Asthma Management Handbook

Managing exercise-induced bronchoconstriction in adults

Recommendations

If the person is involved in competitive sport (including recreational sport), check which medicines are permitted in the particular sport by consulting the Australian Sports Anti-Doping Authority (ASADA) before prescribing any medicine.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

For an adult with asthma who does not need maintenance inhaled corticosteroid treatment (e.g. mild exercise-induced bronchoconstriction with no symptoms at other times), recommend salbutamol to be taken 15 minutes before exercise. The usual dose range is salbutamol 1–4 puffs via pMDI (100 mcg/actuation). Advise the person to take their reliever as needed to relieve asthma symptoms at other times.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Parsons et al. 20131
  • Weiler et al. 20102

For an adult who experiences exercise-related symptoms on most days and is not already using a preventer, consider daily treatment with an inhaled corticosteroid starting at a low dose. Advise the person to use salbutamol 15 minutes before exercise until the full effect of inhaled corticosteroid has been achieved (usually 2–4 weeks, but can be up to 12 weeks).

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (mcg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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Table. Initial treatment choices (adults and adolescents not already using a preventer)

Clinical situation

Suggested starting regimen †

Alternative options and notes

Symptoms less than twice per month and no flare-up that required oral corticosteroids within previous 12 months

SABA as needed

 

Symptoms twice per month or more

Regular ICS starting at a low dose (plus SABA as needed)

Montelukast

Cromones§

Waking due to asthma symptoms at least once during the past month

Regular ICS starting at a low dose (plus SABA as needed)

If patient also has frequent daytime symptoms consider either of:

  • medium- to high-dose ICS (plus SABA as needed)
  • (private prescription) combination low-dose ICS/LABA#

Oral corticosteroids required for an asthma flare-up within the last 12 months (even if symptoms infrequent, e.g. less than twice per month on average)

Regular ICS starting at a low dose (plus SABA as needed)

 

History of artificial ventilation or admission to an intensive care unit due to acute asthma (even if symptoms infrequent, e.g. less than twice per month on average)

Regular ICS starting at a low dose (plus SABA as needed)

  • Monitor frequently

 

Patient not currently taking a preventer whose symptoms are severely uncontrolled or very troublesome

Regular ICS (plus SABA as needed)

For very uncontrolled asthma at presentation (e.g. frequent night waking, low lung function), consider (either of):

  • high-dose ICS (then down-titrate when symptoms improve)
  • a short course of oral corticosteroids in addition to ICS

Consider (private prescription) combination ICS/LABA#

† When prescribing inhaled asthma medicines, take into account the person’s preferences, ability to use the device, and cost issues.

§ Requires multiple daily doses and daily maintenance of inhaler.

‡ PBS status as at October 2016: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for Department of Veteran’s Affairs gold card holders or white card holders with approval for asthma treatments.

# PBS status as at October 2016: ICS/LABA combination therapy as first-line preventer treatment is not subsidised by the PBS, except for patients with frequent symptoms while taking oral corticosteroids.

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Parsons et al. 20131
  • Weiler et al. 20102

For patients starting inhaled corticosteroid treatment, review efficacy after 4–12 weeks’ treatment. If exercise-induced bronchoconstriction has resolved, advise patient to try omitting pre-exercise salbutamol to test whether it is no longer needed.

Note: All patients with asthma should carry a reliever at all times, for use as needed in response to symptoms.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

For patients who are taking regular combination inhaled corticosteroid/long-acting beta2 agonist treatment and have significant exercise-induced symptoms despite correct inhaler technique and good adherence, consider replacing with inhaled corticosteroid alone as regular maintenance treatment (with as-needed short-acting beta-agonist).

A higher dose of inhaled corticosteroid may be needed to maintain good control.

Regular montelukast can be used in addition to inhaled corticosteroid.

  • Stopping a long-acting beta2-agonist may cause flare-ups or loss of asthma control.
  • Do not prescribe long-acting beta2-agonists as monotherapy, either intermittently or regularly.

