Aerosol drug delivery in the treatment of children has gained importance over the years. Since delivering aerosolized drugs to infants and pediatrics is a challenge, many factors should be taken into consideration when selecting an aerosol device, interface, and the method of administration. This paper will review those factors as they apply to aerosol administration to infants and pediatrics.

Aerosol devices used for the treatment of children can be divided into four categories: nebulizers, pressurized metered-dose inhalers, dry-powder inhalers, and soft-mist inhalers.

Nebulizers

Nebulizers transform liquid formulations and suspension into medical aerosol using one of three types of aerosol generators: jet, mesh, and ultrasonic nebulizers. Jet nebulizers (JNs) require 2 to 10 LPM of pressurized gas to draw medication up through a capillary tube from the nebulizer reservoir, where it is shorn from the tube into a wide range of particle sizes that are blasted into one or more baffles, which take larger particles out of suspension and return them to the reservoir.1,2 Jet nebulizers are classified as: 1) JNs often with a 6-inch corrugated tube acting as a reservoir; 2) JNs with valved collection bag; 3) breath-enhanced JNs; and 4) breath-actuated JNs.1 Much of the innovation of the JN has been oriented toward increasing the inhaled dose of medication by reducing the amount of emitted aerosol that is lost to the atmosphere during expiration. For instance, JNs with collection bags use reservoir bags to eliminate loss of aerosol during expiration, while breath-actuated and breath-enhanced JNs use one-way valves to increase aerosol delivery to patients by decreasing the loss of medication to the environment. Also, breath-actuated JNs create aerosol only during inspiration, resulting in as much as a threefold greater inhaled dose but at the cost of proportionally longer treatment time.3

In contrast, both the vibrating-mesh and ultrasonic nebulizers are powered by electricity and utilize a piezo element to transform electricity into mechanical energy. Therefore, they require no gas flow to generate aerosol. The vibrating-mesh nebulizer generates aerosol by pumping or pushing medication through a mesh with as many as 4,000 apertures, while the ultrasonic nebulizer transfers high-frequency vibrations to the surface of the solution, forming standing waves that generate aerosol.1,4,5

Nebulizers typically deliver larger volumes of drug and require more time to administer therapy than do other aerosol options. They also require a power source, are less portable than inhalers, and need routine cleaning and disinfection.

Metered Dose Inhalers

Unlike nebulizers that may be used with a variety of formulations, inhalers are drug/device combinations, meaning the inhalers are designed to provide consistent, reproducible drug delivery with a specific formulation. Inhalers tend to be light, small, portable, and quiet, with treatments consisting of two or more inhalations requiring seconds rather than the many minutes required with nebulizers.

The pressurized metered-dose inhaler (pMDI) is the most common aerosol device worldwide. It is small, portable, and relatively inexpensive to manufacture and provides multidose convenience. Although pMDIs are popular in the treatment of children, the press-and-breathe design is difficult for younger patients to master, and its large oropharyngeal deposition is a disadvantage.

Pressurized metered-dose inhalers are divided into two categories: conventional pMDIs and breath-actuated pMDIs.1 While the conventional pMDI is the standard pMDI with press-and-breathe design, the breath-actuated pMDI eliminates the need for hand-breath coordination as it is actuated with each breath.

Dry-Powder Inhalers

Dry-powder inhalers (DPIs) are breath-actuated inhalers that require sufficient inspiratory flow to disperse the medication and draw it from the DPI into the airways. Like the pMDI, DPIs are small, portable, and easy to use, with the advantage that they do not require coordination of actuation and inhalation. The three different types of DPIs include single-dose, multiple-unit-dose, and multiple-dose.1 Both single-dose and multiple-unit-dose DPIs require either capsule-based or blister-based systems that necessitate manual loading of the drug into the device. Multiple-dose DPIs have a powder reservoir or blister strips from which premetered individual doses are dispersed. Young children may not have the cognitive skills and sufficient inspiratory flow to use the DPI effectively; but inspiratory flows increase as the child grows, and a child may be physically able to generate sufficient inspiratory flow to operate some DPIs prior to the age of 4 years.6,7

Soft-mist inhalers are a relatively new category of small, portable devices that use mechanical energy to produce aerosol from liquid formulation. With each actuation, drug volumes of between 11 and 15 µL are transformed into a plume of aerosol generated over 1.2 to 1.5 seconds.

