Delivery of inhaled medication in children

INTRODUCTION — The delivery of aerosolized medication is an important component of treatment for many respiratory disorders and is a critical aspect of asthma management in children [1-15]. A basic knowledge of the uses and limitations of aerosol delivery systems, the properties of effective aerosols, and the anatomic considerations affecting aerosol delivery in infants and children is essential to the optimal use of this therapeutic modality [16-18].

An overview of the delivery of inhaled medication in children is presented here. Specific aspects of medication delivery using nebulizers, pressurized metered dose inhalers (pMDIs) and soft mist inhalers (SMIs), and dry powder inhalers (DPIs) are discussed separately. (See "Use of medication nebulizers in children" and "The use of inhaler devices in children".)

Delivery of aerosolized medications in adults is also reviewed separately. (See "Delivery of inhaled medication in adults".)

ADVANTAGES OF AEROSOLIZED DRUG DELIVERY — There are several advantages to delivering drugs by aerosol rather than systemically:

●Delivery of agents directly to their sites of action decreases the dose required for therapeutic effect.

●Faster onset of action (compared with intravenous delivery) of bronchodilating medications allows more rapid reversal of acute bronchoconstriction.

●Reduced systemic bioavailability minimizes side effects.

●Ability to achieve high in-situ drug concentrations.

TYPES OF AEROSOL DELIVERY DEVICES — Three types of aerosol delivery devices are widely employed in the management of children with respiratory disease (table 1A-B):

●Nebulizers, which use a jet flow of driving gas, ultrasound, or vibrating membrane to aerosolize medications

●Pressurized metered dose inhalers (pMDIs) and soft mist inhalers (SMIs)

●Dry powder inhalers (DPIs)

Specific issues related to the use of these devices are discussed separately. (See "Use of medication nebulizers in children" and "The use of inhaler devices in children".)

TYPES OF MEDICATIONS DELIVERED — Glucocorticoids, bronchodilators, antibiotics, antivirals, pulmonary vasodilators, and mucolytic agents can be administered via aerosol using different aerosol-generating devices [1-4]. In addition, the inhalation route is also used for systemic delivery (insulin, opioids, and sedatives). Antifungals, immunosuppressants, and anticoagulants are used off label [9,10].

LUNG DISEASES MANAGED USING AEROSOL THERAPY — A wide range of pediatric disorders can be treated effectively using aerosol therapy as a central component of management. Examples include:

●Obstructive airway diseases, including asthma, congenital emphysema, and bronchiectasis [19]

●Processes that result in acute upper airway obstruction, usually croup or postextubation upper-airway edema

●Chronic lung diseases, including bronchopulmonary dysplasia and cystic fibrosis [20]

●Tracheitis in tracheostomized children [21]

●Pulmonary hypertension [22]

●Infectious diseases, including Pneumocystis jirovecii pneumonia (treatment and prophylaxis), respiratory syncytial virus infection, and some pulmonary fungal infections [23-28]

Less common off-label indications for aerosol therapy include intractable cough, which may respond to inhaled lidocaine, and administration of analgesia in the setting of palliative care, using inhaled morphine [29-31]. Aerosol delivery of gene constructs are under investigation for diseases such as cystic fibrosis [9,11,32].

PROPERTIES OF AN IDEAL AEROSOL THERAPY DEVICE — The ideal aerosol delivery device varies depending upon the medication to be administered and the clinical situation. To maximize the advantages of inhaled medications described above, the device selected should:

●Deliver an adequate dose of medication to the lungs

●Minimize oropharyngeal deposition

●Minimize systemic side effects

●Match the needs of the patient

●Be acceptable and simple for the patient to use

●Be cost effective

FACTORS AFFECTING DRUG DEPOSITION — A number of factors influence the ultimate amount of medication delivered to the appropriate anatomic region within the lung.

Properties of the device — Devices vary greatly in their efficiencies in delivering particles to the lungs. From 0.5 to 60 percent of the total dose of medication is delivered to the peripheral airways when these devices are used optimally. (See "Delivery of inhaled medication in adults".)

Aerosol properties — Pharmaceutical aerosols are characterized by measures of central tendency and dispersion. The former is the mass median aerodynamic diameter (MMAD), which represents the particle diameter at which half of the aerosol particles by mass are larger and half are smaller [4,17,33,34]. The geometric standard deviation (GSD) differentiates a monodisperse (GSD <1.2) from a polydisperse aerosol (GSD >1.2). The other parameter frequently described is the respirable fraction, which corresponds to the percent of particles <5 micrometers. This is considered the fraction of aerosol likely to deposit in the lungs. However, some experts argue that smaller sizes are more optimal for infants and children.

