short‐term treatment. The few available data on concomitant therapy with inhaled corticosteroids did not allow a firm statement about their potential influence on the response to beta2‐agonists.

Discussion

Summary of main results

Evidence emerging from the meta‐analysis of 45 short‐term (single administration) studies shows that both short‐ and long‐acting beta2‐agonists administered as preventive treatment (within the time‐effect period set at one hour for SABA and at 12 hours for LABA) prevent exercise‐induced asthma, as shown by the primary outcomes related to the FEV1 fall. This pharmacological effect appears to be clinically relevant and independent of the exercise challenge adopted (treadmill, cycle ergometer, free run). The assessment of secondary outcomes considered shows that the beta2‐agonist preventive effect is also documented by the number of participants protected (complete protection detectable in 68% of participants) and by other pulmonary function variables (PEF, FEF 25%‐75%, MEF 50%) and beta2‐agonists did not cause side effects.

Overall completeness and applicability of evidence

The choice to include only double‐blind randomised trials may influence the completeness of the present review but was thought to reinforce the quality of evidence.

Quality of the evidence

The quality of the evidence gathered for the primary outcome of maximal percentage fall in FEV1 and the number of participants with a fall in FEV1 greater than 10% were moderate owing to some concerns about risk of bias (unclear allocation concealment) and detected and not completely explained inconsistency and indirectness (relation of FEV1 to patient‐important outcomes). The same concerns apply to all other outcomes reported in the 'Summary of findings' (SoF) Table. In addition, for the outcomes of maximal percentage fall in PEF, maximal percentage fall in FEF 25‐75 and side effects, the quality was lowered further by the small numbers of participants for these outcomes and the resulting wide confidence intervals. It can be argued that this review started with the premise that pulmonary function measures are patient‐important outcomes and that, therefore, the quality of evidence should not be lowered for indirectness because the primary outcome was measured in these studies. However, despite these considerations, the meaning of the degree of change in FEV1 for patients remains unclear (as well as how it relates to their well‐being). Furthermore, (small) concerns about inconsistency and risk of bias justify an overall rating of quality as presented in the SoF Table. Further research should focus on patient‐important outcomes and the imprecision that was encountered for many of the secondary outcomes.

Potential biases in the review process

The review process was protected from bias by adherence to a prepublished protocol. We tried to prevent bias in our search process by using comprehensive search terms and by asking study authors to identify other published and non‐published studies. We minimised bias by assessing studies independently and resolving differences of opinion by discussion. Extraction of data and assessment of risk of bias were performed in duplicate as well. We performed only subgroup analyses that were specified a priori in the protocol.

Agreements and disagreements with other studies or reviews

Our results appear to be in agreement with those obtained by Spooner and coworkers in a Cochrane review and meta‐analysis published in 2009 and focused on quantitative comparison of the effects of inhaling mast cell stabilisers (nedocromil sodium or sodium cromoglycate) versus beta2‐agonists (Spooner 2003). However, the review authors confined their review to single‐dose administration and to short‐acting beta2‐agonist molecules. As far as we know, no recent systematic reviews have specifically addressed the efficacy and safety of both SABA and LABA, in short‐term and long‐term administration, for prevention of exercise‐induced asthma.

Authors' conclusions

Implications for practice.

Beta2‐agonists, both SABA and LABA, when administered in a single dose before exercise is undertaken, are effective and safe in preventing exercise‐induced asthma. Long‐term regular administration of inhaled beta2‐agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for regular prolonged use of beta2‐agonists as monotherapy in the pretreatment of EIA, despite the drug agencies' warning on LABA.

Implications for research.

Further research should focus on the following.

  • Distinguishing between EIA (exercise‐induced bronchoconstriction with asthma) from exercise‐induced bronchoconstriction without coexisting asthma as different phenotypes, in relation to clinical features, pathophysiological mechanisms, patterns of inflammation and response to treatments, including beta2‐agonists.

  • Evaluating the potential influence of different genotypes (i.e. beta2‐adrenergic receptor polymorphisms) and phenotypes on exercise‐induced bronchoconstriction severity and response to beta2‐adrenergic treatment.

  • Better defining response to therapy, not only according to functional parameters, but also on the basis of clinical endpoints (symptoms, disease control and patient‐related outcomes), markers of inflammation and omic approaches.

  • Defining standardised operational procedures (i.e. exercise challenges, diagnostic thresholds, outcome measures) for clinical trials in EIA.

