Inertial Impaction

Inertial impaction occurs when suspended particles in motion collide with and are deposited on a surface; this is the primary deposition mechanism for particles larger than 5 µm. The greater the mass and velocity of a moving object, the greater its inertia, and the greater the tendency of that object to continue moving along its set path (Figure 36-1). When a particle of sufficient (large) mass is moving in a gas stream and that stream changes direction, the particle tends to remain on its initial path and collide with the airway surface.

Because inertia involves both mass and velocity, the higher the flow of a gas stream, the greater the tendency for particles to impact and be deposited in the airways. Turbulent flow patterns, obstructed or tortuous pathways, and inspiratory flow rates greater than 30 L/min are associated with increased inertial impaction. Turbulent flow and convoluted passageways in the nose cause most particles larger than 10 µm to impact and become deposited. This process produces an effective filter that protects the lower airway from particulates such as dust and pollen. However, particles 5 to 10 µm tend to become deposited in the oropharynx and hypopharynx, especially with the turbulence created by the transition of air as it passes around the tongue and into the larynx.

Sedimentation

Sedimentation occurs when aerosol particles settle out of suspension and are deposited owing to gravity. The greater the mass of the particle, the faster it settles (Figure 36-2). During normal breathing, sedimentation is the primary mechanism for deposition of particles 1 to 5 µm. Sedimentation occurs mostly in the central airways and increases with time, affecting particles 1 µm in diameter. Breath holding after inhalation of an aerosol increases the residence time for the particles in the lung and enhances distribution across the lungs and sedimentation. A 10-second breath hold can increase aerosol deposition 10% and increase the ratio of aerosol deposited in lung parenchyma to central airway by fourfold.⁴

Diffusion

Brownian diffusion is the primary mechanism for deposition of small particles (<3 µm), mainly in the respiratory region where bulk gas flow ceases and most aerosol particles reach the alveoli by diffusion. These aerosol particles have very low mass and are easily bounced around by collisions with carrier gas molecules. These random molecular collisions cause some particles to contact and become deposited on surrounding surfaces. Particles 1 to 0.5 µm are so stable that most remain in suspension and are cleared with the exhaled gas, whereas particles smaller than 0.5 µm have a greater retention rate in the lungs.

Figure 36-3 summarizes the relationships between particle size and aerosol deposition in the respiratory tract. The depth of penetration and deposition of a particle in the respiratory tract tend to vary with size and tidal volume (V_T).⁵ With this knowledge, it may be possible to target aerosol deposition to specific areas of the lung by using the proper particle size and breathing pattern.

Breath-Actuated Pressurized Metered Dose Inhaler

A variation of a pMDI is a breath-actuated model, which incorporates a trigger that is activated during inhalation. This trigger theoretically reduces the need for the patient or caregiver to coordinate MDI actuation with inhalation.²⁴ However, patients may stop breathing when the MDI is actuated (“cold Freon effect”) or have suboptimal inspiration. Evaluation of the efficacy of breath-actuated pMDIs in children younger than 6 years is limited, and their use should be restricted to older children and adults. Oropharyngeal deposition of steroids using these devices is still very high.

The Aerocount Autohaler is a flow-triggered pMDI developed and marketed by the 3M Corporation (St. Paul, MN) (Figure 36-8). The device is designed to eliminate the need for hand-breath coordination by automatically triggering in response to the patient’s inspiratory effort.²⁴ To use the Autohaler, the patient cocks a lever on the top of the unit, which sets in motion a downward spring force. Using the closed-mouth technique, the patient draws through the mouthpiece. When the patient’s flow rate exceeds 30 L/min, a vane releases the spring, which forces the canister down and triggers the pMDI. In the United States, the Autohaler is available only with pirbuterol, a bronchodilator similar to albuterol. Current data indicate that the device reduces pharyngeal impaction and enhances lung deposition. A possible limitation of the device is that it can be breath actuated only. Patients experiencing an acute exacerbation of bronchospasm may be unable to generate sufficient flows to trigger the Autohaler. This theoretical concern has not been widely observed in clinical studies of patients with severe exacerbation of asthma receiving treatment in emergency departments. Nevertheless, caution may be appropriate in ordering breath-triggered pMDIs for small children and patients prone to severe levels of airway obstruction.

The Easihaler (GlaxoSmithKline, Philadelphia) is a breath-actuated pMDI that has been developed with a range of medications and is currently available in Europe and Canada. Release in the United States is anticipated in the near future. A new generation of pMDIs such as the Tempo (MAP Pharmaceuticals, Mountain View, CA) have been designed to be breath actuated with lower force of the plume exiting the mouthpiece, reducing oropharyngeal deposition and increasing lung dose (Figure 36-9).

Dose Counters

A serious limitation of pMDIs is the lack of a “counter” to indicate the number of doses remaining in the canister. After the number of label doses have been administered, the pMDI may seem to give another 20 to 60 doses, which may deliver little or no medications as the doses “tail-off.” Tail-off effect refers to variability in the amount of drug dispensed toward the end of the life of the canister. The result of tail-off is swings from normal to almost no dose emitted from one breath to the next with no reliable indicator to the user. Without a dose counter, there is no viable method to determine remaining drug in a pMDI other than manually keeping a log of every dose taken. The U.S. Food and Drug Administration (FDA) is requiring all new pMDIs to have a counter technology to track pMDI actuations remaining. Third-party dose counters may be added to older pMDI models but may not have the accuracy of built-in technology (Figure 36-10).

