How Should Aerosols Be Delivered During Invasive Mechanical Ventilation?

Jet Nebulizers.

In a jet nebulizer, a jet of compressed air or oxygen under high pressure passes through a narrow opening near the tip of a capillary tube whose base is immersed in the drug solution to be nebulized.^38,39 The low pressure created by the expansion of the jet draws the liquid up the capillary tube. The shearing force of the jet stream produces a liquid film that breaks up into small droplets secondary to surface-tension forces. Larger particles deposit on a baffle placed upstream of the aerosol stream and on the walls of the nebulizer, whereas the smallest droplets leave the nebulizer. In a mechanical ventilator circuit, the resulting aerosol is carried into the stream of gas from the ventilator to the patient.³⁹

Jet nebulizers are easy to use and inexpensive compared with mesh and ultrasonic nebulizers. However, use of a jet nebulizer during mechanical ventilation entrains an additional 6–8 L/min of gas into the ventilator circuit, which influences the tidal volume delivered to the patient. Jet nebulizers may also inactivate or denature the drug due to shear forces.^38,40 Other disadvantages of jet nebulizers are the requirement for a power source, inconveniently long treatment time, need for equipment set up and cleaning, and significant variations in the performance of various nebulizers, both within the same brand and across different brands.^41–43 Therefore, it is important to characterize the efficiency of a jet nebulizer before using it to deliver aerosolized drugs to mechanically ventilated patients. Jet nebulizers continue to be commonly employed in ventilator-supported patients because of familiarity with their use, ease of operation, and low cost.

Ultrasonic Nebulizers.

Ultrasonic nebulizers also use electricity in creating high-frequency vibrations that are transferred to the surface of the solution to be aerosolized. A standing wave is created in the liquid and droplets breaking off from the crest of this wave generate an aerosol. The higher the frequency of vibration, the smaller the particle size generated, and the higher the amplitude of vibrations, the higher is the drug output delivered to the patient.³⁸ Although there are several brands of ultrasonic nebulizers available for use in mechanically ventilated patients, they have not been routinely employed in this clinical setting due to problems associated with their use such as their bulk, relative inefficiency, high cost, inability to aerosolize viscous solutions, settling of suspensions, and larger particle size.^44–46 Another problem with ultrasonic nebulizers is that the drug solution becomes more concentrated during operation, and the solution temperature increases by 10–15°C after a few minutes of ultrasonic nebulization.^44,45 The increase in temperature has the potential to denature some drug formulations.

Several commercial brands of ultrasonic nebulizers have been adapted for aerosol delivery with specific ventilators.^31,47–49 Most ultrasonic nebulizers have a higher rate of nebulization and require a shorter time of operation than jet nebulizers.⁴⁸ To overcome the problem of size, smaller-volume ultrasonic nebulizers with smaller residual volumes than jet nebulizers have been employed.^44,48,50

Placement of ultrasonic nebulizers proximal or distal to the Y-piece in the ventilator circuit does not influence the efficiency of aerosol delivery.^31,51 Likewise, placing the ultrasonic nebulizer in the inspiratory limb of the ventilator circuit 50 cm from the Y-piece did not improve its efficiency.⁵¹ The efficiency of aerosol delivery with ultrasonic nebulizers could be modestly improved by using a longer inspiratory time, by reducing the minute ventilation, and by employing a lower breathing frequency.^31,51 Notably, the efficiency of aerosol delivery with ultrasonic nebulizers is doubled by the addition of a cylindrical storage chamber (volume, 500–600 mL) in the inspiratory limb of the ventilator circuit.^31,51

Vibrating Mesh Nebulizers.

Vibrating mesh nebulizers employed during mechanical ventilation are newer and more efficient than jet or ultrasonic nebulizers. These nebulizers employ batteries or electricity to vibrate a piezoelectric crystal and move the liquid drug through a micron mesh at a very high frequency to generate aerosols.^6,46,52–56 The diameter of the mesh affects the particle size of aerosols produced by vibrating mesh nebulizers. Vibrating mesh nebulizers are more efficient than jet nebulizers because of their small residual volume (ranging from 0.1 mL to 0.5 mL). Because aerosols produced by vibrating mesh nebulizers have a higher respirable fraction, the nominal dose of drugs to be administered for clinical response could be reduced compared to jet or ultrasonic nebulizers.^6,52,56,57 Also, vibrating mesh nebulizers are quieter than jet nebulizers. Because vibrating mesh nebulizers neither cool nor heat the solution, there is minimal risk of denaturation, and they are thus recommended for use with complex microstructures and large molecules.^58,59 Suspensions or viscous drugs could clog the pores of the mesh nebulizer without making a noticeable difference to the nebulizer output.⁶⁰ Despite concerns about the consistency with which some vibrating mesh nebulizers deliver the volume placed in the reservoir,⁶¹ their popularity for aerosol delivery in mechanically ventilated patients has grown.⁶² Some manufacturers, such as the Hamilton SI and G5 ventilators, have integrated Aerogen's aerosol drug delivery technology. Aerogen's Aeroneb Solo nebulizer is now available as an integrated unit with the Maquet Servo-i ventilator.⁶³

