Aerosol Therapy in Pulmonary Critical Care

Nebulizers

Jet nebulizers convert liquids into aerosols that can be inhaled by patients into the lungs. They are pneumatic and incorporate baffles into their design to produce aerosols, whereas mesh and ultrasonic nebulizers use electricity to convert liquid into respirable aerosols. Using pressurized gas, the liquid solution or suspension in the cup of a jet nebulizer is entrained into the gas stream and sheared into a liquid stream that is unstable and breaks into droplets due to surface tension.^1–7 Baffles in the aerosol stream of jet nebulizers redirect the formulation back to the nebulizer cup to produce smaller particles. Liquid in the cup of the jet nebulizer cools during aerosol therapy and becomes concentrated due to evaporative loss within the nebulizer. Aerosol output and particle size thus vary directly with the temperature of the solution.^8,9

Ultrasonic nebulizers use a piezoelectric transducer that produces ultrasonic waves that pass through the liquid medication in the nebulizer cup and generate aerosols at the surface of the solution. Aerosol particles are then delivered to the patient either through a fan in the ultrasonic nebulizer or by the inspiratory flow of the patient. The frequency of ultrasonic waves is inversely related to the particle size of aerosols produced by ultrasonic nebulizers, whereas the amplitude of crystal vibration is directly related to drug output delivered by the nebulizer.^10,11 Several factors affect output from ultrasonic nebulizers: the characteristics of the liquid solution (viscosity, density, surface tension, and vapor pressure), the piezoelectric transducer (vibration frequency, vibration amplitude, and transducer configuration), the medication chamber (size and baffles), coupling of the medication chamber to the transducer, and flow from fans used with ultrasonic nebulizers. Ultrasonic nebulizers are not efficient in nebulizing suspensions.¹² Just like jet nebulizers, the concentration of solutions increases during aerosol therapy via ultrasonic nebulizers. However, unlike jet nebulizers, they increase the solution temperature up to 15°C after 10 min of nebulization.^8,13 Although small ultrasonic nebulizers are available for use in ventilator-dependent patients, the cost and size of ultrasonic nebulizers and their inefficiency in nebulizing suspensions make them undesirable for aerosol therapy in critical care.¹⁴

Mesh nebulizers can be divided into 2 categories: active and passive (static). Although active mesh nebulizers have a vibrating mesh with multiple apertures, passive (static) mesh nebulizers use a vibrating horn to generate aerosols.^15–17 Active mesh nebulizers with a vibrating mesh contract and expand a vibrational element, moving a domed aperture plate with > 1,000 tapered holes that are larger on the liquid side and smaller on the side that the droplets emerge. The drug is placed in the reservoir of the nebulizer, which is above the aperture plate. Particle size and aerosol flow are determined by the exit diameter of the holes on the aperture plate. Passive mesh nebulizers with a vibrating horn system use a piezoelectric crystal that vibrates a transducer horn interacting with the liquid formulation and a static aperture plate, pushing fluid through the mesh. Previous research has shown that the mesh nebulizer is superior to the jet nebulizer in aerosol drug delivery due to the small residual drug volume and ability to operate without adding gas to the circuit.^18–20 Mesh nebulizers have very low residual volume, fast treatment time, and the ability to nebulize a variety of solutions and suspensions. Aerosol delivery can be optimized with adjustment of the size of the pore in the mesh, the aerosol chamber, the reservoir, and the output rate of mesh nebulizers. However, like jet and ultrasonic nebulizers, these nebulizers have some disadvantages. For example, the pores of the nebulizer can become clogged with some suspensions or viscous drugs, and it may be difficult to determine this from the output of the device. Although the cost of mesh nebulizers is similar to that of ultrasonic nebulizers, they are both much more expensive than jet nebulizers. However, expensive aerosol devices such as mesh nebulizers may be more cost-effective over time. Differences in delivery efficiency between mesh and jet nebulizers may be > 3-fold; therefore, drug doses may need to be adjusted to eliminate adverse effects that may occur due to overdose.

