Abstract
BACKGROUND: Intrapulmonary percussive ventilation (IPV) is frequently used for airway clearance, together with delivery of aerosolized medications. Drug delivery via IPV alone increases with decreasing percussion frequency and correlates with tidal volume (
), whereas drug delivery via IPV during invasive ventilation is not well characterized. We hypothesized that drug delivery via IPV–invasive ventilation would differ from IPV alone due to control of ventilation by invasive ventilation.
METHODS: An adult ventilator circuit was used for IPV–invasive ventilation. A normal or a diseased lung model was configured to airway resistance of 5 cm H2O/L/s and lung compliance of 100 mL/cm H2O or to airway resistance of 20 cm H2O/L/s and lung compliance of 50 mL/cm H2O, respectively. The ventilator settings were the following: pressure control continuous mandatory ventilation mode, 10 breaths/min; PEEP, 5 cm H2O; 
, 0.21; inspiratory time, 1 s; no bias flow; and inspiratory pressure, 10 or 15 cm H2O for the normal or the diseased lung model, respectively, to reach 
500 mL with IPV off. Albuterol nebulized from an IPV device was captured in a filter placed before the lung model and quantitated by spectrophotometry.
RESULTS: The maximum efficiency of albuterol delivery via IPV–invasive ventilation was not different from that via IPV alone (mean ± SD of loading dose, 3.7 ± 0.2% vs 4.2 ± 0.3%, respectively; P = .12). The mean ± SD albuterol delivery efficiency with IPV–invasive ventilation was lower for the diseased lung model versus the normal model (1.6 ± 0.3% vs 3.2 ± 0.5%; P < .001), which increased with decreasing percussion frequency. In contrast, the mean ± SD 
was lower for the normal lung model versus the diseased model (401 ± 14 mL vs 470 ± 11 mL; P < .001).
CONCLUSIONS: Albuterol delivery via IPV–invasive ventilation was modulated by percussion frequency but was not increased with increasing 
. The delivery efficiency was not sufficiently high for clinical use, in part due to nebulizer retention and extrapulmonary deposition.
Introduction
Patients receiving mechanical ventilation have a risk of secretion retention due to the presence of artificial airways and insufficient humidification.1,2 Such secretion retention is associated with a variety of problems, including airway obstruction, increased work of breathing, and deterioration of gas exchange,3 which leads to ventilator-associated pneumonia,1 or atelectasis4 for example. Therefore, airway clearance is important for mechanically ventilated patients, and airway clearance devices that inflate the lungs with gas have been developed, including intrapulmonary percussive ventilation (IPV), continuous high-frequency oscillation, and mechanical insufflation-exsufflation. IPV is high-frequency percussive ventilation that delivers small bursts of gas into the lungs. IPV can provide both ventilation and delivery of nebulized drugs, including bronchodilators simultaneously and has been used in patients with cystic fibrosis,5 asthma,6 atelectasis,7 and lungs of brain-dead organ donors for lung transplantation.8 An in vitro study on drug delivery via IPV alone has shown that the efficiency of drug delivery is ∼2% in an adult model9 and can be increased with decreasing percussive frequency and increasing IPV operational pressure.
However, drug delivery optimization via IPV superimposed on invasive ventilation is not well understood. The combination therapy of IPV and invasive ventilation is frequently performed for airway clearance,10-14 and the use of the manufacturer’s in-line adapter allows the operation of IPV without disconnection of patients on mechanical ventilation from the ventilator circuit, reducing the risk of ventilator-associated pneumonia and lung de-recruitment with high PEEP.14 When IPV is superimposed on invasive ventilation (IPV–invasive ventilation), the volume of gas added by IPV generates intrinsic PEEP,11 and pressure controlled continuous mandatory ventilation is shown to be safer than volume controlled continuous mandatory ventilation, avoiding hyperinflation.13 Compared with the efficiencies of drug delivery via jet nebulizer (3–7%) and vibrating mesh nebulizer (10–15%) in mechanically ventilated adults,15,16 IPV–invasive ventilation has been shown to be less efficient at drug delivery in a pediatric model (∼4%).12 However, little is known about drug delivery via IPV–invasive ventilation in an adult ventilator model by using the Phasitron 5 device (Percussionaire, Sandpoint, Idaho). We hypothesized that drug delivery via IPV–invasive ventilation would differ from IPV alone due to control of ventilation by invasive ventilation. In this study, we investigated the effects of the combination of invasive ventilation with IPV, IPV percussion frequency, and lung mechanics on drug delivery efficiency and drug depositions in the ventilator circuit of an adult model without spontaneous breathing.