A breath-synchronized vibrating mesh nebulizer, the Pulmonary Drug Delivery System (PDDS) Clinical is a single-use drug delivery system that is primarily designed for delivery of aerosolized medications to mechanically ventilated patients.⁶⁴ Therapy with the PDDS could be continued when a patient is able to breathe spontaneously and has been successfully extubated. The device could also be employed for inhalation therapy in patients receiving noninvasive ventilation. Aerosol generation is synchronized to a specific portion of the inspiratory cycle by a control module that operates from an AC/DC adapter. A pressure transducer measures airway pressure in the inspiratory limb of the ventilator circuit. During mechanical ventilation, a rise in airway pressure signals the onset of mechanical pressure from the ventilator and is sensed by the microprocessor in the control module to provide power to the nebulizer during a specific portion of the inspiratory cycle. The controller has 2 software algorithms, one for use during mechanical ventilation and the other for use when the patient is off the ventilator. In the spontaneous breathing mode, the control module operates in a simple, breath-synchronized mode, and it generates aerosol during the entire inspiratory phase. For this purpose, the pressure transducer monitors the fall in airway pressure during inspiration. The PDDS Clinical is being investigated for delivery of inhaled amikacin in patients with ventilator-associated pneumonia.⁶⁵

Factors Influencing Drug Delivery via Nebulizers.

Aerosol drug delivery from a nebulizer to the distal airways/alveoli of a mechanically ventilated patient is not only influenced by the type of nebulizer employed, but also by residual volume, mode of nebulization, position of the nebulizer in the ventilator circuit, gas flow, and bias flow in the circuit.⁹ Such factors influence the emitted dose and make it difficult to provide objective comparisons of clinical outcomes.

Residual volume (also termed dead volume) is the amount of medication remaining in the nebulizer at the end of a treatment. The residual volume can range from 0.1 mL to 2.4 mL depending on the type of nebulizer used for the treatment. The greater the residual volume, the lower will be the amount of drug that is nebulized. Generally, ultrasonic and vibrating mesh nebulizers have smaller residual volumes than jet nebulizers.^{48,50,56,61,64} For jet nebulizers, it is recommended to use a fill volume of 4–5 mL if the nebulizer is not specifically designed for a smaller fill volume.⁴³ This precaution increases the treatment time, while diluting the medication and allowing for a greater proportion to be nebulized during mechanical ventilation.

Each brand of jet nebulizer is designed to work best at a specific flow, ranging from 2 L/min to 8 L/min, which should be specified by the manufacturer. Operating any jet nebulizer at a lower flow or pressure will increase the particle size of the aerosol produced. Gas flow and nebulization time are inversely related. Although operating a jet nebulizer at a higher gas flow will decrease treatment time needed to deliver the specified amount of drug to mechanically ventilated patients, it can be detrimental because higher gas flows may increase the delivered tidal volume. The tidal volume needs to be adjusted to account for this additional volume, but this correction is not precise. In contrast to jet nebulizers, ultrasonic and vibrating mesh nebulizers are operated by electricity and are not influenced by gas flow. The techniques of operating jet and vibrating mesh nebulizers in patients receiving mechanical ventilation are described in Tables 3 and 4, respectively.

Placement of the nebulizer in the ventilator circuit affects aerosol drug delivery during mechanical ventilation. Previous studies reported that placing the jet nebulizer farther from the ETT improves drug delivery, leading to the recommendation to place the nebulizer proximal to the humidifier, ie, close to the ventilator.^{31,37,51,66–68} It was believed that the continuous output from the jet nebulizer filled the inspiratory limb of the circuit between inspirations, increasing the percent of output delivered with each breath through a ventilator. Wan and colleagues⁶⁹ compared 3 jet nebulization modes, ie, inspiratory intermittent, continuous, and expiratory intermittent modes, in adult and pediatric lung models with the jet nebulizer placed proximal to the humidifier. Drug delivery did not differ between the nebulization modes or between adult and pediatric settings, but the time for nebulization was longer with the inspiratory intermittent mode compared to the continuous and expiratory intermittent modes. Moreover, Moraine and coworkers⁷⁰ showed that, in mechanically ventilated patients, the placement of an ultrasonic nebulizer in the ventilator circuit proximal to the humidifier had no effect on the pulmonary bioavailability of drug.

Nebulizers may be operated continuously by pressurized gas or synchronized with gas flow from the ventilator. While continuous jet nebulization is powered by pressurized gas from a 50-psi wall outlet or gas cylinder, breath-synchronized nebulization is operated by a separate line to provide driving pressure and gas flow from the ventilator. When nebulization is synchronized with inspiratory flow from the ventilator, aerosol losses during exhalation are minimized and the efficiency of drug delivery is enhanced by as much as 4 times compared to continuously operated nebulization.^16,68 However, some ventilators do not provide adequate driving gas pressure, which may have an adverse influence on the particle size of the aerosol and the efficiency of drug delivery from the nebulizer. Some newer ventilators have a built-in nebulizer function that could facilitate reproducible and consistent dosing.^63,71 Nebulizers could also be adapted to deliver aerosols continuously for extended periods by using a dual-channel volumetric infusion pump that mixes the drug with normal saline prior to nebulization and allows the dose to be titrated according to clinical requirements.⁷²

Jet nebulizers are less expensive, but ultrasonic and vibrating mesh nebulizers are more efficient than jet nebulizers as they provide a higher rate of nebulization in a shorter period of time.^{6,37,48,52,66,73} The relative expense of ultrasonic and vibrating mesh nebulizers is a limiting factor for their widespread use in ventilated patients.⁷⁴

Type of Artificial Airway.

