INTRODUCTION — The delivery of aerosolized medication is an important component of treatment for many respiratory disorders in children. Glucocorticoids, bronchodilators, antibiotics, mucus hydration agents, and mucolytic agents can be administered via aerosol.
Nebulizer devices are widely used to deliver aerosol therapy, especially in children. A wide variety of nebulizers are available for use in the home and hospital, with varying capacities to deliver drugs to the lungs . Clinicians must consider how a particular nebulizer performs with the specific drug to be administered to ensure its clinical suitability [1-4].
The use of medication in nebulizers for children is presented here. An overview of aerosolized medication delivery in children and the use of pressurized metered dose inhalers are discussed separately. (See "Delivery of inhaled medication in children" and "The use of inhaler devices in children".)
INDICATIONS — Nebulizers are used to provide aerosol therapy to patients too ill or too young to use handheld devices and in situations where large drug doses are necessary. These devices also are required for some medications available only in liquid form, including pentamidine, ribavirin, DNAase, hypertonic saline, and tobramycin.
The potential benefits of nebulizers need to be balanced with the disadvantages associated with the use of these devices. These include higher costs, longer set-up and delivery time, decreased portability, variable nebulizer performance, and (with jet nebulizers) the need for a source of compressed air or oxygen.
BASIC TYPES OF NEBULIZERS — There are three types of nebulizers: jet nebulizers, ultrasonic nebulizers, and vibrating mesh (membrane) nebulizers. There are differences in performance among these types of nebulizers and also among nebulizers of the same type produced by various manufacturers. These differences have potential clinical implications [5,6]. Jet nebulizers are the most frequently used form of nebulizer in the clinical setting. The advantages and disadvantages of the jet [7-10], ultrasonic [7,9], and mesh [11,12] nebulizers are reviewed in the table (table 1).
Jet nebulizers — Jet nebulizers utilize a driving gas of compressed air or oxygen through a jet, creating a negative pressure, which entrains large aerosolized liquid droplets into the gas stream. These particles then are reduced in size by their impaction upon internal baffles, resulting in the generation of smaller, respirable particles of 1 to 5 microm in size [7-10]. Aerosolized medication then is delivered through a patient interface, usually a mouthpiece or facemask (figure 1). Most aerosolized medications are best delivered by this method of nebulization.
Ultrasonic nebulizers — Ultrasonic nebulizers consist of a power unit and transducer, with or without an electric fan. Electrical energy from the power unit is converted to high-frequency (1.63 megahertz) ultrasonic waves by a piezoelectric element in the transducer [7,9]. These ultrasonic waves are transmitted to the surface of the solution to create an aerosol. A fan is used to deliver the aerosol to the patient, or the aerosol is evacuated from the nebulization chamber by the inspiratory flow of the patient. Small-volume ultrasonic nebulizers are commercially available for delivery of inhaled bronchodilators. Large-volume ultrasonic nebulizers are used for sputum induction.
Vibrating mesh nebulizers — Mesh nebulizers use a perforated membrane to generate the aerosol (figure 2). Electronic nebulizers can generate aerosolized particles that are highly uniform and respirable (mass median diameter of 3.6 +/- 0.1 microm) and deliver drugs in less than five minutes [11,12]. Other available vibrating mesh nebulizers include the Aeroneb, MicroAIR/NE-U22, and the I-neb. (See "Delivery of inhaled medication in children", section on 'Aerosol properties'.)
FACTORS AFFECTING JET NEBULIZER PERFORMANCE — Jet nebulizers are the most commonly used type of nebulizer in most countries because of their lower cost and other considerations described above. An effective nebulizer should deliver at least 50 percent of the total dose as respirable aerosol within 10 minutes . However, nebulizer performance can vary greatly based upon a number of factors (table 2). Conventional jet nebulizers are highly inefficient because of output lost during exhalation during normal breathing and because more than 90 percent of the primary droplets become trapped on the baffles or internal structures . In addition, conventional jet nebulizers produce a constant flow rate during aerosolization, leading to further drug wastage and inefficiency. Enhanced jet nebulizers have been designed that address specific delivery issues. (See 'Enhanced jet nebulizer designs' below.)
