Asthma Management Handbook

Considering if regular preventer treatment is indicated in children 6 years and over

Recommendations

Discuss the goals of asthma treatment with the child’s parents and the child (as appropriate to the child’s age and maturity). Explain that the overall aims of treatment are to make sure asthma does not interfere with the child’s quality of life and to minimise the side effects of treatment by using the lowest level of medication required to maintain good asthma control.

Figure. Stepped approach to adjusting asthma medication in children Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/figure/show/18

How this recommendation was developed

Consensus

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

Prescribe a reliever. Educate children and parents how and when to use reliever, and advise them to carry reliever at all times.

Table. Non-emergency use of bronchodilators (relievers) in children aged 6–12 years

Option

Notes

Dose and delivery

Salbutamol

Suitable for children any age

A spacer should be used during acute flare-ups (exacerbations)

2–4 puffs (100 mcg per puff) via pressurised metered-dose inhaler and spacer

Terbutaline

Generally suitable for children 6 years and older

1–2 inhalations (500 mcg/inhalation) via breath-actuated powder inhaler

Note: This table lists usual doses to be administered by carers in the community to manage symptoms as needed. Doses are higher during acute asthma, including emergencies.

† If able to use this type of inhaler correctly

  • Do not prescribe oral salbutamol.

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How this recommendation was developed

Consensus

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

Consider regular preventer treatment according to pattern of symptoms. Explain to parents that preventer treatment should be taken every day and continued long term.   

Table. Initial preventer treatment for children aged 6 years and over

Pattern of symptoms *

Management options and notes †

Infrequent intermittent asthma ‡

Regular preventer treatment is not recommended

Frequent intermittent asthma

Consider a treatment trial with montelukast 5 mg once daily; assess response after 2–4 weeks

A cromone (sodium cromoglycate or nedocromil) can be trialled as an alternative§

Mild persistent asthma

Consider a treatment trial with montelukast 5 mg once daily; assess response after 2–4 weeks

If inadequate response after checking adherence, consider treatment trial with inhaled corticosteroid (low dose)

A cromone (sodium cromoglycate or nedocromil) can be trialled as an alternative§

Moderate-to-severe persistent asthma

Consider a treatment trial with regular inhaled corticosteroid (low dose); assess response after 4 weeks.

  • Advise parents about potential adverse psychiatric effects of montelukast

* Pattern of symptoms when not taking regular preventer treatment

† In addition to use of rapid-onset inhaled beta2 agonist when child experiences difficulty breathing

‡ Also applies to children who wheeze only during upper respiratory tract infections and do not have a diagnosis of asthma

§ E.g. sodium cromoglycate 5 mg/actuation; 10 mg (two inhalations) three times daily, then 10 mg twice daily when stable. Note: Cromone inhaler device mouthpieces require daily washing to avoid blocking

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Table. Definitions of asthma patterns in children aged 6 years and over not taking regular preventer

Category

Pattern and intensity of symptoms (when not taking regular treatment)

Infrequent intermittent asthma †

Symptom-free for at least 6 weeks at a time (flare-ups up to once every 6 weeks on average but no symptoms between flare-ups)

Frequent intermittent asthma

Flare-ups more than once every 6 weeks on average but no symptoms between flare-ups

Persistent asthma

Mild

FEV1 ≥80% predicted and at least one of:

  • Daytime symptoms more than once per week but not every day
  • Night-time symptoms more than twice per month but not every week

Moderate

Any of:

  • FEV1 <80% predicted
  • Daytime symptoms daily
  • Night-time symptoms more than once per week
  • Symptoms sometimes restrict activity or sleep

Severe

Any of:

  • FEV1 ≤60% predicted
  • Daytime symptoms‡ continual
  • Night-time symptoms frequent
  • Flare-ups frequent
  • Symptoms frequently restrict activity or sleep

† It may not be appropriate to make the diagnosis of asthma in children aged 6 or older who wheeze only during upper respiratory tract infections. These children can be considered to have episodic (viral) wheeze.

‡ Symptoms between flare-ups. A flare-up is defined as a period of worsening asthma symptoms, from mild (e.g. symptoms that are just outside the normal range of variation for the child, documented when well) to severe (e.g. events that require urgent action by parents and health professionals to prevent a serious outcome such as hospitalisation or death from asthma).