Selecting the best aerosol device for neonates, infants, toddlers, and children can be challenging. The efficacy of nebulizer, pMDI, and DPI is equivalent if the device is age appropriate and used correctly by patients.6,8,9 Patient age and physical and cognitive abilities, as well as patient’s tolerance, acceptance, and preference of aerosol device and interface, should guide the selection of the optimal aerosol device for neonates through the range of pediatrics.

How Does It Work?

It is important to know the technical aspects of aerosol delivery devices. Most drugs come with a specific aerosol device. For instance, nebulizers should be used to deliver drugs such as rhDNase (Pulmozyme®), tobramycine for inhalation (TOBI), acetylcysteine, colimycine, and saline, which cannot be delivered by pMDIs or DPIs.10 Using an alternative nebulizer that is not approved for specific drug formulations can cause problems in terms of efficacy and toxicity.11 The use of the conventional pMDIs should be restricted to patients with good hand-breath coordination. In patients who are not able to coordinate actuation of the pMDI with breathing, either a spacer or a valved holding chamber (VHC) that can be combined with the pMDI or the breath-actuated pMDI can be the system of choice. DPIs should not be used with patients who cannot generate the sufficient flow required by the device. It is known that bronchodilator delivery by pMDIs with spacer is as effective as nebulizers in acute asthma attacks.12 In fact, pMDIs and DPIs deliver bronchodilators and steroids much faster than nebulizers.

Since a child 3 years of age or younger may not be able to master specific breathing techniques, the nebulizer or pMDI with VHC should be selected in the administration of aerosol therapy for this patient population.7,13,14 By the age of 4, children may understand how to use a pMDI or DPI successfully and generate sustained inspiratory flow rates required to use these inhalers. Once children reach 5 years of age, they may be able to use the breath-actuated pMDI or the breath-actuated nebulizer. Therefore, it is essential to assess the patient’s physical and cognitive abilities to use these aerosol devices.

Interfaces

Face mask, mouthpiece, blow-by, hood, high-flow nasal cannula, and spacer/valved holding chamber are interfaces used with aerosol delivery devices. A face mask is the most commonly used interface in children. Regardless of age, a face mask should be used until the child can comfortably use a mouthpiece. Factors such as weight, flexibility, anatomic contours, dead volume, and face-mask seal influence drug delivery. A light and flexible face mask with anatomical contour may be better tolerated and accepted by children. When a face mask is used with children, an optimal seal (a light pressure resulting in no leaks) between face and face mask will maximize the efficiency of aerosol therapy. Studies showed that it is difficult to obtain an optimum face-mask seal,15,16 and even small leaks cause significant reduction in aerosol drug delivery to neonates and pediatrics.17,18 Several studies explained the importance of face-mask designs and reported differences in efficiency in achieving a good face-mask seal for the different designs.19-22

It should be noted that inappropriate use of the mouthpiece can cause underdosing, and, since children younger than 3 years of age cannot use a mouthpiece properly, utilizing another interface, such as a face mask, can be a good alternative. Unfortunately, up to 49% of young patients tend to fuss and fight the face mask. The more they fuss, the less aerosol reaches the lungs.18

Blow-by is the act of directing aerosol from a jet nebulizer toward the patient’s face and is used for aerosol therapy in crying and uncooperative children. Use of blow-by in aerosol drug delivery to children should be discouraged. Researchers have reported that blow-by is less efficient than a face mask, because aerosol deposition decreases as the distance from the device to the child’s face is increased.23-25

For infants and toddlers, a hood is as efficient as a mask in terms of aerosol drug delivery and leads to a better therapeutic index with minimal deposition at the infant’s eyes.26-29 Since it is better tolerated by some patients, using a hood can be a good alternative—especially for neonates who do not tolerate face masks—and it may be preferred by parents for aerosol drug administration.