Factors Affecting Pressurized Metered Dose Inhaler Performance and Drug Delivery

Aerosol Delivery Characteristics

Although pMDIs can produce particles in the respirable range (MMAD 2 to 6 µm),²⁰ the initial velocity and dispersion of the aerosol plume generate larger particles that decrease in size as they leave the pMDI, resulting in approximately 80% of the dose leaving the actuator to impact and become deposited in the oropharynx. A significant proportion of this oropharyngeal deposition is swallowed and may be a factor in systemic absorption of some drugs. Pulmonary deposition ranges from 10% to 20% in adults and larger children (less in infants).²⁶ The exact amount of drug delivered to an individual patient is unpredictable because of high variability between patients and because pMDI drug administration is technique-dependent.

Technique

The successful administration of aerosol drugs by pMDI is highly technique-dependent. Two-thirds of patients and health care professionals who should teach pMDI use do not perform the procedure properly.²⁷ Box 36-1 outlines the recommended steps for self-administering a bronchodilator by simple pMDI. Thorough preliminary patient instruction can last 10 to 30 minutes and should include demonstration, practice, and confirmation of patient performance (demonstration pMDIs with placebo are available from manufacturers for this purpose). Repeated instruction improves performance; repeat instruction is done most appropriately with follow-up clinic or home visits. Demonstration and return demonstration must occur several times for best patient adherence to device use.

For best effect, the pMDI should be actuated once at the beginning of inspiration. Common hand-breath coordination problems include actuating the pMDI before or after the breath. Some patients, especially infants, young children, elderly adults, and patients in acute distress, may be unable to coordinate actuation of the pMDI with inspiration. Some patients exhibit a “cold Freon effect,” which occurs when the cold aerosol plume reaches the back of the mouth and the patient stops inhaling. All of these problems reduce aerosol delivery to the lung to the point that the patient does not benefit from the medication, but they can be corrected entirely or in part by use of the proper pMDI accessory device.

Most pMDI labels call for placing the mouthpiece between the lips. However, research has shown that positioning the outlet of the pMDI approximately 4 cm (two fingerbreadths) in front of the mouth improves lung deposition by decreasing oropharyngeal impaction.²⁸ Holding the canister outside the open mouth (at two fingerbreadths) provides a space for the particles to decelerate while evaporating, allowing particle size to reduce to respirable size. Use of the open-mouth technique with a low inspiratory flow rate can result in a doubling of the dose delivered to the lower respiratory tract of an adult from approximately 7% to 10% to 14% to 20%. However, this technique is more difficult for patients to perform reliably than the closed-mouth technique. Although it may reduce oropharyngeal deposition, the technique has not been shown to improve the clinical response to pMDI bronchodilators.

Concerns have been raised about use of the open-mouth technique with ipratropium bromide because poor coordination can result in drug being sprayed into the eyes. Use of anticholinergic agents has been associated with increased ocular pressure, which could be dangerous for patients with glaucoma. For avoidance of ocular exposure, the drug manufacturer recommends patients use the closed-mouth technique with ipratropium.

The high percentage of oropharyngeal drug deposition with use of steroid pMDIs can increase the incidence of opportunistic oral yeast infection (thrush) and changes in the voice (dysphonia). Rinsing the mouth after steroid use can help avoid this problem, but most pMDI steroid aerosol impaction occurs deep in the hypopharynx, which cannot be easily rinsed with gargling. For this reason, steroid pMDIs should not be used alone but always in combination with a spacer or valved holding chamber. See Box 36-2 for instructions for determining dosage left in the pMDI.

Pressurized Metered Dose Inhaler Accessory Devices

Various pMDI accessory devices have been developed to overcome the two primary limitations of these systems: hand-breath coordination problems and high oropharyngeal deposition. Accessory devices include breath-actuated pMDIs, spacers, and holding chambers.

Spacers and Holding Chambers

Spacers and valved holding chambers are pMDI accessory devices designed to reduce both oropharyngeal deposition and the need for hand-breath coordination. Despite differences in design, all spacers add distance between the pMDI and the mouth, reducing the initial forward velocity of the pMDI droplets, which occurs with partial evaporation of propellant in the time the aerosol traverses the length of the spacer. The reduction in initial forward velocity decreases the number of nonrespirable particles reaching the airway. With retention of the larger droplets in the spacer or holding chamber and evaporation of propellants before entering the airway, the “cold Freon effect,” which causes many children to stop inhaling, is reduced, as is the foul taste associated with some of the drug aerosols. The same drug used with different accessory devices may produce differences in MMAD, GSD, and fine-particle fraction. The quantity of respirable drug available at the spacer or valved holding chamber exit depends on spacer volume and design and on formulation factors. The placement of a valve between the pMDI and the chamber and the mouthpiece works like a baffle reducing the size of particles inhaled. A simple tube spacer may reduce oral deposition by 90%, whereas a valved holding chamber can reduce oral deposition by 99%.

Valved holding chambers protect the patient from poor hand-breath coordination, with exhaled gas venting to the atmosphere, allowing aerosol to remain in the chamber available to be inhaled with the next breath. Valved holding chambers allow infants, small children, and adults who cannot control their breathing pattern to be treated effectively with pMDIs.

It is increasingly common practice to provide asthmatic patients an accessory device to use with the pMDI and to teach them to use the pMDI with and without the accessory device. The patients are instructed to use the device with the pMDI whenever they feel short of breath. Many of these patients find that they get much better relief from the pMDI with an accessory device than with the pMDI alone.

Basic concepts for spacer devices include (1) small volume adapters, (2) open tube designs, (3) bag reservoirs, and (4) valved holding chambers (Figure 36-11). More than a dozen different devices with volumes ranging from 15 to 750 ml have been developed over the past 30 years.