●Nebulization time – The majority of nebulized dose is delivered during the first five minutes in most cases , and little additional benefit is gained by extending nebulization time beyond 5 to 10 minutes . Furthermore, aerosol output drops dramatically and further nebulization is unproductive once sputtering begins . Continuous nebulization is employed in the management of acute severe asthma in children and is discussed below. (See 'Continuous nebulization' below.)
●Chamber design – Nebulizers vary widely in the ability to efficiently aerosolize medications and generate aerosol particles in the "respirable range," with total lung deposition of starting medication ranging from approximately 2 percent up to 20 percent or greater with more efficient nebulizers [4,5,17,18]. The efficiency also varies as a function of patient age. As an example, the mean total lung deposition of albuterol delivered using a breath-enhanced, open-vent-assisted nebulizer expressed as a percentage of starting dose was 5 percent in children younger than four years of age and 11 percent in children four to nine years of age . (See 'Breath-enhanced open-vent nebulizer' below.)
●Driving gas – The fraction of particles in the respirable range also is altered by the flow rate of the driving air or oxygen, with flow rates of 8 liters per minute providing optimal mass median aerodynamic diameter (MMAD) of the aerosol particles, aerosol volumes, and nebulization times when using conventional small-volume nebulizers [5,8,19]. For these nebulizers, decreasing the driving flow rate from 8 to 6 L/min may reduce the output of respirable particles by 25 to 30 percent . However, many home compressors are not capable of delivering flow rates this high, resulting in a larger MMAD of the aerosol particles. Alternatively, breath-enhanced nebulizers function efficiently at driving flow rates of 3 to 5 L/min, making them much more effective when used with home compressors .
Such variances in output highlight the importance of trying to match recommended nebulizers and medical compressors for the medication being delivered, as indicated in package inserts. For instance, pivotal trials for budesonide inhalation suspension used Pari nebulizers and compressors to provide optimal drug delivery. For some drugs, such as short-acting beta agonists, there are no recommendations for specific nebulizers or compressors. In addition, in the hospital setting, the set flow rate may not reflect the true flow exiting the nebulizer when using a dry gas source to drive the nebulizer. This can reduce the flow rate by up to 2 L/min due to inadequate back pressure compensation of the flow meter  and may result in a larger MMAD and decreased pulmonary deposition of the aerosolized agent [1,20].
To avoid some of the variation in drug delivery seen with jet nebulizers, a suitable alternative for some medications is to switch to metered dose inhalers with valved-holding chambers. These devices are effective for the chronic delivery of inhaled glucocorticoids and the delivery of short-acting beta agonists in acute asthma, including in the emergency department setting. (See "The use of inhaler devices in children".)
Finally, the density of the gas powering the nebulizer affects nebulizer performance. As an example, the inhaled mass of albuterol is significantly reduced when a nebulizer is powered with a mixture of 60 to 80 percent helium and 20 to 40 percent oxygen (heliox). Accordingly, the flow to the nebulizer should be doubled if it is powered with heliox . Heliox may improve aerosol delivery to the lower respiratory tract because the decrease in density results in the creation of smaller particles; however, the clinical benefit of this approach is unclear [24-30]. (See "Physiology and clinical use of heliox".)
●Dead volume – Dead volume refers to the residual medication solution remaining in the nebulizer reservoir after therapy. This residual solution is incapable of activating further nebulization, and the amount can vary considerably between different nebulizer models [17,31]. The concentration of drug within this dead volume is increased by the evaporation of the solute, such as normal saline, during nebulization. This can lead to considerable drug wastage.