  • Performing additional independent trials to address long‐term beta2‐agonist administration in EIA, with special reference to concomitant inhaled corticosteroid treatment, to better assess the risk/benefit ratio between drug efficacy and potential cardiovascular side effects and onset of tolerance.

  • Establishing whether pretreatment of EIA with beta2‐agonists may exert, beyond the bronchodilator effect, an anti‐inflammatory action, as suggested by recent findings on the role of mechanical factors in inflammation and airways remodelling.

  • Designing protocols specifically addressed to clarify the potential role of generics and different devices in influencing the efficacy and safety of beta2‐agonist prevention of EIA.

  • Developing systematic reviews and meta‐analyses to assess which is the most appropriate and effective treatment strategy, among those available, for prevention of exercise‐induced asthma.

Acknowledgements

We thank Brian Rowe for conceiving the original idea for this review and drafting the first version of the protocol.

The authors would like to thank the staff of the Cochrane Airways Group, especially Toby Lasserson and Emma Welsh, who provided invaluable assistance in developing and refining the systematic review. Special thanks to Chris Cates for statistical support, Elizabeth Stovold for her precious assistance in the electronic search and retrieval of papers and Barbara Prediger for her kind help with the SoF Tables.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRAL (The Cochrane Library) Monthly
MEDLINE (Ovid) Weekly
EMBASE (Ovid) Weekly
PsycINFO (Ovid) Monthly
CINAHL (EBSCO) Monthly
AMED (EBSCO) Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma & Immunology (AAAAI) 2001 onwards
American Thoracic Society (ATS) 2001 onwards
Asia Pacific Society of Respirology (APSR) 2004 onwards
British Thoracic Society Winter Meeting (BTS) 2000 onwards
Chest Meeting 2003 onwards
European Respiratory Society (ERS) 1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti‐asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1‐15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. Cochrane Airways Group Register search strategy

(physical* OR exercis* OR exert* or train* or bronchoconstrict* or bronchospasm* or EIB or EIA OR athlet*)

AND

(bronchodilat* or ((beta* or B2) and (agonist* or adrenergic*)) or salmeterol or formoterol or salbutamol or albuterol or terbutaline or clenbuterol)

[Limited to records coded as 'asthma']