A spacer is a simple valveless extension device that adds distance between the pMDI outlet and the patient’s mouth. This distance allows the aerosol plume to expand and the propellants to evaporate before the medication reaches the oropharynx. Larger particles leaving the pMDI tend to impact on the spacer walls. In combination, this phenomenon reduces oropharyngeal impaction and increases pulmonary deposition. Proper use of a simple open-tube spacer still requires some hand-breath coordination because a momentary delay between triggering and inhaling the discharged spray results in a substantial loss of drug and reduced lung delivery. Exhalation into a simple spacer after pMDI actuation clears the aerosol from the device and wastes most of the dose to the atmosphere. This reduction in dose also occurs with small volume reverse-flow design spacers if there is no provision for “holding” the aerosol in the device.³⁰

Similar to spacers, holding chambers allow the aerosol plume to develop and reduce oropharyngeal deposition. A holding chamber also incorporates one or more valves that prevent aerosol in the chamber from being cleared on exhalation. This allows patients with a small V_T to empty the aerosol from the chamber over two or more successive breaths. Generally, holding chambers provide less oropharyngeal deposition, higher respirable drug dosages, and better protection from poor hand-breath coordination than simple spacers.

The MMAD of the aerosol emitted from the pMDI exiting a spacer decreases approximately 25%, whereas the fraction containing particles less than 5 µm in diameter increases. This change is largely due to rapid evaporation of propellant in the spacer. With valved holding chambers, in addition to evaporation of the plume, the valves act as baffles of larger particles, increasing the respirable fraction further.

Holding chambers produce a finer, slower moving, more “respirable” aerosol with less impaction of drug in the oropharyngeal area (1% of dose) than simple spacers (10%) or a pMDI alone (80% of dose). Deposition after inhalation of a radiolabeled pMDI solution aerosol from the AeroChamber, compared with deposition from the same pMDI inhaled with the open-mouth technique, showed a 10-fold to 17-fold decrease in the amount of radioactivity deposited in the oropharyngeal-laryngeal area while a similar lung dose was maintained. This finding was true for both healthy subjects and patients with chronic obstructive pulmonary disease (COPD).³¹ The advantage of reduced oropharyngeal deposition is fewer side effects from steroid aerosols, as shown in numerous published clinical trials. If multiple actuations of one or more drugs are placed into a spacer, both the total dose and the respirable dose of drug available for inhalation are reduced. The extent of these losses may vary for different drugs and spacer designs.²⁰

Holding chambers with masks are available for use in the care of infants, children, and adults. These units allow effective administration of aerosol from a pMDI to patients who are unable to use a mouthpiece device (because of their size, age, coordination, or mentation). Holding chambers are helpful in administration of pMDI steroids because deposition of the drug in the mouth is largely eliminated, and systemic side effects can be minimized.

Even with a holding chamber, respirable particles containing drug settle out and become deposited within the device, causing a whitish buildup on the inner chamber walls. This residual drug poses no risk to the patient but may be rinsed out periodically. Drug output from plastic spacers has been shown to decrease owing to the presence of an electrostatic charge. With these devices, a buildup of material can be seen on the walls of the chamber. As more material builds up on the wall of the chamber, the charge is dissipated, and more drug is inhaled by the patient. Washing the chamber with water (without soap) causes the electrostatic charge to be reestablished, making the device less effective for the next few puffs, until the static charge in the chamber (which attracts small particles) is again reduced.³² Optimal technique is outlined in Box 36-3.

Box 36-3   Optimal Technique for Use of a Metered Dose Inhaler With a Valved Holding Chamber

1. Warm the pMDI to hand or body temperature.

2. Assemble the apparatus, ensuring there are no objects or coins in the chamber that could be aspirated or obstruct outflow.

3. Hold the canister vertically, and shake it vigorously. Prime if necessary.

4. Place the pMDI in the holding chamber inlet, position chamber outlet in the mouth (or place the mask over nose and mouth), and encourage the patient to breathe through the mouth. Visually inspect for proper valve function.

5. With normal breathing, actuate the pMDI once and have the patient breathe through the device for three to seven breaths (three breaths for adults and seven breaths for infants).*

6. Allow 30 to 60 seconds between actuations.

---

^*For a cooperative patient, synchronizing actuation at the beginning of larger breaths with breath holding may be encouraged. However, this maneuver has not been shown to increase clinical response to inhaled bronchodilators.

Use of conductive metal or nonelectrostatic plastic chambers or washing the plastic chamber periodically with deionizing detergent (liquid dishwashing soap) can overcome the loss of fine-particle mass owing to electrostatic charge and increase the inhaled mass from 20% to 50% of the emitted dose of the pMDI, even in children (Figure 36-12).³² The effect of washing the chamber with conventional dishwashing soap reduces this static charge for up to 30 days. All valved holding chambers and spacers should be cleaned regularly, typically monthly, as recommended by the manufacturer. Use of dilute liquid dishwashing soap, with or without rinsing, and allowing to air dry are recommended.

The addition of a one-way valve to convert an open tube into a reservoir for the aerosol, the incorporation of the actuator in the pMDI, the shape of the device, flow of air through the device, edge effects, masks, and manufacturing materials all affect aerosol characteristics and yield. The inhalation valve, which is used to contain the aerosol, also acts as a baffle to reduce oropharyngeal deposition. This valve must be able to withstand the initial pressure from the pMDI when the device is triggered to retain aerosol and have sufficiently low resistance to open readily when the user inhales, in particular, when the user is a child or an infant. Exhalation valves in a face mask attached to a spacer device must also provide low resistance. Issues of spacer volume, V_T, frequency of breathing, and mechanical dead space between the spacer and mouth are of particular concern when these devices are used by children.³³ Differences of twofold to threefold in the amount of drug available at the mouth have been measured among spacers used at the present time to treat infants. Clinicians should determine the delivery efficiencies of spacer devices before using the devices in the care of a particular population.