Note: PBS status as at October 2016: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over (Special Authority is available for DVA gold card holders, or white card holders with approval for asthma treatments), or for people of any age when used in addition to a long-acting beta-agonist.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Parsons et al. 20131
  • Weiler et al. 20102

If exercise-induced symptoms do not resolve after adjusting medicines, and checking adherence and inhaler technique, consider:

  • alternative diagnoses
  • referral to an accredited respiratory function laboratory for indirect challenge testing
  • referral to a respiratory physician for assessment.
How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Advise warm-up before planned exercise.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • Parsons et al. 20131
  • Weiler et al. 20102

More information

Challenge tests for exercise-induced bronchoconstriction

Role of challenge tests

Self-reported symptoms are not sensitive enough to detect exercise-induced bronchoconstriction reliably or specific enough to rule out other conditions, particularly in elite athletes.234 Single office FEV1 readings or peak expiratory flow measurement are not adequate to demonstrate exercise-induced bronchoconstriction.1

Standardised, objective bronchial provocation (challenge) tests using spirometry are necessary for the investigation of suspected exercise-induced bronchoconstriction in elite athletes. These tests involve serial spirometry measurements after challenge with exercise (or exercise surrogates e.g. dry powder mannitol, eucapnic voluntary hyperpnoea or hyperventilation, or hyperosmolar aerosols such as 4.5% saline).21, 56 Severity of exercise-induced bronchoconstriction is assessed by percentage fall in FEV1 after challenge.1

Challenge testing is mandated by sports governing bodies before the athlete is given permission to use some asthma medicines, and the required testing protocol varies between specific sports. The latest information is available from the Australian Sports Anti-Doping Authority (ASADA) and the World Anti-Doping Agency (WADA).

Challenge tests are also used in the investigation of exercise-related symptoms in recreational and non-athletes, when objective demonstration of exercise-induced bronchoconstriction is needed to guide management decisions.

Choice of challenge test

There is no single challenge test that will identify all individuals with exercise-induced bronchoconstriction.2 The most appropriate test or tests for an individual depend on clinical and individual factors:

  • The eucapnic voluntary hyperpnoea test can provoke a severe response.2 For safety reasons, the eucapnic voluntary hyperpnoea test should only be used in adults who regularly exercise at high intensity (e.g. elite athletes).2 It should not be used in children.
  • When an exercise challenge test is used, inhalation of dry air is recommended to diagnose or exclude exercise-induced bronchoconstriction because it increases the sensitivity of the test.2
  • Mannitol challenge can be used as an alternative to exercise provocation testing to investigate suspected exercise-induced bronchoconstriction, 2, 7, 8 including in children.9, 10
  • For safety reasons, exercise challenge in dry air should be avoided in patients with FEV1 <70% predicted2

Referral

If challenge testing is needed, consider referring to a respiratory physician for investigation, or discussing with a respiratory physician before selecting which test to order. Do not test during a respiratory infection, or initiate inhaled corticosteroid treatment in the few weeks before challenge testing, because these could invalidate the result.

A list of accredited respiratory function laboratories is available from the Australian and New Zealand Society of Respiratory Science.

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Medical treatment for exercise-induced bronchoconstriction

The effectiveness of medicines for exercise-induced bronchoconstriction varies between individuals.2

An individual may experience different effects over time due to various factors including changes in asthma, environmental conditions, the intensity of the exercise stimulus, or down-regulation of beta2 receptors.2

The management of exercise-induced bronchoconstriction in elite athletes who do not have asthma is an emerging area of research and is not yet well understood.2

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Beta-2 agonists for exercise-induced bronchoconstriction

Inhaled beta2-adrenergic receptor agonists are the most effective medicines for short-term protection against exercise-induced bronchoconstriction and for accelerating recovery of lung function after exercise.2

However, short-acting beta2 agonists should only be taken intermittently (i.e. less than daily), as necessary for preventing exercise-induced bronchoconstriction or relieving exercise-induced bronchoconstriction.2 Daily use of short-acting beta2 agonists may actually increase the severity of exercise-induced bronchoconstriction.2

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Beta-2 agonists for exercise-induced bronchoconstriction: doses

Intermittent short-acting beta2 agonists administered by inhalation 5 to 20 minutes before exercise are effective in protecting against exercise-induced bronchoconstriction for 2–4 hours.2 Salbutamol and terbutaline are equally effective.2

Recommended doses are as follows:

  • salbutamol 100–400 micrograms by inhalation, 15 minutes before exercise
  • terbutaline 500–1000 micrograms by inhalation, 15 minutes before exercise.