The amount of wasted drug can be reduced by adjusting the starting volume of nebulizer solution to at least 4 mL, an amount that generally can be administered within 10 minutes using flow rates of 8 L/min [5,17]. Tapping on the nebulizer chamber during nebulization may further reduce dead volume.
●Physical properties of the solution – The primary droplet size produced during nebulization is proportional to the viscosity and surface tension of the nebulized liquid, which increase as the solution cools during nebulization, potentially resulting in decreased output and longer nebulization times .
●Other factors – The level of cooperation of the patient ; changes in breathing patterns, such as occurs with persistent cough; and type of facemask used  may also impact drug delivery. In addition, the filters on the medical compressor units should be changed every approximately six months; failure to do so can affect performance.
Breath-enhanced open-vent nebulizer — Open-vent jet nebulizers incorporate an opening in the reservoir that allows the continuous entrainment of air during nebulization, resulting in increased airflow within the nebulizer chamber, smaller aerosol particle size, shorter nebulization times, and greater aerosol output during inspiration [14,34]. However, these increased flows can result in greater drug loss during exhalation.
The drug wastage of the open-vent jet nebulizer can be partially overcome by using a breath-enhanced system because these nebulizers entrain gas only during inspiration [14,22]. Use of a breath-enhanced nebulizer may increase the delivered dose by as much as 20 to 50 percent .
Advantages of breath-enhanced, open-vent nebulizers include [10,35,36]:
●Production of smaller particles in aerosol
●Faster nebulization rates as compared with conventional nebulizers
●Increased aerosol delivery to the patient with less wastage
●Lower compressed airflow required
The disadvantages of open-vent jet nebulizers are that they are dependent upon the patient's inspiratory flow rate and tidal volume for optimum function  and they cost more than conventional nebulizers.
These nebulizers have not been fully evaluated in infants and very young children, although they appear to be more efficient than the conventional nebulizers generally used in the management of this patient population [37,38].
Storage bag nebulizers — Some nebulizers incorporate a storage bag with a one-way valve in the mouthpiece connector. Aerosol is collected in the bag during the expiratory phase and delivered to the patient on the subsequent inhalation, reducing medication waste.
Intermittent nebulizers — Older intermittent nebulizers use a thumb control that allows the patient to manually cease gas flow to the nebulizer during exhalation, which greatly decreases drug wastage. However, these systems require good hand-breath coordination and increase nebulization times up to fourfold , making them unsuitable for most young children.
Breath-actuated nebulizers — Breath-actuated nebulizers generate aerosols in coordination with inspiration and are capable of delivering higher drug doses, although with longer nebulization times [34,39]. These nebulizers are activated by a breath-actuated diaphragm at inspiratory flow rates as low as 15 L/min. A study of children presenting to an emergency department with acute asthma suggests that the delivery of a single dose of albuterol using a breath-actuated nebulizer (AeroEclipse) (picture 1) is more effective than a single dose or one hour of continuous albuterol administration using a conventional jet nebulizer . Of note, children as young as six months of age were able to breath-actuate the nebulizer, although a few initially required manual activation for four to six breaths due to their high clinical respiratory scores.
AEROSOL DELIVERY IN SPECIAL SITUATIONS
Mixing nebulized medications — Some patients need more than one nebulized medication, such as one or more bronchodilators or a bronchodilator plus glucocorticoid or hypertonic saline. Certain preparations are compatible and can be mixed into a single nebulizer treatment, thus improving patient convenience. However, caution is necessary as certain mixtures are incompatible due to changes in particle size or other characteristics. As an example, hypertonic sodium chloride is compatible with budesonide, but not with albuterol, formoterol, ipratropium, or fluticasone. A listing of compatible and incompatible solutions is provided in the table (table 3).
When mixing nebulized medications, freshly opened, single-use formulations should be used.
Nebulizers for specific medications — Specially constructed small-volume nebulizers with closed scavenging systems were developed to prevent potentially toxic aerosolized medications from entering the general environment . The Respirgard II for aerosolized pentamidine, for example, is fitted with one-way valves and filters to minimize gross contamination of the environment.
