Asthma Management Handbook

Guide to reliever medicines

Overview

Relievers are bronchodilator medicines used for rapid resolution of bronchoconstriction. They can also be used pre-emptively to prevent exercise-induced bronchoconstriction.

Every patient with asthma (or their carers) should:

  • carry a reliever medicine at all times
  • replace it whenever it reaches the expiry date.

Relievers contain rapid-onset beta2 receptor agonists, which include:

  • short-acting beta2 agonists (salbutamol and terbutaline)
  • the combination of an inhaled corticosteroid (budesonide) and long-acting beta2 agonist (formoterol) in a single inhaler. This option only applies to patients using combination budesonide/formoterol in a maintenance-and-reliever regimen.

Table. Classification of asthma medicines Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/table/show/79

More information

Short-acting beta-2 agonist relievers for children: 0–5 years

Inhaled short-acting beta2 agonists are effective bronchodilators in children aged 0–5 years.1

Short-acting beta2 agonists may be less effective for wheezing in children under 2 years old than in older children.2 However, many clinical trials in infants have included those with bronchiolitis, so there is limited evidence for the effects of short-acting beta2 agonists specifically in asthma.2 Studies conducted in emergency departments have shown that short-acting beta2 agonists are more effective than placebo in controlling acute wheeze in children under 2 years, but may not achieve clinically significant improvements.2

Paradoxical responses to inhaled short-acting beta2 agonists have been reported in infants.1 Bronchodilators are generally not recommended in children under 6 months old, consistent with current guidelines for the management of acute bronchiolitis.3

Inhaled short-acting beta2 agonists are generally well tolerated in children aged 0–5 years.1 Adverse effects (e.g. muscle tremor, headache, palpitations, agitation or hypokalaemia) have been reported at high doses.1

Oral short-acting beta2 agonists are associated with adverse effects1 and should not be used in any age group.

Close
Short-acting beta-2 agonist relievers for children: 6 years and over

Inhaled short-acting beta2 agonists are the major class of bronchodilators used for relief of symptoms in asthma.4 They are the most effective bronchodilators available and are recommended by international guidelines for use in children of all ages as well as in adults.5

Children with controlled asthma need little or no reliever (on no more than 2 days per week).

Increased use of short-acting beta2 agonists for relief of asthma symptoms, especially daily use, indicates deterioration of asthma control.56

Table. Definition of levels of recent asthma symptom control in children (regardless of current treatment regimen)

Good control Partial control Poor control

All of:

  • Daytime symptoms ≤2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • No limitation of activities
  • No symptoms§ during night or when wakes up
  • Need for reliever# ≤2 days per week

Any of:

  • Daytime symptoms >2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • Any limitation of activities*
  • Any symptoms during night or when wakes up††
  • Need for reliever# >2 days per week

Either of:

  • Daytime symptoms >2 days per week (lasting from minutes to hours or recurring, and partially or fully relieved by rapid-acting bronchodilator)
  • ≥3 features of partial control within the same week

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including short-acting beta2 agonist taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

* e.g. wheeze or breathlessness during exercise, vigorous play or laughing

†† e.g. waking with symptoms of wheezing or breathing problems

Note: Recent asthma control is based on symptoms over the previous 4 weeks. Each child’s risk factors for future asthma outcomes should also be assessed and taken into account in management.

Adapted from

Global Initiative for Asthma (GINA). Global strategy for the diagnosis and management of asthma in children 5 years and younger. GINA, 2009. Available from: http://www.ginasthma.org/

Asset ID: 23

Close
Close
Short-acting beta-2 agonist relievers for adults and adolescents

Short-acting beta2 agonists are used to:

  • relieve asthma symptoms
  • prevent exercise-induced bronchoconstriction
  • relieve exercise-induced bronchoconstriction.

The duration of therapeutic effect is approximately 4 hours.

When using a pressurised metered-dose inhaler for salbutamol, the use of a large-volume spacer increases the proportion of drug delivered to the lung.7 For adults, it is not essential to use a spacer with salbutamol for day-to-day symptoms if adequate relief is obtained with a pressurised metered dose inhaler alone.

Patients with well-controlled asthma do not need to use their reliever on more than 2 days per week, not counting doses taken before exercise to prevent exercise-induced bronchoconstriction.

Increased use of short-acting beta2 agonists for relief of asthma symptoms, especially daily use, indicates worsening asthma control.56

Note: Routine preventive doses of short-acting beta2 agonist taken before exercise are not counted when assessing recent asthma symptom control. However, persistent exercise-induced bronchoconstriction generally indicates inadequate asthma control.

