When it comes to aerosol delivery, infants and small children are not simply small adults, and might require different methods, doses, and devices

Aerosol delivery to infants and children appears to be a relatively simple proposition: Smaller patients receive less aerosol than larger patients (adults), with a lower percentage of the initial drug dose reaching their lungs. When it comes to aerosol delivery, however, infants and small children are not simply small adults, and they may require different methods, doses, and devices for effective aerosol drug delivery.¹ 

The available evidence suggests that, pound for pound, children receive similar or higher amounts of medication from aerosols, per unit of body weight, than adults receive. Very few drugs, though, have been developed for administration to infants and small children. Virtually none of the common respiratory drugs were approved based on extensive, placebo-controlled studies involving children younger than 6 years. For example, albuterol sulfate was originally approved with a label indicating its use for patients 12 years or older. Over time, the label indication has reduced the treatment age to 2 years and older, but without benefit of rigorous study of children less than 6 years of age.

Likewise, the label indication for AccuNeb (Dey LP, Napa, Calif) was based on research by Kemp et al,² who studied the use of reduced doses of albuterol in 349 children aged 6 to 12 years, supporting the label indicating doses of 1.25 mg and 0.625 mg. This research showed that the two lower doses were safe and effective, but Kemp et al compared the two dosages only against a placebo, not the standard 2.5-mg dose of albuterol sulfate. Consequently, we do not know whether the reduced doses are superior (more effective or having fewer adverse effects) to standard doses of albuterol in children 6 to 12 years of age. In addition, the study provides no guidance to proper dosages for infants and children under 2 years of age.

In clinical practice, aerosol administration to infants and small children is largely based on anecdotal evidence and on adjusting doses until therapeutic or adverse effects are observed. Which dose is best? There is no simple formula for reducing the dose to provide size-appropriate or age-appropriate dosing. Some clues reside in the differences seen across the age/size continuum.

Infants Are Different
The size of an infant, including lungs and airways, changes dramatically in the first years of life. Inspiratory flows, breathing patterns, and lung volumes change with growth and development. In the first year of life, a tidal volume of approximately 7 mL per kg results in a 300% increase in tidal volume over the course of that year. Inspiratory flow increases with vital capacity. Resting respiratory rate decreases with age, as tidal volume and minute ventilation increase. The combination of low tidal volume, low vital capacity, low functional residual capacity, and a short respiratory cycle provides a short residence time for aerosol in the airways, reducing pulmonary deposition.³

While the data are limited regarding inhaled particle mass, lung deposition, and regional distribution of aerosols in neonates, infants, and young children, they suggest that aerosol delivery is substantially less efficient in that population. Pulmonary deposition of medical aerosol in neonates may be 0.5% to 1% of the nominal dose, compared with 8% to 22% in adults.⁴ 

The primary job of the upper airways is to filter out particulates from the air. The smaller the airways, the more efficient the filtering system and the lower the deposition rate. With medical aerosols, the smaller diameter of the airways in infants and children result in a greater percentage of particles being deposited in the upper airways. In addition, preferential nose breathing filters aerosols from inspired gas, reducing the mass of the drug available for pulmonary deposition.

Factors Affecting Delivery
A study by Dolovich ⁵ presented bench-study data on the relationship among patient age, breathing pattern, nebulizer output, and drug inhaled using the PARI LC Star nebulizer (PARI GmbH, Starnberg, Germany). Nebulizer output is the same for infant, child, and adult breathing patterns, but infants and small children inhale a smaller percentage of the emitted aerosol than do larger patients. Tidal volume, inspiratory-expiratory (I:E) ratio, and inspiratory flow are key to efficiently inhaling medical aerosols. In infants less than 6 months old, low inspiratory flow and low I:E ratio (for example, 1:5) result in less aerosol being inhaled.¹

In the first Neonatal Pediatric Specialty examination offered by the National Board of Respiratory Care, there were four questions about how to reduce the dose of terbutaline for administration to infants. The assumption that smaller patients need smaller doses of aerosol may be intuitive, but is not supported by any firm evidence. The reduction of aerosol efficiency with size is consistent enough to suggest that children appear to receive weight-appropriate doses of aerosols when given adult doses.⁶ Wildhaber et al⁶ demonstrated that pulmonary deposition from a pressurized metered-dose inhaler (pMDI) with a nonelectrostatic chamber ranged from 5% to 40%, with higher doses correlating with greater age among children from 1 to 12 years of age (Figure). Their findings suggest that there is a body-weight–equivalent dose across the age groups studied.

In the case of an infant receiving a standard dose (2.5 mg) of albuterol with a deposition efficiency of 0.5%, the lung dose of 12.5 mg in a 4-kg infant would be 3.1 mg per kg. Typical 10% deposition (250 mg) in a 70-kg adult would provide a similar 3.6 mg per kg.⁷ It appears that the low efficiency of deposition in infants compensates for the fact that a standard adult dose may be too large. This low deposition in infants and children provides a safety-and-efficacy profile comparable to that found in adults. Consequently, rationales to reduce doses of b-adrenergic bronchodilators that have not been well substantiated in the literature for infants and small children should not form the basis of practice.