The World Anti-Doping Agency (WADA) no longer requires a Therapeutic Use Exemption application for an athlete to use salbutamol (maximum 1600 mcg per day) or to declare use during drug testing.

  • Terbutaline is prohibited by WADA. Exemption may be given in certain circumstances. WADA guidelines prohibit all beta2 agonists except salbutamol (maximum 1600 micrograms over 24 hours), formoterol (maximum 36 micrograms over 24 hours) and salmeterol when taken by inhalation in accordance with the manufacturers’ recommended therapeutic regime.
  • When prescribing for competitive athletes, check which substances are permitted. Refer to ASADA or WADA for a current list of prohibited substances.
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Over-use of short-acting beta-2 agonists

High use of short-acting beta2 agonists may, itself, increase the risk of asthma flare-ups:1112

  • Data from population and case-control studies has led to concerns that the frequent use of short-acting beta2 agonists, including salbutamol, is associated with increased risk of asthma deaths.13 The risk of asthma deaths was greatest for fenoterol, which has since been withdrawn from use.11 For salbutamol, the risk is greatest for doses above 1000 mcg/day (10 puffs).
  • Regular use of salbutamol 16 puffs/day (rather than as-needed use during symptoms) was associated with increased risk of asthma flare-ups requiring oral corticosteroids in a placebo-controlled clinical trial.14 Subsequent statistical modelling showed that the risk was associated with increased fluctuation in lung function.15
  • Regular use of short-acting beta2 agonists leads to receptor tolerance (down-regulation) to their bronchoprotective and bronchodilator effects. Tolerance becomes more apparent with worsening bronchoconstriction. In severe asthma, this could result in a poor response to emergency treatment.16

When high doses of short-acting beta2 agonist are needed (e.g. dose repeated at intervals of less than 4 hours in a person with acute severe asthma), the patient should be under medical supervision and should usually also be receiving systemic corticosteroids.

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Beta-2 agonists for exercise-induced bronchoconstriction: receptor tolerance

Regular daily use of short-acting beta2 agonists and long-acting beta2 agonists results in loss of efficacy due to receptor tolerance (tachyphylaxis), regardless of whether these medicines are used in combination with an inhaled corticosteroid.2

Laboratory studies suggest that receptor tolerance may result in:

  • a reduction in the degree of protection against exercise-induced bronchoconstriction when a short-acting beta2 agonist or long-acting beta2 agonist is taken before exercise2
  • a reduction in the duration of protection against exercise-induced bronchoconstriction when a short-acting beta2 agonist or long-acting beta2 agonist is taken before exercise2
  • a reduction in the effectiveness of short-acting beta2 agonist taken as reliever after exercise if the person experiences exercise-induced bronchoconstriction, seen as an increase in the time to recovery from the episode of bronchoconstriction.2

Receptor tolerance may resolve within 72 hours of discontinuing a short-acting beta2 agonist or long-acting beta2 agonist.2

Implications for use of short-acting beta2 agonists

International consensus recommends against the over-use of short-acting beta2 agonists.17

Implications for use of long-acting beta2 agonists

The evidence for adverse effects due to beta2 receptor down-regulation in patients with asthma is unclear and the implications of current evidence are controversial.181920 Most of the available evidence is from laboratory studies.