Mechanisms of deposition — There are three basic mechanisms of aerosol deposition: inertial impaction, gravitational sedimentation, and Brownian diffusion [4,35,36].

●Particles with an MMAD greater than 5 micrometers and those travelling at high velocity are deposited by impaction largely in the oropharynx. This is the rationale for using valved holding chambers or spacers with pressurized metered dose inhalers (pMDIs) to allow deceleration of the aerosol.

●Particles with an MMAD between 3 and 5 micrometers are optimal for deposition in the proximal airways and are deposited largely by inertial impaction.

●Particles with an MMAD between 0.5 and 3 micrometers are deposited in distal airways by gravitational sedimentation. This is the rationale for using a breath-holding maneuver to increase residence time when using pMDIs or dry powder inhalers (DPIs).

●Particles with MMAD smaller than 0.5 micrometers are deposited at the alveolar level by random motion (Brownian diffusion).

Properties of medication to be delivered — The ultimate effect of the dose is dependent upon the site of deposition of the drug within the lung, the rate of drug clearance from the airway, and the site of action of the medication [35,37]. To be effective, drugs must be able to withstand the shear forces required to generate the aerosol and often must penetrate the mucus layer and airway mucosa to reach their target receptors or cells.

Disease state and ventilatory pattern — Anatomic and pathologic factors, as well as ventilatory patterns, alter the efficiency of aerosolized drug delivery. Aerosol particles may be deposited in the central, rather than lower, airways in diseases that are associated with decreased airway caliber such as asthma [2,35]. In a study of infants with acute bronchiolitis, only 1.5 percent of aerosolized drug released from the nebulizer was deposited in the lung and 0.6 percent penetrated to the peripheral airways [38].

Diseases causing mucus plugging or atelectasis, such as cystic fibrosis, may lead to reduction and marked heterogeneity in the distribution of particle deposition. Other factors such as tidal volume, breath-holding time, respiratory rate, and nose versus mouth breathing can dramatically alter the deposition of aerosolized particles in the lungs [4,13,17,35,39].

Patient technique, acceptance, and preference — Improper technique is a common cause for a suboptimal response to aerosolized medication and worse outcomes [40], and poor understanding or acceptance may lead to nonadherence. Patient education and health care worker knowledge are essential for the effective use of any aerosol delivery device [4,17]. However, studies on inhaler technique show low rates of correct patient inhaler technique that are most likely due to poor knowledge on the subject by health care workers [41,42].

Rapid inspiration from pMDIs may increase inertial impaction of droplets in the central airways and decrease lung delivery. Many valved holding chambers incorporate a whistle to alert the patient that their inspiratory flow is too high (above 30 L/min). However, this feature is inaccurate and may falsely reassure patients that they are using the correct technique [43].

Review of inhaler technique at each encounter using the teach back method is recommended. Device selection is influenced by health care worker and patient/caregiver preferences, third-party-payer, drug availability, and patient characteristics that hinder the operation/use of certain inhalers (eg, weakness, severe arthritis or contractures, altered mental status).

SPECIAL CONSIDERATIONS IN INFANTS AND YOUNG CHILDREN

Anatomic and physiologic differences — The delivery of aerosolized medication to infants and young children poses some challenges due to anatomic and physiologic differences in their respiratory systems compared with adults [4]. The anatomic differences from adults include a higher larynx, epiglottis closer to the palate, more collapsible pharynx and supraglottic tissues, and relatively larger tongue. Physiologically, children have faster breathing rates, lower tidal volumes, and shorter inspiratory times. The deposition of medication in peripheral airways and alveoli is reduced in infants and young children due to these anatomic and physiologic differences, which combine to lower the resident time of small particles in the airway [3,4,13-15,44-46].

Dose — Data suggest that drug deposition in children older than five to six years of age is similar to that observed in adults, and identical doses in children and adults result in similar plasma concentrations [37,47]. Thus, aerosol doses generally do not need to be decreased, except possibly in infants and young children. However, it is probable that variability exists based upon the specific medication used, drug delivery technique (tidal volume breathing compared with inspiratory breath hold), and delivery device employed. These data support the concept that younger children self-adjust their dose [48].

The output of the aerosol-generating device may exceed inspiratory flow rate in children younger than six months of age, resulting in the loss of air entrainment (mixing of inspired air with nebulizer output) and a higher concentration of drug delivered [46]. Overall, this effect can lead to a higher inhaled dose per kilogram of body weight in the infant younger than six months of age, increasing the possibility of side effects, although increased side effects have not been reported in this age group, nor are there recommendations to decrease any drug dose because of this effect. However, if clinicians decide to decrease the dose, a reduction of the treatment time is preferred rather than a reduction in loading volume of the nebulizer [49].