QUICK LOOK
Current Knowledge
Inhaled therapy via in-line intrapulmonary percussive ventilation (IPV) during invasive ventilation has drawn increasing attention but remains to be well characterized with regard to the influence of percussion frequency, tidal volume, and lung mechanics on drug delivery efficiency.
What This Paper Contributes to Our Knowledge
The efficiency of albuterol delivery via IPV–invasive ventilation by using the Phasitron 5 was comparable with via IPV alone, influenced by lung mechanics, and increased with decreasing percussion frequency but not with increasing tidal volume. However, drug delivery via IPV–invasive ventilation was inefficient due to nebulizer retention and extrapulmonary deposition.
Methods
Nebulization of Albuterol with IPV Alone
An IPV device (IPV-1C, Phasitron 5, TRUE In-Line Valve, Percussionaire) was connected to a trachea model (condenser tube, 20 mm × 30 cm, Percussionaire), flow analyzer (PF-300, IMT Medical, Buchs Switzerland) and a lung model (model 1600, Dual Adult TTL, Michigan Instruments, Grand Rapids, Michigan) (Fig. 1). A filter in a cartridge housing (inspiratory/expiratory breathing circuit filters, RT019, Fisher & Paykel, Auckland, New Zealand) to capture albuterol was placed between the trachea model and the flow analyzer. A cuffed endotracheal tube (ETT) (8.0 mm × 36 cm) (TaperGuard, Medtronic, Dublin, Ireland) was placed to connect the Phasitron 5 device to the trachea model with 25 cm H2O of cuff pressure. One mL of albuterol solution (0.5% Ventolin, GlaxoSmithKline, London, United Kingdom) was diluted with 10 mL of saline solution and nebulized from the IPV device toward the lung model for 15 min. Configuration parameters of the IPV device were 30 psi of operational pressure and fully easy or hard mode of percussion. The pulse-to-interval ratio setting was 1:2.5. The normal or the diseased lung model was configured to airway resistance (
) of 5 cm H2O/L/s and lung compliance (
) of 100 mL/cm H2O or to 
of 20 cm H2O/L/s and 
of 50 mL/cm H2O, respectively. A filter in a cartridge housing to capture albuterol was placed between the trachea model and the flow analyzer, separated from the tip of the ETT by 2 cm (filter A) (Fig. 1). The flow analyzer measured peak inspiratory flow, peak expiratory flow, PEEP, peak inspiratory pressure, and tidal volume (
) (Supplementary Fig. 1 [see the supplementary materials at http://www.rcjournal.com]). These variables were measured 1 min after the start of IPV in 3 independent experiments.
Experimental setups for analysis of albuterol delivery via intrapulmonary percussive ventilation (IPV) alone and IPV–invasive ventilation. For IPV–invasive ventilation, a flow analyzer (FA) was placed at the position FA1, FA2, or FA3. Only one filter was placed for each experiment at the position A, B, C, or D of the ventilator circuit, which was repeated 3 times. ETT = endotracheal tube; N = nebulizer bowl; Ins = inspiratory limb; Exp = expiratory limb.