In adults, clinical trials and meta-analyses assessing regular use of long-acting beta2 agonists in combination with inhaled corticosteroids indicate that the benefits outweigh the risks,21 but extremely large studies would be necessary to define the risk of very rare events.21

There is evidence that the risk of adverse events associated with long-acting beta2 agonist use (severe asthma episodes, hospitalisation, loss of effectiveness of short acting beta2 agonists, and loss of protection against exercise-induced bronchoconstriction) may be higher in children than adults.1820 A beta2 receptor genotype (Arg16 polymorphism in the beta2 receptor gene) pre-disposes children with asthma to down-regulation of the beta2 receptor and increased susceptibility to flare-ups during regular treatment with long-acting beta2 agonists.22 A recent study in children with this genotype, and with asthma not adequately controlled despite inhaled corticosteroid treatment, demonstrated that the addition of montelukast was more effective than the addition of salmeterol.22 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

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Inhaled corticosteroids for exercise-induced bronchoconstriction

Inhaled corticosteroids taken regularly long term (4 weeks or more23) are effective in reducing the frequency and severity of exercise-induced bronchoconstriction in 30–60% of people with asthma.2 The degree of protection experienced by individuals ranges from complete to minimal.2

Patients may need to take inhaled corticosteroid for 12 weeks to experience maximal therapeutic effect.2 If exercise-induced symptoms have resolved, the person may no longer need to take a beta2 agonist before exercise.2 However, some patients taking regular inhaled corticosteroids may still need to take short-acting beta2 agonists before exercise.2

Few comparative studies have compared the effectiveness of inhaled corticosteroid with that of other classes of medicines.23

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for exercise-induced bronchoconstriction
  • To avoid the possibility of patients taking a long-acting beta2 agonist without an inhaled corticosteroid, long-acting beta2 agonists should (whenever possible) be prescribed as inhaled corticosteroid/long-acting beta2 agonist combination in a single inhaler, rather than in separate inhalers. If no combination product is available for the desired medications, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid.

Intermittent long-acting beta2 agonists administered by inhalation before exercise are effective in protecting against exercise-induced bronchoconstriction:2

  • for formoterol, onset of bronchodilation and bronchoprotective action is 1-3 minutes after administration24
  • for salmeterol, onset of bronchodilation and bronchoprotective action is 10 - 30 minutes after administration25

The duration of effect of both formoterol and salmeterol is up to 12 hours for patients who have not taken a short-acting beta2 agonist or long-acting beta2 agonist within the previous 72 hours. However, the duration of bronchoprotection is reduced for subsequent doses due to receptor tolerance.2

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Montelukast for exercise-induced bronchoconstriction

Montelukast is less effective against exercise-induced bronchoconstriction than short-acting beta2 agonists, but regular use is not associated with receptor tolerance.2

Montelukast taken either intermittently before exercise or daily is at least partially effective in protecting against exercise-induced bronchoconstriction in some, but not all patients.2 Some experience strong protection against exercise-induced bronchoconstriction while others experience only partial protection or no effect.2 Very few patients experience complete protection against exercise-induced bronchoconstriction.2

In children, regular montelukast, either as the child’s only preventer or in combination with an inhaled corticosteroid, is more effective than long-acting beta2 agonists in protecting against exercise-induced bronchoconstriction,26, 27 and is associated with a greater bronchodilator response to short-acting beta2 agonist after exercise.26

The onset of protection occurs within 2 hours of dosing. The duration of protective effect is 12–24 hours. Recommended doses are as follows:27

  • children aged 2–5 years 4 mg daily, or 1–2 hours before exercise
  • children aged 6–14 years 5 mg daily, or 1–2 hours before exercise
  • adults 10 mg daily, or 1–2 hours before exercise.

Notes 

PBS status as at October 2016: Montelukast treatment is not subsidised by the PBS for:

  • people aged 15 years or over (Special Authority is available for DVA gold card holders, or white card holders with approval for asthma treatments.)
  • children aged 2 to 5 years in combination with any other preventer
  • children aged 6 to 14 years with moderate to severe asthma, when used use as a single second-line preventer as an alternative to corticosteroids
  • people of any age, when used in addition to a long-acting beta-agonist.
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Cromones for exercise-induced bronchoconstriction

Cromolyn sodium and nedocromil sodium administered by inhalation as single doses before exercise partially protect against exercise-induced bronchoconstriction in approximately half of patients.2

The onset of action is rapid. The duration of action is up to 2 hours.2

Recommended doses are as follows:27

  • nedocromil sodium 4–8 mg by inhalation, 5–10 minutes before exercise
  • sodium cromoglycate 10–20 mg by inhalation, 5–10 minutes before exercise.