The high-flow nasal cannula (HFNC) is a relatively new interface that is being used for aerosol therapy in neonates and pediatrics. The efficiency of HFNC has been reported by a few in vitro studies.30,31 Although clinical studies in this area of research are lacking, using HFNC may be a good alternative, especially for babies who do not tolerate masks during aerosol therapy.

The use of valved holding chambers has facilitated delivery of aerosols from inhalers such as pMDIs and possibly soft-mist inhalers to the smallest of patients. Use of VHCs rather than simple spacers is important, as they reduce rebreathing of mechanical dead space for the smaller patients. Valved holding chambers are made of metal, paper, or plastic. While electrostatic charge is not a problem with a metal or paper, the plastic may have either electrostatic or nonelectrostatic properties. If the plastic spacer is not “nonelectrostatic,” it should be washed with liquid dishwashing detergent periodically in order to minimize the electrostatic charge before it is used. Otherwise, electrostatic charges draw small particles to the walls of the chamber and will decrease aerosol delivery. The volume of a VHC needs to be considered for children with small tidal volumes, as emptying a small volume spacer takes less time and the concentration of aerosol in the chamber is higher.10

Administration Technique

The administration technique is important for the success of aerosol therapy. Reading and following the manufacturer’s instructions for proper assembly and use are important to ensure correct use of the device and interface, which will lead to effective aerosol therapy in children.

If a therapy fails, health care providers should evaluate cooperation, face-mask seal, inhalation delay after firing, and acceptance of the aerosol device and interface by patients and their parents. Any delay between pMDI actuation and inhalation will decrease the lung dose because of gravitational forces that will make aerosol particles sediment onto the spacer wall. For children who cry during treatment, administering the aerosol during sleep can be an option. Crying children receive no aerosol to the lungs, and inhaled drugs should be given to infants when they are settled and breathing quietly. Although sleep breathing patterns increase drug dose delivered to children,32 a study showed that 69% of the children woke up when aerosol is given during sleep.33 Other techniques such as encouragement and positive reinforcement, play activities, magic, etc can be used when a child cries or refuses aerosol therapy. Parents of young children should be educated about aerosol therapy and the importance of an optimal face-mask seal, a good administration technique, and quiet breathing, as well as good cooperation during therapy. As children grow, their needs and preferences for aerosol devices change. Therefore, frequent follow-up and demonstration are essential.

Conclusion

Most aerosol devices have been designed for use in adults, requiring some level of adaptation for use with neonates, infants, toddlers, and small children. Identifying and selecting the appropriate device, interface, and administration techniques is essential to optimize patient acceptance and clinical efficacy.


Arzu Ari, PhD, RRT, PT, CPFT, FAARC, is associate professor, and James B. Fink, PhD, RRT, FAARC, FCCP, is adjunct professor, division of respiratory therapy, Georgia State University, Atlanta. For further information, contact [email protected]