The placement of an artificial airway with a cuffed tube allowing application of positive pressure, preventing aspiration, and facilitating suctioning to maintain airway patency is important for delivery of high concentrations of oxygen. However, the artificial airway is the narrowest portion of the ventilator circuit and the site of the highest resistance to air flow. The narrower diameter of the artificial airway compared to the normal airway coupled with high inspiratory air flows employed during mechanical ventilation predispose the system to air flow turbulence and higher particulate losses due to impaction.¹²⁸ Aerosol impaction on the ETT poses a significant barrier to effective drug delivery in infant and pediatric mechanical ventilation (ETT inner diameter 3–6 mm),^129,130 with aerosol delivery efficiency being lower with narrower ETTs.¹³¹ In adult mechanical ventilation, there was no difference in nebulizer efficiency with ETTs with inner diameters of 7 mm versus 9 mm.⁶⁷ Drug losses within the ETT could be minimized by placing the aerosol generator at a distance from the ETT instead of being directly connected to it.¹²⁸ A greater proportion of the aerosol is lost in the ETT when the circuit is humidified compared to a dry circuit, and this difference contributes to the reduced efficiency of drug delivery in humidified circuits.¹¹ In vitro studies have shown minimal drug deposition within ETTs with jet nebulizers; however, significant ETT deposition of aerosol occurs with ultrasonic nebulizers.⁴⁸

Aerosol deposition in tracheostomy tubes has not been studied in as much detail as with ETTs. By using a mass balance technique, O'Riordan and colleagues¹³ found that approximately 10% of the nominal dose from a nebulizer deposited in the tracheostomy tube of mechanically ventilated subjects. The majority of aerosol deposition (∼7%) occurred during exhalation, and < 3% was deposited in the tube during inhalation. Because in vitro studies are unable to directly determine aerosol deposition during exhalation, such studies could significantly underestimate the actual deposition of aerosol in the artificial airway. Ari and co-workers¹³² found in a bench model of mechanical ventilation that a greater percentage of the dose was delivered via a tracheostomy tube compared to an ETT with either jet nebulizer or pMDI. Piccuito and Hess¹³³ reported that drug delivery through a tracheostomy tube in a bench model of mechanical ventilation was influenced by the delivery device (nebulizer or pMDI), bias gas flow, and the patient interface. Specifically, these investigators reported that, in spontaneously breathing patients with a tracheostomy, the use of a nebulizer without additional gas flow and a T-piece adapter resulted in a 3-fold higher drug delivery compared to high flow through the circuit (30 L/min) and connection of the nebulizer to a tracheostomy mask.¹³³ Another in vitro study found that removing the inner cannula of the tracheostomy tube prior to aerosol administration increased drug delivery.¹³⁴ With in vitro and in vivo models (3 of the 6 subjects had tracheostomies), Miller and co-workers demonstrated that breath-actuated nebulization and humidity were the most important factors influencing aerosol delivery during mechanical ventilation.¹⁶ In contrast, one group of investigators who compared pulmonary deposition of ^99mTc-labeled fenoterol administered by pMDI and spacer to mechanically ventilated patients found no difference in aerosol delivery between tracheostomy and ETTs (6.1% ± 2.8% vs 4.6% ± 3.0%, respectively; P < .12).¹³⁵

Heat and Humidity.

Bench models of mechanical ventilation have consistently demonstrated a reduction of up to 40 – 50% in heated and humidified ventilator circuits compared to dry circuits at room temperature.^{10,11,30,66,136,137} While higher deposition with delivery of cold dry gas might seem attractive to deliver more drug to the lung, the increased efficiency of aerosol delivery must be weighed against the potential damage to the respiratory mucosa from prolonged ventilation with cold dry gas.⁹ Active heated humidifiers are commonly used during mechanical ventilation of infants and small children, and a substantial proportion of adults. The heat and humidity of an inhaled gas to body-temperature-and-pressure-saturated conditions promotes more normal mucociliary clearance, prevents drying of the airway mucosa, and reduces bronchospastic responses to breathing cold dry air. The heated humidity in the ventilator circuit is associated with increases in aerosol particle size during mechanical ventilation.^{10,11,30,66,136,137} When a pMDI is used in a ventilator circuit, humidity probably interferes with propellant evaporation so that drug particles remain of a larger size and impaction losses are increased.^9,138 Even though humidity has an unwanted effect on drug delivery, removing the humidifier is not recommended for routine aerosol therapy as it requires breaking the circuit and waiting several minutes for the circuit to dry. Even then, as shown by Lin and colleagues, such interventions may not improve aerosol delivery.¹³⁹ These investigators reported that delivery efficiency of albuterol from a pMDI with a spacer chamber during mechanical ventilation with a heated wire circuit was not reduced for more than 1 h after turning on the heated humidifier. Reduction of aerosol delivery occurred as substantial condensation formed in the spacer and tubing, with reductions to levels previously reported with a humidified ventilator circuit. After 3 h of humidifier operation, turning off the humidifier for up to 30 min prior to administration of aerosol via pMDI did not improve drug delivery.¹³⁹ The authors suggested that the presence of water condensate in the circuit and chamber was sufficient to achieve a high enough absolute humidity that continued to reduce efficiency of inhaled drug delivery even after the humidifier was turned off.¹³⁹

For inexpensive drugs, such as salbutamol or ipratropium bromide, increasing the dose may be safer than turning off the humidifier. For more expensive drugs, such as antibiotics, the potential efficiency advantage of a dry ventilator circuit may be cost-effective. If a dry ventilator circuit needs to be used for aerosol delivery, the ventilator should be used with an HME, and the administration of medication should be achieved in a short period (< 10 min) to minimize the effects of dry gas on the airway mucosa.⁸³

