Delivery of Inhaled Medication in Adults

Delivery of inhaled medication in adults

Dean Hess, RRT, PhD

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INTRODUCTION — The inhalation of therapeutic aerosols is an effective method of drug delivery frequently applied to the management of respiratory disease. Inhalation (or aerosol) therapy can be employed with a range of medications using a number of different techniques. Examples include:

• Inhaled beta agonists and anticholinergic bronchodilators are used to treat chronic obstructive lung diseases

• Inhaled steroids have a central role in the management of asthma

• Inhaled antibiotics and mucokinetic agents are therapies for cystic fibrosis and bronchiectasis

• Inhaled pulmonary vasodilators are used to manage pulmonary hypertension [1]

• In the future, patients with nonrespiratory disease may benefit from aerosol delivery of drugs, including insulin and opiates [2]

OVERVIEW — Three principal types of devices are used to generate therapeutic aerosols: nebulizers, metered dose inhalers, and dry powder inhalers. All three generate aerosols using different mechanisms. In many cases, clinicians must choose the most appropriate device for drug delivery as well as the appropriate therapeutic agent [3].

In addition, the patient technique for proper use differs among these devices. The patient-aerosol generator interface is an important, but often overlooked, component of patient compliance and therapeutic response. Ineffective use of any of these devices will result in suboptimal drug deposition. As a result, patient instruction and compliance are crucial aspects of prescription and use of these devices.

All three types of devices can be used to efficiently deliver medication to spontaneously breathing patients. Only nebulizer systems and metered dose inhalers can be used in intubated patients; dry powder inhalers should not be used in intubated patients.

NEBULIZERS — The basic design and performance of pneumatic (or jet) nebulizers have changed little over the past 25 years (show figure 1). Nebulizer performance is affected by both technical and patient-related factors (show table 1) [4,5]. Jet nebulizers are often considered interchangeable. However, differences in performance among nebulizers produced by various manufacturers have been reported, some of which have clinical implications [6,7]. This may be less important for inhaled bronchodilators, although newer nebulizer designs should be considered for more expensive formulations where precise dosing is required. (See "New nebulizer designs" below).

In addition to differences in design, the performance of nebulizers is influenced by several common factors, including mechanism, use of mouthpiece or facemask, and drug formulation.

Mechanism — The operation of a pneumatic nebulizer requires a pressurized gas supply, which acts as the driving force for liquid atomization. Compressed gas is delivered as a jet through a small orifice, generating a region of negative pressure above the medication reservoir. The solution to be aerosolized is first entrained, or pulled into the gas stream and then sheared into a liquid film. This film is unstable, and rapidly breaks into droplets due to surface tension forces.

A baffle placed in the aerosol stream allows formation of smaller particles and recycling of larger droplets into the liquid reservoir. The aerosol is entrained into the inspiratory gas stream inhaled by the patient.

The correct technique for use of a nebulizer is important (show table 2) [8,9]. A number of factors determine the efficiency of a nebulizer system, including the respirable dose, nebulization time, dead volume of the device, and the gas used to drive the nebulizer.

• Respirable dose — The most important characteristic of nebulizer performance is the respirable dose delivered to the patient. The respirable dose is a function of the mass output of the nebulizer and the size of the particles produced. Droplet size should be 2 to 5 µm for airway deposition and 1 to 2 µm or smaller for parenchymal deposition. Droplet size is usually reported as mass median aerodynamic diameter (MMAD), which is the median diameter around which the mass of the aerosol is equally divided.

• Nebulization time — Nebulization time, the time required to deliver a dose of medication, is an important determinant of patient compliance in the outpatient setting. In addition, a reduction in nebulization time may decrease the need for clinical supervision in hospitalized or emergently-treated patients. In general, the greater the volume of drug to be delivered and the lower the flow rate of the driving gas, the longer the nebulization time. Treatment is complete when the nebulizer begins sputtering.

Although usually given on a scheduled basis, continuous aerosolized bronchodilators can be administered in the treatment of acute asthma. The available evidence suggests that this therapy is safe, at least as effective as intermittent nebulization, and may be superior to intermittent nebulization in patients with the most severe pulmonary dysfunction [4,10]. (See "Pathogenesis and management of status asthmaticus in adults").

Several configurations have been described for continuous nebulization, including frequent refilling of the nebulizer, use of a nebulizer and infusion pump, and use of a large volume nebulizer [4].

• Dead volume — The volume of medication trapped inside the nebulizer, and therefore not available for inhalation, is referred to as the dead volume of the device. The dead volume is typically in the range of 1 to 3 mL. Increasing the amount of solution within the nebulizer (the fill volume) reduces the proportion of the dose lost as dead volume. Although nebulizer output increases with a greater fill volume, this also results in an increase in nebulization time. Considering both factors, a nebulizer fill volume of 4 to 6 mL is recommended [7].