Pressurized Metered-Dose Inhalers

pMDIs are small, portable, convenient, multi-dose devices that use a propellant under pressure to deliver a metered dose of an aerosol through an atomization nozzle. There are several components of pMDIs, including the canister, propellant, drug formulation, metering valve, and actuator. The pMDI canister is made of aluminum, which helps prevent adhesion of drug particles and chemical degradation of drugs through a coating on the canister's inner surface. A pressurized mixture in the canister includes propellants (chlorofluorocarbon [CFC] or hydrofluoroalkane [HFA]), preservatives, flavoring agents, and active drugs. Although most pMDIs used CFC propellants, CFC pMDIs have been phased out in the United States, and newer-generation pMDIs include HFA propellants.^21,22 The formulations of pMDIs can be solutions or suspensions.²³

Spacers/Adapters

Because pMDIs are not designed for delivery of inhaled medications to critically ill patients who are ventilator-dependent, spacer/adapters have been developed after substantial innovation and experimentation. Spacers/adapters are add-on devices that allow a pMDI to be used in a closed pressurized circuit during mechanical ventilation.^24–26 The types of spacers/adapters that are used in critical care can be divided into 3 categories: unidirectional adapters, bidirectional adapters, and chamber spacers. Unidirectional adapters direct the aerosol plume in one direction, whereas bidirectional adapters release the aerosol in 2 opposite directions. Chamber spacers vary in volume from 50 to 150 mL. They are larger than unidirectional and bidirectional adapters. Figure 1 shows commercially available spacers that are used to connect pMDI canisters in the ventilator circuit.²⁷

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Fig. 1.

Commercially available spacers that are used to connect pressurized metered-dose inhaler canisters in the ventilator circuit. ID = inner diameter; OD = outer diameter; DHD = Diemolding Healthcare Division; MDI = metered-dose inhaler. From Reference 27.

Effect of Particle Size

The size of an aerosol particle has a major impact on aerosol deposition in critically ill patients. It is known that a higher proportion of aerosol particles in a respirable fraction of 1–5 μm are deposited in the lung. Large particles generated by any aerosol device are trapped in the ventilator circuit and artificial airways. Moreover, the percentage of the emitted drug that is delivered past artificial airways as aerosol is lower with larger particle size. Therefore, aerosol devices producing particles of < 2 μm are more efficient than those generating large particles during mechanical ventilation.^33,43 Both pMDIs and nebulizers have equivalent aerosol delivery beyond the endotracheal tube (ETT) during mechanical ventilation.³⁴ Although the size of aerosol particles with mesh nebulizers varies,^44,45 a significant proportion are < 3.3 μm.^45,46 The vapor pressure of the propellant mixture, ambient temperature, design of the valve stem and actuator orifice, and drug concentration affect aerosol particle size produced from the pMDI.^47,48 For example, high vapor pressure of propellants generates finer aerosol particles, whereas a higher drug concentration increases the size of aerosol particles produced from the pMDI.

Effect of Drug Formulation

Inhaled β agonists and anticholinergics are widely used in ICUs. However, there are other aerosolized medications that are used for the treatment of critically ill patients. Table 2 lists the classes of medications currently administered as aerosols in critical care.^4,49 Previous research has shown that drug formulations influence the efficiency of aerosol devices.^27,50–53 For example, Rau et al²⁷ compared aerosol delivery via an albuterol and flunisolide CFC pMDIs using 5 different spacers and found that aerosol delivery with flunisolide was lower than with albuterol with all spacers tested (Table 3). Although newer drug solutions have been approved for specific nebulizers, clinicians may be confused about the best choice of aerosol device if the label does not specify which nebulizer to use for aerosol therapy or whether the same clinical outcome will occur if a nebulizer other than those used in clinical trials is used. Moreover, mixing drug formulations in the same nebulizer cup can be an issue if the combined formulations are not compatible.^54–57

Factors Affecting the Performance of Aerosol Devices

Factors Affecting Aerosol Drug Delivery to Ventilator-Dependent Patients

Although aerosol therapy is commonly employed for critically ill patients, many factors influence aerosol drug delivery to ventilator-dependent patients, and it is important to understand the effect of these factors on aerosol drug delivery in critical care. Previous studies showed that the ventilation mode, breathing parameters, heat and humidity, gas density, and artificial airways influenced aerosol delivery to critically ill subjects.^{18,19,31,87–89} The following section describes contributing factors that affect aerosol drug delivery during mechanical ventilation: ventilation mode, ventilator parameters, heat and humidity, gas density, artificial airways, and right-angle elbow adapters.