A separate device was developed to allow the safe delivery of aerosolized ribavirin, which is potentially teratogenic. The Small-Particle Aerosol Generator (SPAG) was designed specifically to aerosolize ribavirin. It consists of a jet nebulizer and drying chamber that together reduce the mass median aerodynamic diameter (MMAD) to a mean of 1.3 micrometers, which optimizes drug delivery to distal airspaces. The SPAG is used with a scavenging system to minimize contamination of the ambient environment.
Other medication solutions for nebulization, including DNase I (dornase alfa, Pulmozyme; Hudson, Marquest, and Pari LC nebulizers), tobramycin (TOBI; Pari LC Plus nebulizer), and aztreonam (Cayston; Altera nebulizer) should only be delivered using nebulizers specifically approved by the drug manufacturer for use with these agents. Results may not be the same if other nebulizers are used instead of those studied with the drug.
Continuous nebulization — Beta agonists are commonly administered as a continuously nebulized aerosol in children with severe asthma exacerbations (table 4). Multiple studies have demonstrated the efficacy and safety of this technique, even when high doses (eg, 20 mg/hour of albuterol) are used [41-46]. In addition, drug delivery over time by continuous nebulization appears similar to that with frequent intermittent nebulization but potentially with a reduction in medical personnel time and costs of therapy . However, studies of continuous nebulization versus intermittent nebulization are uncontrolled and lack objective data (ie, pulmonary function) to support the use of one method over the other.
Continuous nebulization requires a special delivery system to avoid the need for refilling the standard nebulizer every 10 to 15 minutes. Several strategies have been employed for administering continuously nebulized aerosols:
●A small- or medium-volume nebulizer may be fitted with an intravenous infusion pump that drips premixed bronchodilator solution into the nebulizer chamber [13,44,48]. A simple set-up is used in the nonventilated patient (figure 3), but a more complicated set-up is required in the patient on mechanical ventilation (figure 4). This is the preferred method at the author's institution for the nonventilated patient (due to cost and desire to limit inventories and devices). For the patient on mechanical ventilation, the author's institution uses a small-particle-generating vibratory mesh nebulizer positioned on the dry side of the humidifier.
Continuous aerosolized albuterol also can be delivered effectively using a mixture of helium and oxygen (Heliox), although a higher driving flow rate (11 L/min) should be used . (See "Physiology and clinical use of heliox".)
USING A JET NEBULIZER — Patients and caregivers should receive explicit instruction on the appropriate use of jet nebulizers (table 5). Several technical factors complicate the use of these devices in the home. (See "Delivery of inhaled medication in children".)
Compressors for home use — The use of jet nebulizers in the home requires a compressor to generate the driving airflow. However, commercial compressors vary widely in the flow rates they generate, and different nebulizer/compressor combinations may have marked differences in how efficiently they generate respirable output [13,21,49]. Compressors generating flow rates that are too low to drive a given nebulizer will result in negligible respirable output and ineffective therapy .
Only those nebulizer/compressor combinations that are known to deliver at least 50 percent of each ordered drug as respirable particles within 10 minutes should be prescribed [13,49]. The standard compressor used in many studies of nebulizer performance in the United States is the DeVilbiss Pulmo-Aide compressor, which is specified for use when administering aerosolized tobramycin (TOBI) [22,50,51]. Unfortunately, there are no minimal standards for nebulizer/compressor performance in North America, although such standards do exist in Europe [1,13]. Most compressors for home use have a five-year warranty.