HMEs are utilized as an alternative to heated humidifiers.¹⁴⁰ The filter in the HME captures the heat and moisture in the exhaled breath and transfers part of it to the air in the following inspiration, providing about 70% absolute humidity at 30°C. The HME filter captures drug particles in the aerosol and markedly reduces the efficiency of drug delivery. Therefore, the HME must be removed from the circuit during aerosol treatments or the pMDI should be placed between the HME and ETT. While placement of a pMDI between the HME and ETT could provide adequate drug delivery, with a nebulizer placed distal to the HME, backflow of aerosol could deposit on the HME filter and increase its air flow resistance, thus increasing the work of breathing for the patient.¹⁴¹ Some manufacturers have introduced HMEs that accommodate aerosol delivery. In these HMEs, the inspiratory gas flow bypasses the filter in the HME during aerosol delivery so that is possible to achieve adequate aerosol delivery without removing the HME from the circuit.¹⁴²

Density of Inhaled Gas.

The density of the inhaled gas also influences drug delivery during mechanical ventilation. High inspiratory flows employed during mechanical ventilation are associated with turbulence. Inhalation of a less dense gas, such as a 70:30 helium-oxygen (heliox) mixture, makes air flow less turbulent and more laminar, which may improve aerosol deposition by decreasing particle-impaction losses caused by air flow turbulence.¹⁴³ The use of heliox mixtures improved drug delivery in a pediatric model of mechanical ventilation.¹⁴⁴ In a bench model of adult mechanical ventilation, drug delivery from a pMDI was noted to be 50% higher with a 80:20 heliox mixture than with oxygen alone.¹⁴⁵ In contrast, nebulizer operation with heliox reduced drug output and respirable mass.^145,146 A preferred strategy in maximizing aerosol deposition with a nebulizer is to power it at 6–8 L/min with oxygen and entrain the aerosol into a ventilator circuit that contains heliox.¹⁴⁵ Aerosol deposition to the lower airways is increased by 50% with that technique compared to using oxygen by itself in the ventilator circuit.¹⁴⁵ It is important to remember that heliox may adversely affect the function of some ventilators and therefore the system must be tested before use to prevent detrimental effects on patients.^147,148

Heliox has been used in clinical practice for many decades; however, its role in treatment of patients with severe asthma, exacerbations of COPD, or bronchiolitis has provided mixed results.^149,150 Moreover, treatment with heliox is costly and technically complex, and its role in treatment of mechanically ventilated patients has not been established.¹⁵¹

Obstruction in the Ventilator Circuit.

Any obstruction in the ventilator circuit or ETT, whether due to accumulation of water, bends, or kinks, could lead to greater aerosol impaction at the site of narrowing. The exit angle at the opening of the airway also affects the aerosol flow properties and the potential for particle impaction. Mucus plugs blocking the artificial airway should be effectively suctioned before administering aerosols. After the tube is placed inside the airway, there is build-up of an alginate, polysaccharide matrix known as a biofilm.¹⁵² The narrowing and roughening of the inner surface of the artificial airway produced by these biofilms could have an additive effect on aerosol losses.

Bias Flow.

With flow-triggering, a bias flow through the ventilator circuit helps reduce the patient's work of breathing. The presence of a bias flow increases the transport of aerosol from the aerosol generator and increases the washout of aerosol from the circuit during exhalation when a continuously operating nebulizer is used for aerosol delivery, but it does not have a similar influence on drug delivery from pMDIs.¹⁰ Ari and colleagues⁶⁶ studied the influence of bias flow with a jet and vibrating mesh nebulizer on albuterol delivery in a model of adult mechanical ventilation. They reported that increasing bias flows through the ventilator circuit decreased the amount of aerosol deposited and lower bias flows (≤ 2 L/min) are recommended for greater aerosol delivery with nebulizers that operate continuously.⁶⁶ The impact of the bias flow is greater for jet nebulizers than for vibrating mesh nebulizers because the clearance of aerosol from the ventilator circuit is increased by the bias flow in addition to the continuous flow from the jet nebulizer.

Swivel Connector/In-line Suction Catheters.

Significant aerosol losses occur at the connection between the Y-piece and ETT.¹¹ Larger drug particles in the aerosol have difficulty in negotiating the right-angled bend of the swivel connector. A streamlining approach that eliminates sudden changes in the diameter of the ventilator circuit components and applies a smooth curvature to changes in the path of the aerosols is a proposed alternative that could lead to improved efficiency of aerosol delivery.¹⁵³ Likewise, some in-line suction catheters could impede aerosol delivery. Manthous and colleagues found a significantly greater effect of nebulized albuterol on airway resistance in 3 mechanically ventilated patients when they connected the Y-piece directly to the ETT compared to the effect observed with an in-line suction catheter and connector in place.¹⁵⁴

Obstruction in Major Airways.

Obstruction in the trachea and major bronchi distal to the artificial airway, produced by tumors, stenosis, tracheomalacia, stricture, edema, or granulation tissue, could adversely affect aerosol delivery to the lower airways. Tracheal stenosis may have a greater impact on deposition of larger drug particles (10 μm) than smaller drug particles (2.5 μm).¹⁵⁵ In such clinical situations, heliox could be used as an adjunctive therapy to reduce airway resistance¹⁵⁶ and improve delivery of aerosols beyond the area of critical obstruction.