Accessory devices are used with either the manufacturer-designed boot that comes with the pMDI or with a “universal adapter” that triggers the pMDI canister. Different formulations of pMDI drugs operate at different pressures and have a different-sized orifice in the boot that is specifically designed by the manufacturer for use exclusively with that pMDI. The output characteristics of a pMDI change when an adapter with a different-sized orifice is used. With HFA pMDIs, the diameter of the actuator orifice is smaller, and the spray is predictably finer. When the HFA pMDI is used in an actuator designed for use with CFC pMDIs, output is reduced. When these HFA formulations are used with any particular spacer, it is important to know how comparable the available dose and particle size distribution are to the dose and particle size from an existing CFC pMDI.²⁰

Equipment Design and Function

Most passive dry powder–dispensing systems require the use of a carrier substance (lactose or glucose) mixed into the drug to enable the drug powder to deaggregate more readily and flow out of the device. Reactions to lactose or glucose seem to be fewer than reactions to the surfactants and propellants used in pMDIs, even though the amount of these substances is substantially greater than the amount of the drug and can represent 98% or more of the weight per inhaled dose in some formulations.

As shown in Figure 36-14, there are numerous DPIs on the market, which can be divided into three categories based on the design of their dose containers: (1) unit-dose DPI, (2) multiple unit-dose DPI, and (3) multiple dose drug reservoir DPI.

Unit-dose DPIs, such as the Aerolizer (Schering-Plough, Kenilworth, NJ) and the HandiHaler (Boehringer Ingleheim, Ingelheim am Rhein, Germany), dispense individual doses of drug from punctured gelatin capsules. Multiple unit-dose DPIs (Diskhaler; GlaxoSmithKline, Philadelphia) contain a case of four or eight individual blister packets of medication on a disk inserted into the inhaler. Multiple dose DPIs include the Twisthaler (Schering-Plough), Flexhaler (AstraZeneka, London), and the Diskus (GlaxoSmithKline). The Twisthaler and Flexhaler have a multidose reservoir powder system preloaded with a quantity of pure drug sufficient for dispensing 120 doses of medication, and the Diskus incorporates a tape system that contains up to 60 sealed single doses (Figure 36-15).

The particle size of the dry powder particles of drug ranges from 1 to 3 µm. However, the size of the lactose or glucose particles can range from approximately 20 to 65 µm, so most of the carrier (≤80%) is deposited in the oropharynx.

Factors Affecting Dry Powder Inhaler Performance and Drug Delivery

Performance of DPIs can be affected by the materials used in production and manufacturing.

Patient’s Inspiratory Flow Ability

The high peak inspiratory flow rates (>60 L/min) required to dispense the drug powder from most current DPI designs result in a pharyngeal dose comparable to the dose received from a typical pMDI without an add-on device. If inhalation is not performed at the optimal inspiratory flow rate for a particular device, delivery to the lung decreases as the dose of drug dispensed decreases and the particle size of the powder aerosol increases (Figure 36-16).³⁴

Despite the foregoing issues, DPIs generally are convenient and easy to use. Newer designs are being developed that provide aerosols with higher fine-particle fractions and more reproducible dosing, independent of inspiratory flow rate.

Passive, or patient-driven, DPIs rely on the patient’s inspiratory effort to dispense the dose. The result is differences in lung delivery and clinical response. Active or powered DPI devices, which deaggregate the powder before inhalation, are independent of patient effort. Active DPIs use an energy source to deaggregate the powder and suspend the powder into an aerosol, allowing the dose to be suspended independent of patient inspiratory flow rates. One example of an active DPI is the Exubera powder insulin delivery system (Pfizer, New York). This device is manually powered using pneumatic pressure to disperse the powder into a reservoir chamber from which the aerosol is inhaled.

Technique

As with pMDIs, to derive the maximum benefit from a DPI, proper technique is essential. Box 36-4 outlines the basic steps for ensuring optimal drug delivery. The most critical factor in using a passive DPI is the need for high inspiratory flow. Patients must generate an inspiratory flow rate of at least 40 to 60 L/min to produce a respirable powder aerosol. Because infants, small children (<5 years old) (Figure 36-17), and patients who are unable to follow instructions cannot develop flow this high, these patients cannot use DPIs. Also, patients with severe airway obstruction may be unable to achieve the required flow; DPIs should not be used in the management of acute bronchospasm.

Box 36-4

Optimal Technique for Use of a Dry Powder Inhaler

1. Assemble the apparatus.

2. Load dose, keeping device upright.

3. Exhale slowly to functional residual capacity.

4. Seal lips around the mouthpiece.

5. Inhale deeply and forcefully (>60 L/min). A breath hold should be encouraged but is not essential.

6. Repeat the process until dose is completed.

7. Monitor adverse reactions.

8. Assess beneficial effects.

Modified from Pedersen S: How to use a Rotahaler. Arch Dis Child 61:11, 1986; and Hansen OR, Pedersen S: Optimal inhalation technique with terbutaline. Turbuhaler Eur Respir J 2:637, 1989.

Although hand-breath coordination is not as important with DPIs as it is with pMDIs, exhalation into the device before inspiration can result in loss of drug delivery to the lung. Some devices also require assembly, which can be cumbersome or difficult for some patients, especially in an emergency. It is important that patients receive demonstrations with their inhalers and have the opportunity to assemble and use the DPI (return demonstration) before self-administration. Although the DPI may require cleaning in accordance with the product label, the device should never be submerged in water. Moisture in the device dramatically reduces available dose. Based on the different types of DPIs and the various drug container closure systems, Table 36-1 provides methods to determine the dose in the DPI.

