Asthma Management Handbook

Managing flare-ups in children aged 6 years and over

Recommendations

Ensure all children with asthma have a short-acting inhaled bronchodilator (reliever) inhaler (and spacer, if needed) with them at all times. Educate parents/carers how and when to give reliever.

Note: The recommended dose for non-emergency bronchodilator in children aged 6–11 years is salbutamol 2–4 puffs (100 microg per puff) as needed, 1 puff at a time, via pressurised metered-dose inhaler plus spacer, and repeated 4 hours later, if needed.

  • Advise parents/carers to get medical advice if reliever is needed again within 4 hours.
  • Do not prescribe oral salbutamol. Inhalation is the recommended route for delivering relievers for all children and adults.

Table. Non-emergency use of bronchodilators (relievers) in children aged 6–11 years

Option

Dose

Mode of delivery

Salbutamol
100 microg per actuation (puff)

2–4 puffs  as needed (one at a time)

Repeat if needed

Pressurised metered-dose inhaler plus spacer

Terbutaline
500 microg/actuation

1–2 actuations

Repeat if needed

Dry-powder inhaler

Note: This table lists usual doses to be administered by parents/carers in the community to manage symptoms as needed. Higher during may be given 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).

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Consider prescribing a short course of prednisolone for a child with acute asthma if beta2 agonist reliever is needed approximately every 4 hours over a period of 24 hours.

Note: the recommended dose is 1 mg/kg (maximum 50 mg) orally each morning for 3 days.

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

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If oral corticosteroids are needed to manage severe acute flare-ups, reassess regular medicine regimen (including adherence and inhaler technique) and consider specialist referral.

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

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Do not start long-term oral corticosteroids except on the advice of a paediatric specialist (respiratory physician or paediatrician).

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

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For all children using a regular preventer (montelukast, inhaled corticosteroid, or combination of inhaled corticosteroid plus long-acting beta2 agonist) explain to children and parents that the child should keep taking it during asthma flare-ups, including acute asthma episodes that require treatment in an emergency department.

How this recommendation was developed

Consensus

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

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Do not routinely prescribe antibiotics for children with upper respiratory tract infections who experience acute wheeze or asthma associated with viral respiratory infections.

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):

  • Normansell et al. 20182
  • Johnston et al. 20163
  • Fonseca-Aten et al. 20064

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More information

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

Inhaled short-acting beta2 agonists is the major class of bronchodilators used for relief of symptoms in asthma.5

Children with well-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.

Dispensing of 3 or more canisters in a year (average 1.6 puffs per day) is associated with increased risk of flare-ups.1 Dispensing 12 or more canisters in a year (average 6.6 puffs per day) is associated with increased risk of asthma death.2

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 SABA 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 SABA 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 SABA reliever)
  • ≥3 features of partial control within the same week

SABA: short-acting beta2 agonist

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including doses 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

Notes:

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.

Validated questionnaires can be used for assessing recent symptom control:
Test for Respiratory and Asthma Control in Kids (TRACK) for children < 5 years
Childhood Asthma Control Test (C-ACT) for children aged 4–11 years

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Parent/carer-initiated oral corticosteroids for wheezing and asthma flare-ups
  • Oral corticosteroids are associated with adverse effects on behaviour and bone health. Frequent courses may affect the hypothalamus–pituitary–adrenal axis.

Children aged 1–5 years

Short courses of oral corticosteroids initiated by parents/carers in response to children’s wheezing, or at the first sign of a cold, are not effective in managing symptoms in preschool children.6, 7, 8

There is inconsistent evidence for the benefits of systemic corticosteroids in preschool children with acute viral-induced wheezing presenting to acute care services.8, 9, 10 Current evidence does not strongly support their use in this age group.11

The Thoracic Society of Australia and New Zealand position statement on the use of corticosteroids in children1 recommends that oral corticosteroid treatment in preschool children, particularly those with intermittent viral-induced wheezing, should be limited to children with wheeze severe enough to need admission to hospital.

