Comparison of Lung Deposition in Two Types of Nebulization

Comparison of Lung Deposition in Two Types of Nebulization* Intrapulmonary Percussive Ventilation vs Jet Nebulization Gregory Reychler, PT; Andre´ Keyeux, MD; Caroline Cremers, PT; Claude Veriter, Ing; Daniel O. Rodenstein, PhD; and Giuseppe Liistro, PhD

Background: So-called intrapulmonary percussive ventilation (IPV), frequently coupled with a nebulizer, is increasingly used as a physiotherapy technique; however, its physiologic and clinical values have not been rigorously assessed. Study objective: To compare in vitro and in vivo characteristics of the nebulizer of the IPV device (Percussionaire; Percussionaire Corporation; Sandpoint, ID) with those of standard jet nebulization (SST) [SideStream; Medic-Aid; West Sussex, UK]. Design: Aerodynamic particle size was studied by an cascade impactor. The deposition of 99m Tc-diethylenetriaminepenta-acetic acid was measured in 10 healthy subjects by tomoscintigraphy during spontaneous breathing with both nebulizers. Measurements and results: The mass median aerodynamic diameter (0.2 ␮m vs 1.89 ␮m for IPV and SST, respectively) and the fine-particle fraction (16.2% vs 67.5%, respectively) were significantly smaller with IPV. In vivo, respiratory frequency (RF) was lower with the IPV device (10.1 ⴞ 3.4 breaths/min vs 14.6 ⴞ 3.4 breaths/min, p ⴝ 0.002). Whole-body deposition was significantly higher with IPV (15.63% vs 9.31%), but it was due to a higher extrapulmonary deposition. Although intrapulmonary deposition (IPD) was not different with both devices (4.20% for SST vs 2.49% for IPV), it was much more variable with IPV, compared to SST. The penetration index into the lung was higher with IPV than SST when normalized for RF (0.045 ⴞ 0.018 breaths/min vs 0.026 ⴞ 0.013 breaths/min, p ⴝ 0.007). Conclusion: The two techniques showed comparable lung deposition despite a large difference in particle size. However, IPV IPD was too variable and thus too unpredictable to recommend its use for drug delivery to the lung. (CHEST 2004; 125:502–508) Key words: intrapulmonary percussive ventilation; lung deposition; nebulization; respiratory therapy; enetriaminepenta-acetic acid

99m

Tc diethyl-

Abbreviations: CD ⫽ central deposition; ED ⫽ emitted dose; FPF ⫽ fine-particle fraction; ID ⫽ initial dose; IPD ⫽ intrapulmonary deposition; IPV ⫽ intrapulmonary percussive ventilation; MMAD ⫽ mean median aerodynamic diameter; PD ⫽ peripheral deposition; PI ⫽ penetration index; RF ⫽ respiratory frequency; ROI ⫽ region of interest; RW ⫽ residual weight; SST ⫽ standard jet nebulization; Ti ⫽ inspiratory time; Vt ⫽ tidal volume; WBD ⫽ whole-body dose

are widely used in the treatment of N ebulizers pulmonary diseases such as asthma, COPD, and cystic fibrosis. Many patients find nebulizations attractive. However, deposition of nebulized medications may be highly variable. The therapeutic effect depends on the quality of the nebulization,1 on the drug solution, on the conditions of the nebulization, *From the Departments of Physical Medicine and Rehabilitation (Ms. Cremers), and Pediatry (Mr. Reychler), Nuclear Medicine (Dr. Keyeux), and Pneumology Unit (Mr. Veriter and Drs. Rodenstein and Liistro), Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium. Partly supported by the Belgian “Fonds National de la Recherche Scientifique” grant No. 3.4536.98. 502

on the individual patient (pattern of breathing, anatomy, underlying lung pathology), and on the device characteristics. All those variables influence the nebulization.2 Jet nebulization has been studied with different devices in various groups of patients and in different Manuscript received April 14, 2003; revision accepted July 17, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Giuseppe Liistro, PhD, Pneumology Unit, Cliniques Universitaires St-Luc (UCL), Avenue Hippocrate 10, 1200 Brussels, Belgium; e-mail: [email protected] Clinical Investigations