Cromolyn sodium and nedocromil sodium are less effective than short-acting beta2 agonists in protecting against exercise-induced bronchoconstriction.28 However, they have a good safety profile and tolerance does not occur when either of these medicines is taken regularly.2

Sodium cromoglycate and nedocromil sodium inhalers must be washed daily to prevent blockage.

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Adjunctive strategies for managing exercise-induced bronchoconstriction

The following strategies may help people with exercise-induced bronchoconstriction manage their symptoms:

  • warming up before exercise2 (may enable the athlete to achieve a refractory period)
  • being as fit as possible – increasing fitness raises the threshold for exercise-induced bronchoconstriction, so that moderately strenuous exercise will not cause an attack29
  • exercising in a warm humid environment
  • avoiding environments with high levels of allergens, irritant gases or airborne particles5
  • breathing through nose
  • after strenuous exercise doing cooling down exercise, breathing through the nose and covering the mouth in cold, dry weather
  • reducing sodium intake21
    • Some small clinical trials have suggested that a low-sodium diet might improve lung function after exercise in people with exercise-induced bronchoconstriction, but the clinical importance of this is unknown30
  • fish oil supplementation2, 1
    • Some very small, short-term clinical trials reported that fish oil reduced the severity of exercise-induced bronchoconstriction in elite athletes or improve lung function in people with exercise-induced bronchoconstriction,3132 but overall evidence does not support the use of fish oil in asthma.33 
  • ascorbic acid supplementation.2
    • A very small, short-term clinical trial reported that ascorbic acid supplementation improved exercise symptoms and asthma control in people with exercise-induced bronchoconstrictionbut the clinical importance of this is unknown.34
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Use of medicines in sport

Many sporting bodies require athletes to provide objective evidence of exercise-induced bronchoconstriction before they are permitted to use asthma medicines during competition.

The Australian Sports Anti-Doping Authority provides information about Therapeutic Use Exemptions for athletes who require treatment with prohibited substances.