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How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • van Asperen et al. 20101

If a child needs to use a short-acting beta2 agonist reliever more than twice per week (not counting doses taken prophylactically before exercise for those with exercise-induced bronchoconstriction), consider starting regular preventer treatment.

How this recommendation was developed

Consensus

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

When starting regular inhaled corticosteroid treatment, begin with a low dose.

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (mcg)

Low

High

Beclometasone dipropionate

100–200

>200 (up to 400)

Budesonide

200–400

>400 (up to 800)

Ciclesonide

80–160

>160 (up to 320)

Fluticasone propionate

100–200

>200 (up to 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

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

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How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • van Asperen et al. 2010 1

More information

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.2 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.3

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.34

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/

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Montelukast for children

Montelukast is registered by the TGA for use in children aged 2 years and older.5

Based on data from placebo-controlled trials, it has not been possible to define clinical indicators that predict which children will benefit most from montelukast therapy, compared with other treatment options.67

Comparative studies suggest that the main role for montelukast is as an alternative to low-dose inhaled corticosteroid in children with frequent intermittent asthma or mild persistent asthma.6

Children 0–5 years

In preschool children with multiple-trigger wheeze, montelukast protects against airway hyperresponsiveness when taken with or without inhaled corticosteroids.8 Inhaled corticosteroids are more effective than montelukast in children with multiple-trigger wheeze aged 2–8 years,9 but this comparison has not been made in preschool children as a separate group.8

In children aged 2–5 years with episodic (viral) wheeze, regular montelukast treatment reduces the risk of wheezing episodes.10 However, montelukast may not reduce symptoms in children aged 6–24 months with recurrent wheeze.11 

Note: Montelukast is not TGA-registered for use in children younger than 2 years.

A short course of montelukast, introduced at the first signs of an asthma episode or upper respiratory tract infection, can achieve a small reduction in symptoms, school absence and medical consultations in preschool and school-aged children with episodic wheeze.12 However, montelukast is not TGA-registered for intermittent use.

Children 6 years and over

In school-aged children with persistent asthma, inhaled corticosteroids are more effective than montelukast for a range of measures, including lung function.6

In school-aged children with persistent exercise-induced symptoms despite taking regular inhaled corticosteroids, montelukast is effective in controlling symptoms and is more effective than long-acting beta2 agonists.113

In children who are already taking regular inhaled corticosteroids and have a beta2 receptor genotype associated with increased susceptibility to flare-ups during regular long-acting beta2 agonist therapy,14 montelukast may be more effective than salmeterol in reducing symptoms, reliever use and days absent from school due to asthma, based on the findings of a small randomised controlled clinical trial.14

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Montelukast for children: warning parents about potential psychiatric adverse effects

Montelukast is generally very well tolerated.1 However, post-marketing surveillance reports suggested a slight increase in the rate of psychiatric disorders that was possibly associated with use of leukotriene receptor antagonists in children;15 this association may have been confounded by asthma severity and concomitant medication.1 Montelukast use has also been associated with suicidal ideation, but a recent nested case-control study concluded that children with asthma aged 5–18 years taking leukotriene receptor antagonists were not at increased risk of suicide attempts.16 Behavioural and psychiatric adverse effects were rare in clinical trials.17,18

A recent analysis of databases of adults and children taking montelukast suggests it is associated with nightmares, depression, and aggression.19 Allergic granulomatous angiitis has also been reported, but a causal relationship has not been established.19

The Thoracic Society of Australia and New Zealand advises that it is prudent to mention to parents the potential association of montelukast with behaviour-related adverse events when commencing treatment, and to cease therapy if such adverse events are suspected.1

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Cromones for children

0-5 years

Few clinical trials have assessed the use of inhaled sodium cromoglycate in preschool children and none have assessed nedocromil.8 Overall, sodium cromoglycate has not been shown to be effective in preschool children with multiple-trigger wheeze.8, 20

However, cromones are well tolerated and registered for use in infants. Therefore, a treatment trial can be considered before considering other preventers, particularly for children less than 2 years old.

6 years and over

Cromones are rarely prescribed in school-aged children.