References
  1. Ari A, Hess D, Myers TR, Rau JL. A Guide to Aerosol Delivery Devices for Respiratory Therapists. Dallas: American Association for Respiratory Care; 2009.
  2. Hess DR. Nebulizers: principles and performance. Respir Care. 2000;45:609-22.
  3. Rau JL, Ari A, Restrepo RD. Performance comparison of nebulizer designs: constant-output, breath-enhanced, and dosimetric. Respir Care. 2004;49:174-9.
  4. Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2010;377:1032-45.
  5. Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care. 2002;47:1406-16.
  6. Ari A, Fink J. Guidelines to aerosol devices in infants, children and adults: which to choose, why and how to achieve effective aerosol therapy? Expert Rev Respir Med. 2011;5:561-72.
  7. National Asthma Education and Prevention Program. Expert Panel III: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute; 2007.
  8. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005;127:335-71.
  9. Geller DE. Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler. Respir Care. 2005;50:1313-21.
  10. Janssens H, Tiddens H. Aerosol therapy: the special needs of young children. Pediatr Respir Rev. 2006;7(suppl 1):S83-5.
  11. Tiddens H. Matching the device to the patient. Pediatr Pulmonol Suppl. 2004;26:26-9.
  12. Cates CJ, Rowe BH, Bara A. Holding chambers versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2002(2):CD000052.
  13. Everard ML. Inhalation therapy for infants. Adv Drug Deliv Rev. 2003;55:869-78.
  14. Everard ML. Aerosol delivery to children. Pediatr Ann. 2006;35:630-6.
  15. Janssens HM, Heijnen EM, de Jong VM, et al. Aerosol delivery from spacers in wheezy infants: a daily life study. Eur Repir J. 2000;16:850-6.
  16. Smaldone GC, Berg E, Nikander K. Variation in pediatric aerosol delivery: importance of facemask. J Aerosol Med. 2005;18:354-63.
  17. Esposito-Festen JE, Ates B, van Vliet FJ, Verbraak AF, de Jongste JC, Tiddens HA. Effect of a facemask leak on aerosol delivery from a pMDI-spacer system. J Aerosol Med. 2004;17(1):1-6.
  18. Erzinger S, Schueepp KG, Brooks-Wildhaber J, Devadason SG, Wildhaber JH. Facemasks and aerosol delivery in vivo. J Aerosol Med. 2007;20 Suppl 1:S78-83.
  19. Amirav I, Newhouse MT. Aerosol therapy with valved holding chambers in young children: importance of the facemask seal. Pediatrics. 2001;108:389-94.
  20. Esposito-Festen J, Ates B, van Vliet F, Hop W, Tiddens H. Aerosol delivery to young children by pMDI-spacer: is facemask design important? Pediatr Allergy Immunol. 2005;16:348-53.
  21. Smaldone GC. Assessing new technologies: patient-device interactions and deposition. Respir Care. 2005;50:1151-60.
  22. Hayden J, Smith N, Woolf D, Barry P, O’Callaghan C. A randomised crossover trial of facemask efficacy. Arch Dis Child. 2004;89:72-3.
  23. Rubin BK. Bye-bye, blow-by. Respir Care. 2007;52:981.
  24. Lin HL, Restrepo RD, Gardenhire DS, Rau JL. Effect of face mask design on inhaled mass of nebulized albuterol, using a pediatric breathing model. Respir Care. 2007;52:1021-6.
  25. Restrepo RD, Dickson SK, Rau JL, Gardenhire DS. An investigation of nebulized bronchodilator delivery using a pediatric lung model of spontaneous breathing. Respir Care. 2006;51:56-61.
  26. Amirav I, Shakked T, Broday DM, Katoshevski D. Numerical investigation of aerosol deposition at the eyes when using a hood inhaler for infants—a 3D simulation. J Aerosol Med Pulm Drug Deliv. 2008;21:207-14.
  27. Amirav I, Balanov I, Gorenberg M, Groshar D, Luder AS. Nebuliser hood compared to mask in wheezy infants: aerosol therapy without tears! Arch Dis Child. 2003;88:719-23.
  28. Amirav I, Oron A, Tal G, et al. Aerosol delivery in respiratory syncytial virus bronchiolitis: hood or face mask? J Pediatr. 2005;147:627-31.
  29. Kugelman A, Amirav I, Mor F, Riskin A, Bader D. Hood versus mask nebulization in infants with evolving bronchopulmonary dysplasia in the neonatal intensive care unit. J Perinatol. 2006;26:31-6.
  30. Ari A, Harwood R, Sheard M, Dailey P, Fink JB. In vitro comparison of heliox and oxygen in aerosol delivery using pediatric high flow nasal cannula. Pediatr Pulmonol. 2011;46:795-801.
  31. Bhashyam AR, Wolf MT, Marcinkowski AL, et al. Aerosol delivery through nasal cannulas: an in vitro study. J Aerosol Med Pulm Drug Deliv. 2008;21:181-8.
  32. Janssens H, van der Wiel E, Verbraak A, de Jongste J, Merkus P, Tiddens H. Aerosol therapy and the fighting toddler: is administration during sleep an alternative? J Aerosol Med. 2003;16:395-400.
  33. Esposito-Festen JE, Ijsselstjin H, Hop W, van Vliet F, de Jongste J, Tiddens H. Aerosol therapy by pMDI-spacer in sleeping young children: to do or not to do? Chest. 2006;130:487-92.