During nebulization, the solution within the nebulizer becomes increasingly concentrated as water evaporates from the solution. Thus, on a per breath basis, more medication is delivered late in the course of a treatment. Evaporative effects also result in cooling of the nebulizer solution over time. Treatment is complete when the nebulizer begins sputtering.

• Driving gas — Increasing the flow rate of the driving gas results in an increase in nebulized output and a reduction in particle size. A flow of 8 L/min is recommended to optimize drug delivery [7]. This may be problematic when a compressor is used to power the nebulizer, as the flow from these is often <8 L/min, resulting in sub-optimal drug aerosolization and delivery [11-13].

• Gas density — The density of the gas powering the nebulizer affects nebulizer performance. For example, the inhaled mass of albuterol is significantly reduced when a nebulizer is powered with a mixture of helium and oxygen (heliox). Accordingly, the flow to the nebulizer should be increased by 50 percent if it is powered with heliox [14]. 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 [15-20]. (See "Physiology and clinical use of heliox").

Mouthpieces and facemasks — Inhaled aerosols can be administered using a mouthpiece or a facemask. Bronchodilator response appears similar with either interface, and some have argued that the selection of patient interface should be based upon patient preference. Significant facial and eye deposition of aerosol can occur when a face mask is used, especially in young children [21]. Eye deposition is of particular concern when aerosolized anticholinergic agents are administered, as this can result in blurring of vision, pupil dilation, and worsening of narrow angle glaucoma. When a facemask is used, it is important to instruct the patient to inhale through the mouth to minimize nasopharyngeal deposition of medication. We generally favor use of a mouthpiece, rather than a face mask, for aerosol administration.

Breathing pattern — The breathing pattern of the patient affects the amount of aerosol deposited in the lower respiratory tract. Airflow obstruction increases the need for inhaled bronchodilator therapy, but can decrease the effectiveness of that treatment. To improve aerosol penetration and deposition in the lungs, the patient should be encouraged to use a slow breathing pattern with an occasional deep breath.

Drug formulation — Drug formulation can affect nebulizer performance [22-24]. Metered dose inhalers and dry powder inhalers have always been tested and approved as a drug-delivery system combination. Some drug solutions are only approved for delivery with specific nebulizers [25]. Examples of medications that should be delivered only by approved nebulizer include pentamidine, ribavirin, rhDNAase, and tobramycin.

Nebulizers for specific medications — Specially constructed small-volume nebulizers, such as the Respirgard II for aerosolized pentamidine, should be used when contamination of the ambient environment with the aerosolized drug needs to be avoided [4]. The Respirgard II 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 nebulizer and drying chamber that reduce the MMAD to about 1.3 µm, which optimizes drug delivery to distal airspaces. The SPAG is used with a scavenging system to minimize contamination of the ambient environment.

New nebulizer designs — With the traditional nebulizer design, an aerosol is generated throughout the patient's respiratory cycle. This results in considerable waste of aerosol during exhalation. Newer designs reduce aerosol waste during the exhalation phase .

• Breath-enhanced nebulizers, such as the Pari LC, are designed to allow release of more aerosol during inhalation. With this design, exhaled gas is routed out the expiratory valve in the mouthpiece and aerosol is contained in the nebulizer chamber during the expiratory phase.

• The Circulaire nebulizer reduces waste from a constant-output nebulizer by attachment of a storage bag with a one-way valve in the mouthpiece connector. During the expiratory phase, aerosol is collected in the bag and delivered to the patient on the subsequent inhalation.

• The AeroEclipse nebulizer has a breath-actuated valve that triggers aerosol generation only during inhalation, eliminating the need for a storage bag or reservoir [26].

Ultrasonic nebulizers — Ultrasonic nebulizers consist of a power unit and transducer, with or without an electric fan [4]. The power unit converts electrical energy to high-frequency ultrasonic waves with a frequency of 1.63 megahertz. A piezoelectric element in the transducer vibrates at the same frequency as the applied wave. 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. A potential issue with the use of ultrasonic nebulizers is drug inactivation by ultrasonic waves; however, to date this has not been shown to occur with medications commonly delivered using this system.

Vibrating mesh nebulizers — Several manufacturers have developed aerosol devices that use a vibrating mesh or plate with multiple apertures to produce a liquid aerosol (show figure 3) [27]. A common feature of these devices is their ability to generate aerosols with a high fine-particle fraction, which results in more efficient drug delivery compared to conventional nebulizers. The aerosol is generated as a fine mist, and no internal baffling system is required. These nebulizers are portable, battery-operated, and they have minimal residual medication volume; some are breath-actuated [27]. They are being developed in cooperation with pharmaceutical companies to deliver expensive formulations with which precise dosing is needed.

