How to match the optimal currently available inhaler device to an individual child with asthma or recurrent wheeze.

Inhaled medications are the cornerstone of treatment in early childhood wheezing and paediatric asthma. A match between patient and device and a correct inhalation technique are crucial for good asthma control. The aim of this paper is to propose an inhaler strategy that will facilitate an inhaler choice most likely to benefit different groups of children. The main focus will be on pressurised metered dose inhalers and dry powder inhalers. In this paper we will discuss (1) practical difficulties with the devices and with inhaled therapy and (2) the optimal location for deposition of medicines in the lungs, and (3) we will propose a practical and easy way to make the best match between the inhaler device and the individual patient. We hope that this paper will contribute to an increased likelihood of treatment success and improved adherence to therapy.

Introduction

Inhaled medications are the cornerstone of treatment in early-childhood wheezing and paediatric asthma. They should be targeted to areas in the lungs where they will be most effective. Treating paediatric asthma (children aged 5 years or older) with inhaled corticosteroids (ICSs) and bronchodilators has resulted in improvements in asthma control.[1] In early-childhood wheezing (0–4 years), treatment outcomes are less positive probably because of diverse clinical phenotypes. In this young age it is difficult to achieve and maintain an optimal inhalation technique.[2,3]

The most important advantage of inhaled delivery of medicines is that they are delivered directly into the airways and lungs, resulting in higher local concentrations, lower systemic exposure and fewer systemic side effects compared with the oral or intravenous route. However, inhalation of medicines can be complicated and difficult for some children. Drug deposition in the lungs depends on the type of inhaler device, the characteristics of the inhaled medicine, and on patient-related characteristics.[4]

There are many reports of treatment failure due to poor inhalation technique.[5] The number of inhalation devices is immense. Physicians and pharmacists who prescribe and supply them may lack knowledge on the best choice of device for each individual or may be unaware of the specific inhalation technique that best matches the patient’s needs.

Several studies have demonstrated that large numbers of patients do not use their inhalers correctly, thereby gaining little or no therapeutic benefit from the prescribed treatment.[6-8] Focussing on which inhalers are the easiest to use correctly by children of varying ages is at least as important as the in vitro output characteristics of any inhaler. Because of patient heterogeneity, no single inhaler will satisfy the needs of all. This is particularly true in children where different age groups possess different psychomotor skills. Cost is another important consideration, but will vary from country to country and is beyond the scope of this review.

The aim of this paper is to propose an inhaler strategy that will facilitate an inhaler choice most likely to benefit different groups of children. The main focus will be on pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs), highlighting practical difficulties with the devices and with inhaled therapy. In addition, we will discuss the optimal location for depositing the medicines in the lungs. Finally, we will propose a practical and easy way to make the best match between the inhaler device and the individual patient. The hope is that this will improve consistency of inhaler prescribing in primary and secondary care, in children with early-childhood wheeze and asthma (Box 1).

Difficulties with inhaled therapy

A device that is easy to use and also allows optimal lung deposition seems crucial for disease control. This is particularly important for ICSs and short-acting β2-agonists.

The optimal inhalation technique differs between devices. Many children experience problems using their inhaler correctly, resulting in poor asthma control.[5] Meta-analyses (including studies in children from 7 months and older) indicate that if the correct inhaler technique is taught, different devices produce similar clinical outcomes.[9,10] However, patients and parents were well trained in device usage and some were excluded if they were unable to inhale correctly.

Poor inhaler technique was found in 70% of 3,955 asthma patients who used a pMDI and was associated with decreased asthma stability.[6] Other studies have reported poor inhaler technique in 32–96% of patients.[7,11] Inhalation technique often remains poor after several teaching sessions.[10] Comprehensive training and repeated checks are needed to ensure a reliable inhalation technique.[12] Many physicians have poor knowledge and training in the correct use of inhaler devices,[13] resulting in inconsistency in the choice of inhaler device and lack of explanation and training.