Nebulization of Albuterol with IPV–Invasive Ventilation
The IPV device was connected to an adult ventilator circuit (PB980, Medtronic; Evaqua2 RT380, Fisher & Paykel) between the inspiratory limb and the Y-piece via an in-line adapter (TRUE-IPV In-Line valve, Percussionaire) (Fig. 1). The pressure relief port of the adapter was closed. The cuffed ETT was connected to the Y-piece in the ventilator circuit, and the other side was cuffed in a trachea model. The flow analyzer was placed at the patient port of the Phasitron 5 (flow analyzer 1), the lung model (flow analyzer 2), or the expiratory limb (flow analyzer 3) (Fig. 1), and flow analyzer 2 measured 
, peak inspiratory pressure, peak pressure, PEEP, peak inspiratory flow, peak expiratory flow, and frequency (Supplementary Fig. 2 [see the supplementary materials at http://www.rcjournal.com]). The inspiratory pressure was adjusted to 10 or 15 cm H2O with the normal or the diseased lung model, respectively, to reach a target 
of 500 mL with IPV off.13 Configuration parameters of ventilator were pressure controlled continuous mandatory ventilation, 10 breaths/min breathing frequency, 5 cm H2O PEEP, 0.21 
, 1 s inspiratory time, 20 cm H2O of pressure trigger, and no bias flow. The heated humidifier was off. The easy and the hard percussion settings corresponded to frequencies of ∼315 cycles/min and ∼120 cycles/min, respectively (Supplementary Figs. 1 and 2 [see the supplementary materials at http://www.rcjournal.com]).
Measurement of Albuterol
Albuterol delivery to the lung model (position A) was compared between IPV alone and IPV–invasive ventilation, the easy and hard modes, and the normal and diseased lung models. To examine any deposition of albuterol other than the lung model in the ventilator circuit, a filter was placed at the ETT (position B), the Y-piece–expiratory limb junction (position C), or invasive ventilation exhalation valve (position D) (Fig. 1) at the hard mode of the normal lung model. In addition, the in-line adapter and the Y-piece, the Phasitron device, and the nebulizer bowl were rinsed with 20 mL of saline solution to recover albuterol (Fig. 1). The amount of albuterol in the filter at position A, B, C, or D was measured in 3 independent experiments. The filter cartridges were removed from the circuit immediately after IPV sessions, and the filters recovered from the filter cartridges were immersed in 2 mL of 100% ethanol in 15-mL Falcon tubes (Corning, Corning, New York) and centrifuged at 200 × g for 10 min after elution with agitation for 2–3 h. The albuterol concentration (µg/mL) was determined at 230 nm with an ND-100 spectrophotometer (Nanodrop Technologies, Wilmington, Delaware) by using the standard curve of albuterol dissolved in ethanol or saline solution. The minimum measurable concentration was 8 μg/mL. The efficiency of albuterol delivery was estimated as the following:
Efficiency (%) = (the amount of albuterol in filter [μg]/5,000) × 100.
Rationale for Parameter Settings of the Lung Model
The 
and 
of healthy individuals are reported to be <5 cm H2O/L/s and >80 mL/cm H2O, respectively.17,18 In this study, the parameters of the lung model were configured to mimic typical symptoms of a patient receiving IPV therapy as follows: the normal lung model to simulate healthy lungs were 5 cm H2O/L/s 
and 100 mL/cm H2O 
,9 whereas, for the diseased lung model, these were 20 cm H2O/L/s 
and 50 L/cm H2O 
.19,20
Statistical Analysis
One-way analysis of variance with the Tukey multiple-comparison test was used to analyze the differences in the amounts of albuterol delivered to the lung model between IPV alone and IPV–invasive ventilation, the easy and hard settings, and the normal and diseased lung models. The amount of gas provided by IPV or 
, or that expelled from the invasive ventilation exhalation valve during inhalation was analyzed by one-way analysis of variance with the Tukey multiple-comparison test for comparison of these amounts between the easy and hard settings and the normal and diseased lung models. The correlation between 
and albuterol delivery was evaluated by the Pearson product-moment correlation coefficient. All statistical analyses were conducted by using SPSS version 25.0 (IBM, Armonk, New York), and P < .05 was considered statistically significant.