Methods of Delivery
Children under the age of 3 years are usually unable to form a good seal on a mouthpiece and inhale when requested. For these toddlers, it is best that medications be delivered using a device, such as a nebulizer or a pMDI with a valved holding chamber (VHC), that can be combined with a comfortable, tight-fitting mask. If properly used, these two methods of administration are equally effective for the treatment of young children with asthma.⁸ 

Aerosols are best given to infants and children during relaxed breathing. The crying and struggling child or infant has very short inhalations and high flows, combined with a long exhalation. This pattern decreases the amount of medication deposited in the lower respiratory tract by as much as 90%. Aerosol medication should not be given to a child who is upset, fighting the delivery device, or crying.⁹

Medication should never be given by the blow-by method (using a mouthpiece, mask, tubing, or disposable cup that is held more than 2.5 cm in front of the face). Virtually no medication delivered using the blow-by method makes it into the lungs.¹⁰ 

The face mask and mouthpiece appear to be equally effective with a nebulizer.^11,12 Older children are usually able to place the mouthpiece directly in their mouths. When aerosols are given using a mouthpiece, it is important for the patient to breathe in slowly and deeply.

Guidelines from the Global Initiative for Asthma,¹³ a collaboration of the US National Heart, Lung, and Blood Institute and the World Health Organization, recommend a pMDI with a VHC plus a face mask for infants and preschool children; a pMDI with a VHC plus a mouthpiece for children 4 to 6 years of age; and a dry-powder inhaler (DPI), breath-actuated pMDI, or pMDI with a spacer for children 6 or more years old (see Table).

Device Selection and Compliance
Whenever possible, patients should use only one type of aerosol-generating device for all their inhalation therapy. The technique for using each device is different, and repeated instruction is necessary to ensure that the patient uses the device appropriately. The use of different devices for inhalation can be confusing for patients and may decrease their compliance with therapy. This has been referred to as device dementia.

DPIs do not substitute for pMDIs in all clinical situations. DPIs may be considered as alternatives to pMDIs for children who can generate inspiratory flow rates of more than 30 to 60 L per minute, if they are unable to use pMDIs effectively. Dose adjustment may be needed when a drug is administered using a DPI instead of a pMDI. Determining the appropriate dose of inhaled corticosteroids may be a particularly vexing problem because it is difficult to determine bioequivalence for these agents. Further research is needed to determine equivalent dosages when both the drug and the device used for inhalation therapy are altered.

To improve compliance, regularly scheduled aerosol therapy should be administered along with some easily remembered activity of daily living. For twice-daily administration, medications can be kept with the toothbrush and inhaled just before brushing the teeth. This approach helps to reduce corticosteroid levels in the mouth and hypopharynx.¹⁴ 

The availability of rescue medication at the patient's school, day-care center, or caregiver’s home must be ensured. Prepare written guidelines for medication use. Distribute these guidelines to all the places where the child stays. In contrast, avoid the regular use of inhaled medication at school. The child’s embarrassment and the inconvenience may significantly reduce compliance. Instruct the child's parents and other caregivers to keep a diary of medication use. It is important to know how regularly drugs are administered for both scheduled and as-needed medications.

Lack of response to inhaled medication can be related to a number of factors. Poor education of the care provider or child (with the resulting inability to operate the nebulizer or inhaler properly) is a frequent problem. Poor device selection can result in mismatching of the child, drug, and device. Due to lack of dose counters, patients may be unwittingly be inhaling from empty canisters of medication.¹⁵ In addition, failure to take preventive medications as prescribed, changes in the child’s environment, and misdiagnosis also have been identified as problems.

James B. Fink, MS, RRT, FAARC, is a fellow, Respiratory Science, Nektar Inc, Mountain View, Calif. For more information, contact jfink@nektar.com

References
1. Rubin BK, Fink JB. Aerosol therapy for children. Respir Care Clin N Am. 2001:7:175-213.

2. Kemp J, Nayak AS, Noonan M, Oren J, Kaplan A, Covington P. Reduced doses of nebulized albuterol are effective for maintenance treatment of children with asthma. Available at: www.accuneb.com/ClinicalStudies.htm. Accessed December 8, 2006.

3. Rubin BK, Fink JB. The delivery of inhaled medication to the young child. Pediatr Clin North Am. 2003; 50:1-15.

4. Fok TF, Monkman S, Dolovich M, et al. Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia. Pediatr Pulmonol. 1996; 21:301-309.

5. Dolovich MB. Assessing nebulizer performance. Respir Care. 2002; 47:1290-1301.

6. 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.

7. Fink JB. Aerosol delivery to ventilated infant and pediatric patients. Respir Care. 2004; 49:653-665.

8. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest. 2005; 127:335-371.

9. Iles R, Lister P, Edmunds AT. Crying significantly reduces absorption of aerosolised drug in infants. Arch Dis Child. 1999; 81: 163-165.

10. Everard ML. Inhalation therapy for infants. Adv Drug Deliv Rev. 2003; 55:869-878.

11. Mellon M, Leflein J, Walton-Bowen K, et al. Comparable efficacy of administration with face mask or mouthpiece of nebulized budesonide inhalation suspension for infants and young children with persistent asthma. Am J Respir Crit Care Med. 2000; 162:593-598.

12. Lowenthal D, Kattan M. Facemasks versus mouthpieces for aerosol treatment of asthmatic children. Pediatr Pulmonol. 1992; 14: 192-196.

13. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, Md: NIH; 2003.

14. Rubin BK, Fink JB. Optimizing aerosol delivery by pressurized metered-dose inhalers. Respir Care. 2005; 50:1191-1200.

15. Rubin BK, Durotoye L. How do patients determine that their metered-dose inhaler is empty? Chest. 2004; 126:1134-1137.