Pediatric Annals

Asthma Delivery Devices: Age-Appropriate Use

Jacqueline A Pongracic, MD

Abstract

A variety of holding chambers and spacer is available in the United States. Some are simple reservoirs, such as Inspirease™ (Schering Corporation) or the Azmacort™ spacer (Aventis Pasteur). Most are valved, which prevents escape of medication during use. Aerochamber™ (Forest Pharmaceuticals), Optichamber™ (Respironics), Ellipse™ (GlaxoSmithKline) and Volumatic™ (Allen and Hanbury's) are valved devices of various shapes and sizes. Some devices are equipped with a whistle that serves as a warning signal that the child is inspiring too quickly, causing turbulent flow which increases impaction in the oropharynx and large airway, effectively reducing delivery to the lower airways. Most products possess a mouthpiece; others provide facemask attachments or alternatives as well. Holding chambers with masks are advantageous for infants and young children, since they tend to be nasal breathers. Although nasal breathing decreases drug deposition in the lungs as compared to mouth breathing, some drug does reach the lungs nonetheless. Flexible seals on masks, such as that on Aerochamber™, help prevent air leaks around facial contours.

Holding chambers and spacers are inconsistently covered by insurance plans and are sometimes not affordable. As a result, there are a number of reports of homemade spacers, using plastic bottles and other everyday items. Some of these innovative and inexpensive devices have been shown to reduce the proportion of large particles while increasing the proportion of particles in the respirable range.8 It is interesting to note that global organizations such as World Health Organization endorse the use of homemade spacers in countries where commercial devices are not an option.9

A variety of special concerns exists in children compared to adults. Anatomic and physiologic differences, as well as behavioral and developmental factors, are especially important.10 The oropharynx of a child is characterized by relatively larger tongue size. For inhaled medications, this may promote oral deposition and potential side effects due to increased bioavailability. From a physiologic viewpoint, young children are habitual nose breathers. Nasal breathing also adversely affects pulmonary deposition while increasing bioavailability. Children have low flow rates, perhaps a result of small airways, which may make the use of certain devices such as DPIs inadvisable, since these devices require a threshold inspiratory flow rate in order to generate aerosolized particles suitable for inhalation and deposition into lower airways. Children also tend to exhibit irregular, shallow breathing, which also adversely affects delivery to the lungs. Cooperation is challenging in an ill, irritable, or upset child. Behavioral concerns, such as crying, lead to prolongation of exhalation and short, irregular inspiratory efforts. Crying reduces lung deposition even if a face mask is used.11 Distractions such as books and toys may help improve acceptance. Alternatively, administration during sleep may be tried. Given these issues, pediatricians need to select easy to use, efficient, and effective delivery systems for use in children, and they must do this while balancing benefits and risks.

So which inhaler and/or spacer devices does the busy pediatrician prescribe for youngsters with asthma? Recent review articles have provided practical recommendations on selection and technique.12·13 Table 4 (page 000) presents guidelines for selecting appropriate inhalational devices for chronic outpatient management of children in the United States. The reader should bear in mind that there will be instances in which exceptions will be necessary. Such situations may be medical, such as the lack of clinical efficacy or the onset of side effects; financial, due to everincreasing formulary restrictions; practical, related to the use of nebulization when time constraints exist; or social, as may be the case for the child with more than one caregiver or for teenagers who wish to be inconspicuous. Unfortunately, head-to-head studies are lacking for many…

Since their introduction, inhaled medications have become the prédominent modality in the management of asthma in adults and, more recently, in children. A variety of aerosolized delivery systems exists, including single and multiple dose inhalers and nebulizers. Advantages of inhaled administration include rapid delivery to the lungs, prompt onset of action, efficacy balanced with reduced risk for adverse effects, and lower dosing requirements as compared to the oral route. Despite these features, existing inhaled medications have several disadvantages. Inhalers are relatively inefficient and many devices require cooperation, coordination, and appropriate technique. These problems have made the use of inhalational therapy especially challenging in children. This article reviews basic concepts of aerosol therapy, types of delivery systems available in the United States, special issues for children with regard to inhalation therapy, and appropriate use of these devices at various developmental stages of childhood.

In order to be effective, aerosol therapy must reach its target, the lungs, and must be deposited within the airways. Particles must be of a certain size range for these two objectives to be met. Particles larger than 5 microns are trapped in the upper airway. Particles less than 2 microns are inhaled and deposited into the alveoli or exhaled without deposition in the airways. Those particles that are between 2 and 5 microns are able to escape me fate of both smaller and larger particles and successfully penetrate the lower respiratory tract. The greater the proportion of aerosolized particles in this "respirable range," the more pulmonary delivery is achieved and the less oral deposition (and its resultant side effects) occurs.