Education and perception

Before starting inhaled therapy, an explanation about the aims of treatment must be given. The key question to ask when regular, preventative therapy fails is whether the child is actually taking the medication. Parents are naturally concerned about the possible side effects of ICSs, such as growth retardation and dependence on medicines.[14,15] A recent long-term follow-up study in children with asthma who were treated for at least 4 years with budesonide (BUD) or nedocromil indicated that children who used ICSs were 1 cm shorter with respect to their final height compared with the group that used nedocromil (a non-steroid anti-asthma drug).[16] Possible barriers need discussion; a dialogue between careprovider and family should result in a shared perception about the disease and its treatment goals leading to a good starting point for eventual successful management and control.[17-19]

Requirements for inhalation

The requirements for inhalation are different for very young children. The deposition in the lower airways during crying is markedly reduced.[20,21] The facemask seal is critical for efficient aerosol delivery to infants and young children.[22,23] There are also differences in anatomy and physiology of the upper airways: the pharynx and supraglottic area are less rigid; the epiglottis is narrow and floppy and closer to the palate; and the larynx is higher and close to the base of the tongue.[3] Delivery through the nose has been shown to be less effective than through the mouth, probably because of higher resistance, the high flow rate and increased turbulence in the nostrils and the nasopharynx.[24,25] High inspiratory flows cause impaction of drug particles in the upper airways, especially the larger particles (3–5 μg).[26] Smaller particles, inhaled with lower inspiratory flows, have a greater chance to bypass the upper airways and deposit in the lower airways. Young children are not able to hold their breath and are more likely to exhale much of their medication. Amirav et al. reviewed the differences in lung deposition of aerosol therapeutics with large and small particles and concluded that small-particle aerosols provide better deposition than larger ones in young children.[3]

Children 7 years and older usually have a sufficient inspiratory flow rate to inhale through all of the different types of inhalers, such as pMDI–spacer combinations, breath-actuated inhalers (BAI) and DPIs.

Current prescribing shows a range of devices being used, some of which may have advantages in certain patients over a pMDI plus spacer, and we have therefore set out to explain when they can and cannot be used.

Practical difficulties in the use of inhalers

Pressurised metered-dose inhalers

These are widely used in the treatment of childhood asthma and in young children with recurrent wheezing. An aerosol dose is generated by the patient pressing down the canister into the actuator seating. Canisters of suspension aerosols should be shaken. A good press and breathe (hand–breath) coordination is needed to inhale the medication into the peripheral airways. With the introduction of HydroFluoroAlkane propellants, some aerosols kept their initial characteristics (large particle size, high velocity), such as fluticasone propionate (FP) and beclomethasone dipropionate (BDP; Clenil, GlaxoSmithKline, London, UK), but some aerosols have changed characteristics; for example, extra-fine HydroFluoroAlkane BDP (Qvar, Teva Pharmaceuticals, Tel Aviv, Israel) changed to a smaller median mass aerodynamic diameter (‘median particle size’; 1.1 μm).

The use of a pMDI looks simple: ‘press and breathe’. However, it is complex because it requires hand–breath coordination and the need to breath-hold afterwards. Poor hand–breath coordination results in reduced lung deposition.[26] Almost all children and adults with asthma have problems in coordinating the pMDI actuation together with their inhalation of the released aerosol.[27-29] One way to solve this poor coordination is the use of a valved holding chamber or spacer.[30] Another possibility in children 7 years or older and in adults is a breath-actuated device.[31]

Breath-holding after inhalation is essential for an optimal deposition of the inhaled medication in the smaller airways.[32] A breath-hold pause of 5 s is suggested in children up to 10 years of age. This recommendation is based on a study in trained 5–17-year-old children who inhaled extra-fine HydroFluoroAlkane BDP via an AeroChamber-Plus (Trudell, London, ON, Canada) with a mouth piece.[30] Lung (filter) deposition was highest in the group that breath-held (56.6% in 5–7-year-olds, 56.6% in 8–10-year-olds, and 58.4% in 11–17-year-olds) compared with the group that took five tidal breaths (35.4% in 5–7-year-olds, 47.5% in 8–10-year-olds and 54.9% in 11–17-year-olds).