TABLE 36-1

Determining Doses Left in the Dry Powder Inhaler

		Drug Container	Doses	Type Indicator	Meaning of Dose Indicator
Unit-Dose DPI	Aerolizer or HandiHaler	Single capsule	1	None	Check capsule to ensure full dose was inhaled. Repeat to empty capsule
Multiple Unit-Dose DPI	Diskhaler	Dose blisters	4 or 8	None	Inspect visually to confirm use of all blisters
	Diskus	Blister strip	60	Red numbers	Red numbers indicate that ≤5 doses are left in DPI
Multiple Dose DPI	Flexhaler	Reservoir	60 or 120	“0”	Marked in intervals of 10 doses; “0” indicates empty
	Twisthaler	Reservoir	30	“01”	“01” indicates last dose

Pneumatic (Jet) Nebulizers

Gas-powered jet nebulizers (Figure 36-18, A) have been in clinical use for longer than 100 years. Most modern jet nebulizers are powered by high-pressure air or oxygen (O₂) provided by a portable compressor, compressed gas cylinder, or 50-psi wall outlet.

Small Volume Nebulizers

Four categories of jet SVNs include (1) continuous nebulizer with simple reservoir, (2) continuous nebulizer with collection reservoir bag, (3) breath-enhanced nebulizer, and (4) breath-actuated nebulizer (Figure 36-19). The most commonly used SVN is the constant output design. Supplemental air is entrained across the top of the device and dilutes the aerosol produced within the nebulizer as it exits toward the patient. 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. Continuous nebulization wastes medication because the aerosol is produced throughout the respiratory cycle and is largely lost to the atmosphere, as shown in Figure 36-20. Patients with an I : E ratio of 40 : 60 (or 1 : 1.5) lose 60% of the aerosol generated to the atmosphere. If 50% of the total dose is emitted from the nebulizer, and 50% of that aerosol is in the respiratory range and 40% of that is inhaled by the patient, less than 10% deposition is commonly measured in adults receiving continuous nebulizer therapy. In neonates and infants, given the small minute volumes and small airways with increased impaction and reduced sedimentation, deposition can be only 0.5%.

Aerosolized medication can also be conserved with reservoirs.⁴¹ A reservoir on the expiratory limb of the nebulizer conserves drug aerosol.

Breath-Enhanced Nebulizers

Breath-enhanced nebulizers generate aerosol continuously, using a system of vents and one-way valves to minimize aerosol waste.⁴² In the Pari LC Sprint (Pari, Midlothian, VA) breath-enhanced nebulizer (Figure 36-21), 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 can increase inhaled mass by 50% over standard continuous nebulizers and reduces aerosol waste to the atmosphere.

Mini Clini

Home Nebulizer Therapy

 Problem

Many patients are sent home with a prescription for home nebulizer therapy prescribed with the intention of giving the patient the same quality of aerosol therapy he or she received in the hospital. However, the patient often is given the same type of nebulizer used in the hospital because it is inexpensive. These nebulizers provide an aerosol that is too large for optimal deposition in the lungs. What should be done instead?

Solution

Home nebulizers designed for use with compressors should be matched to ensure an MMAD of 1 to 5 µm with the medication being administered. Nebulizer manufacturers such as Pari and Medic-Aid offer matched nebulizer-compressor systems for home use. Although these devices cost a little more, they are more likely to meet therapeutic objectives.

Breath-Actuated Nebulizers

Breath-actuated nebulization can increase inhaled aerosol mass by threefold to fourfold over conventional continuous nebulization. Historically, this increase was accomplished with a patient-controlled finger port that directed gas to the nebulizer only during inspiration. Although this system wastes less aerosol, it can increase treatment time fourfold. This approach requires good hand-breath coordination, something not all patients possess, especially when they are distressed.

Breath-actuated SVNs have been introduced that synchronize aerosol generation based on the patient’s breathing pattern. Breath-actuated nebulizers generate aerosol only during inspiration. This feature eliminates waste of aerosol during exhalation and increases the delivered dose threefold or more over continuous and breath-enhanced nebulizers. Dosimeters, used in pulmonary function laboratories, sense inspiration and pulse airflow to the jet orifice and transform a conventional nebulizer into a breath-actuated system.

AeroEclipse (Trudell Medical International, London, Ontario, Canada) is a breath-actuated SVN. A unique, spring-loaded, one-way valve design draws the jet to the capillary tube during inspiration and causes nebulization to cease when the patient’s inspiratory flow decreases below the threshold or the patient exhales into the device (Figure 36-22). Expiratory pressure on the valve at the initiation of exhalation moves the nebulizer baffle away from its position directly above the jet orifice, reduces the pressure, and stops aerosolization. Because aerosol is generated only during inhalation, exhaled aerosol and contamination of the environment during the expiratory phase of the breathing cycle are largely eliminated.

It can be difficult to determine when a nebulizer treatment is complete. Malone and colleagues⁴³ found that with three different fill volumes, albuterol delivery from the nebulizer ceased after the onset of inconsistent nebulization (sputtering) (Figure 36-23). Aerosol output declined one-half within 20 seconds of the onset of sputtering. The concentration of albuterol in the nebulizer cup increased significantly when the aerosol output declined, and further weight loss in the nebulizer was caused primarily by evaporation. The authors concluded that aerosolization past the point of initial nebulizer sputter is ineffective.

Table 36-2 summarizes some of these key factors for many commercially available SVNs.⁴⁴ Numerous SVNs are on the market, and they vary widely in design and performance. SVNs of the same design and lot number can exhibit variable performance, even to the point that some nebulizers of the same model number do not work at all.⁴⁵ Managers and clinicians always must evaluate SVNs carefully before purchasing or using them. Manufacturers should provide data on the performance of their nebulizers under common use conditions.