Appendix 3. Raw data for the maximal percent fall in FEV1 calculations

Study ID Beta‐agonist arm Placebo arm Correlation
Mean SD N Mean SD N  
Anderson 2001 Salb Disk 13.42 13.23 27 39.4 17.58 27 0.46
Anderson 2001 Salb MDI 8.51 13.75 27 39.4 17.58 27 0.46
Blake 1999 Salb 180 3.8 7.5 25 13.5 12.7 24  
Blake 1999 Salm 25 7.99 10.2 26 14.0 11.5 23  
Blake 1999 Salm 50 7.34 10.3 24 14.0 11.5 23  
Boner 1994 Form 12 2.2 8.3 15 14.5 13.4 15  
Bronski 1995 Salb MDI 16.0 11.0 44 23.0 20.0 44  
Bronski 1995 Salb Pwd 26.0 13.0 44 23.0 20.0 44  
Bronski 1999 Salm Disk 5.6 10.2 24 12.1 15.6 24  
Bronski 1999 Salm Diskhal 5.7 6.36 24 12.1 15.6 24  
Bronski 2002 Form 12 17.0 0.0 17 38.3 0.0 18  
Bronski 2002 Form 24 14.6 0.0 17 38.3 0.0 18  
Bronski 2002 Salb 8.6 0.0 17 37.1 0.0 18  
Carlsen 1995 Salm 25 19.0 16.7 23 30.0 16.7 23  
Carlsen 1995 Salm 50 18.0 14.3 23 30.0 16.7 23  
Cavagni 1993 Salb Jet 7.15 4.9 8 34.7 22.3 8  
Cavagni 1993 Salb MDI 15.9 9.3 9 28.9 21.8 9  
Clarke 1990 Fen ‐19.9 0.0 20 9.8 0.0 20  
Daugbjerg 1996 Form 12 11.0 0.0 16 35.0 0.0 16  
Debelic 1988 Reproterol 12.6 0.0 16 38.5 0.0 16  
DeBenedictis 1996 Salm 25 19.0 12.0 12 35.0 16.0 12 0.28
DeBenedictis 1996 Salm 50 15.0 13.0 12 35.0 16.0 12 0.33
DeBenedictis 1998 Salb 3.7 4.4 12 25.7 18.9 12  
Del Col 1993 Salb Jet 20.76 2.1 15 29.14 15.1 15  
Del Col 1993 Salb MDI 12.37 5.1 15 26.6 16.1 15  
Dinh Xuan 1989 Terb ‐2.24 17.7 10 35.2 22.1 10  
Egglestone 1981 Terb 250 10.0 8.24 17 32.0 16.49 17  
Ferrari 2000 Form 12 5.9 7.2 14 29.3 14.3 14  
Green 1992 Salm 50 3.2 4.8 13 26.6 10.27 13 0.30
Gronnerod 2000 Form 4.5 9.2 8.5 27 18.4 10.1 27  
Gronnerod 2000 Form 9 5.4 8.5 27 18.4 10.1 27  
Gronnerod 2000 Terb 500 3.3 10.2 27 18.4 10.1 27  
Hawksworth 2002 Salb HFA 15.4 9 23 33.7 8.3 24  
Hawksworth 2002 Salb MDI 14.9 9 24 33.7 8.3 24  
Henricksen 1983 Terb 26.0 22.4 14 37.0 14.9 14  
Henricksen 1992 Salb 18.0 17.3 12 44.0 13.8 12  
Henriksen 1992 Form 12 8.0 10.4 12 44.0 13.8 12  
Hills 1976 Salb ‐4.6 0.0 19 35.5 0.0 19  
Hills 1976 Salmefamol ‐2.6 0.0 19 35.5 0.0 19  
Kemp 1994 Salb 7.0 0.0 54 27.0 0.0 52  
Kemp 1994 Salm 42 13.0 0.0 53 27.0 0.0 52  
Konig 1981 Metaprot 19.0 12.0 24 36.0 15.0 24  
Konig 1984 Fen 0.4 4.3 10.1 12 27.8 14.9 12  
Konig 1984 Fen 0.8 2.5 13.0 12 27.8 14.9 12  
Larsson 1982 Fen ‐2.7 0.0 8 11.0 0.0 8  
McAlpine 1990 Form 12 7.7 8.6 11 32.7 16.5 11  
McFadden 1986 Salb (I) 1.1 0.0 15 10.8 0.0 15  
McFadden 1986 Salb (II) ‐1.1 0.0 20 14.1 0.0 20  
Morton 1989 Rimet 2.8 5.5 10 24.5 8.4 10  
Newnham 1993 Salb 200 3.8 18.2 11 27.1 15.9 11  
Newnham 1993 Salm 50 12.8 16.9 12 32.0 23.2 11  
Patel 1986 Salb 200 6.0 0.0 9 27.9 0.0 9  
Patel 1986 Tulob 200 9.7 0.0 9 27.9 0.0 9  
Patel 1986 Tulob 400 7.7 0.0 9 27.9 0.0 9  
Patessio 1991 Form 24 10.0 0.0 12 30.5 0.0 12  
Pearlman 2006 Form 12 7.6 0.0 22 13.2 0.0 20  
Pearlman 2006 Form 24 5.9 0.0 23 13.2 0.0 20  
Pearlman 2006 Salb 180 3.5 0.0 22 11.1 0.0 19  
Pearlman 2007 Salb 90 4.8 10.8 15 22.5 10.8 15 0.39
Philip 2007 Salm 50 10.7 8.1 46 21.8 8.1 46  
Richter 2002 Form 12 5.7 5.3 24 25.1 12.2 24  
Richter 2002 Salm 50 7.6 7.5 24 25.1 12.2 24  
Richter 2002 Terb 500 8.5 8.3 24 25.1 12.2 24  
Shapiro 2002 Form 12 12.4 14.6 19 32.9 16.8 17  
Shapiro 2002 Form 24 17.5 17.5 17 32.9 16.8 17  
Shapiro 2002 Salb 180 10.0 18.6 19 31.1 18.7 17  
Sturani 1983 Fen 400 15.8 7.9 12 36.0 6.9 12  
Sturani 1983 Salb 200 23.2 8.6 12 36.0 6.9 12  
VanHaitsma 2010 Salb 4.0 16.4 10 14.3 11.1 10  
Vasquez 1984 Salb 400 ‐0.3 4.9 13 14.3 9.8 12  
Walker 1986 Bitolterol 5.0 11.4 12 23.2 16.2 12  
Wolley 1990 Terb 500 17.0 6.9 12 34.0 13.8 12  