Children aged 6 years and over

A Cochrane systematic review found that there was insufficient evidence supporting the use of parent-initiated courses of oral corticosteroids in school-aged children,12 although some clinical trials have reported benefits.

In a clinical trial in children aged 6–14 years with a history of recurrent episodes of acute asthma, short courses of oral prednisolone (1 mg/kg a day), initiated by parents in response to an asthma flare-ups, reduced asthma symptoms and the number of missed school days.13 Another quasi-experimental study found that home initiation of corticosteroids reduced the rate of emergency department visits among school-aged children with moderate-to-severe persistent asthma, compared with rates pre-intervention.14

The Thoracic Society of Australia and New Zealand position statement on the use of corticosteroids in children1 recommends a short course of systemic corticosteroid therapy for children with moderate-to-severe acute asthma or when there is an incomplete response to beta-agonists, and does not recommend against parent/carer-initiated courses.

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Back-to-school asthma care

Each year during February, a few days after the school year starts, there is an annual increase in asthma flare-ups among children with asthma. 

Asthma flare-ups in children, including those resulting in emergency department presentations and hospitalisations, surge during the first month of the school year. 15, 16, 17, 18 There are smaller increases at the beginning of the other school terms.19 These flare-ups may be due to changes in exposure to virus, allergens, pollution and/or stress during the early days after school return.20

Primary care health professionals can help parents/carers prepare for back-to-school flare-ups by:

  • recommending a full asthma review at the end of the school holidays to check asthma control, adherence to preventer and inhaler technique
  • ensuring that each child has an up-to-date written asthma action plan and the child and/or parents/carers understand how to follow it
  • reminding parents/carers to get their child back into their asthma routine before the school year starts, including taking preventer medications every day, if prescribed

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Increasing the inhaled corticosteroid dose to control flare-ups in children

In children taking regular inhaled corticosteroid-containing preventers, there is conflicting evidence for whether, and by how much, the dose should be increased when symptoms worsen or at the onset of an acute flare-up.

Overall, current evidence from highly controlled randomised controlled trials does not support increasing the dose of inhaled corticosteroid as part of a self-initiated action plan to manage flare-ups in children younger than 12 years.21

There is some evidence that high doses of inhaled steroids used pre-emptively might be effective in preventing severe acute asthma in children aged under 5 years, based on studies in children not taking regular inhaled corticosteroids.22 However, very high pre-emptive doses affect children’s growth23 and are not recommended.

Recent randomised controlled trials reported a lack of effect with a range of dose increases:

  • A five-fold increase in the inhaled corticosteroid dose at early signs of worsening asthma did not reduce the rate of severe acute asthma in children aged 5–11 years with well-controlled asthma while taking maintenance inhaled corticosteroid treatment (with high adherence).24 This strategy was associated with a small reduction in linear growth.24
  • Dose increases of four or eight times usual inhaled corticosteroid maintenance dose at the onset of an acute flare-up in children aged 2–17 years did not reduce requirement for oral corticosteroids, compared with doubling the dose.25

A Cochrane systematic review21 in children and adults reported that increasing the inhaled corticosteroid dose did not prevent severe flare-ups, regardless of how soon the increase was initiated after the onset of symptoms or the magnitude of the dose increase (doubling versus quadrupling). The results did not differ between children under 15 and adults or older adolescents.21 However, there were too few studies in children to make firm conclusions.

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Oral corticosteroids for children: adverse effects

Oral corticosteroids may have adverse psychiatric effects in children, including aggression and hyperactivity.26 Effects in the general population include euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour.27

A short course of oral corticosteroid therapy (less than 2 weeks) is associated with little risk of long-term suppression of the hypothalamus–pituitary–adrenal axis.1 However, risk can accumulate if frequent courses (four or more per year) are given.1

Recurrent courses of oral corticosteroids may also affect bone mineral density, especially in boys.1,28

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Thunderstorm asthma

Certain types of thunderstorms in spring or early summer in regions with high grass pollen concentrations in the air can cause life-threatening allergic asthma flare-ups in individuals sensitised to rye grass, even if they have not had asthma before.3,5,6,8,9

Sensitisation to rye grass allergen is almost universal in patients who have reported flare-ups consistent with thunderstorm asthma in Australia.