pMDI–spacer combination

pMDI–spacer combinations can be used by almost everyone. They overcome hand–breath coordination difficulties and decrease oro-pharyngeal deposition, thereby increasing deposition into the lower airways. Because the larger aerosol particles deposit in the spacer, local unwanted side effects in the mouth and throat, such as thrush and hoarseness, are much reduced.

The volume of the spacer is important, especially for young children with low tidal volumes. Higher aerosol concentration in the smaller volume chambers increases drug delivery to where it is needed.[33] Multiple breaths may also increase drug delivery into the airways. Schultz et al. [34] recorded the breathing patterns in 2–7-year-old children inhaling placebo using four different spacers. Two tidal breaths were adequate to inhale the aerosol using small-volume spacers (Aerochamber Plus, Funhaler, ITL design & Manufacturing, Eveleigh NSW, Australia) and three tidal breaths were adequate using the larger spacer (Volumatic, GlaxoSmithKline).

Other factors also influence the variation in the delivered dose. The electrostatic charge in a spacer reduces delivery into the lung. In a randomised crossover study Janssens et al. [35] investigated children with stable asthma aged 1–4 years and 5–8 years. They assessed the dose variability delivered to the mouth through a metal Nebuchamber (AstraZeneca, Luton, UK) (no electric charge) and through two plastic spacers: the Babyhaler (Glaxo Wellcome, Greenford, UK) in 1–4-year-olds and the Volumatic in 5–8-year-olds. They found substantial within-subject dose variability in aerosol delivery. The variability was lower for the metal spacer (currently rarely used) than for the plastic spacer in the 5–8-year age group. The dose delivered to the mouth through the metal spacer was twice that delivered through the plastic spacers.

The dose delivered through a spacer also varies with a child’s age and with the child’s breathing pattern. Lung deposition was determined in two groups of asthmatic children. All inhaled five puffs of radio-labelled salbutamol pMDI through a plastic spacer: the younger group (up to 48 months) used a Babyhaler with a facemask and the older group (⩾48 months) used a Volumatic. The younger children used five tidal breaths between actuations. The older children inhaled with five tidal breaths or one single slow breath with maximal inhalation and held their breath for 10 s. Lung deposition varied from 16.4% in the younger children to 28.2 or 41.8% in the older group inhaling with different breathing patterns.[36] Table 1 shows the wide differences in lung deposition in children inhaling with a pMDI and spacer combination and with different breathing patterns.

Table 1

Mean lung deposition in children with a pMDI spacer combination

Author/Journal	Age	Device	Breathing pattern	Drug	Mean lung deposition
Agertoft and Pedersen[37] Arch Dis Child, 1994	10–25 mo	Nebuhaler (750 ml) Aerochamber Babyspacer	30 s tidal breathing 30 s tidal breathing 30 s tidal breathing	Budesonide	26.7% (17–44) 19.7% (9–33) 27.7% (19–38)
Tal et al. [55] J Pediatrics, 1996	0.25–5 y	pMDI -Aerochamber	30 s tidal breathing	Salbutamol	1.97% (1.4)
Wildhaber et al. [56] J Pediatrics, 1999	2–4 y 5–9 y	pMDI- Aerochamber	5 Tidal breaths in the 5–9-y group	Salbutamol	5.4% (2.1) 9.6% (3.9)
Wildhaber et al.[36] J Pediatrics, 2000	<48 mo ⩾48 mo	Babyhaler Volumatic Volumatic	Tidal breathing Tidal breathing Single breath	Sabutamol	16.4% (5.5) 28.2% (6.7) 41.8% (3.8)
Roller et al.[30] Eur Respir J, 2007	5–7 y 8–10 y 11–7 y 5–7 y 8–10 y 11–7 y	Aerochamber Aerochamber	Tidal breathing Breath-hold	Extra-fine HFA beclomethasone Extra-fine HFA beclomethasone	35.4% (8.3) 47.5% (13.0) 54.9% (11.2) 58.1% (6.6) 56.6% (5.2) 58.4% (9.2)
Schulz et al.[34] Pediatrics, 2010	2–7 y	Aerochamber plus	2 Tidal breaths 9 Tidal breaths Funhaler 2 Tidal breaths 9 Tidal breaths Volumatic 2 Tidal breaths 9 Tidal breaths	Salbutamol	40% (95% CI: 34–46%) 41% (95% CI: 36–47%) 39% (95% CI: 34–43%) 38% (95% CI: 35–42%) 37% (95% CI: 33–41%) 43% (95% CI: 40–46%)

