by: James B. Fink, PhD, RRT, FAARC, FCCP, and Arzu Ari, PhD, RRT, PT, CPFT
All liquid nebulizers generate aerosols from solutions and suspensions, but choosing the right one requires knowing how they work and what result you hope to achieve.
Liquid nebulizers generate aerosols from solutions and suspensions and vary in design and performance.1-6 These designs include pneumatic jet nebulizers; ultrasonic nebulizers; and mesh nebulizers, with volumes of medication ranging from small (5 to 20 mL: small volume nebulizer [SVN]) to large (30 to 200 mL: large volume LVN).
Gas-powered jet nebulizers have been in clinical use for more than 100 years. Most modern jet nebulizers are powered by high-pressure air or oxygen provided by a portable compressor, compressed gas cylinder, or 50 psi wall outlet. Too low a gas pressure or flow can result in negligible nebulizer output. Consequently, nebulizers used for home care should be matched to the compressor being provided. Manufacturers and suppliers should be asked to provide information on particle size and output for any nebulizer/compressor combination provided for home or hospital use.
There are four categories of SVNs:
- constant output nebulizer with simple reservoir tube;
- constant output nebulizer with collection reservoir bag;
- breath-enhancednebulizer (BEN); and
- breath-actuated nebulizer (BAN).1-6 Only the constantoutput nebulizer with a simple reservoir tube is suitable for use during mechanical ventilation.
Constant Output Nebulizer with Simple Reservoir Tube
This is the most commonly used SVN. Aerosol is generated continuously, with 30% to 60% of the nominal dose being trapped as residual volume in the nebulizer, and more than 60% of the emitted dose is wasted to the atmosphere. Many disposable SVNs are packaged with a 6-inch (15 cm) piece of aerosol tubing to be used as a reservoir. This may increase inhaled dose by 5% to 10%, increasing the total inhaled dose from 10% to 11% with the reservoir tube.
Constant Output Nebulizer with Collection Resevoir Bag
Bag reservoirs hold a portion of the aerosol generated during exhalation and allow the small particles to remain in suspension to be available for inhalation with the next breath, while larger particles rain out. These systems may increase inhaled dose by 30% to 50% over standard continuous jet nebulizers. The collection bag on the expiratory side of the nebulizer T collects aerosol, leaving the SVN when the patient is not inhaling and allowing some of the aerosol in the bag to be inhaled with the next inspiration. These devices increase inhaled dose compared to conventional nebulizers. The bag reservoir is difficult to dry between doses.
Breath-enhanced nebulizers generate aerosol continuously, utilizing a system of vents and one-way valves to minimize aerosol waste. An inspiratory vent allows the patient to draw in air through the nebulization chamber generating and containing aerosolized drug. On exhalation, the inlet vent closes, and aerosol exits by a one-way valve near the mouthpiece. This process increases inhaled mass by as much as 50% over standard continuous nebulizers (up to 15%), and partially reduces aerosol waste to the atmosphere.
Breath-actuated nebulizers generate aerosol only during inspiration. This feature eliminates waste of aerosol during exhalation and increases the treatment time as well as delivered dose threefold or more over conventional and breathenhanced nebulizers. As aerosol is only generated during inhalation, exhaled aerosol and contamination of the environment during the expiratory phase of the breathing cycle are largely eliminated.
Dosimeters, used in pulmonary function laboratories, utilize a control box with transducer to sense inspiration and pulse airflow to the jet orifice and transform conventional nebulizers into breath-actuated systems.
LARGE-VOLUME JET NEBULIZERS
Large-volume jet nebulizers are particularly useful when traditional dosing strategies are ineffective in the management of severe bronchospasm. For example, when a patient with airway obstruction does not respond to a standard dosage of bronchodilator, it is common practice to repeat the treatment as often as every 15 minutes. An alternative approach is to provide continuous nebulization with a specialized large-volume nebulizer. These nebulizers have a greater than 200 mL reservoir or have a smaller reservoir with a continuous feed system. Some nebulizers have a standard luer adapter to allow medication to enter the nebulizer via an infusion pump. The US Food and Drug Administration has issued cautions concerning accidental misconnections from non-IV medication being attached to IV access points. In the European Union, use of luer attachments for non-IV drugs has been banned, and similar regulatory efforts are under way in the United States.
Actual output and particle size vary with the pressure and flow at which the nebulizer operates. A potential problem with continuous bronchodilator therapy (CBT) is drug-concentration increase over time.
The ultrasonic nebulizers (USNs) use a piezoelectric crystal to generate high-frequency (1.2 to 2.4 MHz) acoustic vibrations, to form a standing wave that generates a geyser of droplets that break free as fine aerosol particles above the transducer. Large volume USNs are capable of higher aerosol outputs (0.2 to 1.0 mL/min) and higher aerosol densities than are conventional jet nebulizers, making them effective for sputum inductions. Output is determined by the amplitude setting (sometimes user-selected); the greater the signal amplitude, the greater the nebulizer output. Particle size is inversely proportional to the frequency of vibrations. Once the aerosol is produced, it requires a fan or patient inspiratory flow to move aerosol from the reservoir.
A number of small volume USNs have been marketed for aerosol drug delivery. These units are typically battery operated, which increases portability. These devices often have no blower/fan; the patient's inspiratory flow draws the aerosol from the nebulizer into the lung. Small volume USNs have been promoted for administration of a wide variety of formulations ranging from bronchodilators to anti-inflammatory agents and antibiotics. Due to the small particle size, USNs are not recommended for administration of suspensions such as budesonide. The small volume USNs may have residual drug volume remaining in the medication cup at end of dose similar to jet SVNs. This may reduce the need for a large quantity of diluent to ensure delivery of the drugs. The advantages of the USNs are outweighed by relatively high purchase costs and poor reliability.