People with allergic rhinitis and allergy to ryegrass pollen (i.e. most people with springtime allergic rhinitis symptoms) are at risk of thunderstorm asthma if they live in, or are travelling to, a region with seasonal high grass pollen levels – even if they have never had asthma symptoms before. This includes people with undiagnosed asthma, no previous asthma, known asthma.3, 5 Lack of inhaled corticosteroid preventer treatment has been identified as a risk factor.3

Epidemics of thunderstorm asthma can occur when such a storm travels across a region and triggers asthma in many susceptible individuals. Epidemic thunderstorm asthma events are uncommon, but when they occur can they make a high demand on ambulance and health services.1, 9, 10

Data from thunderstorm asthma epidemics suggest that the risk of asthma flare-ups being triggered by a thunderstorm is highest in adults who are sensitised to grass pollen and have seasonal allergic rhinitis (with or without known asthma).3

The worst outcomes are seen in people with poorly controlled asthma.1 Treatment with an inhaled corticosteroid asthma preventer was significantly protective in a well-conducted Australian case-control study.5

There is insufficient evidence to determine whether intranasal corticosteroids help protect against thunderstorm asthma. Intranasal corticosteroids reduce symptoms of allergic rhinitis and limited indirect evidence suggests they may protect against asthma flare-ups in people not taking inhaled corticosteroids.11

The effectiveness of specific allergen immunotherapy in protecting against thunderstorm asthma has not been evaluated in randomised clinical trials, but data from a small Australian open-label study suggest that short-term treatment with five-grass sublingual immunotherapy may have been protective in individuals.4

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Administration of inhaled medicines in children: 6 years and over

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

School-aged children (depending on the child’s age, ability, and with individualised training) can learn to use a range of inhaler types, including manually actuated pressurised metered-dose inhalers with spacers, breath-actuated pressurised metered-dose inhalers (e.g. Autohaler), and dry-powder inhalers (e.g. Accuhaler, Turbuhaler).29, 30, 31, 32, 33

Table. Types of inhaler devices for delivering asthma and COPD medicines Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/75

A pressurised metered-dose inhaler and spacer is an appropriate first choice for most children.31

School-aged children are unlikely to use their inhaler device correctly without careful training and repeated checking.34

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Preparation of new spacers before first use

Spacers are made of plastic, antistatic polymer/polycarbonate polyurethane, or cardboard.

Plastic spacers (e.g. Breath-A-Tech, Volumatic)

Electrostatic surface charge on new spacers made of plastic (e.g. Breath-A-Tech, Volumatic) reduces the proportion of medicine available for delivery to the airway. This charge can be reduced by washing the plastic spacer in dishwashing liquid and allowing it to air dry or drip-dry without rinsing or wiping.35

Alternatively, priming the spacer by actuating the device several times into the spacer also overcomes the charge, but this wastes medicine. The optimal number of actuations for priming is not known and the findings of in vitro studies vary widely. One study (using older, CFC-based formulations of asthma medicines) reported that up to 40 actuations fired into a new plastic spacer overcame the effect of the electrostatic charge.36 Others have concluded that the electrostatic charge on plastic spacers does not reduce in vivo efficacy of bronchodilator therapy in children with asthma.37 The number of actuations necessary may be known when the results of recent studies become available.

When a new plastic spacer must be used immediately (e.g. for a person with asthma symptoms), patients, parents and carers should follow the manufacturer's priming instructions. In hospitals and emergency departments, a new spacer that has not been pre-treated by washing can be primed using multiple (at least 10) puffs of salbutamol. (This is an arbitrary number of actuations in the absence of evidence that would enable a precise guideline.)

Non-plastic spacers

Disposable cardboard spacers (e.g. DispozABLE, LiteAire) and polyurethane/antistatic polymer spacers (e.g. Able A2A, AeroChamber Plus, La Petite E-Chamber, La Grande E-Chamber) do not require preparation before first use.35

Note: The term 'priming' is also used for the preparation process that is necessary for new pressurised metered-dose inhalers that have not been used for more than a week. This involves first actuating the inhaler into the air (away from the patient). Users should follow the manufacturer’s instructions for the particular brand of inhaler, which specify the number of actuations required.