diseases.3–7 Lung deposition by jet nebulization was also studied using different drugs.3,5–9 By contrast, intrapulmonary percussive ventilation (IPV) has been poorly studied from this point of view.10 The device was designed by F.M. Bird in 1979. It consists of a high-frequency percussive ventilation method combined with a nebulizer. It delivers rapid minibursts of air and aerosol solution through a unique sliding Venturi, and it was originally designed, according to the manufacturer, to increase the mucociliary clearance, to improve the gas exchange, to stabilize airway patency, to humidify the airway, and to improve the lung mechanics. Aerosolized antibiotics are used in patients with cystic fibrosis and, combined with albuterol aerosolization, IPV may help to mobilize airway secretions in these subjects.11 However, there is no published study on deposition properties of the IPV. There is therefore a need for validation studies. The aim of this study was to compare IPV combined with nebulization to a validated jet nebulizer. Comparison of particle deposition with both devices can give important information on their respective efficacy and indications. The aerodynamic particle size analysis was performed, and the lung deposition was investigated by tomoscintigraphy.

Materials and Methods Subjects Ten healthy men, all nonsmokers (mean age, 28 years; range, 23 to 43 years), were investigated. All subjects underwent standard spirometry according to American Thoracic Society guidelines.12 The Ethics Committee of our institution approved the study, and a written, informed consent was obtained from the volunteers.

The nebulizer and IPV were directly connected to the cascade impactor. For both nebulization devices, 2 mL of sulforhodamine solution were nebulized during 1 min with an inspiratory flow of 28.3 L/min. Fluorescence of the deposited particles was measured by a spectrometer (Luminescence Spectrometer LS50B; Perkin-Elmer; Norwalk, CT) [excitation ⫽ 586 nm, emission ⫽ 602 nm]. The drug quantities found on each stage were added to determine the emitted dose (ED). The cumulative mass of nebulized solution retained in the successive stages of the cascade impactor was calculated and plotted on a log-probability scale (as percentage of total mass recovered in the impactor) against the effective cutoff diameter. According to Clark and Borgstrom,13 the experimental mass median aerodynamic diameter (MMAD) of the particles was defined from this graph as the interpolation of the regression line at 50%. The percentage of particles with a size between 1 ␮m and 5 ␮m, defined as the fine-particle fraction (FPF), was calculated. Output flow of both nebulizers was measured using a spirometer (Expirograph; Godart; Bilthoven, the Netherlands). The nebulizers were connected to the tubing of the spirometer, and the volume of the nebulized solution was measured as a function of time to calculate flow. The measurements were done in triplicate and the mean values are reported. In Vivo Measurements For SST, a Hans Rudolf 1410 valve (Hans Rudolf; Kansas City, MO) was inserted between the filter and the mouthpiece to avoid rebreathing (Fig 1). We added a filter on the expiratory airway of both systems to avoid atmospheric contamination by radioactive particles. The subjects breathed spontaneously through the same mouthpiece with a nose clip in place. According to manufacturer of the IPV device, 1 mL of solution is nebulized per minute. However, after preliminary testing, we noticed that 4 mL of solution were nebulized in 3 min with IPV. We therefore reduced the nebulization time to 3 min for IPV with continuous percussions. For SST, the duration of nebulization was fixed at 4 min. All the nebulizations were done in the same room at ambient temperature (mean, 22.9°C [⫾ 1.1°]; range, 22° to 25°C) at the same time of the day (2 pm). All the subjects were submitted to both nebulization systems. The first six subjects started with SST followed by IPV 3 days later, whereas the last four volunteers performed the maneuvers in the reverse order.

Nebulizers Both devices were driven by the same pressure: 3.5 bars of compressed air. For standard jet nebulization (SST), we chose a well-studied nebulizer (SideStream; Medic-Aid; West Sussex, UK). Since the collector device is made up of two pieces, we abraded the borders to optimize the sealing of the collector and avoid leaks to the atmosphere. For IPV, an IPV apparatus (Percussionaire; Percussionaire Corporation; Sandpoint, ID) with an operating pressure of 20 cm H2O for a frequency of 250 cycles per minute was used. The same collector and top of both nebulizers were used throughout all the in vitro and in vivo measurements. In Vitro Measurements Particle size was measured by a cascade impactor (1 ACFM Eight Stage NonViable Cascade Impactor; Graseby Andersen; Atlanta, GA) at ambient temperature (23°C). Each stage of the impactor (10 to 0.7 ␮m) was coated with a hydroxypropylmethylcellulose gel (22.5% weight/volume in water). www.chestjournal.org