Table. Definition of levels of recent asthma symptom control in adults and adolescents (regardless of current treatment regimen)

Good control

Partial control

Poor control

All of:

  • Daytime symptoms ≤2 days per week
  • Need for reliever ≤2 days per week
  • No limitation of activities
  • No symptoms during night or on waking

One or two of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

Three or more of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

† Not including SABA taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

Note: Recent asthma symptom control is based on symptoms over the previous 4 weeks.

Adapted from:

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org/

Asset ID: 33

Close
Close
Over-use of short-acting beta-2 agonists

High use of short-acting beta2 agonists may, itself, increase the risk of asthma flare-ups:89

  • 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.4 The risk of asthma deaths was greatest for fenoterol, which has since been withdrawn from use.8 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.10 Subsequent statistical modelling showed that the risk was associated with increased fluctuation in lung function.11
  • 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.12

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.

Close
Combination budesonide/formoterol maintenance-and-reliever regimen in adults and adolescents: overview of efficacy

Low-dose budesonide/formoterol combination can be used as reliever for asthma symptoms (instead of using a short-acting beta2 agonist reliever), in addition to its use as regular long-term preventer treatment.13, 14,  15,  1617, 18 The following formulations can be used in maintenance-and-reliever regimens:

  • dry-powder inhaler (Symbicort Turbuhaler) 100/6 mcg or 200/6 mcg
  • pressurised metered-dose inhaler (Symbicort Rapihaler) 50/3 mcg or 100/3 mcg.

Neither the 400/12 mcg dry-powder inhaler nor the 200/6 mcg pressurised metered-dose inhaler should be used in this way.

Overall, clinical trials show that budesonide/formoterol combination as maintenance and reliever reduces the risk of flare-ups that require oral corticosteroids, compared with other current preventer regimens and compared with a fixed higher dose of inhaled corticosteroids.19

Pooled data from five randomised controlled trials assessing budesonide/formoterol maintenance-and-reliever regimens showed that similar or better levels of asthma control were achieved with budesonide/formoterol maintenance-and-reliever compared with the conventional maintenance regimen comparators:15

  • higher-dose budesonide
  • same dose budesonide/formoterol
  • higher-dose inhaled corticosteroid/long-acting beta2 agonist (budesonide/formoterol or fluticasone propionate/salmeterol).

In randomised clinical trials in patients with a history of asthma flare-up within the previous 12 months (and therefore at greater risk of flare-up in the next 12 months), the use of formoterol/budesonide as maintenance-and-reliever regimen reduced the risk of asthma flare-ups that required treatment with oral corticosteroids, compared with the use of any of the following (plus a short-acting beta2 agonist reliever as needed):152021

  • the same combination as maintenance treatment only
  • higher-dose combination as maintenance treatment only
  • higher-dose inhaled corticosteroids.

Meta-analysis of six randomised controlled trials found that maintenance-and-reliever treatment with budesonide/formoterol reduced the risk of severe asthma flare-ups (use of oral corticosteroids for 3 days or more, hospitalisation or emergency department visits), compared with higher-dose inhaled corticosteroid alone, or in combination with a long-acting beta2 agonist.22

In open-label studies in which patients were not selected for a previous history of flare-ups, there was no overall difference in time to first flare-up between budesonide/formoterol as maintenance-and-reliever regimen and conventional maintenance regimens (including inhaled corticosteroid or inhaled corticosteroid/long-acting beta2 agonist combinations, leukotriene receptor antagonists, xanthines or any other asthma medicines) with rapid-onset beta2 agonist reliever (selected according to clinician’s choice).23 However, the inhaled corticosteroid dose was higher with conventional maintenance regimens.

Note: The fluticasone propionate/formoterol combination is approved by the Therapeutic Goods Administration only for regular maintenance therapy.

Close
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.24

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.24 Daily use of short-acting beta2 agonists may actually increase the severity of exercise-induced bronchoconstriction.24

Close
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.24 Salbutamol and terbutaline are equally effective.24

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.
Close
Salbutamol in acute asthma: dosing regimens

One placebo-controlled study showed that, for patients who showed clear improvement after the first dose of salbutamol via pressurised metered-dose inhaler and spacer, there was no advantage in repeating the dose more often than every 60 minutes until full recovery (extra doses can be given as needed).25

However, in patients who did not show a clear response to the first salbutamol dose, repeating the dose at intervals of 30 minutes or less was more effective than every 60 minutes.25

Close
Salbutamol in acute asthma: route of administration

Inhaler plus spacer, or nebuliser

Salbutamol delivered via a pressurised metered-dose inhaler with spacer is at least as effective as salbutamol delivered via nebuliser in patients with moderate-to-severe acute asthma who do not require ventilation.262729 The use of nebulisers increases the risk of transmitting respiratory infections to staff and other patients.