Infection control — Repeated use of disposable nebulizers may lead to bacterial contamination and nosocomial infection [52-55]. Home nebulizers meant for longer-term use also are frequently contaminated with bacteria, but standardized guidelines for disinfecting home nebulizers are not available . At a minimum, home nebulizers should be cleaned by rinsing and air-dried between uses to prevent clogging of the Venturi and to reduce microbial contamination . It is also recommended that nebulizers be disinfected by soaking one to two times per week in an acetic acid solution for 30 minutes (one part distilled white vinegar to three parts warm water) or in a commercial quaternary ammonium compound for 10 minutes, although even these measures may not provide adequate sterilization [56,57]. The final rinse should be with tap water. Home nebulizers and the compressor filter should be replaced every six months. (See "Infection prevention: Precautions for preventing transmission of infection".)
Allergen control — The reservoirs of home nebulizers also may be contaminated by indoor allergens. In one study, the reservoirs of 5 of 17 nebulizers collected from the homes of children with asthma were contaminated by at least one antigen (cockroach, cat, dog, mouse) . Proper cleaning of nebulizers, as described above, and storage of nebulizers in plastic bags may prevent contamination with allergens.
Performance deterioration — There is some potential for performance deterioration of nebulizers used at home repeatedly over time [59,60], although this risk appears minimal if these units are properly maintained and rinsed between uses . The replacement time interval is based upon the manufacturer's recommendation for each specific nebulizer but should not exceed six months. The tubing is generally supplied with the nebulizer cup and should be changed at the same time.
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 5th to 6th 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 10th to 12th 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.)
●Beyond the Basics topics (see "Patient education: Asthma symptoms and diagnosis in children (Beyond the Basics)" and "Patient education: Asthma treatment in children (Beyond the Basics)" and "Patient education: Asthma inhaler techniques in children (Beyond the Basics)")
●Nebulizers are used to provide aerosol therapy to patients too ill or too young to use handheld devices and in situations where large drug doses and combination therapy are necessary. These devices also are required for some medications available only in aerosol form. (See 'Indications' above.)
•Jet nebulizers (figure 1) are the most commonly used form of nebulizer due to their lower cost and comparable clinical efficacy in many situations.
•Ultrasonic nebulizers can nebulize large volumes of liquid more quickly and, unlike jet nebulizers, do not require a source of driving gas. However, particle sizes may be larger with these devices, and the high-density aerosols generated are associated with bronchospasm and increased airway resistance in some patients. In addition, ultrasonic nebulizers do not nebulize suspensions efficiently and potentially could break down complex molecules, reducing their effect.
•Vibrating mesh nebulizers (figure 2) are more efficient than other conventional nebulizers but are also more costly and must be disassembled and cleaned after each use to prevent clogging of the pores within the membrane. They are generally selected for use with expensive medications to minimize drug waste.
●Factors that can affect jet nebulizer performance include nebulization time, chamber design, driving gas used, dead volume, and physical properties of the solution or suspension. (See 'Factors affecting jet nebulizer performance' above.)
●Enhancements to the design of jet nebulizers have improved performance and reduced aerosol waste during the exhalation phase (picture 1). These types include breath-enhanced open-vent, storage bag, intermittent, and breath-actuated nebulizers. (See 'Enhanced jet nebulizer designs' above.)
●Specially constructed small-volume nebulizers with closed scavenging systems were developed to prevent potentially toxic aerosolized medications from entering the general environment. (See 'Nebulizers for specific medications' above.)
●Beta agonists are commonly administered as a continuously nebulized aerosol in children with severe asthma exacerbations in emergency departments and inpatient units. Continuous nebulization requires a special delivery system to avoid the need for refilling the standard, small-volume nebulizer every 10 to 15 minutes (figure 4 and figure 3). (See 'Continuous nebulization' above.)
●Patients and caregivers should receive explicit instruction on the appropriate use of jet nebulizers (table 5). Several technical factors complicate the use of these devices in the home, including the ability of the compress to deliver sufficient flow rate and infection and allergen control. Drug delivery can be improved with several simple measures, such as increasing the fill volume to at least 4 mL and warming the solution. (See 'Using a jet nebulizer' above.)
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