Figure 1. Circuit used for the nebulization. 1 ⫽ collector; 2 ⫽ top of the nebulizer; 3 ⫽ mouthpiece; 4 ⫽ Hans Rudolf valve; 5 ⫽ filter. Arrows show the direction of airflow. CHEST / 125 / 2 / FEBRUARY, 2004

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Data Acquisition and Treatment The collectors of SST (element 1 in Fig 1) and IPV were filled with 4 mL of a final solution of 99mTc-diethylenetriaminepentaacetic acid aerosol for nebulization, prepared with ethanol according to the recommendations of the provider (Mallinckrodt; Petten, Holland). 99mTc-diethylenetriaminepenta-acetic acid aerosol is a diagnostic radiopharmaceutical specially designed for administration by inhalation. As determined by chromatography, the labeling efficiency is ⬎ 95% and the complex is stable during 6 h in vitro. The absence of modification of the radioactive background in the tissues surrounding the lungs (except the digestive tract) indicated that the radioactive marker was not released during the data acquisition process. Thus, the regional quantification of radioactivity in the lungs is a reliable means for studying aerosol distribution. Radioactivity of the collector was measured before (initial dose [ID]) and after nebulization with a radioisotope calibrator (Capintec CRC-12; Capintec; Ramsey, NJ). By subtraction of both measurements, the nebulized dose was calculated and expressed in megabecquerels. The collector was weighed (Mettler H10W Mettler Instrumente AG; Greifensee, Switzerland) empty, before, and then after the nebulization. By subtracting these weights, we obtained the residual weight (RW) of the doses. The emitted weight was obtained by subtracting the weight of the collector after nebulization from the weight of the filled collector. Respiratory frequency (RF), tidal volume (Vt), minute ventilation, and inspiratory time (Ti) were measured by inductance plethysmography (Respitrace; Ambulatory Monitoring; Ardsley, NY) after calibration with a spirometer (Expirograph) to determine the pattern of breathing during nebulization. Calibration of the inductance plethysmograph was done using the isovolume maneuver.14 As soon as nebulization was completed, the subjects were driven in a wheelchair to the gamma camera. The subjects were then placed in supine position on the moving bed of a three-head gamma camera (Triad XLT20; Trionix; Twinsburg, OH) fitted with low-energy ultra-high resolution collimators. A 60°-angle emission tomography of the entire thorax was acquired in a 64 ⫻ 64 matrix for a total duration of 10 min. With the subjects remaining in the same position, emission tomography was immediately followed by a transmission tomography using the displacement of a linear 153Gd source over the thorax for each of the 30 angles of a 180° rotation of the camera with a total duration of 30 min. At the end of the study, the radioactivity of the inhalation material (elements 2, 3, 4, 5 in Fig 1) was measured by use of a head of the camera as detector. Activity in cycles per minute was expressed in megabecquerels after calibration of the detector by a source of technetium. One-pixel (8.96 mm)-thick transverse planes were reconstructed by convolution back projection and a first-order Chang attenuation correction15 using a constant coefficient as derived from the transmission data. For each subject, reconstructed transmission tomography images were used to define right lung