Intravenous salbutamol

Overall, intravenous short-acting beta2 agonists do not appear to be superior to inhaled short-acting beta2 agonist.30

Benefits have not been demonstrated in adults.30 Very limited evidence from one study suggested that the addition of IV salbutamol to inhaled salbutamol reduced recovery time in children with severe acute asthma in the emergency department.30

However, there is a lack of consensus on the appropriate dose of IV salbutamol for children.31 Recommendations differ between guidelines in Australia32 and elsewhere.31 Doses have not been calculated based on age-specific pharmacokinetic and pharmacodynamic data. The doses recommended in guidelines are generally relatively higher than for adults on a micrograms per kilogram body weight basis.

Compared with inhaled salbutamol, intravenous salbutamol is associated with increased risk of adverse effects including tremor and hypokalaemia.3031  Concomitant use of the inhalation and IV routes may increase the risk of salbutamol toxicity.33

Note: Salbutamol concentrate for infusion is available in 5 mL ampoules containing salbutamol sulfate equivalent to 5 mg (1 mg/mL) salbutamol in a sterile isotonic solution (Ventolin obstetric injection). Salbutamol for injection is also available in ampoules of salbutamol sulphate equivalent to 500 mcg salbutamol in 1 mL sterile isotonic solution (Ventolin injection).

Close
Beta-2 receptor tolerance

Short-acting beta2 agonists

In laboratory studies, regular use of short-acting beta2 agonists leads to receptor tolerance (down-regulation) to their bronchoprotective and bronchodilator effects.12

In clinical trials, regular use of short-acting beta2 agonists is associated with greater instability of lung function and a higher risk of asthma flare-ups.1011

In clinical practice, frequent use of short-acting beta2-agonists may lead to worsening of asthma symptoms. This may be improved by deliberately reducing short-acting beta2 agonist use and, in some cases, using ipratropium bromide as an alternative reliever medicine medication to allow restoration of beta2-receptor responsiveness.34

Long-acting beta2 agonists

In laboratory studies, regular use of long-acting beta2 agonists results in reduced duration of protection against airway hyperresponsiveness, and prolonged recovery of airway function after short-acting beta2 agonist, which is thought to be due to receptor tolerance (down-regulation) of beta2 receptors in bronchial smooth muscle and mast cells (evidence from laboratory studies).35 These findings have led to concerns about reduced effectiveness of beta2 agonists when needed for preventing exercise-induced bronchoconstriction or reversing acute asthma due to trigger exposure.35 Sensitivity to short-acting beta2 agonists returns to normal within 72 hours of stopping long-acting beta2 agonist treatment.35

However, the clinical effects of beta receptor tolerance in patients taking long-acting beta2 agonists are unclear.36 Clinical trials assessing regular use of long-acting beta2 agonists in combination with inhaled corticosteroids have not reported clinically significant adverse effects attributable to beta receptor tolerance.37 Two Emergency Department studies in patients with acute asthma did not observe increased risk of hospitalisation among those taking salmeterol.3839

The use of budesonide/formoterol as a reliever may result in lower total use of beta2 agonist compared with the use of short-acting beta2 agonist relievers, based on a study in patients taking regular maintenance budesonide/formoterol, which monitored inhaler actuations electonically.20

Close
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.24

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 exercise24
  • 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 exercise24
  • 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.24

Receptor tolerance may resolve within 72 hours of discontinuing a short-acting beta2 agonist or long-acting beta2 agonist.24

Implications for use of short-acting beta2 agonists

International consensus recommends against the over-use of short-acting beta2 agonists.5

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.404142 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,43 but extremely large studies would be necessary to define the risk of very rare events.43

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.4042 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.44 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.44 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