Results
Albuterol Delivery to the Lung Model
The efficiency of albuterol delivery to the lung model (at position A [Fig. 1]) was compared between IPV alone and IPV–invasive ventilation with pressure controlled continuous mandatory ventilation, the easy (high frequency) and hard (low frequency) settings, and the normal (
5 cm H2O/L/s, 
100 mL/cm H2O) and diseased (
20 cm H2O/L/s, 
50 mL/cm H2O) lung models (Fig. 2). The maximum efficiency of albuterol delivery via IPV–invasive ventilation at the hard mode in the normal lung model was comparable with that via IPV alone (mean ± SD loading dose, 3.7 ± 0.2% and 4.2 ± 0.3%, respectively; P = .12) (Fig. 2). The mean ± SD albuterol delivery efficiency was lower for the diseased lung model versus the normal model (1.6 ± 0.3% vs 3.2 ± 0.5%; P < .001) and increased at the hard mode.
The efficiency of albuterol delivery via intrapulmonary percussive ventilation (IPV) alone and IPV–invasive ventilation to the normal and the diseased lung models. The efficiencies of albuterol delivery via IPV alone and IPV–invasive ventilation to the normal and the diseased lung models (position A, Fig. 1) at the easy and hard modes were compared by using one-way analysis of variance with the Tukey multiple-comparison test. Normal lung model,
Raw 5 cm H2O/L/s and 
100 mL/cm H2O; diseased lung model,
Raw 20 cm H2O/L/s and 
50 mL/cm H2O. The error bars represent SDs of 3 independent experiments.
Raw = airway resistance; 
= lung compliance.
Ventilation Measurements
We measured ventilation by IPV–invasive ventilation with differing frequency settings and lung mechanics (Fig. 3). The quantity of gas provided by IPV in the inspiratory time (1 s) ranged from 745 ± 10 to 814 ± 15 mL, which exceeded the target 
of 500 mL (flow analyzer 1) (Fig. 3). There was a ventilator–generated flow that contributed to 
as estimated later. The mean ± SD 
measured with flow analyzer 2 at the lung model was higher for the diseased lung model versus the normal model (470 ± 11 mL vs 401 ± 14 mL; P < .001), in part due to the higher inspiratory pressure setting for the former (flow analyzer 2) (Fig. 3), and, during inhalation, the excess gas was simultaneously released from the ventilator exhalation valve for pressure relief (flow analyzer 3) (Fig. 3).
Ventilation measurements in the ventilator circuit during inhalation. Flow analyzer (FA) 1 measured the amount of gas provided by intrapulmonary percussive ventilation (IPV). FA2 measured the tidal volume (
) delivered to the lung model. FA3 measured the amount of gas expelled from the ventilator exhalation valve. The error bars represent SDs of 3 independent experiments. TI, = inspiratory time.
Thus, in pressure controlled continuous mandatory ventilation,
depended on release of the excess gas from the ventilator exhalation valve and did not correlate with albuterol delivery (Fig. 4A), in contrast to albuterol delivery via IPV alone (Fig. 4B). The inspired volume from invasive ventilation was calculated by subtracting the quantity of gas from IPV (measured with flow analyzer 1) from the sum of 
(measured with flow analyzer 2) and the quantity of gas expelled from the invasive ventilation exhalation valve (measured with flow analyzer 3). The inspired volume from invasive ventilation in inspiratory time (1 s) was estimated to be 10 mL or 13 mL at the easy or hard mode in the normal lung model, respectively, which was 32 mL or 22 mL at the easy or hard mode in the diseased lung model, respectively. The ∼2-fold increase in ventilator–generated flow and its mixing with the air flow provided by IPV may be related to the decrease in albuterol delivery for the diseased lung model, despite the larger 
(Figs. 2 and 3).
The relationships between 
and albuterol delivery for A: intrapulmonary percussive ventilation (IPV)–invasive ventilation and B: IPV alone. Tidal volume (
) is the amount of gas delivered to the lung model in inspiratory time (TI) and is measured with flow analyzer 2 (Fig. 1).