Data and analyses

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

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Maximal percentage fall in FEV1 72 799 Mean Difference (Random, 95% CI) ‐17.67 [‐19.51, ‐15.84]
2 Number of participants with an FEV1 fall > 10% 19 773 Odds Ratio (M‐H, Random, 95% CI) 0.08 [0.06, 0.13]
3 Number of participants with an FEV1 fall > 15% 13 457 Odds Ratio (M‐H, Random, 95% CI) 0.06 [0.03, 0.15]
4 Number of participants with an FEV1 fall > 20% 25 1021 Odds Ratio (M‐H, Random, 95% CI) 0.09 [0.06, 0.14]
5 Maximal percentage fall in PEF 14 92 Mean Difference (Random, 95% CI) ‐24.61 [‐37.57, ‐11.65]
6 Maximal percentage fall in FEF 25‐75 8 106 Mean Difference (Fixed, 95% CI) ‐20.75 [‐27.17, ‐14.32]
7 Side effects 55 2165 Odds Ratio (M‐H, Random, 95% CI) 0.83 [0.43, 1.59]
8 Subgroup analysis: maximal percentage fall in FEV1 SABA vs LABA 72   Mean Difference (Random, 95% CI) ‐17.67 [‐19.51, ‐15.84]
8.1 SABA 44   Mean Difference (Random, 95% CI) ‐18.99 [‐21.38, ‐16.60]
8.2 LABA 28   Mean Difference (Random, 95% CI) ‐15.60 [‐18.29, ‐12.92]
9 Subgroup analysis: maximal percentage fall in FEV1: salmeterol versus formoterol 28   Mean Difference (Random, 95% CI) ‐15.60 [‐18.29, ‐12.92]
9.1 Salmeterol 13   Mean Difference (Random, 95% CI) ‐12.73 [‐16.10, ‐9.37]
9.2 Formoterol 15   Mean Difference (Random, 95% CI) ‐18.24 [‐22.15, ‐14.34]
10 Subgroup analysis: maximal percentage fall in FEV1: adults versus children 51   Mean Difference (Random, 95% CI) ‐16.75 [‐19.12, ‐14.39]
10.1 Adults 19   Mean Difference (Random, 95% CI) ‐18.77 [‐20.78, ‐16.76]
10.2 Children 32   Mean Difference (Random, 95% CI) ‐15.32 [‐18.88, ‐11.75]

1.1. Analysis.

1.1

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 1 Maximal percentage fall in FEV1.

1.7. Analysis.

1.7

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 7 Side effects.

1.8. Analysis.

1.8

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 8 Subgroup analysis: maximal percentage fall in FEV1 SABA vs LABA.

1.9. Analysis.

1.9

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 9 Subgroup analysis: maximal percentage fall in FEV1: salmeterol versus formoterol.

1.10. Analysis.

1.10

Comparison 1 Beta2‐agonists versus placebo (single administration), Outcome 10 Subgroup analysis: maximal percentage fall in FEV1: adults versus children.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anderson 2001 Salb Disk.

Methods Study 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
Participants Number of subjects: 29
% of males: 40%
Age range: 18‐40 years
Ethnicity: Not reported
Withdrawal or drop out: 2
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall, % protection
Secondary available: Number of patients with a max FEV1 % fall <10%, <15%, <20%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Anderson 2001 Salb MDI.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Anderson 2001 Salb Disk
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Blake 1999 Salb 180.

Methods Study 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
Participants Number of subjects: 26
% of males: 65%
Age range: 4‐11 years
Ethnicity: 81% Caucasians, 15% Blacks, 4% Hispanic
Withdrawal or drop out: 3
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall, % protection, FEV1 fall AUC
Secondary available: Side effects
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Blake 1999 Salm 25.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Blake 1999 Salb
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Blake 1999 Salm 50.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Blake 1999 Salb
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Boner 1994 Form 12.

Methods Study 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
Participants Number of subjects: 16
% of males: 68%
Age range: 6‐12 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall, % protection, FEV1 fall AUC
Secondary available: Side effects
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Boner 1994 Salb 200.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Boner 1994 Form
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Boulet 1989 Salb.

Methods Study 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
Participants Number of subjects: 12
% of males: 36%
Age range: 19‐49 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: % protection
Secondary available: None
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes High risk Data on primary and secondary outcomes are reported incompletely
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 1995 Salb MDI.

Methods Study 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
Participants Number of subjects: 46
% of males: 59%
Age range: 4‐11 years
Ethnicity: 87% Caucasians, 13% Others
Withdrawal or drop out: 2
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall, % protection
Secondary available: Side effects, Number of patients with a max FEV1 % fall <20%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 1995 Salb Pwd.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Bronski 1995 Salb MDI
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 1999 Salm Disk.