TABLE 36-2

Comparison of Different Nebulizers

	Jet	Ultrasonic	Vibrating Mesh
Features
Power source	Compressed gas or electrical mains	Electrical mains	Batteries or electrical mains
Portability	Restricted	Restricted	Portable
Treatment time	Long	Intermediate	Short
Output rate	Low	Higher	Highest
Residual volume	0.8-2.0 ml	Variable but low	≤0.2 ml
Environmental Contamination
Continuous use	High	High	High
Breath-activated	Low	Low	Low
Performance variability	High	Intermediate	Low
Formulation Characteristics
Temperature	Decreases*	Increases†	Minimum change
Concentration	Increases	Variable	Minimum change
Suspensions	Low efficiency	Poor efficiency	Variable efficiency
Denaturation	Possible‡	Probable‡	Possible‡
Cleaning	Required, after single use	Required, after multiple use	Required after single use
Cost	Very low	High	High

^*For jet nebulizers, the temperature of the reservoir fluid decreases about 15° C during nebulization because of evaporation.

^†For ultrasonic nebulizers, vibration of the reservoir fluid causes a temperature increase during aerosol generation, which can be 10° C to 15° C.

^‡Denaturation of DNA occurs with all the nebulizers.

Modified from Dolovich MB, Dhand R: Aerosol drug delivery: developments in device design and clinical use. Lancet 377:1032, 2011.

Large Volume Jet Nebulizers

Large volume jet nebulizers are also used to deliver aerosolized drugs to the lung. A large volume nebulizer is particularly useful when traditional dosing strategies are ineffective in the management of severe bronchospasm. When a patient with airway obstruction does not respond to a standard dosage of bronchodilator, it is common to repeat the treatment every 15 minutes. An alternative approach is to provide continuous nebulization with a specialized large volume nebulizer.

The high-output extended aerosol respiratory therapy nebulizers HEART (Cardinal Health, Dublin, OH), and HOPE (B & B Medical Technologies, Carlsbad, CA) are examples of devices designed for this purpose. These nebulizers have a reservoir greater than 200 ml that produces an aerosol with an MMAD of 2.2 to 3.5 µm. 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 increase in drug concentration. Patients receiving CBT need close monitoring for signs of drug toxicity (e.g., tachycardia and tremor). An additional strategy is to use an intravenous infusion pump to drip premixed bronchodilator solution into a standard SVN. Although an equipment-intensive approach, this technique can provide dosing equivalent to every 15 minutes.⁴⁸

Another special-purpose large volume nebulizer is a small particle aerosol generator (SPAG) (Figure 36-24). The SPAG was manufactured by ICN Pharmaceuticals specifically for administration of ribavirin (Virazole) to infants with respiratory syncytial virus infection. The device is unique in clinical respiratory care practice in that it incorporates a drying chamber with its own flow control to produce a stable aerosol. The SPAG reduces medical gas source from the normal 50 pounds per square inch gauge (psig) line pressure to 26 psig with an adjustable regulator. The regulator is connected to two flowmeters that separately control flow to the nebulizer and drying chamber. The nebulizer is located within the glass medication reservoir, the fluid surface and wall of which serve as primary baffles. As it leaves the medication reservoir, the aerosol enters a long, cylindrical drying chamber. Here the second (separate) flow of dry gas is entrained, reducing particle size by evaporation, creating a monodisperse aerosol with an MMAD of 1.2 to 1.4 µm. Nebulizer flow should be maintained at approximately 7 L/min with total flow from both flowmeters not less than 15 L/min. The latest model operates consistently even with back pressure and can be used with masks, hoods, tents, or ventilator circuits.

Two specific problems are associated with SPAG use to deliver ribavirin. The first is caregiver exposure to the drug aerosol. Approaches to limit caregiver exposure are discussed later (see the section on Controlling Environmental Contamination). The other problem occurs only when the SPAG is used to deliver ribavirin through a mechanical ventilator circuit. Drug precipitation can jam breathing valves or occlude the ventilator circuit. This problem can be overcome by (1) placing a one-way valve between the SPAG and the circuit and (2) filtering out the excess aerosol particles before they reach the exhalation valve, changing filters frequently to avoid increasing expiratory resistance.⁴⁶

Hand-Bulb Atomizers and Spray Pumps

Hand-bulb atomizers and nasal spray pumps are used to administer sympathomimetic, anticholinergic, antiinflammatory, and anesthetic aerosols to the upper airway, including nasal passages, pharynx, and larynx (see also Chapter 32). These agents are used to manage upper airway inflammation and rhinitis, to provide local anesthesia, and to achieve systemic effects. Guidelines for the delivery of drugs to the upper airway have been developed by the American Association for Respiratory Care (AARC).⁴⁹

Because the spray pump generates relatively low pressure and does not have baffles, it produces an aerosol suspension with large particle size (high MMAD and GSD), which are ideal for upper airway deposition. (Nasopharyngeal deposition is greatest for particles 5 to 20 µm.) Deposition with the hand-bulb atomizer applied to the nose occurs mostly in the anterior nasal passages with clearance to the nasopharynx. The 100-mcl puffs appear to deposit more medication than 50-mcl puffs, and deposition to a greater surface area occurs with a 35-degree spray angle than with a 60-degree angle.

Ultrasonic Nebulizers

The USN uses a piezoelectric crystal to generate an aerosol. The crystal transducer converts an electrical signal into high-frequency (1.2- to 2.4-MHz) acoustic vibrations. These vibrations are focused in the liquid above the transducer, where they disrupt the surface and create oscillation waves (Figure 36-25). If the frequency of the signal is high enough and its amplitude strong enough, the oscillation waves form a standing wave that generates a geyser of droplets that break free as fine aerosol particles.

USNs are capable of higher aerosol outputs (0.2 to 1.0 ml/min) and higher aerosol densities than conventional jet nebulizers. 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. Frequency is device-specific and is not user-adjustable. For example, the DeVilbiss (Somerset, PA) Portasonic nebulizer operating at a frequency of 2.25 MHz produces particles with an MMAD of 2.5 µm, whereas the DeVilbiss Pulmosonic nebulizer operating at 1.25 MHz produces particles in the 4- to 6-µm range. Particle size and aerosol density also depend on the source and flow of gas conducting the aerosol to the patient.