Heat and Humidity.

It is well known that heat and humidity impact aerosol drug delivery during mechanical ventilation. In vitro studies have reported up to 40% less aerosol deposition with heated and humidified gas compared with unheated and non-humidified ventilator circuits.^{19,31,32,87,91,93} However, although using an unheated and non-humidified ventilator circuit leads to a significant improvement in aerosol deposition in the lung, ventilator-dependent patients need heated and humidified gas to avoid drying airway mucosa and to promote mucus clearance during mechanical ventilation.^94,95

The decrease in aerosol deposition with a heated and humidified ventilator circuit is due to changes in aerosol particle size during mechanical ventilation. For example, Miller et al⁷⁰ found that providing humidity during aerosol therapy in ventilator-dependent subjects increased particle size from 1.5 ± 0.1 to 2.3 ± 0.2 μm. However, Lange and Finlay⁹⁶ reported that the reduction in aerosol deposition was directly related to the mole fraction of water vapor in the inspired air instead of the heat and humidity of the inhaled gas. According to their hypothesis, the main reason for excessive drug loss during mechanical ventilation is not hygroscopic growth but an interaction between the water molecules in the air and the surfactant (pMDI) present in the propellant/drug suspension.

Lin et al⁹⁷ studied aerosol delivery via a pMDI with a spacer during mechanical ventilation using a heated-wire circuit attached to a heated humidifier. They operated the humidifier for 3 h during mechanical ventilation and found that pMDI delivery efficiency did not decrease for > 1 h after turning on the humidifier. They also found that turning off the humidifier for 10 min before aerosol therapy did not improve aerosol delivery via a pMDI attached to a spacer. According to their findings, there was a reduction in aerosol delivery when substantial condensation formed in the ventilator tubing and the pMDI spacer.

Although humidity has been associated with reduced aerosol delivery to ventilator-dependent patients, neither removing the heated humidifier from the circuit nor turning off the humidifier before aerosol therapy is recommended.^4–7,97 Delivery efficiency can be increased by achieving optimum technique during aerosol therapy and increasing the dose when a heated humidifier is used. Although using a dry circuit may be cost-effective with expensive drugs such as antibiotics, it is important to complete aerosol therapy in < 10 min to minimize the effect of dry gas on the airway mucosa.⁶⁵ Therefore, clinicians should consider increasing the dose instead of turning off the heated humidifier when they use inexpensive drugs such as bronchodilators for aerosol therapy during mechanical ventilation.

Heat-and-moisture exchangers (HMEs) are also used to provide heat and humidity to mechanically ventilated patients. Because the filter in the HME acts as a barrier to drug delivery, HMEs should not be placed between the artificial airway of the patient and the aerosol device. Disconnection of the ventilator circuit to remove the HME from the circuit before aerosol therapy interrupts the ventilation of critically ill patients and may cause derecruitment of the lungs, which might take considerable time to re-establish. To overcome issues with the use of standard HMEs during inhalation therapy, new HMEs have been designed for aerosol delivery (HME-AD) to ventilator-dependent patients. Figure 2 shows the different types of HME-ADs available on the market. Although HME-ADs differ in design, they all have 2 configurations: (1) HME configuration and (2) aerosol configuration. The HME configuration functions like a standard HME, whereas the aerosol configuration bypasses the HME configuration to deliver aerosolized medications during mechanical ventilation. However, an in vitro study showed some variation in drug delivery depending on the design and composition of HME-ADs.⁹⁸ Further research is thus needed to determine the delivery efficiency of HME-ADs with different aerosol delivery devices during mechanical ventilation.

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Fig. 2.

Heat-and-moisture exchangers (HMEs) designed for aerosol delivery during mechanical ventilation. A: CircuVent HME/hygroscopic condenser humidifier bypass with an HME, courtesy Hudson RCI. B: Humid-Flo HME, courtesy Hudson RCI. C: AirLife bypass HME, courtesy CareFusion.