boundaries in coronal views. Three consecutive (one pixel) coronal slices centered on the hilum of the right lung were summed together. On this 26.88-mm thick slice, a peripheral strip and central square areas were drawn in order to delineate a peripheral region of interest (ROI) and a central pulmonary ROI according to the criteria proposed by Phipps et al.16 Radioactivity Deposition Parameters Comparison of both ROIs allowed the calculation of the penetration index (PI) as follows: PI ⫽ peripheral ROI (counts per second per pixel)/central ROI (counts per second per pixel). Activity distributed to both lungs was obtained by summing the activities of all the coronal slices taking care to avoid the activities of the trachea and of the digestive tract. Global lung activity (intrapulmonary deposition [IPD]) was expressed in percentage of the initial dose. Activity distributed to the whole body (whole-body dose [WBD]) was obtained by subtracting the residual activities of the nebulization accessories from the ID and expressing the result as a percentage. The IPD/WBD ratio was calculated as follows: WBD ⫽ ID ⫺ residual activity (in the collector, the filter, and the instrumental dead space). During the first test, the expired gas was collected in a neoprene balloon connected to the filter to check its efficacy. Since no significant level of radioactivity was recorded in the balloon at the end of the test, this precaution was no longer taken. Statistical Methods The RW and radioactivity of both collectors were compared using an unpaired Student t test. A Student paired t test was used with a level of significance of p ⬍ 0.05 for the comparisons of ventilatory and scintigraphic parameters. We compared respiratory parameters and deposition results between the two methods. Each subject was his own control. We also compared the IPV-first group with the SST-first group to assess an eventual training effect. A standard linear regression analysis was used to examine the relationship between ventilatory and scintigraphic variables, as well as between gravimetric parameters. The coefficient of variation was used to evaluate the variability (SD/ mean ⫻ 100).

Results Lung Function Tests Table 1 presents average anthropometric and lung function data of the subjects. All volunteers had spirometric values in the normal range. Aerodynamic Particle Size Analysis The FPFs were 67.5% and 16.2% for SST and IPV, respectively. The EDs were 13.4% and 1.45%

Table 1—Anthropometric and Lung Function Data of the Subjects Variables

Age, yr

Weight, kg

Height, cm

Vital Capacity, % Predicted

Total Lung Capacity, % Predicted

FEV1, % Predicted

Mean SD Minimum Maximum

27 6 23 43

77.3 7.5 67 91

180 4.0 175 187

96.5 5.6 86 106

94.6 7.4 82 107

94.6 6.0 86 104

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Table 2—Pattern of Breathing for the Two Groups During Nebulization V˙e, L/min

RF, min

Vt,* L

Ti, s

Ti/Total Time

Variables

SST

IPV

SST

IPV

SST

IPV

SST

IPV

SST

IPV

Mean SD Coefficient of variation p Value

12.02 4.53 0.38 0.568

11.11 4.25 0.38

14.61 4.13 0.28 0.002†

10.09 3.39 0.34

0.85 0.34 0.40 0.090

1.26 0.82 0.65

93.7 18.1 0.19 0.396

83.0 22.9 0.28

0.39 0.08 0.21 0.261

0.46 0.13 0.28

*Body temperature and pressure, saturated. †Indicates significance.

for SST and for IPV, respectively. MMADs were 1.89 ␮m for SST and 0.2 ␮m for IPV. Output flow of the nebulizers was 10.3 L/min for SST and 70.6 L/min for IPV.

parable for the PI in the two groups (37% and 29% for SST and IPV, respectively) [Table 3]. The amount of aerosol (␮Ci/100 pixels) deposited in both central (central deposition [CD]) and peripheral (peripheral deposition [PD]) areas of the right lung was also comparable between SST and IPV (Table 3). The pattern of breathing during nebulization (Table 2) was not influenced by the system used except for RF, which was 45% higher with SST than with IPV. Vt was also increased with IPV, albeit not significantly because of a large variability. There was no significant relationship between RF and IPD for both devices. By contrast, we found a significant correlation between RF and PI for SST (r ⫽ ⫺0.65, p ⬍ 0.05) but not for IPV (Fig 3). There was no significant training effect between the subjects starting with the SST or the IPV in terms of WBD, IPD, or PI. We normalized the results for RF (Table 4) because this parameter showed a significant difference between the two groups. Normalized PI was significantly higher for IPV (p ⫽ 0.007) but IPD showed no difference (p ⫽ 0.882). WBD remained significantly higher with IPV (p ⫽ 0.005).