Vibrating Mesh Nebulizers

Two types of VM nebulizers, active and passive, are available commercially.⁵² Active VM nebulizers use a dome-shaped aperture plate, containing more than 1000 funnel-shaped apertures. This dome is attached to a plate that is also attached to a piezoceramic element that surrounds the aperture plate. Electricity applied to the piezoceramic element causes the aperture plate to be vibrated at a frequency of approximately 130 kHz (or one-tenth that of a USN), moving the aperture plate up and down by 1 µm or 2 µm, 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 (<4 m/sec), and the particle size can range from 2 to 3 µm (MMAD), varying with the exit diameter of the apertures (Figure 36-26). Examples of an active VM nebulizer include the Aeroneb Go, Pro, and Solo nebulizers (Aerogen, Inc, Galway, Ireland) and the eFlow (Pari, Midlothian, VA). An active VM nebulizer can provide nebulization with single drops 15 mcl of formulations containing small and large molecules, suspensions, microsuspensions, and liposomes.

Passive VM nebulizers use a mesh separated from an ultrasonic horn by the liquid for nebulization. A piezoelectric transducer vibrates the ultrasonic horn, which pushes fluid through the mesh. Passive VM nebulizers include the NEU-22 (Omron, Kyoto, Japan) and the I-Neb (Philips Respironics, Murraysville, PA).

The residual drug volumes with either type of VM nebulizer range 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.

New-Generation Nebulizers

Low-velocity (soft mist) aerosol, smaller particle size distribution, and systems that minimize 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. The key is to be able to target an effective delivered dose to the lungs.

Smart Nebulizers

The I-Neb (Phillips Respironics, Murrysville, PA) is a breath-actuated passive VM nebulizer with adaptive aerosol delivery that monitors pressure changes and inspiratory time for the patient’s first three consecutive breaths (Figure 36-27).⁵⁵ Drug is then aerosolized over 50% of the inspiratory maneuver during the fourth and all subsequent breaths. Targeted inhalation mode guides the patient to take serially longer inspirations to achieve optimal inhalation duration, reducing the time for administration. When the prescribed emitted dose has been aerosolized, the system provides an audible signal indicating the treatment should be stopped and the remaining medication discarded. Built-in electronics monitor patient treatment schedules and delivered doses with the goal to improve compliance with therapy. The I-Neb has been released for delivery of prostacyclin.

The Akita (Activaero, Gemuenden/Wohra, Germany) allows controlled inhalation of aerosol produced by either a jet or VM nebulizer. The Akita controls inspiratory flow to keep it slow (12 to 15 L/min) reducing impaction loss of aerosols in the upper airways. Patient pulmonary function is stored on a smart card programmed to tell the device when to generate aerosol during inspiration. Aerosol generated early targets distal airways, whereas aerosol generated later in the breath targets larger, more central airways.⁵⁶ Smart nebulizers can track the actual time, duration, and dose administered for each treatment and provide logs of use that can be downloaded for the medical or research record.

Use and Limitations of Peak Flow Monitoring

Because the peak flow measurement is effort-dependent and volume-dependent, evaluation of patient performance is subjective, and there are no good acceptability criteria. In addition, agreement between conventional spirometry values, such as forced vital capacity (FVC) and FEV₁, and bedside PEFR values may be poor for individual patients. Although peak flow measurement can be used at the bedside to assess treatment effectiveness and to monitor trends, conventional spirometry remains the standard for determining bronchodilator response.⁶⁶

Some peak flowmeters are more accurate and reliable than others. Even different units of the same model may give variable results. For this reason, the AARC recommends that when monitoring trends, the same unit be used for a given patient and that the patient’s range be reestablished if a different flowmeter is used.⁶⁶

Other Components of Patient Assessment

Sole dependence on tests of expiratory airflow for assessing patient response to therapy is unwise because not all patients can perform these maneuvers. Other components of patient assessment useful in evaluating bronchodilator therapy include patient interviewing and observation, measurement of vital signs, auscultation, blood gas analysis, and oximetry.

When possible, the patient should be interviewed to determine the pertinent respiratory history and current level of dyspnea. A validated dyspnea rating scale may be useful for this purpose. Initial determination of patient age and level of consciousness is helpful in selecting both delivery device and starting drug dosage. Observing the patient for signs of increased work of breathing (e.g., tachypnea, accessory muscle use) provides a baseline for assessing status as therapy progresses. Restlessness, diaphoresis, and tachycardia also may indicate severity of airway obstruction but must not be confused with bronchodilator overdose.

Increased cough has been associated with the onset of asthma. The frequency, severity, and effectiveness of cough should be assessed before and after therapy.

In terms of breath sounds, a decrease in wheezing accompanied by an overall decrease in the intensity of breath sounds indicates worsening airway obstruction or patient fatigue. Improvement is indicated when wheezing decreases and the overall intensity of breath sounds increases.

All patients with acute airway obstruction should be monitored for oxygenation status with pulse oximetry. This value can be used in conjunction with observational assessment to titrate the level of inspired O₂ given to the patient (see Chapter 35). Arterial blood gases are not essential for determining patient response to bronchodilator therapy but may be needed for patients in severe distress to assess for hypercapnic respiratory failure.

Dose-Response Assessment

Poor patient response to bronchodilator therapy often occurs because an inadequate amount of drug reaches the airway. To determine the “best” dose for patients with moderate obstruction, the respiratory therapist (RT) should conduct a dose-response titration.

A simple albuterol dose-response titration involves giving an initial 4 puffs (90 mcg/puff) at 1-minute intervals through a pMDI with a holding chamber. After 5 minutes, if airway obstruction is not relieved, the RT gives 1 puff per minute until symptoms are relieved, heart rate increases to more than 20 beats/min, tremors increase, or 12 puffs are delivered. The best dose is the dose that provides maximum relief of symptoms and the highest PEFR without side effects.