Table

TABLE 2Comparison of MDIs and DPIs

TABLE 2

Comparison of MDIs and DPIs

Devices that are effective clinically ideally generate a significant particulate fraction in the respirable range. The most popular devices, personal handheld asthma inhalers, have been in existence for more than 40 years as metereddose inhalers (MDIs). Metered-dose inhalers are pressurized canisters in which aerosolized particles are generated via propellants, usually chlorofluorocarbons (CFCs). Metered-dose inhalers produce aerosols travelling at high velocities (30m/sec) so that 80% of the dose is trapped in the oropharynx if a spacer is not used.1 Although CFCs have been used for their ability to enhance asthma therapy, they also have been shown to deplete the ozone layer, and their use is associated with health risks including skin cancer and cataracts. An international agreement, the Montreal Protocol on Substances that Deplete the Ozone Layer, was established in 1996 to address these concerns. The treaty has mandated the phase-out of health devices that use CFCs. Recent government rulings have set 2005 as the target date. In response, the pharmaceutical industry has already introduced MDIs containing alternative propellants, such as hydrofluoroalkanes (HFAs). Differences between CFC-MDIs and HFA-MDIs are outlined in Table 1. Although HFAs appear to contribute to global warming, their propensity to do so is much less than CFCs, while they offer superior pulmonary delivery and deposition.2 In fact, the lung deposition with HFA-MDIs is so high that the dose of corticosteroid may be halved when switching patients from CFC-MDIs to HFA-MDIs.3 Hydrofluoroalkane metered-dose inhalers also exhibit consistent dosing, even as the canister nears empty and at low ambient temperatures. Propellant issues aside, the need for coordination between actuation and inhalation is a limiting factor in the efficacy of most MDIs, and this is especially true for children. One MDI, Autohaler™ (3M Pharmaceuticals), is breath-activated, eliminating the need for coordination. An inspiratory flow rate of at least 30 L/min is required for delivery of me drug from me device. Ouher advantages enjoyed by Autohaler™ over traditional MDIs include consistent dosing throughout tiie life of me canister and at cold temperatures.

Table

TABLE 1Features of CFC-MDIs Versus HFA MDIs

TABLE 1

Features of CFC-MDIs Versus HFA MDIs

Given me disadvantages of propellant-based devices, alternative handheld devices have been in demand. Dry powder inhalers (DPIs) contain drug in a solid form and do not use propellents in their design. Over die past 30 years, many devices have been used, but they have not enjoyed sustained popularity. Many were cumbersome to use. Recent improvements in meir design have provided us with more convenient alternatives, including multi-dose devices mat do not require loading of medication, including Turbuhaler™ (Astra-Zeneca) and Diskus™ (GlaxoSmiÜiKline). CKhers require insertion of the medication prior to use, as is the case for Diskhaler™ (GlaxoSmithKline) and Aerosolizer® (Novartis). Like Autohaler™, DPIs are bream-actuated.

Table

TABLE 3Lung Deposition of Various Asthma Therapies in Children

TABLE 3

Lung Deposition of Various Asthma Therapies in Children

Perceived advantages of DPIs versus MDIs include ease of administration and die dose counters/warning systems that have been integrated into some of mese devices. The ease of use associated with DPIs allows for a reduction in dose administration wim the same clinical effect.4 The benefit of knowing how much medication remains available for use is true for bom multi-dose and single-dose devices, but the frequent need to reload devices like the Diskhaler™ and Aerosolizer™ is cumbersome and time consuming. It is also important to note mat diese devices require inspiratory flow rates of 30 to 60 IVmin to generate a particle fraction within me respirable range. This has implications for die use of mese devices in children. Differences between DPIs and MDIs are highlighted in Table 2 (Page 000).