Inhaled sodium cromoglycate might be effective in school-aged children, but interpretations of available evidence are inconsistent.1 Sodium cromoglycate is less effective than inhaled corticosteroid in achieving asthma control and improving lung function in children with persistent asthma.21

Nedocromil sodium appears to be have some benefit in children with persistent asthma, but its relative effectiveness compared with inhaled corticosteroids is not clear.22 Long-term (4–6 years) treatment with budesonide achieved better asthma control than long-term nedocromil in children with mild-to-moderate asthma aged 5–12 in a randomised placebo-controlled clinical trial.23

Practical issues

Cromones (sodium cromoglycate and nedocromil) may not be practical for some patients, because they require three–four times daily dosing until control is gained, and inhaler devices for cromones tend to block easily.1

Nedocromil can cause an unusual or unpleasant taste24 and is not tolerated by some children.

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Inhaled corticosteroids for children: overview

The effectiveness of ICS in children appears to depend on several factors including the child’s age, which triggers are causing symptoms, wheezing phenotype, tobacco smoke exposure and genotype.25 Overall, inhaled corticosteroids seem to be more effective in older children and those with more severe disease.1

Early introduction of inhaled corticosteroid for children with recurrent wheeze does not prevent airway remodelling, improve long-term lung function or prevent the onset of persistent asthma, according to current evidence from long-term randomised controlled clinical trials in preschool children and school-aged children with intermittent or mild persistent asthma.1

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Inhaled corticosteroids for children: 6 years and over

Most clinical trials of regular inhaled corticosteroid treatment in children have been conducted among children with persistent asthma.1 Beclometasone dipropionate, budesonide, ciclesonide and fluticasone propionate have all been shown to be effective in children. However, there have been relatively fewer studies of ciclesonide (a newer inhaled corticosteroid)1 but, overall, randomised clinical trials show that it is equally effective as budesonide or fluticasone propionate in improving asthma symptoms and reducing flare-ups.26

In school-aged children with mild persistent asthma, regular low-dose daily inhaled corticosteroid treatment reduces the rate of flare-ups that require treatment with oral corticosteroids, compared with no regular treatment and as-needed short-acting beta2 agonist for wheezing episodes.27

The Thoracic Society of Australia and New Zealand’s current position statement on the use of inhaled corticosteroids in children recommends regular treatment with inhaled corticosteroid for school-aged children with moderate-to-severe persistent asthma, or those with frequent intermittent asthma or mild persistent asthma if symptoms are not controlled by a 2- to 4-week treatment trial with a cromone (nedocromil or sodium cromoglycate) or montelukast.1

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Inhaled corticosteroids for children: doses

In the majority of children, asthma control can be achieved with any of the following initial doses:1

  • budesonide 400 mcg/day
  • beclometasone (Qvar) 200 mcg/day
  • ciclesonide 160 mcg/day
  • fluticasone propionate 200 mcg/day.

If these doses do not achieve control of symptoms, possible explanations include alternative diagnoses, adherence, incorrect inhaler technique, psychosocial factors and exposure to tobacco smoke or other triggers such as allergens.1

Dose–response studies of inhaled corticosteroids show that the maximal efficacy is generally achieved at a dose equivalent to approximately 200 mcg/day fluticasone propionate,1 while the risk of adrenal suppression increases exponentially at doses above 500 mcg/day.1 Therefore (based on theoretical equivalents between different agents), upper limits of daily doses for children are:

  • budesonide 800 mcg/day
  • beclometasone dipropionate [Qvar] 400 mcg/day
  • ciclesonide 320 mcg/day
  • fluticasone propionate 500 mcg/day.

Higher doses are unlikely to be more effective, and are likely to cause systemic effects.1

Most studies of inhaled corticosteroids in children have used twice-daily dosing.1  Ciclesonide is effective when given once daily.1 The dose of inhaled corticosteroid delivered to the lungs will depend on many factors, including the delivery device, the age of the child, individual variation in inhaler technique, and adherence.1

Note: Do not use beclometasone dose recommendations from outdated or overseas guidelines based on older formulations containing CFC propellant – doses are different.

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (mcg)

Low

High

Beclometasone dipropionate

100–200

>200 (up to 400)

Budesonide

200–400

>400 (up to 800)

Ciclesonide

80–160

>160 (up to 320)

Fluticasone propionate

100–200

>200 (up to 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

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

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Inhaled corticosteroids for children: adverse effects

Topical

Hoarseness and pharyngeal candidiasis are not commonly reported among preschool children when using a metered-dose inhaler with spacer,8 or among school-aged children.1

Inhaled corticosteroids, particular dry-powder formulas with pH <5.5, may dissolve tooth enamel in children.1

Topical effects can be reduced by use of spacer devices (which reduce oropharyngeal deposition), and by mouth-rinsing and spitting after use.1 Immediate quick mouth-rinsing removes more residual medicine in the mouth than delayed rinsing.28

Systemic

Systemic effects of inhaled corticosteroids in children depend on the dose, but clinically significant adverse effects are uncommon.1 The use of spacers and mouth rinsing will not reduce systemic effects, but may increase efficacy so that a lower dose is required.