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References

  1. Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2013; 187: 1016-27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23634861
  2. Weiler JM, Anderson SD, Randolph C, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010; 105: S1-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21167465
  3. Rundell KW, Im J, Mayers LB, et al. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc. 2001; 33: 208-13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11224807
  4. Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: Challenges for diagnosis. J Allergy Clin Immunol. 2002; 110: 374-80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12209082
  5. Fitch KD, Sue-Chu M, Anderson SD, et al. Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008. J Allergy Clin Immunol. 2008; 122: 254-260. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18678340
  6. Anderson SD, Kippelen P. Assessment and prevention of exercise-induced bronchoconstriction. Br J Sports Med. 2012; 46: 391-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22247297
  7. Brannan JD, Koskela H, Anderson SD, Chew N. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma. Am J Respir Crit Care Med. 1998; 158: 1120-6. Available from: http://www.atsjournals.org/doi/full/10.1164/ajrccm.158.4.9802087
  8. Holzer K, Anderson SD, Chan HK, Douglass J. Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med. 2003; 167: 534-7. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200208-916OC
  9. Kersten ET, Driessen JM, van der Berg JD, Thio BJ. Mannitol and exercise challenge tests in asthmatic children. Pediatr Pulmonol. 2009; 44: 655-661. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19499571
  10. Barben J, Kuehni CE, Strippoli MP, et al. Mannitol dry powder challenge in comparison with exercise testing in children. Pediatr Pulmonol. 2011; 46: 842-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21465681
  11. Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J. 1994; 7: 1602-1609. Available from: http://erj.ersjournals.com/content/7/9/1602.abstract
  12. Taylor DR. The beta-agonist saga and its clinical relevance: on and on it goes. Am J Respir Crit Care Med. 2009; 179: 976-978. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200901-0055CC
  13. Walters EH, Walters JA, Gibson PG, Jones P. Inhaled short acting beta2-agonist use in chronic asthma: regular versus as needed treatment. Cochrane Database Syst Rev. 2003; Issue 1: CD001285. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001285/full
  14. Taylor DR, Town GI, Herbison GP, et al. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax. 1998; 53: 744-752. Available from: http://thorax.bmj.com/content/53/9/744.full
  15. Frey U, Brodbeck T, Majumdar A, et al. Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature. 2005; 438: 667-670. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16319891
  16. Hancox RJ. Concluding remarks: can we explain the association of beta-agonists with asthma mortality? A hypothesis. Clin Rev Allergy Immunol. 2006; 31: 279-88. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17085800
  17. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org
  18. van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: http://www.thoracic.org.au/clinical-documents/area?command=record&id=14
  19. van Asperen PP. Long-acting beta agonists for childhood asthma. Aust Prescr. 2012; 35: 111-3. Available from: http://www.australianprescriber.com/magazine/35/4/111/3
  20. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting β2-adrenergic receptor agonists. Pediatrics. 2011; 128: e1147-1154. Available from: http://pediatrics.aappublications.org/content/128/5/e1147.long
  21. Ortega VE, Peters SP. Beta-2 adrenergic agonists: focus on safety and benefits versus risks. Curr Opin Pharmacol. 2010; 10: 246-53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20452285
  22. Lipworth BJ, Basu K, Donald HP, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond). 2013; 124: 521-528. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126384
  23. Koh MS, Tee A, Lasserson TJ, Irving LB. Inhaled corticosteroids compared to placebo for prevention of exercise induced bronchoconstriction. Cochrane Database Syst Rev. 2007; : CD002739. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002739.pub3/full
  24. AstraZeneca Pty Ltd. Product Information: Oxis (eformoterol fumarate dihydrate) Turbuhaler. Therapeutic Goods Administration, Canberra, 2008. Available from: https://www.ebs.tga.gov.au/
  25. GlaxoSmithKline Australia Pty Ltd. Product Information: Serevent Accuhlaer. Therapeutic Goods Administration, Canberra, 2013. Available from: https://www.ebs.tga.gov.au/
  26. Fogel RB, Rosario N, Aristizabal G, et al. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Ann Allergy Asthma Immunol. 2010; 104: 511-517. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20568384
  27. Stelmach I, Grzelewski T, Majak P, et al. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. J Allergy Clin Immunol. 2008; 121: 383-389. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17980416
  28. Spooner CH, Spooner GR, Rowe BH. Mast-cell stabilising agents to prevent exercise-induced bronchoconstriction. Cochrane Database Syst Rev. 2003; 4: CD002307. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002307/full
  29. Hallstrand TS, Bates PW, Schoene RB. Aerobic conditioning in mild asthma decreases the hyperpnea of exercise and improves exercise and ventilatory capacity. Chest. 2000; 118: 1460-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11083702
  30. Pogson Z, McKeever T. Dietary sodium manipulation and asthma. Cochrane Database Syst Rev. 2011; Issue 3: CD000436. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000436.pub3/full
  31. Mickleborough TD, Murray RL, Ionescu AA, Lindley MR. Fish Oil Supplementation Reduces Severity of Exercise-induced Bronchoconstriction in Elite Athletes. Am J Respir Crit Care Med. 2003; 168: 1181-1189. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200303-373OC
  32. Mickleborough TD, Lindley MR, Ionescu AA, Fly AD. Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma. Chest. 2006; 129: 39-49. Available from: http://journal.publications.chestnet.org/article.aspx?articleid=1084219
  33. Thien FC, De Luca S, Woods RK., Abramson MJ. Dietary marine fatty acids (fish oil) for asthma in adults and children. Cochrane Database Syst Rev. 2002; Issue 2: CD001283. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001283/full
  34. Tecklenburg SL, Mickleborough TD, Fly AD, et al. Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med. 2007; 101: 1770-1778. Available from: http://www.resmedjournal.com/article/S0954-6111(07)00088-1/fulltext