Methods Study 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
Participants Number of subjects: 24
% of males: 58%
Age range: 4‐11 years
Ethnicity: 91% Caucasians, 9% Blacks
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall, % protection, FEV1 fall AUC
Secondary available: Side effects, Number of patients with a max FEV1 % fall <15%, <20%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 1999 Salm Diskhal.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Bronski 1999 Salm Disk
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 2002 Form 12.

Methods Study 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
Participants Number of subjects: 18
% of males: 78%
Age range: 13‐36 years
Ethnicity: 88% Caucasians, 12% Others
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: max FEV1 % fall; % protection; FEV1 fall AUC
Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%; Max PEF % fall
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 2002 Form 24.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Bronski 2002 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Bronski 2002 Salb.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Bronski 2002 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Carlsen 1995 Salm 25.

Methods Study 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
Participants Number of subjects: 23
% of males: 47%
Age range: 8‐16 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Number of patients with a max FEV1 % fall <15%; Max MEF25‐50 % fall
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Carlsen 1995 Salm 50.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Carlsen Salm 25
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Cavagni 1993 Salb Jet.

Methods Study 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
Participants Number of subjects: 9
% of males: 66%
Age range: 5‐9 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Side effects; Max PEF % fall; Max FEF25‐75 % fall
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Cavagni 1993 Salb MDI.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Cavagni 1993 Salb Jet
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Clarke 1990 Fen.

Methods Study 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
Participants Number of subjects: 20
% of males: 70%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: None
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Daugbjerg 1996 Form 12.

Methods Study 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
Participants Number of subjects: 16
% of males: 81%
Age range: 10‐14 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: None
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Daugbjerg 1996 Salb.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Daugbjerg 1996 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Debelic 1988 Reproterol.

Methods Study 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
Participants Number of subjects: 16
% of males: Not reported
Age range: 8‐20 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

DeBenedictis 1996 Salm 25.

Methods Study 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
Participants Number of subjects: 12
% of males: 83%
Age range: 7‐14 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

DeBenedictis 1996 Salm 50.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: De Benedictis 1996 Salm 25
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

DeBenedictis 1998 Salb.

Methods Study 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
Participants Number of subjects: 12
% of males: 66%
Age range: 7‐13 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Del Col 1993 Salb Jet.

Methods Study 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
Participants Number of subjects: 15
% of males: 60%
Age range: 9‐13 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Max PEF % fall
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Del Col 1993 Salb MDI.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Del Col 1993 Salb Jet
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Dinh Xuan 1989 Terb.

Methods Study 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
Participants Number of subjects: 10
% of males: 70%
Age range: 6‐16 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Number of patients with a max FEV1 % fall <10%, <15% and <20%
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Egglestone 1981 Terb 250.

Methods Study 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
Participants Number of subjects: 17
% of males: Not reported
Age range: 18‐32 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Max FEF25‐75 % fall;
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Ferrari 2000 Form 12.

Methods Study 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
Participants Number of subjects: 14
% of males: 92%
Age range: 12‐28 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) High risk Statistical analysis and manuscript writing made by drug industry staff
Other bias Unclear risk Insufficient information

Garcia 2001 Form 12.

Methods Study 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
Participants Number of subjects: 19
% of males: 42%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Green 1992 Salm 50.

Methods Study 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
Participants Number of subjects: 13
% of males: 61%
Age range: 8‐15 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Gronnerod 2000 Form 4.5.

Methods Study 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
Participants Number of subjects: 27
% of males: 55%
Age range: 8‐17 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Side effects
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Gronnerod 2000 Form 9.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Gronnerod 2000 Form 4.5
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Gronnerod 2000 Terb 500.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Gronnerod 2000 Form 4.5
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Hancox 2002.

Methods Study 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
Participants Number of subjects: 9
% of males: 11%
Age range: 18‐44 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Tolerance
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Hawksworth 2002 Salb HFA.

Methods Study 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
Participants Number of subjects: 24
% of males: 75%
Age range: 18‐45 years
Ethnicity: Caucasian 83%; Asian 17%
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Hawksworth 2002 Salb MDI.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Hawksworth 2002 Salb HFA
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Henricksen 1983 Terb.

Methods Study 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
Participants Number of subjects: 14
% of males: Not reported
Age range: 8‐15 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Unclear risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Henricksen 1992 Salb.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Henricksen 1992 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Henriksen 1992 Form 12.

Methods Study 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
Participants Number of subjects: 12
% of males: Not reported
Age range: 8‐15 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Hills 1976 Salb.

Methods Study 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
Participants Number of subjects: 19
% of males: 42%
Age range: 5‐15 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: None
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Hills 1976 Salmefamol.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Hills 1976 Salb
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Inman 1996.