Ventilator-Related Factors.

The characteristics of the ventilator breath have an important influence on aerosol drug delivery. A tidal volume of 500 mL or more (in an adult),¹⁰ longer inspiratory time, and slower inspiratory flows improve aerosol delivery.¹⁰ An inspiratory flow of 30–50 L/min is optimal for aerosol delivery; however, slow inspiratory flows may increase inspiratory time and, by reducing the time for exhalation, may have the unintended consequence of increasing PEEPi.¹⁴⁸ Drug delivery is linearly correlated with a longer duty cycle (inspiratory time/total breath duration) for both pMDIs and nebulizers.^10,11,67 Moreover, drug delivery is improved when a pMDI is synchronized with a simulated spontaneous breath compared with a controlled ventilator breath of similar tidal volume.¹⁰

The inspiratory waveform influences drug delivery from nebulizers, but it has much less influence on drug delivery from a pMDI.¹⁵⁷ Unlike pMDIs, nebulizer efficiency could be different during pressure-controlled ventilation than during volume-controlled ventilation. The use of a spacer with a pMDI improves the efficacy of bronchodilator therapy in ventilator-supported patients. The best results are obtained when the pMDI actuation is synchronized with the onset of inspiration.^5,28

In mechanically ventilated patients with COPD, the application of external PEEP at a level that counterbalances PEEPi enhances the bronchodilator effect of albuterol.⁹⁷ The additive effects of external PEEP and albuterol could be explained by the effect of albuterol in reducing time-constant inequality, thereby producing alveolar recruitment during tidal ventilation, and the application of external PEEP maintains this alveolar recruitment. The net effect is that the level of PEEPi is markedly reduced by the combination of albuterol and external PEEP.⁹⁷ In contrast, Guérin and colleagues reported that after administration of nebulized fenoterol, respiratory mechanics improved when PEEP was set at zero.¹⁵⁸ Increasing the PEEP level to 85% of the PEEPi level did not enhance the bronchodilator response.¹⁵⁸ With careful attention to the technique of administration, a bronchodilator response can be expected in most mechanically ventilated patients with asthma or COPD. However, most mechanically ventilated patients do not show incremental effects with higher drug doses.¹⁷

Patient Position.

Spontaneously breathing patients usually adopt a sitting or standing posture during aerosol inhalation. In contrast, most patients are recumbent or semi-recumbent while receiving mechanical ventilation and inhaled drug therapy. Ventilator-dependent patients should preferably sit in bed or in a chair during inhalation therapy. In patients with exacerbations of COPD, administration of bronchodilator aerosols to semi-recumbent patients produced a significant response.^{5,17–19,20,22,36,82} A semi-recumbent position, with the head end of the bed elevated to 20–30° above horizontal, should suffice for ventilator-supported patients who are unable to sit upright during aerosol administration.

Use Appropriate Methods to Assess the Response.

The response to bronchodilators depends on several variables: patient airway geometry, degree of airway responsiveness, severity of disease, quantity and type of secretions, and counter-regulatory effects of airway inflammation and other drugs. Most investigators assess response by measuring inspiratory airway resistance. Airway resistance in ventilated patients is commonly measured by performing rapid airway occlusions at constant flow inflation.¹⁵⁹ This technique involves performing a breath-hold at end-inspiration by occluding the expiratory port. Total or maximal inspiratory resistance can be partitioned into minimal inspiratory resistance, which reflects ohmic resistance of the airways, and additional effective resistance (ie, the difference between maximal and minimal inspiratory resistance).¹⁵⁹ Similarly, airway occlusion at end-expiration produces an increase in airway pressure to a plateau value, signifying PEEPi.³⁶

Most ventilated patients with COPD demonstrate a decrease in airway resistance and PEEPi after bronchodilator administration. That the difference between maximal and minimal inspiratory resistance does not decrease significantly after albuterol delivery with a pMDI^17,36 suggests that the bronchodilator effect occurs predominantly in the central airways with little effect on viscoelastic behavior or time-constant inhomogeneities in the lung. Moreover, albuterol does not significantly influence the elastic properties of the lung.³⁶ In contrast, a greater decline in the difference between maximal and minimal inspiratory resistance was noted after nebulizer delivery of fenoterol and ipratropium bromid.⁸² This difference in response between pMDIs and nebulizers could be explained by higher drug deposition in peripheral airways with a nebulizer.

Kondili and colleagues measured expiratory resistance of the respiratory system in mechanically ventilated patients with COPD exacerbations.¹⁶⁰ They found that albuterol significantly reduced expiratory inspiratory resistance and enhanced the rate of lung emptying to the end of expiration. Interestingly, these investigators did not find any correlation between changes in expiratory inspiratory resistance and changes in end-inspiratory resistance after albuterol administration.¹⁶⁰ This discrepancy could be attributed to additional contributions by flow limitation and airway narrowing during expiration to the total expiratory resistance.