Factors Affecting Aerosol Delivery in Spontaneously Breathing Patients With Artificial Airways

Although artificial airways are used for drug delivery either by administration of aerosolized drugs or by instillation of liquid medications, aerosol drug delivery to spontaneously breathing patients with artificial airways is not well understood. Only a few in vitro studies have been done on aerosol delivery through a tracheostomy tube,^106–109 along with a few case reports on methods used to adapt pMDIs to patients with tracheostomies.^110–112 Previous studies found that a measurable amount of aerosol was delivered through the tracheostomy tube regardless of the type of aerosol device used, and aerosol delivery through the tracheostomy tube ranged from 1 to 45% depending on a variety of measurement conditions.^106–109

Factors affecting pulmonary deposition of aerosols in patients receiving mechanical ventilation are different from those in spontaneously breathing patients. Previous studies have reported that albuterol delivery through artificial airways is influenced by the type and material of artificial airways, electrostatic charge, inner cannula of the tracheostomy tube, type of aerosol device, type of patient interface, and use of bias flow in spontaneously breathing subjects with artificial airways.^{106–109,113–115}

Effect of Disease State and Severity

Critical care departments provide intensive treatment and monitoring for patients in critically ill or unstable conditions. The efficiency of aerosol devices used in pulmonary critical care is influenced by a number of factors that are explained above. Previous in vitro studies have had significant impact on the knowledge of clinicians by exploring the effects of these factors on aerosol drug delivery to critically ill patients. However, although current inhaler devices are designed to generate aerosol particles in the respirable range and consistent amounts of drug can be delivered to a test lung or lung model in bench studies, clinicians may still fail to deliver aerosolized medications to the lungs of critically ill patients because of disease state and severity. Thus, patients may receive little or no benefit from the device. Clinical research is needed to understand the effects of disease state and severity on aerosol drug delivery in critical care, but unfortunately, there has been little such research.

Goal of Therapy

The indications for aerosol therapy in pulmonary critical care have rapidly expanded over the years. Aerosol therapy has several advantages, including direct delivery of drug to the site of action, rapid onset of action, lower dose required than with systemic administration to produce desired clinical outcomes, and minimum systemic adverse effects. The selection of an aerosol device depends upon the needs of the patient and the intent of the clinician. Once clinicians are clear about the goal of aerosol therapy in critically ill patients, they can determine the desired therapeutic outcomes that are patient-specific.

Availability of Drug and Dosage

A variety of drugs are available for the treatment of critically ill patients. Although pMDIs are largely limited to bronchodilators and corticosteroids, nebulizers are used to deliver, in addition, antibiotics, surfactant, mucolytics, and prostaglandins. If a drug formulation is available only with one type of aerosol device, aerosol device selection is simple because there is no other choice. When drugs such as bronchodilators and corticosteroids can be administered with both nebulizers and pMDIs, selection of the device should be made based on the precision and consistency of dosing as well as the efficiency of the device. Also, if a patient needs higher doses, clinicians have 2 choices: they can use a nebulizer, or they can deliver multiple doses with a pMDI attached to a spacer.¹¹⁸

Cost of Device and Dosing

Cost of dosing is an important factor in device selection. In the current climate of cost containment, a device that is expensive is less likely to be used in critical care. Although previous studies have found that bronchodilator administration is more cost-effective with pMDIs than with nebulizers, this may no longer hold true due to the transition from CFC pMDIs to HFA pMDIs. For example, 4 puffs of albuterol delivered from an HFA pMDI ($140 for 200 puffs) costs $2.80, whereas a unit dose of albuterol given by a jet nebulizer costs less than $0.25. It is also important to note that the time spent by respiratory therapists on aerosol therapy is a major consideration for cost analysis.¹¹⁹ Nevertheless, the drug options available with pMDIs are limited; pMDIs are a great option when the prescribed drug/dosage is available because they provide the desired clinical response.

Precision and Consistency of Dosing

Achieving a clinical response to an aerosolized medication depends on the amount of drug delivered to the lower airways,^120,121 and this is affected by the precision and consistency of dosing. Although the total amount of drug delivered to the lungs with each device is important, the precision and consistency of dosing with an aerosol device need to be considered when selecting the best device and interface for critically ill patients.¹²⁰ Loss of medications in the upper respiratory tract, ventilator circuit, and artificial airways can reduce the precision of dosing; therefore, it is important to reduce this drug loss while achieving targeted aerosol deposition in specific regions of the lung, such as peripheral airways and lung parenchyma. Consistency of dosing requires uniformity in the drug delivered with each aerosol device every time it is used with critically ill patients.