Some ventilator manufacturers (eg, Maquet) have promoted the use of USNs for administration of aerosols during mechanical ventilation. Unlike SVNs, USNs do not add extra gas flow to the ventilator circuit during use. This feature reduces the need to change and reset ventilator alarm settings during aerosol administration.
VIBRATING MESH NEBULIZERS
Two types of vibrating mesh (VM) nebulizers, active and passive, are currently available commercially.7 Active VM nebulizers utilize a dome-shaped aperture plate, containing more than 1,000 funnel-shaped apertures. This dome is attached to a plate that is also attached to a piezo ceramic element that surrounds the aperture plate. Electricity applied to the piezo element causes the aperture plate to be vibrated at a frequency of approximately 130 kHz (or one-tenth that of an ultrasonic nebulizer), moving the plate up and down by 1 or 2 mm, creating an electronic micropump. The plate actively pumps the liquid through the apertures, where it is broken into fine droplets. The exit velocity of the aerosol is low, less than 4 m/sec, and the particle size can range between 2 and 3 μm (MMAD), varying with the exit diameter of the apertures. An active VM can nebulize single drops as small as 15 μl of formulations containing small and large molecules, suspensions, micro-suspensions, and liposomes. Passive VM nebulizers utilize a mesh separated from an ultrasonic horn by the liquid to be nebulized. A piezo vibrates the ultrasonic horn, which then pushes fluid through the mesh.
The residual drug volume with either type of VM nebulizer ranges from 0.1 to 0.4 mL in contrast to other types of liquid aerosol generators with residual drug volumes of 0.8 to 1.5 mL. Because a greater percentage of standard unit doses are emitted as aerosol, care should be exercised when transitioning to these devices, to ensure that the higher dose does not create adverse effects.
Use of low-velocity (soft mist) aerosol, smaller particle size distribution, and systems that inimize residual volume of medication left in the nebulizer substantially improve aerosol device efficiency. Along with improved performance, some "smart" nebulizers have the capability to monitor patient compliance and aid in managing the patient's treatment schedule.
With pulmonary deposition increased from the old standard of approximately 10% to more than 60% of the nominal dose, these recent device improvements may be accompanied by greater systemic side effects, unless the delivered dose is reduced. Many of these devices are being introduced with specific medications.9
Factors Impacting Performance of Liquid Nebulizers Nebulizers of the same design and lot number can exhibit variable performance.3 Whereas managers and clinicians must always carefully evaluate nebulizers before purchasing or using them,4,5 manufacturers should provide data on the performance of their nebulizers under common use conditions, including use with compressors at home.
Several factors impact performance of any liquid nebulizer:
Particle size. Since the upper airway is designed to filter out aerosols commonly found in nature such as dust and pollens, medical nebulizers generally produce particles with a mass median aerodynamic diameter in the 1 to 5 micron range. Larger particles tend to impact in the upper airways and smaller particles tend to be exhaled, unless they are really small like nanoparticles (eg, cigarette smoke). Most approved inhaled medications target the conducting airway, so there is little data to differentiate differences in MMAD within the 1 to 5 μm range. Even for drugs directed to the lung parenchyma (eg, inhaled insulin), particles in the 4.5 μm range were similar in bioavailability to 2.5 μm particles.2
Residual volume. The residual volume of a 3 mL dose varies from 0.5 mL to 2.2 mL.2 The greater the residual drug volume, the less drug available as aerosol and the less efficient the delivery system. Using a larger fill has been advocated to increase the amount of aerosol available to be inhaled. However, the label dose volumes of drugs are based on clinical response of patients using nebulizers with substantial residual drug volumes, and to date, no significant difference in clinical response has been shown with varying diluent volumes. Consequently, adding volume to the unit dose should be considered an off-label administration technique.
Ease of use and maintenance. The more difficult a device is to use or maintain, the less likely that patients or staff will tolerate it. Failure to clean the nebulizer properly can result in degradation of nebulizer performance.1
Cost. No one should pay more than necessary for medical devices, but the cheapest nebulizer may not provide the best cost/benefit ratio for the patient or institution. A cheap disposable nebulizer and compressor that produce aerosol particles greater than 6 μm may provide poor clinical results compared to a matched system that produces smaller particles. Performance, medication availability and costs, as well as time for administration and costs of cleaning or maintenance, should be considered.
End of dose. It can be difficult to determine when a nebulizer treatment is complete. Malone and colleagues5 found that albuterol delivery from the nebulizer ceased after the onset of inconsistent nebulization (sputtering). Aerosol output declined one half within 20 seconds of the onset of sputtering, and drug concentration increased significantly once the aerosol output declined, suggesting that further weight loss in the nebulizer was caused primarily by evaporation. It is recommended that treatment ends within 1 minute of sputtering.
Infection control issues. The Centers for Disease Control and Prevention recommends that nebulizers be disposed of, cleaned and disinfected, or rinsed with sterile water, or air dried between uses. Liquid in nebulizers provides a medium for bacterial growth between treatments.1,2
Secondhand aerosols. With as much as 70% of emitted medical aerosol entering the atmosphere, secondhand exposure of inhaled medications is a real concern. In addition, droplet nuclei generated by infected patients during aerosol treatments may increase risk to both care providers and other patients. Efforts should be taken to reduce the amount of aerosol entering the atmosphere with both device selection and use of expiratory filters.
SELECTION IS THE KEY
Selecting the right nebulizer and medication for the patient is critical both inside the hospital and for the home. Proper device selection with effective education, demonstration, and return demonstration greatly increases the chances for adherence and therapeutic benefit.10