Methods Study 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
Participants Number of subjects: 10
% of males: 70%
Age range: 19‐37 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Onset of tolerance
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Kemp 1994 Salb.

Methods Study 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
Participants Number of subjects: 161
% of males: 42%
Age range: 12‐35 years
Ethnicity: Not reported
Withdrawal or drop out: 8
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Side effects; Number of patients with a max FEV1 % fall <10% and 20%
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Kemp 1994 Salm 42.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Kemp 1994 Salb
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Konig 1981 Metaprot.

Methods Study 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
Participants Number of subjects: 24
% of males: 67%
Age range: 17‐34 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Max FEF 25‐‐75 % fall; Side effects; Number of patients with a max FEV1 % fall <10%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Konig 1984 Fen 0.4.

Methods Study 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
Participants Number of subjects: 12
% of males: 100%
Age range: 17‐29 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Max FEF 25‐‐75 % fall; Side effects; Number of patients with a max FEV1 % fall <10%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes High risk Data for max FEF 25‐‐75 % fall not reported
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Konig 1984 Fen 0.8.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Konig 1984 Fen 0.4
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes High risk Data for max FEF 25‐‐75 % fall not reported
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Larsson 1982 Fen.

Methods Study 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
Participants Number of subjects: 8
% of males: 69%
Age range: 29‐64 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Number of patients with a max FEV1 % fall <15%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

McAlpine 1990 Form 12.

Methods Study 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
Participants Number of subjects: 12
% of males: 41%
Age range: 19‐41 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Side effects
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

McAlpine 1990 Salb.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: McAlpine 1990 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

McFadden 1986 Salb (I).

Methods Study 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
Participants Number of subjects: 20
% of males: 60%
Age range: 21‐42 years
Ethnicity: Not reported
Withdrawal or drop out: 5
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Max FEF 25‐‐75 % fall; Side effects; Number of patients with a max FEV1 % fall <20%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

McFadden 1986 Salb (II).

Methods Study 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
Participants Number of subjects: 20
% of males: 60%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Max FEF 25‐‐75 % fall; Side effects; Number of patients with a max FEV1 % fall <20%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Morton 1989 Rimet.

Methods Study 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
Participants Number of subjects: 10
% of males: 70%
Age range: 15‐30 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Side effects; Number of patients with a max FEV1 % fall <15%;
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Nelson 1998.

Methods Study 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
Participants Number of subjects: 20
% of males: 45%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Onset of tolerance; Number of patients with a max FEV1 % fall <10%;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Newnham 1993 Salb 200.

Methods Study 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
Participants Number of subjects: 12
% of males: 50%
Age range: 21‐33 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Newnham 1993 Salm 50.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Newnham 1993 Salb 200
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Patel 1986 Salb 200.

Methods Study 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
Participants Number of subjects: 9
% of males: Not reported
Age range: 19‐46 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: None
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Patel 1986 Tulob 200.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Patel 1986 Salb 200
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Patel 1986 Tulob 400.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Patel 1986 Salb 200
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Unclear risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Patessio 1991 Form 24.

Methods Study 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
Participants Number of subjects:12
% of males: 16%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Patessio 1991 Salb 200.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Patessio 1991 Form 24
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Pearlman 2006 Form 12.

Methods Study 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
Participants Number of subjects:23
% of males: 30%
Age range: 4‐11 years
Ethnicity: Not reported
Withdrawal or drop out: 2
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Pearlman 2006 Form 24.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Pearlman 2006 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Pearlman 2006 Salb 180.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Pearlman 2006 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Pearlman 2007 Salb 90.

Methods Study 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
Participants Number of subjects:15
% of males: 86%
Age range: Not reported
Ethnicity: 100% Caucasian
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Philip 2007 Salm 50.

Methods Study 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
Participants Number of subjects:47
% of males: 49%
Age range: 15‐45 years
Ethnicity: 55% Caucasian; 45% Others
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: Side effects
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Ramage 1994.

Methods Study 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
Participants Number of subjects: 12
% of males: 66%
Age range: 19‐36 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Onset of tolerance
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Richter 2002 Form 12.

Methods Study 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
Participants Number of subjects: 25
% of males: 66%
Age range: 19‐36 years
Ethnicity: Not reported
Withdrawal or drop out: 1
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: None
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Richter 2002 Salm 50.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Richter Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Richter 2002 Terb 500.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Richter Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Shapiro 2002 Form 12.