Mean lung deposition (Agertoft), expressed as a percentage of the metered dose±range, or (Schulz) as 95% confidence interval (CI), or (Tal, Wildhaber, Roller) expressed as s.d.

Abbreviations: HFA, hydrofluoroalkane-134a; pMDI, pressurised metered-dose inhaler.

The practical conclusion that can be drawn from these data is that young children up to 7 years most benefit from inhalation with small-volume spacers.[33,37] Most children aged 4 years or older (and sometimes even younger) can use a spacer with a mouthpiece, and the younger children should use a spacer with a mask. Children aged 4 years or older are able to hold their breath for 5–7 s, which improves the lung deposition of the drug.

Breath-actuated inhalers

Breath-actuated metered dose inhalers may overcome hand–breath coordination problems. They release a dose of aerosol triggered by a relatively low inspiratory flow rate (Autohaler 30 l/min (3M, St Paul, MN, USA), Easibreath (PA, London, UK) or Redihaler 20 l/min (Teva Pharmaceuticals, Waterford, Ireland)). They contain extra-fine HydroFluoroAlkane BDP or salbutamol. Because of the short and limited inspiratory flow of young children they are advised to be used in children aged 7 years or older. A deposition study in children aged 5–14 years showed an age-dependent lung deposition from 36.9% up to 54.1% in the older children.[38,39]

Dry powder inhalers

DPIs, such as the Turbuhaler (Astra Zeneca, Lund, Sweden) and the Diskus (GlaxoSmithKline), require a rapid and forceful inhalation. Medication is delivered to the lungs after a deep inhalation through the DPI. Most DPIs contain micronised drug blended with larger lactose particles. These particles are too large to be inhaled, and hence release of the drug particles from carrier particles is needed. The energy for dispersion is derived from the inhaled airstream. The more forceful the inspiratory flow through the DPI, the higher the fraction of released drug particles, the higher the total lung dose and the greater the fine particle fraction.[40] The advantage of DPIs in children with sufficient inspiratory flow is that they overcome hand–breath coordination problems. Disadvantages are that the delivered dose is inspiratory flow and acceleration dependent. Another disadvantage in younger children (e.g., 4–6 years old) is that inhalation may be effective when the child is well but may be insufficient during a period of wheezing.[41]