Efficiency of the Device

As mentioned previously, aerosol delivery devices are equally efficient if they are used correctly.^{4,5,88,101,116,117,122} It is well known that the efficiency of an aerosol device depends on the size of drug particles generated. Both pMDIs and nebulizers generate aerosol particles in the range of 1–5 μm. Although the aerosol delivered from the distal end of an ETT has a mass median aerodynamic diameter of ∼2 μm,³⁴ nebulizers that produce aerosols with a diameter of < 2 μm are more efficient than nebulizers that generate larger particles.^36,87,92 Also, ∼5% of aerosols produced by a pMDI³³ are exhaled during mechanical ventilation compared with 7% of the nominal dose of aerosols generated by a nebulizer.⁸⁷ It is important to note that an efficient device not only delivers a high proportion of the drug placed in the device to the lung of the patient but also minimizes waste of the expensive drugs used in critical care.¹⁶

Risk to Patients and Providers

Aerosol therapy with inhaled medications may create blockages in expiratory filters in ventilators and interfere with vital ventilator functions such as breath sensing. Moreover, aerosols given to ventilator-dependent patients may escape to the environment and create risks to health-care professionals, caregivers, and other patients. Aerosols generated by patients may also pose a greater risk of transmission of airborne diseases such as H1N1, severe acute respiratory syndrome, and tuberculosis. Therefore, it is important to use some form of high-efficiency particulate air filter in the expiratory limb of the ventilator circuit to reduce the escape of aerosols generated by the patient or an aerosol device. Also, the capability of a device to minimize the risk to patients and providers must be considered during the device selection process.

Preference of Clinicians

The time required for therapy, device cleaning, device portability, and ease of drug administration to critically ill patients determine the utilization of an aerosol device in critical care. Any aerosol device that is difficult to use or requires prolonged administration or frequent monitoring will not be preferred by clinicians. Despite the increasing use of pMDIs, nebulizers have been used in clinical settings for many years. Previous research has also shown that the majority of adult ICUs prefer pMDIs for the administration of bronchodilators in critically ill patients.^49,123 According to a survey conducted in 70 countries,⁴⁹ 43% of participants used nebulizers, whereas 55% used pMDIs for aerosol drug delivery in ICUs. This may be because of their convenience, consistent dosing, and reduced chance of bacterial contamination.^124–126 Reported uses of jet, ultrasonic, and mesh nebulizers were 55%, 44%, and 14%, respectively. Although 87% of participants believed that ultrasonic nebulizers outperform jet nebulizers, 69% did not have any ideas about mesh nebulizers.⁴⁹

Drug Development

Efficient delivery of aerosolized medications to critically ill patients has always been desirable. However, the aerosolized medications used in critical care are approved based on treatment of ambulatory patients. No medical aerosols have been approved specifically for administration to very sick patients who are ventilator-dependent and/or have artificial airways. Thus, there are opportunities for development of drugs to treat critically ill patients.

Research on Clinical Outcomes

Previous research has focused on understanding factors that affect aerosol delivery and techniques of mitigating their negative effects during aerosol therapy in critically ill patients. Clinical studies in support of previous in vitro research are limited. Therefore, it is important to conduct clinical research to confirm the benefits of aerosolized medications in both ventilator-dependent patients and spontaneously breathing patients with artificial airways. In addition, we need more information on the effect of inhaled drugs on physiologic variables, cardiovascular and metabolic effects, and clinical outcomes such as duration of mechanical ventilation and stay in ICUs. A cost-benefit analysis should be done for each inhaled drug and aerosol technologies if patient outcomes show improvement after aerosol therapy.

Standards of Practice

Research to determine the effectiveness of aerosolized medications and the best dosing schedule is needed to establish standards of practice for aerosol therapy in not only ventilator-dependent patients but also spontaneously breathing patients with artificial airways. Although there are some studies on bronchodilators, the effectiveness of other aerosolized medications, such as surfactants, antibiotics, and mucolytics, needs to be established through randomized controlled trials in critically ill patients. Effective aerosol therapy in critical care may require modifications in the configuration of device, dose, and frequency of aerosolized medications prescribed, but there is currently little guidance or information on standards of practice in aerosol therapy. With insufficient information on indication, dose, frequency, and optimum method of administration of different inhaled medications, there is a need for the development of standards of practice in pulmonary critical care.