Nebulizers comprise me other major category of inhalation delivery systems for asthma. Two types exist: jet (pressurized) and ultrasonic. Nebulizers, like DPIs, do not require coordination, making them extremely easy to use. However, nebulizers are relatively inefficient, have significant dead space in their tubing, and are time consuming and expensive. Furthermore, a mask or mouthpiece must be used in conjunction wim a nebulizer. The use of blow-by (holding the tube or mask in front of die face) significantly reduces pulmonary delivery and increases me risk for intra-ocular deposition of drug. This is particularly concerning when using nebulized corticosteroids. Although ß-agonist solutions may be used with jet and ultrasonic nebulizers, corticosteroid suspensions such as budesonide should only be used with jet nebulizers.5

Previously mentioned issues of coordination for successful MDI use have led to die creation of various attachments (holding chambers or spacers) to try to improve ease of use. These devices also help to reduce die problem of high velocity particles associated with MDIs. They also have been shown to increase die proportion of particles in the respirable range and trap larger particles Witiiin the device, impeding dieir access to me mourn and upper airway. Different spacers exhibit different lung deposition rates and particle size distributions.6 The pulmonary deposition of various asthma inhalers and holding chambers are presented in Table 3. The ideal holding chamber maximizes drug delivery to the lungs while minimizing oropharyngeal deposition and swallowed drug. Improving pulmonary delivery is desirable because it may enhance clinical efficacy and also allow for a reduction in dose administration. Increased lung deposition may also increase systemic bioavailability, particularly if the medication is not metabolized to a less active metabolite before it leaves the lungs to enter the systemic circulation. On the other hand, oropharyngeal deposition is associated with both local and systemic side effects; holding chambers and spacers help to reduce this risk. Other characteristics of an effective device include ease of use, optimal size, antistatic properties (due to electrostatic charge), re-use, cleaning, durability, portability and low cost. Most devices have a volume of at least 145 cc. Too large a device makes portability and compliance problematic. Antistatic properties are important because electrostatic charges promote adherence of medication to internal surfaces and result in a reduction in the available dose for inhalation. Metal spacers are not associated with this problem, but they are not available for use in the United States. Washing plastic spacers with household detergent and allowing them to air dry decreases the static charge and improves drug delivery.7 Obviously, durability is a particular concern for pediatric use.

Table

TABLE 4Guidelines for Choosing Devices for Chronic Asthma Management in Children

TABLE 4

Guidelines for Choosing Devices for Chronic Asthma Management in Children

A variety of holding chambers and spacer is available in the United States. Some are simple reservoirs, such as Inspirease™ (Schering Corporation) or the Azmacort™ spacer (Aventis Pasteur). Most are valved, which prevents escape of medication during use. Aerochamber™ (Forest Pharmaceuticals), Optichamber™ (Respironics), Ellipse™ (GlaxoSmithKline) and Volumatic™ (Allen and Hanbury's) are valved devices of various shapes and sizes. Some devices are equipped with a whistle that serves as a warning signal that the child is inspiring too quickly, causing turbulent flow which increases impaction in the oropharynx and large airway, effectively reducing delivery to the lower airways. Most products possess a mouthpiece; others provide facemask attachments or alternatives as well. Holding chambers with masks are advantageous for infants and young children, since they tend to be nasal breathers. Although nasal breathing decreases drug deposition in the lungs as compared to mouth breathing, some drug does reach the lungs nonetheless. Flexible seals on masks, such as that on Aerochamber™, help prevent air leaks around facial contours.

Holding chambers and spacers are inconsistently covered by insurance plans and are sometimes not affordable. As a result, there are a number of reports of homemade spacers, using plastic bottles and other everyday items. Some of these innovative and inexpensive devices have been shown to reduce the proportion of large particles while increasing the proportion of particles in the respirable range.8 It is interesting to note that global organizations such as World Health Organization endorse the use of homemade spacers in countries where commercial devices are not an option.9

A variety of special concerns exists in children compared to adults. Anatomic and physiologic differences, as well as behavioral and developmental factors, are especially important.10 The oropharynx of a child is characterized by relatively larger tongue size. For inhaled medications, this may promote oral deposition and potential side effects due to increased bioavailability. From a physiologic viewpoint, young children are habitual nose breathers. Nasal breathing also adversely affects pulmonary deposition while increasing bioavailability. Children have low flow rates, perhaps a result of small airways, which may make the use of certain devices such as DPIs inadvisable, since these devices require a threshold inspiratory flow rate in order to generate aerosolized particles suitable for inhalation and deposition into lower airways. Children also tend to exhibit irregular, shallow breathing, which also adversely affects delivery to the lungs. Cooperation is challenging in an ill, irritable, or upset child. Behavioral concerns, such as crying, lead to prolongation of exhalation and short, irregular inspiratory efforts. Crying reduces lung deposition even if a face mask is used.11 Distractions such as books and toys may help improve acceptance. Alternatively, administration during sleep may be tried. Given these issues, pediatricians need to select easy to use, efficient, and effective delivery systems for use in children, and they must do this while balancing benefits and risks.