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Correct use of inhaler devices

Checking and correcting inhaler technique is essential to effective asthma management.

Most patients with asthma or COPD do not use their inhalers properly,1, 4-7 and most have not had their technique checked or corrected by a health professional.

Incorrect inhaler technique when using maintenance treatments increases the risk of severe flare-ups and hospitalisation for people with asthma or COPD.1, 4, 5, 14, 22, 23

Poor asthma symptom control is often due to incorrect inhaler technique.24, 25

Incorrect inhaler technique when using inhaled corticosteroids increases the risk of local side effects like dysphonia and oral thrush.

The steps for using an inhaler device correctly differ between brands. Checklists of correct steps for each inhaler type and how-to videos are available from the National Asthma Council website.

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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: https://www.thoracic.org.au/journal-publishing/command/download_file/id/25/filename/The_role_of_corticosteroids_in_the_management_of_childhood_asthma_-_2010.pdf
  2. Normansell, R., Sayer, B., Waterson, S., et al. Antibiotics for exacerbations of asthma. Cochrane Database Syst Rev. 2018; 6: CD002741. Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD002741.pub2/full
  3. Johnston, S. L., Szigeti, M., Cross, M., et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med. 2016; 176: 1630-1637. Available from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2553295
  4. Fonseca-Aten, M, Okada, P J, Bowlware, K L, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006; 97: 457-463.
  5. 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
  6. Beigelman A, King TS, Mauger D, et al. Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing?. J Allergy Clin Immunol. 2013; 131: 1518-1525. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23498594
  7. Basheti, IA; Obeidat, NM; Reddel, HK;. Effect of novel inhaler technique reminder labels on the retention of inhaler technique skills in asthma: a single-blind randomized controlled trial.. NPJ Prim Care Respir Med. 2017; 27: 9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28184045
  8. Crane, M. A., Jenkins, C. R., Goeman, D. P., Douglass, J. A.. Inhaler device technique can be improved in older adults through tailored education: findings from a randomised controlled trial. NPJ Prim Care Respir Med. 2014; 24: 14034. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25188403
  9. Giraud, V., Allaert, F. A., Roche, N.. Inhaler technique and asthma: feasability and acceptability of training by pharmacists. Respir Med. 2011; 105: 1815-22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21802271
  10. Lavorini, F.. Inhaled drug delivery in the hands of the patient. J Aerosol Med Pulm Drug Deliv. 2014; 27: 414-8.
  11. Newman, S.. Improving inhaler technique, adherence to therapy and the precision of dosing: major challenges for pulmonary drug delivery. Expert Opin Drug Deliv. 2014; 11: 365-78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24386924
  12. Hesso, I., Gebara, S. N., Kayyali, R.. Impact of community pharmacists in COPD management: Inhalation technique and medication adherence. Respir Med. 2016; 118: 22-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27578467
  13. Berg, E.. In vitro properties of pressurized metered dose inhalers with and without spacer devices. J Aerosol Med. 1995; 8: S3-S10.
  14. Dompeling, E., Oudesluys-Murphy, A. M., Janssens, H. M., et al. Randomised controlled study of clinical efficacy of spacer therapy in asthma with regard to electrostatic charge. Arch Dis Child. 2001; 84: 178-182.
  15. Zöllner, E W, Lombard, C J, Galal, U, et al. Hypothalamic-adrenal-pituitary axis suppression in asthmatic school children. Pediatrics. 2012; 130: e1512-e1519.
  16. Schwartz, R. H., Neacsu, O., Ascher, D. P., Alpan, O.. Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature. Clin Pediatr (Phila). 2012; 51: 1184-90. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23043135
  17. Ahmet, A, Kim, H, Spier, S. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol. 2011; 7: 13.