Close

References

  1. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008; 32: 1096-1110. Available from: http://erj.ersjournals.com/content/32/4/1096.full
  2. Chavasse RJ, Bara A, McKean MC. Short acting beta2-agonists for recurrent wheeze in children under two years of age. Cochrane Database Syst Rev. 2002; Issue 2: CD002873. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002873/full
  3. Ministry of Health, NSW. Infants and children: acute management of bronchiolitis.. Version 2. Ministry of Health, NSW, Sydney, 2012. Available from: http://www0.health.nsw.gov.au/policies/pd/2012/PD2012_004.html
  4. 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
  5. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org
  6. British Thoracic Society (BTS) Scottish Intercollegiate Guidelines Network (SIGN). British Guideline on the Management of Asthma. Quick Reference Guide. Revised May 2011. BTS, SIGN, Edinburgh, 2008.
  7. Lipworth BJ, Clark DJ. Early lung absorption profile of non-CFC salbutamol via small and large volume plastic spacer devices. Br J Clin Pharmacol. 1998; 46: 45-48. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873975/
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. Aubier M, Buhl R, Ekström T, et al. Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy. Eur Respir J. 2010; 36: 524-530. Available from: http://erj.ersjournals.com/content/36/3/524.long
  14. AstraZeneca Pty Ltd. Product Information: Symbicort (budesonide and eformoterol fumarate dihydrate) Turbuhaler. Therapeutic Goods Administration, Canberra, 2010. Available from: https://www.ebs.tga.gov.au/
  15. Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol. 2010; 125: 600-608. Available from: http://www.jacionline.org/article/S0091-6749(09)01770-9/fulltext
  16. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007; 101: 2437-46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17905575
  17. Lundborg M, Wille S, Bjermer L, et al. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study. Curr Med Res Opin. 2006; 22: 809-21. Available from: http://informahealthcare.com/doi/abs/10.1185/030079906X100212
  18. Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008; 32: 545-554. Available from: http://erj.ersjournals.com/content/32/3/545.long
  19. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database Syst Rev. 2013; 4: Cd007313. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23633340
  20. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet. 2013; 1: 32-42. Available from: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70007-9/abstract
  21. Reddel HK, Jenkins C, Quirce S, et al. Effect of different asthma treatments on risk of cold-related exacerbations. Eur Respir J. 2011; 38: 584-593. Available from: http://erj.ersjournals.com/content/38/3/584.full
  22. Edwards SJ, von Maltzahn R, Naya IP, Harrison T. Budesonide/formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials. Int J Clin Pract. 2010; 64: 619-27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20456215
  23. Demoly P, Louis R, Søes-Petersen U, et al. Budesonide/formoterol maintenance and reliever therapy versus conventional best practice. Respir Med. 2009; 103: 1623-1632. Available from: http://www.resmedjournal.com/article/S0954-6111(09)00255-8/fulltext
  24. 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
  25. Karpel JP, Aldrich TK, Prezant DJ, et al. Emergency treatment of acute asthma with albuterol metered-dose inhaler plus holding chamber: how often should treatments be administered?. Chest. 1997; 112: 348-356. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9266868
  26. Dhuper S, Chandra A, Ahmed A, et al. Efficacy and cost comparisons of bronchodilatator administration between metered dose inhalers with disposable spacers and nebulizers for acute asthma treatment. J Emerg Med. 2011; 40: 247-55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19081697
  27. Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2013; 9: Cd000052. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24037768
  28. Cates CJ, Bestall J, Adams N. Holding chambers versus nebulisers for inhaled steroids in chronic asthma. Cochrane Database Syst Rev. 2006; Issue 1: CD001491. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001491.pub2/full
  29. Ferguson C, Gidwani S. Delivery of bronchodilators in acute asthma in children. Emerg Med J. 2006; 23: 471-472. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564350/
  30. Travers AH, Milan SJ, Jones AP, et al. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. 2012; 12: CD010179. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010179/full
  31. Starkey ES, Mulla H, Sammons HM, Pandya HC. Intravenous salbutamol for childhood asthma: evidence-based medicine?. Arch Dis Child. 2014; 99: 873-877. Available from: http://adc.bmj.com/content/99/9/873.abstract
  32. Babl FE, Sheriff N, Borland M, et al. Paediatric acute asthma management in Australia and New Zealand: practice patterns in the context of clinical practice guidelines. Arch Dis Child. 2008; 93: 307-312. Available from: http://adc.bmj.com/content/93/4/307.abstract
  33. Abramson MJ, Bailey MJ, Couper FJ, et al. Are asthma medications and management related to deaths from asthma?. Am J Respir Crit Care Med. 2001; 163: 12-18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11208619
  34. Taylor DR, Hannah D. Management of beta-2 agonist overuse: Why and how?. J Allergy Clin Immunol. 2008; 122: 836-838. Available from: http://www.jacionline.org/article/S0091-6749(08)01355-9/fulltext
  35. Anderson SD. β2-agonists. Clin Rev Allergy Immunol. 2006; 31: 103-105.
  36. Haney S, Hancox RJ. Recovery from bronchoconstriction and bronchodilator tolerance. Clin Rev Allergy Immunol. 2006; 31: 181-96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17085792
  37. Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev. 2013; 3: CD006922. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006922.pub3/full
  38. Liao MM, Ginde AA, Clark S, Camargo CA. Salmeterol use and risk of hospitalization among emergency department patients with acute asthma. Ann Allergy Asthma Immunol. 2010; 104: 478-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945216/
  39. Korosec M, Novak RD, Myers E, et al. Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma. Am J Med. 1999; 107: 209-13. Available from: http://www.amjmed.com/article/S0002-9343(99)00222-3/fulltext
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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