Pattern of Breathing During Nebulization Table 2 summarizes the data of ventilation. Average RF was significantly lower with IPV than with SST. Average Vt was higher with IPV, though not significantly. There was no significant difference between the two groups for the Ti (p ⫽ 0.396), while the duration of nebulization was shorter in the IPV group. The ratio of Ti to total time did not show any significant difference (p ⫽ 0.261). Scintigraphy As shown in Table 3, the mean dose of radioactive aerosol WBD was significantly higher with IPV than with SST. However, interindividual variations were lower with SST than with IPV. Inversely, the mean dose of aerosol deposited in both lungs (IPD) was lower with IPV than with SST. Although this difference was not significant, it should be noted that individual data illustrated in Figure 2 show that IPD was higher with SST in 7 subjects (subjects 1, 2, 4, 5, 6, 8, and 10) of 10. The coefficient of variation of IPD was 35% for SST and 104% for IPV. The IPD/WBD ratio was significantly higher with SST than with IPV (p ⫽ 0.003) [Table 3]. The PI was not different between both nebulization systems. The coefficient of variation was com-

Gravimetric Measurements The emitted weight was comparable with the two devices (p ⬎ 0.05), but the RW in the collector was significantly higher with the SST (1.58 ⫾ 0.44 g) than with the IPV (1.13 ⫾ 0.40 g, p ⫽ 0.028). Accordingly, residual radioactivity measured in the

Table 3—Comparison of SST and IPV in Terms of Radioactivity Deposition Parameters and PI CD, ␮Ci/100 Pixels

PD, ␮Ci/100 Pixels

IPV

SST

IPV

SST

IPV

SST

IPV

0.17 0.18 106

48.4 28.57 59 0.185

25.4 28.52 112

15.0 7.69 51 0.528

11.0 14.33 130

0.34 0.13 37 0.287

0.42 0.12 29

IPD/WBD Ratio

WBD, % ID

IPD, % ID

Variables

SST

IPV

SST

IPV

SST

Mean SD Coefficient of variation, % p value

9.31 1.57 17 0.002*

15.63 4.24 27

4.2 1.2 35 0.090

2.49 2.59 104

0.46 0.15 32 0.003*

PI

*Indicates significance. www.chestjournal.org

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Table 4 —Comparison of SST and IPV Radioactivity Deposition Parameters and PI After Normalization for RF WBD, % ID/RF Variables Mean SD p value

IPD, % ID/RF

PI

SST

IPV

SST

IPV

SST

IPV

0.69 0.22 0.005*

1.73 0.87

0.31 0.14 0.882

0.30 0.33

0.026 0.013 0.007*

0.045 0.018

*Indicates significance.

Figure 2. Individual data of IPD obtained with SST and IPV showing the difference of interindividual variability.

collector, dead space, and filter was higher with SST than IPV (11.98 ⫾ 2.11 mCi vs 8.08 ⫾ 1.14 mCi, p ⬍ 0.001). There was a significant correlation between the residual radioactivity and RW with SST (r ⫽ 0.85 p ⬍ 0.01) but not with IPV (r ⫽ 0.03). Discussion We have found that nebulization combined with IPV resulted in a higher WBD than SST. This was due to a higher extrapulmonary deposition with the IPV. This device delivered intrapulmonary aerosols irregularly in a group of naive healthy subjects. Although in vitro testings present some limitations and may give an overestimation of the lung deposition measured in vivo,17 it remains nevertheless an acceptable way to compare two methods in a standardized protocol. FPF was small, and particle size distribution was theoretically less favorable for IPD with IPV than with SST. The aerodynamic data of the SideStream device reported here are consistent with the literature (FPF, 67.5% vs 71.95%; MMAD, 1.89 ␮m vs 2.1 ␮m).18,19 Then we postulated the

Figure 3. Relationship between PI and RF for both devices. 506

validity of the comparison of the aerodynamic characteristics (FPF, ED, and MMAD) of the two devices. The design of the dead space of IPV might have explained part of the differences in aerodynamic properties, because the larger particles could have remained in the instrumental dead space before reaching the impactor. However, the residual radioactivity measured in the devices, including their dead space, was significantly less with IPV than with SST, ruling out this hypothesis. Classicaly, using a jet nebulizer, ⬍ 10% of a nebulized drug deposits in the lung.4 Lung deposition depends on particle size distribution, which is under the influence of air flow, filling volume, drug solution, and ambient temperature.1,2,6,20 In this study, those parameters were kept constant to avoid variability. We used a fixed driving pressure of compressed air for both nebulizers that corresponded to the minimal pressure recommended by the IPV manufacturer (3.5 bars). The pattern of breathing is also important, as lung deposition depends principally on inspiration.21 In our study, the Ti was comparable in the two groups, and thus the potential influence of the inspiration on deposition was minimized. As shown by previous reports,22,23 the mouthpiece may influence the results. We therefore used an identical mouthpiece with the two devices. The same nebulizers were reused during all measurements. Because each subject was his own control, we avoided the effect of anatomical and mechanical variability as confounding factors. The disease can modify the pattern of breathing,4 but the subjects were all healthy volunteers. We did not calculate the dose retained in the body from the difference between the weight of the ID and the RW. Indeed, we had to take into account the dead space of the devices, which were different (36 mL with SST and 76 mL with IPV), and the loss of solvent during nebulization by the concomitant process of evaporation.24 Scintigraphy of the dead space and the collector enabled us to measure the Clinical Investigations