So which inhaler and/or spacer devices does the busy pediatrician prescribe for youngsters with asthma? Recent review articles have provided practical recommendations on selection and technique.12·13 Table 4 (page 000) presents guidelines for selecting appropriate inhalational devices for chronic outpatient management of children in the United States. The reader should bear in mind that there will be instances in which exceptions will be necessary. Such situations may be medical, such as the lack of clinical efficacy or the onset of side effects; financial, due to everincreasing formulary restrictions; practical, related to the use of nebulization when time constraints exist; or social, as may be the case for the child with more than one caregiver or for teenagers who wish to be inconspicuous. Unfortunately, head-to-head studies are lacking for many device/medication combinations. No studies have directly compared nebulized corticosteroid administration to inhaler and spacer delivery of corticosteroids in children. Once a device is chosen, education is critical to ensure that the child and caregiver are able to perform the maneuvers successfully. Reinforcement with follow-up review is also needed, since many children fail to use inhalers correctly, even if they have had prior instruction.14

In summary, effective aerosol therapy for asthma is dependent upon many factors. Pulmonary deposition is affected by respiratory rate, degree of airflow obstruction, drug, and device. The device must generate particles of the appropriate size for penetration of the lower airway. Attachments such as holding chambers or spacers enhance MDI efficiency and reduce potential side effects. Host factors are important, particularly anatomic and physiologic factors in children, such as upper and lower airway caliber, flow rate, and nasal breathing. In addition, behavioral concerns are a major consideration. Understanding these issues provides a framework for decision making when prescribing inhalation therapy. But our efforts cannot end here. Education and repeated follow-up assessment of inhaler technique are critical to ensure long-term control of asthma.

REFERENCES

1. Ganderton D. Targeted delivery of inhaled drugs: current challenges and future goals. Journal of Aerosol Mediane. 1999;12 suppl (1)S3-S8.

2. Dolovich M. New delivery systems and propellants. Can Respir J. 1999;6:290-295.

3. Gross G, Thompson PJ, Chervinsky P, Vanden Burgt J. Hydrofluoroalkane-134a beclomethasone dipropionate, 400 mcrog, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma. Chesl. 1999;115:343-351.

4. Pauwels RS, Newman S, Borgstrom L. Airway deposition and airway effects of antiasthma drugs delivered from metered dose inhalers. Eur Respir J. 1997;10:2127-2138.

5. Nikander K, Turpeinen M, Wollmer P. The conventional ultrasonic nebulizer proved inefficient in nebulizing a suspension. Journal of Aerosol Medicine. 1999;12(2):47-53.

6. Williams RO, Patel AM, Barron MK, Rogers TL. Investigation of some commercially available spacer devices for the delivery of glucocorticoid steroids from a pMDI. Drug Development and Industrial Pharmacy. 2001; 27:401-412.

7. Wildhaber JH, Janssens HM, Pierart F, Dore ND, Devadason SG, LeSouef PN. High-percentage lung delivery in children from detergent-treated spacers. Pediatr Pulmonol. 2000;29:389-393.

8. Kissoon N, Teelucksingh S, Blake K, Kesser B, Murphy S, Geller D. Plastic bottles as spacers for a pressurized metereddose inhaler: in vitro characteristics. West Indian Med J. 2001;50:189-193.

9. Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Practical Guide for Public Health Officials and Health Care Professionals. NHLBlIWHO Workshop Report. March 1993. Bethesda, MD: National Institutes of Health, National Heart, Lung and Blood Institute; 1995. ?G? Publication 95-3659.

10. Chrystyn H. Anatomy and physiology in delivery: can we define our targets? Allergy. 1999;54:82-87.

11. Murakami G, Igarashi T, Adachi R, et al. Measurement of bronchial hyperreactivity in infants and preschool children using a new method. Annals of Allergy. 1990;64:383-387.

12. Biggart E, Bush A. Antiasthmatic drug delivery in children. Paediatric Drugs. 2002;4:85-93.

13. Pongracic JA. Asthma medications and how to use them. Curr Opin PuIm Med. 2000;6:55-58.

14. Kamps AWA, van Ewijk B, Roorda RJ, Brand PLP. Poor inhalation technique, even after inhalation instructions, in children with asthma. Pediatr Pulmonol. 2000;29:39-42.

TABLE 2

Comparison of MDIs and DPIs

TABLE 1

Features of CFC-MDIs Versus HFA MDIs

TABLE 3

Lung Deposition of Various Asthma Therapies in Children

TABLE 4

Guidelines for Choosing Devices for Chronic Asthma Management in Children

10.3928/0090-4481-20030101-09

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