Respiratory pattern — Normal tidal breathing results in the most efficient delivery of aerosolized medications to the airways. Crying markedly reduces aerosol delivery to the lungs. Caregivers play a major role in keeping the infant calm during treatments [50,51]. Although in vitro studies suggested that administration of medication via a pressurized metered dose inhaler (pMDI) with valved holding chamber resulted in increased drug delivery, a "real-life" study in infants and children showed the opposite due to awakening and distress of the participants [52,53]. Thus, aerosol administration during sleep may be tried for uncooperative infants and children, but caregivers should be informed that the success rate may be low (ie, the infant may awaken and start crying).

The use of breath-actuated devices and dry powder inhalers (DPIs) requires inspiratory flows that are not achieved by infants and toddlers. Thus, these types of devices are not used in this age group. In addition, clinicians should verify that patients are able to open the valves of valved holding chambers and dosimetric nebulizers during inhalation [4]. (See "The use of inhaler devices in children".)

Interface — The interface between the aerosol-generating device and the patient is an important, and often overlooked, component of effective therapy. Administration of aerosols by a mouthpiece rather than a facemask is generally preferred to avoid facial and ocular exposure to inhaled medications [54-56]. Similar clinical responses have been reported for mouthpiece and facemask administration for bronchodilators in children with acute asthma [57] and for nebulized budesonide in chronic asthma [58]. However, most children are not able to reliably breathe through a mouthpiece until approximately four years of age, and patient technique with a mouthpiece must be assessed prior to switching from a facemask [4,59]. Facemasks with a horizontal aerosol path from the device to the face are preferred over those with a vertical aerosol path because they are associated with lower rates of facial and ocular deposition of medication [4,55].

Delivery of fluticasone propionate via a pMDI with an antistatic valved holding chamber is similar when using either a mouthpiece or facemask in children up to nine years of age, and both are associated with higher delivery compared with direct actuation into the mouth [60]. These devices are associated with higher systemic concentrations of glucocorticoids and an increased risk of side effects, particularly with higher drug doses. Thus, doses should be adjusted to the lowest that maintains asthma control.

Poor patient cooperation leads many caregivers to use blow-by techniques for aerosol delivery of nebulized medications. However, removing the facemask 1 or 2 cm from the face may reduce the inspired dose by approximately 33 and 50 percent, respectively [39,61]. When a facemask is used either with a spacer or nebulizer, it should be placed snugly and tightly fitted over the face, as even a small leak may reduce the inhaled mass of drug to <0.5 percent of the total dose [62].

The nose is an efficient filter for particles in aerosol [63]. Thus, when using a facemask, any nose breathing is associated with increased deposition in the upper airway. This may lead to more systemic side effects due to greater drug absorption from the upper airway. This is an area of concern for aerosols delivered through nasal cannulas [44].

Specific aspects of aerosolized medication delivery using nebulizers, pMDIs and soft mist inhalers (SMIs), and DPIs are presented separately. (See "Use of medication nebulizers in children" and "The use of inhaler devices in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: How to use your child's dry powder inhaler (The Basics)" and "Patient education: How to use your child's metered dose inhaler (The Basics)")

●Beyond the Basics topics (see "Patient education: Asthma inhaler techniques in children (Beyond the Basics)" and "Patient education: Asthma symptoms and diagnosis in children (Beyond the Basics)")

SUMMARY

●Types of aerosol delivery devices – There are three main types of aerosol delivery devices used in the management of children with respiratory disease: nebulizers, pressurized metered dose inhalers (pMDIs) and soft mist inhalers (SMIs), and dry powder inhalers (DPIs). (See 'Types of aerosol delivery devices' above.)

●Factors affecting drug deposition – Factors that affect drug deposition include properties of the device, aerosol particle, and medication and patient factors such as disease state, ventilatory pattern, and administration technique. (See 'Factors affecting drug deposition' above.)

●Dose adjustment – In general, aerosol doses do not need to be decreased except possibly in infants and young children. (See 'Dose' above.)

●Respiratory pattern – Normal tidal breathing results in the most efficient delivery to the airways. Crying markedly reduces aerosol delivery to the lungs. Administering the aerosolized medication while the infant/young child is asleep can be attempted, but the child often awakens and becomes distressed. (See 'Respiratory pattern' above.)

●Administration techniques – Administration of aerosols by a mouthpiece rather than a facemask is generally preferred due to decreased ocular and facial exposure. Blow-by techniques significantly decrease the inspired dose and are discouraged. (See 'Interface' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert H Moore, MD, who contributed to earlier versions of this topic review.