The variability of the delivered dose from DPIs is greater than that from pMDIs.[40] The median mass aerodynamic diameter of the Turbuhaler with a low flow (30 l/min) was 6.23 μm, whereas it decreased to ~2.28 μm with an inspiratory flow of 60 l/min.[40] When the Diskus and Turbuhaler were compared for the delivery of FP and BUD, the results showed that the Diskus delivered 87–93% of the label claim, whereas the Turbuhaler delivered 40–58%.[42] Increasing the inspiratory flow through the Turbuhaler from 30 l/min to 60 l/min and to 90 l/min resulted in an increase in BUD delivery from 37.5 to 64.4 to 107.4% of the label claim dose, and the fine particle mass more than doubled.[41] In the only in vivo study, Agertoft and Pedersen compared the lung deposition of BUD inhaled from the Turbuhaler and that of FP inhaled from Diskus.[43] The mean lung deposition in children aged 8–14 years after Turbuhaler and Diskus inhalation was 30.8 and 8%, respectively, when inhalation of BUD and FP took place on separate days and 29.5 and 7.6%, respectively, when inhaled on the same day. These in vivo data indicate a fourfold higher deposition from Turbuhaler than from Diskus.[43] In another study in which the breathing pattern of 4–8-year-old children was simulated,[44] the total emitted dose of FP Diskus was compared with that of BUD Turbuhaler. An overall 87–89% of the label claim was emitted from the Diskus compared with 56–62% from the Turbuhaler. However, the fine particle fraction was slightly lower from the Discus compared with the Turbuhaler (15–18% vs. 21–23%). For both devices, there was an inverse relationship between inspiratory flow rate and particle size

The Novolizer (Sofotec GmbH & Co. KG, Frankfurt, Germany) is a more recently developed breath-activated multidose refillable DPI with dose counter. It has the advantage of a feedback mechanism that guides the patient through the correct inhalation manoeuvre.[45] A study in 4–11-year-old children showed that they were capable of generating twice the minimal PIF (35–50 l/min) to overcome the trigger threshold of the Novolizer.[46] The novolizer may contain BUD, salbutamol or formoterol. The particle size dependency of the flow rate is less apparent in the Novolizer as in other DPIs.[45]

However, clinical head-to-head studies in different age groups should be performed to investigate whether these differences have any clinical relevance.

Table 2 shows an age indication of the different types of inhalers.

Table 2

Age indication of the different types of inhalers

	0–3 y	4–6 y	7 y and older
pMDI	+ Spacer (small) with mask 10 times tidal breathing	+ Spacer (small) with mouth piece 2 deep breaths 5–7 s breath-holding	+ Spacer with mouth piece 1 deep breath 7 s breath-holding
DPI	−	−	Quick and forcefully deep inhalation 5–7 s breath-holding
BAI	−	−	Normal deep inhalation 5–7 s breath-holding

Abbreviations: BAI, breath-actuated inhaler; DPI, dry powder inhaler; pMDI, pressurised metered-dose inhaler.

Where should inhaled corticosteroids and β2-agonists be delivered?

The most important inhaled medicines for the treatment of asthma and early-childhood wheezing are β2-adrenergic bronchodilators and ICSs. The inflammatory process involves the entire airway and, as corticosteroid receptor density increases in the peripheral airways,[47] ICS delivery to small airways is important. As β2 receptors are found equally in the large and smaller airways, targeting wide areas of the airways may be important for bronchodilators as well.[48,49]

Small-particle ICSs, such as ultra-fine HydroFluoroAlkane BDP aerosol and ciclesonide, may offer a potential benefit in young children with smaller airways.[50] These characteristics may be particularly relevant in young children in whom more airways are classified as small (<2 mm in diameter) and whose airway resistance is high.[51]

Recommended doses according to the GINA guidelines are shown in Table 3.

Table 3

Dose indication of different inhaled corticosteroids

Equipotent doses of ICS for adults and children older than 5 years					Low daily doses of ICS in children⩽5 years
Drug	Low dose (μg)	Medium daily dose (μg)	High daily dose (μg)	Products available in different countries	Drug	Low daily dose (μg)
Beclomethasone dipropionate—CFC	200–500	>500–1,000	>1,000–2,000	Beclomethasone Clenil Becotide	Beclomethasone dipropionate	100
Extra-fine Beclomethasone dipropionate—HFA	100–250	>250–500	>500–1,000	Qvar Aerobec	Budesonide MDI+spacer Budesonide nebulised	200 500
Budesonidea	200–400	>400–800	>800–1,600	Budesonide Pulmicort	Ciclesonidea	Not studied in this age group
Ciclesonidea	80–160	>160–320	>320–1,280	Alvesco	Fluticasone propionate	100
Flunisolide	500–1,000	>1,000–2,000	>2,000	Aerobid	Mometasone furoate	Not studied in this age group
Fluticasone propionate	100–250	>250–500	>500–1,000	Fluticasone Flixotide	Triamcinolone acetonide	Not studied in this age group
Mometasone furoatea	200	>400	>800	Asmanex
Triamcinolone acetonide	400–1,000	>1,000–2,000	>2,000	Triamcinolone