nebulized solution retained in the devices. That was the reason why all the components of the ID (residual, retained in the filter, in the dead space) except WBD were measured by their radioactivity. IPD was higher with SST in seven subjects, without reaching statistical significance. However, one of the more striking results was the variability of IPD with IPV. The IPD varied 33-fold with the IPV (Fig 2). All other parameters being constant, the causes of this variability may be related to the changes in pattern of breathing of the subjects or to the device itself. As shown on Table 2, only Vt was more markedly affected by interindividual variation, but there was no relationship between Vt and IPD with the IPV. We have also found that RF was significantly lower during IPV nebulization. As stated before, a low RF would increase lung deposition, but this was not the case. Another explanation is the fact that the subjects reported frequent swallowing during IPV nebulization. Indeed, the IPD/WBD ratio showed that more drug was dispersed in the body and less deposited in the lung with IPV than with SST. This characteristic may explain the variability of IPD and the lower IPD/WBD ratio we observed, the aerosolized particles being swallowed by the subjects, or impacted in the upper extrathoracic airways. Calculated WBD did not give an indication on the exact localization of extrathoracic deposition. A total body deposition imaging would be necessary to evaluate this precisely, but inspection of the scintigraphic images showed systematically an intense spot at the gastric level with IPV. Because some drugs have side effects linked to the extrathoracic deposition (eg, inhaled corticosteroids), this could be a disadvantage for the IPV. The PI, the ratio of PD to CD of aerosolized particles in the lung, is another important characteristic of a aerosol. Both average CD and PD were comparable between the two aerosols, but we observed a trend for a higher PI with IPV, though not significant (Table 3). At variance with previous data from the literature,25 we did not observe a relationship between RF and IPD with either device. This may be due to interindividual anthropometric variability and to the small number of volunteers studied. But the significant correlation between RF and PI for SST shows that the PD is improved with a decrease in RF (Fig 3). To our knowledge, this influence of RF on the PI has not been previously reported. In the IPV group, the changes in RF were not related to PI. We therefore normalized scintigraphic variables with respect to RF. As shown in Table 4, the normalized PI was significantly higher with the IPV, together with normalized WBD, but IPD was unchanged. www.chestjournal.org

Besides the different aerodynamic properties and the pattern of breathing, percussions could also explain the observed lung deposition. They could slow down inhaled small particles in the respiratory tract and could have the same effect as a postinspiratory pause. The superimposed percussions of IPV could also enhance turbulence in the carrier gas stream. These turbulences could increase the coalescence of aerosolized particles, increasing their size and promoting their impaction in the upper airway. Our subjects were not trained before the study. Contrary to a classic nebulizer, the IPV could be rather surprising for a naive subject, and could influence the breathing pattern. But we did not find any difference between the SST-first group and the IPV-first group. However, to verify this hypothesis, a similar study with a previous training or with a fixed RF could be useful. In conclusion, we have found large differences in the aerodynamic properties of IPV and SST nebulizers. The Percussionaire IPV device presents a potential interesting property in terms of a higher PI when normalized for RF, but our study demonstrates that IPV cannot replace a standard nebulizer if a pharmacologic agent must be delivered to the lung. However, our results cannot be extrapolated to patients with COPD or cystic fibrosis. These diseases are characterized by totally different respiratory mechanics and respiratory muscle functions. Because of the high cost of IPV and the large interindividual variability of its IPD, we cannot recommend this device as a first choice for inhaled drug therapy. ACKNOWLEDGMENTS: The authors thank R. Vanbever and C. Bosquillon for help in collecting and interpreting in vitro data.

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