Methods Study 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
Participants Number of subjects: 20
% of males: 45%
Age range: 13‐41 years
Ethnicity: Caucasians 90%; Others 10%
Withdrawal or drop out: 3
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Side effects; Number of patients with a max FEV1 % fall <20%; Max PEF % fall;
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Shapiro 2002 Form 24.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Shapiro 2002 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Shapiro 2002 Salb 180.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Shapiro 2002 Form 12
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Simons 1997.

Methods Study 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
Participants Number of subjects: 16
% of males: 41%
Age range: 12‐16 years
Ethnicity: Not reported
Withdrawal or drop out: 2
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: None
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Stelmach 2008.

Methods Study 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
Participants Number of subjects: 100
% of males: Not reported
Age range: 6‐18 years
Ethnicity: Not reported
Withdrawal or drop out: 9
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Onset of tolerance
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Randomization described explicitly
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Storms 2004.

Methods Study 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
Participants Number of subjects: 122
% of males: Not reported
Age range: 15‐58 years
Ethnicity: Not reported
Withdrawal or drop out: 13
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection; FEV1 % fall AUC
Secondary available: Onset of tolerance
Notes Industry funded study
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Sturani 1983 Fen 400.

Methods Study 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
Participants Number of subjects: 12
% of males: 58%
Age range: 16‐42 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection
Secondary available: None
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Sturani 1983 Salb 200.

Methods  
Participants  
Interventions  
Outcomes  
Notes See: Sturani 1983 Fen 400
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

VanHaitsma 2010 Salb.

Methods Study 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
Participants Number of subjects: 10
% of males: 70%
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Max Pef % fall; Max FEF 25‐‐75 % fall
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Vasquez 1984 Salb 400.

Methods Study 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
Participants Number of subjects: 25
% of males: Not reported
Age range: Not reported
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Number of patients with a max FEV1 % fall <15%; Max MEF50 % fall;
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Walker 1986 Bitolterol.

Methods Study 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
Participants Number of subjects: 12
% of males: 58%
Age range: 14‐25 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Wolley 1990 Terb 500.

Methods Study 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
Participants Number of subjects: 12
% of males: 58%
Age range: 18‐28 years
Ethnicity: Not reported
Withdrawal or drop out: 0
Interventions Drug 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
Outcomes Primary available: Max FEV1 % fall; % protection;
Secondary available: Side effects; Number of patients with a max FEV1 % fall <10%
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information
Allocation concealment (selection bias) Unclear risk Insufficient information
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Double blind study
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information
Incomplete outcome data (attrition bias) 
 All outcomes Unclear risk Insufficient information
Selective reporting (reporting bias) Unclear risk Insufficient information
Other bias Unclear risk Insufficient information