Pressure, flow, and volume waveforms, flow-volume loops, and pressure-volume loops are continuously displayed on most modern ventilators. In mechanically ventilated patients with airway obstruction, assessment of these waveforms at the bedside aid in recognizing abnormalities in function, in optimizing ventilator settings to promote patient-ventilator interaction, and in diagnosing complications before the development of overt clinical signs.¹⁶¹ Pressure, flow, and volume waveforms are helpful in detecting the presence of dynamic hyperinflation. The persistence of flow at the end of relaxed expiration indicates that the system is above passive functional residual capacity and that flow is being driven by positive elastic recoil of the respiratory system at end-expiration, signifying the presence of PEEPi.¹⁶¹ Comparison of flow volume curves and flow-time curves obtained before and after drug administration could be used to assess improvements in peak expiratory flow and reduction in PEEPi with bronchodilators.¹⁶¹

The clinical end points for inhaled antibiotics and other inhalation therapies have been investigated. It is unclear if microbiological cure or clinical cure should be the goal of treatment in mechanically ventilated patients. Use of inhaled antibiotics as adjunctive treatment makes it difficult to show superior efficacy, especially in the presence of infection caused by organisms that are susceptible to the antibiotics that the patient is already receiving.¹¹⁴ Alternative study designs and end points have been suggested to determine the efficacy and safety of inhaled antibiotic therapy.¹⁶² Inhalation of pulmonary surfactant in mechanically ventilated patients with ARDS did not produce improvement in clinical outcomes.^163,164 Likewise, inhaled prostaglandins are employed in patients with ARDS to treat refractory hypoxemia and pulmonary hypertension, but their effect on clinical outcomes in mechanically ventilated patients has not been established.¹²⁵

Particle Size.

During mechanical ventilation, larger particles are trapped in the ventilator circuit and ETT. To optimize drug delivery, devices that produce aerosols with mass median aerodynamic diameter < 2 μm are more efficient during mechanical ventilation than devices that produce aerosols with larger particles.^9,13,130 Nebulizers and pMDIs delivered an equivalent mass of aerosol beyond the ETT in a ventilator model.³⁰ While nebulizers that produce aerosols with smaller particle sizes have been employed during mechanical ventilation, they require a considerably greater time to deliver a standard dose.^13,16,56,64 Vibrating mesh nebulizers produce aerosols with variable particle sizes, but a significant proportion of the aerosol generated is in particles < 3.3 μm in size (the fine-particle fraction).^55–57

Synchronizing Aerosol Generation with Inspiratory Air Flow.

The timing of pMDI actuation in relationship to the ventilatory pattern of the patient has a large impact on delivered dose of medication. Actuation of a pMDI should be synchronized with the precise onset of inspiration to maximize aerosol drug delivery. According to Diot and co-workers,³⁰ failure to synchronize actuations with inspiration reduces inhaled drug mass by 35%. When a pMDI is actuated into a cylindrical spacer synchronized with inspiration, its efficiency increases approximately 30% when compared to actuation during expiration.³⁰ Likewise, nebulizers could be synchronized to generate aerosol during inspiratory air flow from the ventilator.^13,64 During intermittent operation, the nebulizer generates aerosol only during the inspiratory phase, and the ventilator compensates for the flow to the nebulizer to maintain a constant tidal volume and minute ventilation.^5,83 Obviously, intermittent operation is more efficient for aerosol delivery than continuous aerosol generation.^13,66

Avoid Interruption.

Inhalation therapy with pMDIs only requires a few minutes to administer. However, it may require 10–15 min to administer treatments with a jet nebulizer, and treatments may have to be interrupted for other interventions in critically ill patients. The likelihood of treatment interruption is greater with longer therapy duration. The median time for nebulization with jet nebulizers (GaleMed, Taipei, Taiwan) operated in the inspiratory intermittent mode provided via a Galileo Gold ventilator (Hamilton Medical) was almost 40 min.⁶⁹ Antibiotic delivery with the PDDS Clinical device may require administration for a similar duration.⁶⁴ There is a distinct possibility of interruption of treatment with such a long nebulizer duration, and alarms should be incorporated to alert caregivers that the treatment has been stopped. Alternatively, continuous or expiratory intermittent modes of nebulization may be considered to reduce the duration of nebulizer treatment.⁶⁹

Inter-device Variability.

Nebulizer operation during mechanical ventilation could have widely variable efficiency for aerosol delivery unless careful attention is given to a number of factors that influence nebulizer performance. Miller and colleagues¹⁶ found up to 16-fold variation in antibiotic levels in sputum after delivery with a jet nebulizer. Accounting for circuit humidity and breath-actuated nebulization could reconcile most of the observed differences.¹⁶

Inter-provider Variability.

In spontaneously breathing patients, most patients are taught to self-administer their inhaled medications, whereas mechanically ventilated patients rely on clinicians or care providers to administer inhaled drugs. Clinically, it is common to observe substantial variation in the actual practice of aerosol administration between various practitioners. Drug deposition in the lung could be markedly reduced by relatively minor changes in the technique of administration.^5,19,154 When optimal techniques of administration are employed, adequate drug deposition is achieved in the lung and a significant response is observed.

Mucoactive Agents.

The retention of airway secretions could predispose mechanically ventilated patients to development of pneumonia. Mechanical suctioning, the current method to clear secretions in mechanically ventilated patients, is painful and could lead to tracheal injury. Acetylcysteine (Mucomyst) is often used to enhance secretion clearance by reducing sputum viscosity. However, reports of increase in inspiratory airway resistance after administration of mucolytic agents by aerosol¹⁶⁵ or after bolus instillation¹⁶⁶ could pose a problem with the routine use of these agents. Recombinant human DNase (Pulmozyme, Genentech, San Francisco, California) was shown to improve mucus clearance in ventilator-supported patients with spinal cord injury and recurrent atelectasis refractory to conventional treatment.¹⁶⁷ Pulmozyme cannot be recommended for routine use in the management of ventilator-dependent patients with inspissated secretions or mucus plugs because of cost constraints. A systematic review with meta-analysis found only 2 trials comparing nebulized dornase alfa with placebo, no therapy, or hypertonic saline.¹⁶⁸ The evidence was of low quality and did not report any benefit or harm from use of nebulized dornase alfa in critically ill patients. Mucoactive agents may have a role in preventing lung collapse and hypoxemia in ventilated patients with thick inspissated secretions who are refractory to other forms of treatment. At the time of this review, there is not enough evidence to support the use of inhaled mucoactive agents in the management of mechanically ventilated patients, and further investigations are needed.