Short-term suppression of linear growth has been demonstrated in children, but only minimal long-term effects on growth or bone density have been reported.1 Some children may experience delay in the normal pubertal growth spurt due to asthma itself.1 Treatment beginning before puberty is associated with a small (mean approximately 1 cm) reduction in adult height.29

A research study using biochemical testing in a research setting showed that hypothalamic–pituitary–adrenal axis suppression may occur in up to two-thirds of children treated with inhaled corticosteroids, and may occur at even low doses.30 However, clinically cases are rare.

Cases of symptomatic, clinically significant adrenal insufficiency in children due to inhaled corticosteroid treatment have been reported,3132 including cases in Australia.33 Most cases have involved children given more than 500 mcg per day fluticasone propionate.31

The risk of hypothalamic–pituitary–adrenal axis suppression is higher among children receiving concomitant intranasal steroids and those with lower body mass index.30 Risk is lower in obese children.30

There are no nationally accepted protocols for routine assessment of adrenal function because it has not yet been possible to identify precisely which children should be tested, to interpret test results reliably, to identify the appropriate interval for retesting, and because a clinical benefit has not been clearly demonstrated.

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (mcg)

Low

High

Beclometasone dipropionate

100–200

>200 (up to 400)

Budesonide

200–400

>400 (up to 800)

Ciclesonide

80–160

>160 (up to 320)

Fluticasone propionate

100–200

>200 (up to 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

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

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for children: 6 years and over

Available combinations

Three combinations of inhaled corticosteroid and long-acting beta2 agonist in a single inhaler are currently available:

  • The combination of fluticasone propionate and salmeterol xinafoate in a single inhaler is registered for use in children aged 4 years and over.34
  • The combination of budesonide and formoterol in a single inhaler is registered for use in children aged 12 years and older.35
  • The combination of fluticasone propionate and formoterol in a single inhaler is TGA-registered for use in children aged 12 years and older.36

Role of combination therapy in children

Evidence from clinical trials does not support the use of combination therapy with a long-acting beta2 agonist plus an inhaled corticosteroid as initial preventer treatment in children who are not already taking inhaled corticosteroids.3738

Combination therapy is a step-up option for some children whose asthma is not well controlled by low-dose inhaled corticosteroids alone.

Beta2 receptor regulation

Clinical response to long-acting beta2 agonists partly depends on genetics. 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.14 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

Systematic reviews and meta-analyses have led to concern about the possibility that the use of long-acting beta-agonists (even in combination with inhaled corticosteroids) might even increase the risk of flare-ups that require treatment with oral steroids or hospital admission, or of severe flare-ups.1, 39, 40  A meta-analysis by the US Food and Drug Administration found that the use of long-acting beta2 agonists was associated with increased risk of severe asthma-associated adverse events (both overall and among the subset of people using concomitant inhaled corticosteroid and long-acting beta2 agonist), and that this risk was greatest in children aged 4–11 years.40

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Administration of inhaled medicines in children: 6 years and over

School-aged children (depending on the child’s age, ability, and with individualised training) can correctly use a range of inhaler types,41 including manually actuated pressurised metered-dose inhalers with spacers,42 breath-actuated pressurised metered-dose inhalers (e.g. Autohaler), and dry-powder inhalers (e.g. Accuhaler, Turbuhaler).4243

A pressurised metered-dose inhaler and spacer is an appropriate first choice for most children.41

Parents and children need training to use inhaler devices correctly, including inhaler technique, and care and cleaning of inhalers and spacers.