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Aebischer 1984 No beta‐2 agonist pretreatment
Agostini 1983 I Duplicate
Agostini 1983 II No systematic review primary outcomes
Allegra 1976 No clear diagnosi of exercise‐induced bronchoconstriction
Anderson 1975 No double blind
Anderson 1976 No randomization
Anderson 1991 No randomization
Aranda 1992 No double blind
Bakran 1980 No placebo control
Battistini 1980 No inhaled beta‐2 agonist administration
Baur 1979 No systematic review primary outcomes
Berkowitz 1986 No double blind
Boner 1984 No double blind
Boner 1987 No placebo control
Boner 1988 No inhaled beta‐2 agonist administration
Bratteby 1986 No placebo control
Bundgaard 1980 No systematic review primary outcomes
Bundgaard 1983 I No randomization
Bundgaard 1983 II No systematic review primary outcomes
Bundgaard 1983 III No systematic review primary outcomes
Bye 1980 No randomization
Ceugniet 1997 No placebo control
Colice 1999 No double blind
Coreno 2000 No double blind
Corrias 1989 No placebo control
Dal Col 1995 No double blind
Del Bono 1979 No double blind
Di Gioacchino 1987 No inhaled beta‐2 agonist administration
Dockhorn 1997 No double blind
Edelman 2000 No placebo control
Eggleston 1981 No inhaled beta‐2 agonist administration
Ferrari 2002 No placebo control
Fogel 2010 No placebo control
Francis 1980 No clear diagnosi of exercise‐induced bronchoconstriction
Freeman 1989 No clear diagnosi of exercise‐induced bronchoconstriction
Gibson 1978 No randomization
Gimeno 1985 No clear diagnosi of exercise‐induced bronchoconstriction
GlaxoSmithKline 2006 I No placebo control
GlaxoSmithKline 2006 II Duplicate
Godfrey 1975 Duplicate
Godfrey 1976 No inhaled beta‐2 agonist administration
Guerin 1992 No placebo control
Gunawardena 2005 No placebo control
Hermansen 2006 No beta‐2 agonist pretreatment
Higgs 1983 No placebo control
Ienna 1997 No systematic review primary outcomes
Iikura 1988 No randomization
Ioli 1986 No double blind
Johnson 1986 No clear diagnosi of exercise‐induced bronchoconstriction
Koch 1972 No randomization
Kumar 1988 No randomization
Lopes Dos Santos 1991 No beta‐2 agonist pretreatment
Machado 2012 No placebo control
Macucci 2004 No randomization
Magnussen 1984 No double blind
Makela 2012 No placebo control
Martinsson 1985 No inhaled beta‐2 agonist administration
Merck 2005 I Duplicate
Merck 2005 II No placebo control
Mickleborough 2007 No placebo control
Millqvist 2000 No randomization
Morandini 1982 No randomization
Morooka 1987 No clear diagnosi of exercise‐induced bronchoconstriction
Morse 1976 No inhaled beta‐2 agonist administration
Morton 1992 No double blind
Murray 2011 No placebo control
Pearlman 2009 No placebo control
Pfleger 2002 No exercise challenge
Pichaipat 1995 No randomization
Pichon 2005 No clear diagnosi of exercise‐induced bronchoconstriction
Poppius 1973 No placebo control
Rabe 1993 No systematic review primary outcomes
Raissy 2006 No placebo control
Raissy 2008 No placebo control
Revill 1998 No placebo control
Robertson 1994 No clear diagnosi of exercise‐induced bronchoconstriction
Rohr 1987 No placebo control
Sanguinetti 1986 Exercise challenge beyond beta‐2 agonist pharmacological half‐life
Schaanning 1996 No systematic review primary outcomes
Shah 1983 No clear diagnosi of exercise‐induced bronchoconstriction
Shapiro 1981 No inhaled beta‐2 agonist administration
Shapiro 1990 No double blind
Sichletidis 1993 No placebo control
Silverman 1973 No randomization
Singh 1992 No randomization
Sly 1968 No double blind
Sly 1975 No systematic review primary outcomes
Sly 1982 No inhaled beta‐2 agonist administration
Spada 1985 No placebo control
Stark 1981 No clear diagnosi of exercise‐induced bronchoconstriction
Steinshamn 2004 No placebo control
Svenonius 1983 No randomization
Svenonius 1988 No double blind
Svenonius 1994 No beta‐2 agonist pretreatment
Tabas 1985 No inhaled beta‐2 agonist administration
Tammivaara 1979 No randomization
Unnithan 1994 No clear diagnosi of exercise‐induced bronchoconstriction
Verini 1983 No placebo control
Verini 1985 No inhaled beta‐2 agonist administration
Verini 1999 No placebo control
Villaran 1999 No placebo control
Vilsvik 1991 No beta‐2 agonist pretreatment
Vilsvik 2001 No placebo control
Von Berg 2002 No placebo control
Weiler 2005 No placebo control
Weinberg 1982 No double blind
Yeung 1980 No placebo control
Zanconato 1990 No placebo control
Zimmermann 2003 No placebo control

Differences between protocol and review

Compared with what was originally planned in the protocol, given the high number of papers retrieved in full and reviewed (N = 211), the review authors agreed to narrow the inclusion criteria, considering eligible only double‐blind trials that assessed at least one primary outcome of the review. Lack of data reported selected outcomes and the low rate of heterogeneity prevented or made unnecessary some of the subgroup analyses defined a priori. We prepared a 'Summary of findings' table according to recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Contributions of authors

MB updated the protocol and was responsible for drafting the full text of the review. MB, CDM and EC selected the studies to be included in the review and extracted and collected data. EC and MB entered data into the Review Manager software for statistical analysis. HS created the 'Summary of findings' table, acting as expert contact for the assessment of risk of bias and for evaluation of the quality of evidence. GWC, MAC and SD acted as independent review authors for solving disagreements among rating authors. All authors critically reviewed the protocol and were involved in revising the full text of the systematic review.

Sources of support

Internal sources

  • National Research Council, Institute of Translational Pharmacology (IFT), Italy.

External sources

  • Italian National Drug Agency (AIFA), Italy.

  • 21st Century Canada Research Chairs Programme; Government of Canada (Ottawa, Ontario), Canada.

Declarations of interest

Disclosures of interest provided by the review authors did not imply any potential conflict of interest with reference to this review.

New

References

References to studies included in this review

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Godfrey 1975 {published data only}

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