Comparisons based on efficacy data. Doses according to GINA guidelines.[1]

Abbreviation: ICS, inhaled corticosteroid.

Approved for once daily dosing in mild patients.

Making the optimal match between inhalation device and the individual patient

Before prescribing an inhaler device the following questions may be helpful to choose the correct device for the individual patient.

Who?

What is the age of the child? Can he/she consciously inhale? Young infants and disabled children are not aware how to inhale. Young children have a low inspiratory flow and are not able to hold their breath.

Where?

In children with asthma and in those with early wheezing the small airways should be targeted. Small-particle ICSs may have an advantage because of higher deposition in the small airways.[3] The clinical relevance in children for small-particle drugs is weak and mainly based on the findings from a double-blind randomised controlled trial and from one real-life study. In a double-blind randomised controlled dose reduction study in school-aged children, extra-fine HydroFluoroAlkane BDP pMDI plus spacer proved to be equally effective compared with FP pMDI plus spacer.[52] However, in a real-life comparative effectiveness study, increasing the extra-fine HydroFluoroAlkane BPP dose appeared to provide improved outcomes (significantly better asthma control and significantly fewer exacerbations) compared with stepping up ICS as FP or adding a separate long-acting beta-agonist (significantly better asthma control); similar outcomes were seen when compared with a fixed-dose combination of ICS/long-acting β2-agonist.[53]

How?

Age can act as a relative proxy for insufficient inspiratory flow. Under 7 years of age there is insufficient inspiratory flow to inhale a DPI or a BAI; it is also not possible to teach these young children to hold their breath.[54] The only options here are a pMDI–spacer combination, with tidal breathing (5–10 times) after actuation. Medicines delivered through nebulisers should not be used as first-line prescriptions in primary care because higher dosages are licensed with a greater possibility of adverse effects and expense. Especially short-acting β2-agonists in very young children should be nebulised with oxygen rather than air as the flow gas because of the danger of arterial oxygen desaturation.

A DPI or a BAI can be used from 7 years of age. The problem with a breath-actuated device in children from 4 to 6 years of age is that their inspiration time is too short to complete an effective inhalation.

For children aged 3 years or lower, a pMDI–spacer combination with a face mask can be used. In children aged 4 years or older, a pMDI–spacer combination with a mouth piece is preferred. Above 6 years of age many different inhalers may be effective.

The optimal choice for an inhaler device can be summarised in the following two questions and in the use of one algorithm (Figure 1) to make the correct choice for the individual patient.

Figure 1

Algorithm for the optimal choice for an inhaler device. pMDI, pressurised metered-dose inhaler; DPI, dry powder inhaler.

Is the patient conscious of his/her inhaling?Young children (6 years or younger) or children who are mentally not able to follow instructions about a correct inhalation technique should use a pMDI plus spacer and not a pMDI without a spacer, DPI or breath-actuated aerosol.

Is his/her inspiratory flow sufficient?Young children with an insufficient inspiratory flow (6 years or younger) or children with insufficient muscular power to inhale forcefully should not use DPIs or breath-actuated aerosols.

Conclusion

A wrong inhaler technique or inhaler device is one of the most prevalent causes of poor asthma control. An optimal choice for the individual patient, device training and repeated checks of patients' device use and technique are essential for good asthma control.