Inhaled Corticosteroids.

In mechanically ventilated patients, the role of inhaled corticosteroids (ICS) has not been determined. In patients receiving long-term ventilation for severe COPD, Nava and Compagnoni observed a small but statistically significant reduction in airway resistance with fluticasone.¹⁶⁹ A combination of salmeterol and fluticasone administered to mechanically ventilated patients by pMDI (4 doses) reportedly reduced inspiratory resistance,¹⁷⁰ but this effect was probably because of the salmeterol component in the combination. Despite the lack of studies showing efficacy of ICS in the setting of mechanical ventilation, the majority of respondents reported employing inhaled budesonide or methylprednisolone in international surveys.^62,94 In addition, many patients, especially those with exacerbations of asthma or COPD, receive high doses of systemic steroids, either parenterally or enterally. The additional benefit, if any, from a comparatively much smaller dose of ICS (eg, 1 mg of inhaled budesonide vs 240 mg of methylprednisolone intravenously or 60 mg of prednisone orally) is unlikely to be significant. There is also an increased risk of pneumonia with ICS in patients with COPD.^171,172 COPD is a known risk factor for developing pneumonia in mechanically ventilated patients,¹⁷³ and there is a potential for further enhancing the risk of pneumonia with ICS. Furthermore, considerable costs could accrue from use of ICS, especially in combination with a long-acting β-agonist. For the reasons mentioned above, the benefits of ICS in mechanically ventilated patients with COPD are unclear, and their use is not evidence-based. In hypoxemic subjects at risk of developing ARDS, early intervention with inhaled formoterol and budesonide combination was shown to lead to more rapid improvement in oxygenation.¹⁷⁴ In this study, a higher proportion of subjects in the placebo group were in shock at baseline, and the reported differences in need for mechanical ventilation and frequency of ARDS that favored the treatment group were no longer observed after correction for baseline shock.¹⁷⁴ Thus, there is no conclusive benefit of using ICS, and further investigations are needed to determine the appropriate dosing regimen and the risks and benefits of using ICS or ICS and long-acting β-agonist in mechanically ventilated patients.

Inhaled β-agonists.

β-agonists are commonly used as bronchodilators in mechanically ventilated patients.^62,83,94 While there are specific indications for the use of β-agonists in mechanically ventilated patients, they are now being utilized in many clinical situations where their benefits are unclear.⁸⁸ High doses of albuterol administered via pMDI produced cough and tachycardia,¹⁷ and 3–6 times the routine nebulized dose of albuterol produced supraventricular and ventricular ectopy.¹⁹ The occurrence of tachyarrhythmias could be a concern in elderly patients with preexisting heart disease, atrial fibrillation, or prior history of ventricular tachycardia. The results of the large, multi-center BALTI study¹⁰⁵ are somewhat reassuring in this regard. In this study, subjects receiving nebulized albuterol had a higher heart rate compared to those receiving placebo, but the occurrence of new-onset atrial fibrillation (10% in both groups) and other dysrhythmias was similar in the 2 groups. However, in that study, nebulization of albuterol did not improve ventilator-free days or mortality, and the study was stopped early.¹⁰⁵ In addition, the report that administration of β-agonists may increase the risk of VAP needs consideration.¹⁷⁵

Widespread use of β-agonists in mechanically ventilated patients who do not have clear indications for their use, especially in high doses, have not been shown to lead to improvement in clinical outcomes and have the potential to be harmful. Thus, frequent and high doses of nebulized β-agonists should be avoided in mechanically ventilated patients unless there are specific indications for their use.

Intravenous Formulations.

In the past, inhaled antibiotic solutions were made from intravenous formulations that contained preservatives, such as phenol and bisulfites. These solutions were often hypertonic, they did not have a neutral pH, and the presence of the preservatives mentioned above contributed to airway irritation, coughing, and bronchoconstriction.¹⁷⁶ Antibiotics for inhalation need to be specially formulated to avoid irritant effects. Drug solutions for inhalation should have osmolality of 150–550 mOsm/Kg, contain at least 77 mEq/L of chloride ions, and preferably have pH between 4.8 and 8.^177–179 Solutions that do not contain ions (eg, dextrose solutions) are more likely to induce cough. Preservatives in drug solutions such as disodium ethylenediaminetetraacetic acid or benzalkonium chloride may cause bronchoconstriction or airway hyper-responsiveness that may not be completely abrogated by albuterol pretreatment.^180–183

Drug Combinations.