Frequency of Patient Assessment

How frequently patients should undergo assessment for bronchodilator therapy depends primarily on the acuity of the condition. A patient in unstable condition and in acute distress should undergo closer and more frequent scrutiny than a patient in stable condition. Box 36-8 provides guidance regarding the frequency of assessment according to acuity.

Use of a Small Volume Nebulizer During Mechanical Ventilation

The aerosol administered by SVN to intubated patients receiving mechanical ventilation tends to be deposited mainly in the tubing of the ventilator circuit and expiratory filter. Under normal conditions with heated humidification and standard jet nebulizers, pulmonary deposition ranges from 1.5% to 3.0%.70,71 When nebulizer output, humidity level, V_T, flow, and I : E ratio are optimized, deposition can increase to 15%.

There are several disadvantages with SVN use during mechanical ventilation. Although in vitro models showed 40% higher aerosol delivery compared with heated humidity, these effects have not been shown in patients, whereas the risks associated with administering cold and dry gas through an endotracheal tube have. A heat and moisture exchanger should be considered a barrier to aerosol administration and should always be removed if placed between the nebulizer and the patient airway. When available with the specific ventilator being used, breath actuation can increase aerosol delivery by 30%, but it may extend administration time by more than threefold. Introducing additional flow into the ventilator circuit may change parameters of flow and delivered volumes and require changes to alarm settings during and after nebulization. The smaller the patient, the greater the impact of added flow into the ventilator circuit, where 6 L/min of additional gas flow can more than double V_T and inspiratory pressure, placing the patient at risk. Risk is high for not changing ventilator parameters and not returning parameters to pretreatment levels after administration. There is also a tendency for condensate and secretions to drain into the nebulizer reservoir, contaminating medication being delivered to the lungs.

Use of a Vibrating Mesh Nebulizer During Mechanical Ventilation

Aerosol administration by a VM nebulizer has been estimated to deliver greater than 10% deposition in adults and infants without the addition of gas into the ventilator circuit. The low residual drug volume and small particle size are associated with higher efficiency. Similar to the USN, the VM nebulizer does not add gas flow into the ventilator circuit, so ventilator parameters and alarms do not need to be adjusted before, during, or after nebulization. In contrast to jet SVNs and USNs, the medication reservoir of the VM nebulizer is above the circuit and separated from the ventilator tubing by the mesh, reducing the risk of retrograde contamination of medication in the reservoir from the ventilator circuit. Because of the nature of the mesh, the reservoir can be opened and medication can be added to the nebulizer without creating a perceptible leak during ventilation.

Use of a Pressurized Metered Dose Inhaler During Mechanical Ventilation

Results of in vitro studies show that effective aerosol delivery by pMDIs during mechanical ventilation can range from 2% to 30%. Direct pMDI actuation by simple elbow adapters typically results in the least pulmonary deposition, with most of the aerosol impacting in either the ventilator circuit or the tracheal airway. Higher aerosol delivery percentages occur only when an actuator or spacer is placed in-line in the ventilator circuit. These spacers allow an aerosol “plume” to develop before the bulk of the particles impact on the surface of the circuit or endotracheal tube. The result is a more stable aerosol mass that can penetrate beyond the artificial airway and be deposited mainly in the lung. This situation leads to a better clinical response at lower doses.⁵²

Placement During Noninvasive Ventilation

Noninvasive ventilation may be administered with standard and bilevel ventilators. Bilevel ventilators often use a flow turbine, with a fixed valve or leak in the circuit that permits excess flow to vent to atmosphere. Placement of the aerosol generator between the leak and the patient’s airway seems to provide the highest aerosol delivery efficiency.⁷⁴ A VM nebulizer delivers a greater fine-particle dose than an SVN during noninvasive ventilation presumably because of the lower residual drug volume and lower total flow in the circuit.⁷⁵

Placement During High-Flow Nasal Oxygen

Researchers used a VM nebulizer to simulate the delivery of aerosol via a high-flow nasal O₂ setup using infant, pediatric, and adult cannulas, with inhaled dose ranging from 8% to 28%.⁷⁶ Figure 36-35 shows such a setup, including the location of the VM nebulizer. In addition to the type and location of the nebulizer used with high-flow nasal O₂, the inhaled dose seems to vary based on cannula size, respiratory pattern, and O₂ flow. Heliox (80 : 20) appears to improve aerosol delivery at higher flow rates with these setups.⁷⁷

Placement During Intrapulmonary Percussive Ventilation

Intrapulmonary percussive ventilation provides high-frequency oscillation of the airway while administering aerosol particles. During intrapulmonary percussive ventilation, the aerosol generator should be placed in the circuit as close to the patient’s airway as practical. Aerosol administration during intrapulmonary percussive ventilation has been compared with a standard jet nebulizer. The MMAD was smaller with intrapulmonary percussive ventilation than with the jet (0.2 µm vs. 1.89 µm), and the fine-particle fraction was lower (16.2% vs. 67.5%). However, lung dose was similar (2.49% with intrapulmonary percussive ventilation vs. 4.2% with the jet nebulizer). It was concluded that intrapulmonary percussive ventilation was too variable and too unpredictable to recommend for drug delivery to the lung.⁷⁸

Placement During High-Frequency Oscillatory Ventilation

When used in conjunction with high-frequency oscillatory ventilation, administration of albuterol sulfate via a VM nebulizer placed between the ventilator circuit and the patient airway has been reported to deliver greater than 10% of dose to both infants and adults.79,80 A pMDI with adapter placed immediately proximal to the endotracheal tube achieved similar results in adult patients ventilated via high-frequency oscillatory ventilation.⁸¹