School-aged children are unlikely to use their inhaler device correctly without careful training.44

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Correct use of inhaler devices

The majority of patients do not use inhaler devices correctly. Australian research studies have reported that only approximately 10% of patients use correct technique.4546

High rates of incorrect inhaler use among children with asthma and adults with asthma or COPD have been reported,47, 48, 49, 50, 51 even among regular users.52 Regardless of the type of inhaler device prescribed, patients are unlikely to use inhalers correctly unless they receive clear instruction, including a physical demonstration, and have their inhaler technique checked regularly.53

Poor inhaler technique has been associated with worse outcomes in asthma and COPD. It can lead to poor asthma symptom control and overuse of relievers and preventers.47, 54, 52, 55, 56 In patients with asthma or COPD, incorrect technique is associated with a 50% increased risk of hospitalisation, increased emergency department visits and increased use of oral corticosteroids due to flare-ups.52

Correcting patients' inhaler technique has been shown to improve asthma control, asthma-related quality of life and lung function.57, 58

Common errors and problems with inhaler technique

Common errors with manually actuated pressurised metered dose inhalers include:53

  • failing to shake the inhaler before actuating
  • holding the inhaler in wrong position
  • failing to exhale fully before actuating the inhaler
  • actuating the inhaler too early or during exhalation (the medicine may be seen escaping from the top of the inhaler)
  • actuating the inhaler too late while inhaling
  • actuating more than once while inhaling
  • inhaling too rapidly (this can be especially difficult for chilren to overcome)
  • multiple actuations without shaking between doses.

Common errors for dry powder inhalers include:53

  • not keeping the device in the correct position while loading the dose (horizontal for Accuhaler and vertical for Turbuhaler)
  • failing to exhale fully before inhaling
  • failing to inhale completely
  • inhaling too slowly and weakly
  • exhaling into the device mouthpiece before or after inhaling
  • failing to close the inhaler after use
  • using past the expiry date or when empty.

Other common problems include:

  • difficulty manipulating device due to problems with dexterity (e.g. osteoarthritis, stroke, muscle weakness)
  • inability to seal the lips firmly around the mouthpiece of an inhaler or spacer
  • inability to generate adequate inspiratory flow for the inhaler type
  • failure to use a spacer when appropriate
  • use of incorrect size mask
  • inappropriate use of a mask with a spacer in older children.

How to improve patients’ inhaler technique

Patients’ inhaler technique can be improved by brief education, including a physical demonstration, from a health professional or other person trained in correct technique.53 The best way to train patients to use their inhalers correctly is one-to-one training by a healthcare professional (e.g. nurse, pharmacist, GP, specialist), that involves both verbal instruction and physical demonstration.59, 47, 60, 61 Patients do not learn to use their inhalers properly just by reading the manufacturer's leaflet.60 An effective method is to assess the individual's technique by comparing with a checklist specific to the type of inhaler, and then, after training in correct technique, to provide written instructions about errors (e.g. a sticker attached to the device).45, 58

The National Asthma Council information paper on inhaler technique includes checklists for correct technique with all common inhaler types used in asthma or COPD.

Inhaler technique must be rechecked and training must be repeated regularly to help children and adults maintain correct technique.57, 47, 48 

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References

  1. 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
  2. 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
  3. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org
  4. 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.
  5. Merck, Sharp and Dohme Australia Pty Ltd. Product Information: Singulair (montelukast sodium) Tablets. Therapeutic Goods Administration, Canberra, 2013. Available from: https://www.ebs.tga.gov.au/
  6. National Asthma Council Australia. Leukotriene receptor antagonists in the management of childhood asthma. National Asthma Council Australia, Melbourne, 2010. Available from: http://www.nationalasthma.org.au/publication/ltras-their-role-in-childhood-asthma
  7. Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2004; Issue 1: CD003133. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003133.pub2/full
  8. 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
  9. Szefler SJ, Baker JW, Uryniak T, et al. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol. 2007; 120: 1043-50. Available from: http://www.jacionline.org/article/S0091-6749(07)01726-5/fulltext
  10. Bisgaard H, Zielen S, Garcia-Garcia ML, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005; 171: 315-322. Available from: http://ajrccm.atsjournals.org/content/171/4/315.long
  11. Pelkonen AS, Malmström K, Sarna S, et al. The effect of montelukast on respiratory symptoms and lung function in wheezy infants. Eur Respir J. 2013; 41: 664-670. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23060628
  12. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007; 175: 323-329. Available from: http://ajrccm.atsjournals.org/content/175/4/323.long
  13. 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
  14. 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
  15. Wallerstedt SM, Brunlöf G, Sundström A, Eriksson AL. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf. 2009; 18: 858-864. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19551697
  16. Schumock GT, Stayner LT, Valuck RJ, et al. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012; 130: 368-75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22698520
  17. Philip G, Hustad C, Noonan G, et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 691-6.e6. Available from: http://www.jacionline.org/article/S0091-6749(09)01247-0/fulltext
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