The presence of a preservative in a drug solution enhances nebulizer output, probably because of reduction in surface tension, compared to preservative-free solutions.¹⁸⁴ Co-nebulization of albuterol with other drugs could unpredictably affect nebulizer output and aerosol characteristics.¹⁸⁵ Addition of an albuterol solution containing benzalkonium chloride to a nebulizer solution of tobramycin increased tobramycin output without altering the particle size of the aerosol,¹⁸⁶ and addition of surfactants to prevent foaming of a solution of alpha 1 protease inhibitor increased drug output.¹⁸⁷ The physical and chemical compatibility of the drug mixtures also need to be confirmed, and this has been shown with several nebulizer solutions.^188–190 For example, a solution of formoterol fumarate was found to be physically and chemically compatible with several other drug solutions.¹⁹¹ Drug admixtures or sequential administration produced higher drug output than nebulization of single drugs, but there was no significant change in the characteristics of the aerosol produced. Because of the unpredictable effects of drug admixtures, mixing drug solutions should be avoided in clinical practice.

Manual Resuscitation Bag.

Ari and co-workers¹⁹⁹ observed that a manual resuscitation bag connected to an ETT or tracheostomy tube produced a 3-fold higher aerosol delivery compared to other interfaces. This difference could be explained by the fact that capping the end of the tubing allows the circuit to be charged with the drug, and the drug was carried by the nebulizer flow to the collection filter.²⁰⁰ This method of drug administration could be employed when high doses of bronchodilators need to be rapidly administered in a patient with an artificial airway.

Ventilator Settings.

The technique employed may have to compromise between the optimum operating characteristics of the device and the patient's condition. For example, a higher duty cycle increases aerosol delivery,^10,11,13 but it may worsen dynamic hyperinflation in patients with air flow limitation.¹⁴⁸ A higher tidal volume may be advantageous for aerosol delivery, but could be injurious to the lungs, especially in patients with ARDS.²⁰¹

Cleaning.

Unless scrupulously cleaned and disinfected, nebulizers can be a source for aerosolization of bacteria and thus may predispose patients to nosocomial pneumonia.⁸⁶ Because of their design, the risk of bacterial contamination may be less with vibrating mesh nebulizers compared to jet nebulizers. The gas flow driving the nebulizer produces additional air flow in the ventilator circuit, but this is compensated for in most modern ventilators. In contrast, pMDIs are easy to administer, require less personnel time, provide a reliable dose, and do not pose a risk of bacterial contamination. A retrospective analysis of patients receiving ventilator support for > 1 d and aerosol treatments by pMDI or vibrating mesh nebulizer found no differences in the number of days on ventilator (median 5/6 d), VAP rates (5/6%), or in-hospital mortality.²⁰²

Circuit Contamination and Frequent Disconnection.

Jet nebulizers are usually attached to the ventilator circuit with a standard T-adapter, and attaching or removing the nebulizer from the ventilator circuit may interrupt ventilation. Valved T-adaptors allow placement and removal of the jet nebulizer without loss of pressure in the ventilator circuit. In-line devices that avoid breaking the circuit integrity are preferred. Placing vibrating mesh nebulizers on the dry side of the humidifier reduces the concern for repeatedly breaking the circuit. For the same reason, collapsible spacers that remain in the circuit are preferred for use with pMDIs compared to devices that have to be removed from the circuit after each treatment.

Blockage of Expiratory Filter.

Nebulization of drugs could produce obstruction of the filter in the expiratory limb of the ventilator circuit.²⁰³ When this occurs acutely, it can mimic an exacerbation of asthma or lead to more serious consequences, including tension pneumothorax, hypoxemia, or cardiovascular collapse. Obstruction of the filter is more likely to occur with continuous nebulization when the filter becomes supersaturated with humidity and with the use of unheated ventilator circuits.²⁰⁴ Moreover, drug particles in the aerosol or sticky buffers in the drug solution may also contribute to filter blockage.²⁰⁵ The expiratory filter should be checked when any mechanically ventilated patient develops unexplained acute bronchospasm or PEEP.

Drug Toxicity.

Bronchospasm occurs after inhaled antimicrobials, especially after colistin administration,^206,207 and requires pretreatment with a short-acting bronchodilator such as albuterol.^208,209 The occurrence of bronchospasm is reduced, but not totally avoided, by using the preservative-free inhalable tobramycin rather than the intravenous formulation.^210,211 Bronchospasm in some patients with asthma may be refractory to albuterol.²⁰⁹

Administration of high doses of β-adrenergic bronchodilators causes tachycardia and has the potential to cause atrial and ventricular arrhythmias.¹⁹ In the ARDS Network BALTI study, regular administration of nebulized albuterol produced a significant but modest increase in heart rate but did not result in an increased incidence of atrial fibrillation or ventricular arrhythmias.¹⁰⁵

Escape of aerosols into the environment carries potential risks for the environment and persons caring for the patient.^212,213 Escape of antibiotics into the environment could pose serious health risks, such as anaphylaxis in patients or caregivers with a penicillin allergy. Inhalation of aerosolized antimicrobials, particularly pentamidine and polymyxin, has the potential to cause adverse effects on healthcare workers. In addition, a low level of antibiotic exposure in the environment could promote growth of antibiotic-resistant organisms.^211,214 The escape of aerosols into the environment could be reduced by utilizing breath-actuated aerosol delivery devices and high-efficiency particulate filters in the expiratory limb to filter the exhaled air.

Cough and Spread of Infection.

In an era of serious infections for which there are no or limited treatment options, such as Ebola, severe acute respiratory syndrome, Middle East Respiratory Syndrome, H1N1 influenza, or extremely drug-resistant tuberculosis, treatments that induce coughing could lead to transmission of infection.²¹⁵