  18. Priftis, K N, Papadimitriou, A, Anthracopoulos, M B, et al. Endocrine-immune interactions in adrenal function of asthmatic children on inhaled corticosteroids. Neuroimmunomodulation. 2008; 16: 333-339.
  19. Macdessi, J S, van Asperen, P P, Randell, T L, et al. Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma. Med J Aust. 2003; 178: 214-216.
  20. Royal Australian College of General Practitioners,. Supporting smoking cessation. A guide for health professionals. RACGP, 2014. Available from: https://www.racgp.org.au/your-practice/guidelines/smoking-cessation/
  21. Cancer Council Australia,, Position statement - Sun exposure and vitamin D - risks and benefits. **, . Available from: https://wiki.cancer.org.au/policy/Positionstatement-Risksandbenefitsofsunexposure
  22. Paxton, G. A., Teale, G. R., Nowson, C. A., et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement. Med J Aust. 2013; 198: 142-3. Available from: https://www.mja.com.au/journal/2013/198/3/vitamin-d-and-health-pregnancy-infants-children-and-adolescents-australia-and
  23. Sorkness, CA, Lemanske, RF, Mauger, DT, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: The Pediatric Asthma Controller Trial. J Allergy Clin Immunol. 2007; 119: 64-72. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17140647
  24. Calvert, L D, Jackson, J M, White, J A, et al. Enhanced delivery of nebulised salbutamol during non-invasive ventilation. J Pharm Pharmacol. 2006; 58: 1553-1557. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17132219
  25. Kelly, A. M., Kerr, D., Powell, C.. Is severity assessment after one hour of treatment better for predicting the need for admission in acute asthma?. Respir Med. 2004; 98: 777-81. Available from: https://www.resmedjournal.com/article/S0954-6111(04)00042-3/fulltext
  26. Stuart, F. A., Segal, T. Y., Keady, S.. Adverse psychological effects of corticosteroids in children and adolescents. Arch Dis Child. 2005; 90: 500-6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1720409/
  27. Craig, S, Tuszynski, M, Armstrong, D. It is time to stop prescribing oral salbutamol. Aust Prescr. 2016; 45: 245-247. Available from: https://www.racgp.org.au/afp/2016/april/it-is-time-to-stop-prescribing-oral-salbutamol/
  28. Kelly, H. W., Van Natta, M. L., Covar, R. A., et al. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study. Pediatrics. 2008; 122: e53-61. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18595975/
  29. Gillette, C., Rockich-Winston, N., Kuhn, J. A., et al. Inhaler technique in children with asthma: a systematic review. Acad Pediatr. 2016; 16: 605-15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27130811
  30. Capanoglu, M., Dibek Misirlioglu, E., Toyran, M., et al. Evaluation of inhaler technique, adherence to therapy and their effect on disease control among children with asthma using metered dose or dry powder inhalers. J Asthma. 2015; 52: 838-45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26037396
  31. Ram, F S F, Brocklebank, D D M, White, J, et al. Pressurised metered dose inhalers versus all other hand-held inhaler devices to deliver beta-2 agonist bronchodilators for non-acute asthma. Cochrane Database Syst Rev. 2002; Issue 2: .
  32. Nikander, K, Turpeinen, M, Pelkonen, A S, et al. True adherence with the Turbuhaler in young children with asthma. Arch Dis Child. 2011; 96: 168-173.
  33. Pedersen, S., Mortensen, S.. Use of different inhalation devices in children. Lung. 1990; 168 Suppl: 653-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2117175
  34. Sleath, B, Ayala, G X, Gillette, C, et al. Provider demonstration and assessment of child device technique during pediatric asthma visits. Pediatrics. 2011; 127: 642-648.
  35. 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
  36. Berg E. In vitro properties of pressurized metered dose inhalers with and without spacer devices. J Aerosol Med. 1995; 8 Suppl 3: S3-10; discussion S11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10157897
  37. Dompeling E, Oudesluys-Murphy AM, Janssens HM, et al. Randomised controlled study of clinical efficacy of spacer therapy in asthma with regard to electrostatic charge. Arch Dis Child. 2001; 84: 178-182. Available from: http://adc.bmj.com/content/84/2/178.full