The iNeb nebulizer uses vibrating mesh technology with adaptive aerosol delivery (ADD). ADD monitors the patient's breathing pattern and injects the aerosol at the beginning of inhalation. This improves the likelihood of the aerosol penetrating deep into the respiratory tract. This nebulizer is used specifically for the administration of Ventavis® (iloprost) Inhalation Solution (CoTherix, Inc) for the treatment of pulmonary arterial hypertension (show figure 4).

METERED DOSE INHALERS — A metered dose inhaler (MDI) consists of a pressurized canister, a metering valve and stem, and a mouthpiece actuator (show figure 5) [28]. The canister contains the drug suspended in a mixture of propellants, surfactants, preservatives, flavoring agents, and dispersal agents. The propellant has traditionally been a chlorofluorocarbon (CFC). Following adoption of the Montreal protocol, an international agreement to ban CFCs, CFC-free propellants such as hydrofluoroalkane (HFA) 133a have become available [29-43]. Patients should be informed that the plume emitted from an HFA-MDI is warmer and softer than the CFC plume. Without this information, the patient may interpret the difference in sensation as the aerosol passes through the upper respiratory tract as an ineffectively delivered dose.

The mixture is released from the MDI canister through a metering valve and stem into an actuator boot. After volatilization of the propellant, the final volume emitted from the MDI is 15 to 20 mL per dose [44]. The MDI can be actuated as frequently as every 15 seconds [45]. Lung deposition ranges between 10 percent and 25 percent of the nominal dose in adults. The correct technique for using a MDI is shown in the table (show table 3) [8,9]. The Autohaler (3M Corporation), designed for patients with poor hand-breath coordination, is an example of a flow-triggered MDI that actuates in response to the patient's inspiratory effort [46-50].

Patient teaching — Important patient teaching issues related to the use of an MDI include priming, creaming (separation of drug from other ingredients in the canister), and determining when the canister is empty. When an MDI is new, or if it has not been used for several days (eg, a patient using inhaled beta-agonists on an as-needed basis), the first several actuations deliver an inconsistent dose until the metering chamber is primed [51-53]. The clinical effects of this can be avoided by wasting several actuations from the MDI. Creaming is reversed by shaking the canister before use [54,55].

Determining when an MDI is empty — It is important for the patient to have a means to determine when the canister is empty. A few MDIs are now being manufactured with integrated dose counters, including Ventolin-HFA®, available in the United States as of June 2006 (show figure 6) [56]. Another method is to have the patient maintain a log of the number of actuations, and to dispose of the device when the designated number of actuations has been reached. The technique of dropping the canister into a pan of water and observing how it floats has been shown to be unreliable and is no longer recommended [57,58]. (See "Metered dose inhaler techniques in adults" and see "Patient information: Metered dose inhaler techniques").

Spacers and holding chambers — Spacers and valved holding chambers are accessory devices that reduce oropharyngeal deposition of drug, improve distal delivery, and minimize the importance of hand-breath coordination. A spacer device is an open-ended tube or bag that allows the MDI plume to expand and the propellant to evaporate. A valved holding chamber incorporates a one-way valve that permits aerosol delivery from the chamber only during the inspiratory phase.

Accessory devices either use the boot that comes with the MDI or incorporate a universal canister adapter to actuate the MDI (show figure 7). A valved holding chamber can incorporate a mask for patients who are unable to use a mouthpiece due to age, poor coordination, or impaired mental status. The technique for use of a spacer or valved holding chamber is provided (show table 4) [8,9].

Drug particles deposit on the inner surface of the device due to static charge on the plastic material of the chamber [59-61]. For this reason, the chamber may be less effective when it is new compared to after it has been in use. Washing the device with dishwashing detergent and then allowing it to air-dry eliminates this static charge [62,63]. Anti-static devices are commercially available from several manufacturers. It is important to instruct patients to only actuate one dose into the holding chamber at a time, rather than multiple doses, and to inhale the drug from the chamber immediately after the MDI has been actuated [64-66].

DRY POWDER INHALERS — Dry powder inhalers (DPIs) create aerosols by drawing air through a dose of powdered medication (show figure 8 and show figure 9) [67-69]. The release of respirable particles of the drug requires inspiration at relatively high inspiratory flow rates [70,71], which results in pharyngeal impaction of the larger carrier particles that comprise the bulk of the aerosol. The oropharyngeal impaction of carrier particles gives the patient the sensation of having inhaled a dose. DPIs produce aerosols in which most of the drug particles are in the respirable range; however, the distribution of particle sizes differs significantly among various DPIs.