Albuterol Deposition in the Ventilator Circuit
With the normal lung model at the hard mode, albuterol deposition at other than position A was independently examined at several positions of the circuit, that is, at the ETT, the Y-piece–expiratory limb junction, the ventilator exhalation valve, the nebulizer bowl, the Phasitron device, or the in-line adapter–Y-piece (Fig. 5). Nearly half of the loading dose of albuterol was found to be deposited in the nebulizer bowl (35.0 ± 5.3%) and the Phasitron (14.1 ± 6.5%). The in-line adapter and the Y-piece were also major sites of albuterol deposition (11.9 ± 1.3%), possibly because ventilator–generated and IPV-generated flows merge at this site. By subtracting the amount of albuterol deposition at position A (3.7 ± 0.2%) from that at position B (6.7 ± 0.6%), ∼3% of the loading dose was estimated to be deposited in the ETT and the trachea model. In addition, by subtracting that at position D (11.3 ± 0.4%) from that at position C (25.7 ± 2.3%), ∼14.4% was estimated to be deposited in the expiratory limb (Fig. 5). The sum of the amounts of albuterol deposited at these positions accounted for 93.4% of the loading dose.
The deposition of albuterol in the ventilator circuit. The intrapulmonary percussive ventilation (IPV)–invasive ventilation was performed with the normal lung model at the hard mode. Albuterol deposition at the positions B and C were 6.7 ± .6% and 25.7 ± 2.3%, respectively, and these values were used to estimate albuterol deposition in the endotracheal tube (ETT)/trachea model (3.0%) and expiratory limb (14.4%), respectively. The data are the mean of 3 independent experiments with SD.
Discussion
Airway clearance therapies are frequently conducted together with inhaled therapies in mechanically ventilated. By using the Phasitron 5 and manufacturer’s in-line adapter, drug delivery via IPV can be performed without disconnecting a patient from the ventilator circuit, which might contribute to safe and efficacious treatment. This study found comparable albuterol delivery efficiency between IPV–invasive ventilation and IPV alone. The delivery efficiency with IPV–invasive ventilation was increased with decreasing percussion frequency but was not sufficiently high for clinical use. 
did not positively correlate with albuterol delivery via IPV–invasive ventilation at pressure controlled continuous mandatory ventilation.
We adopted pressure controlled continuous mandatory ventilation in accordance with the study by Riffard et al13 to reduce the risk of hyperinflation. As a ventilatory strategy to prevent lung injury, it is necessary to maintain the plateau pressure < 30 cm H2O.21 With IPV alone, the peak inspiratory pressure was > 30 cm H2O for the diseased lung model, but, in IPV–invasive ventilation, it was < 30 cm H2O with the in-line adapter closed (Supplementary Figs. 1B and 2B [see the supplementary materials at http://www.rcjournal.com]). This resulted from pressure relief via the opening of the ventilator exhalation valve. Thus, the addition of IPV to invasive ventilation can be safely performed, but it is important to monitor peak inspiratory pressure with caution in the IPV–invasive ventilation setting.
The comparable efficiency of albuterol delivery between IPV alone and IPV–invasive ventilation is of interest, despite the short inspiratory time for the latter (Fig. 2). In fact, the fate of albuterol emitted from IPV differs between the 2 settings. The exhalation port of the Phasitron device is open for IPV alone, whereas it is closed for IPV–invasive ventilation; instead, during inhalation, the ventilator opens the invasive ventilation exhalation valve to avoid hyperinflation. For IPV alone, albuterol is delivered toward the lung model continuously throughout the operation time (up to 15 min), whereas, for IPV–invasive ventilation albuterol delivery, is limited to inspiratory time (150 s in total, 1 s/breath × 10 breaths/min × 15 min). For IPV–invasive ventilation, the aerosols emitted from IPV merge with the gas from invasive ventilation at the in-line adapter and the Y-piece (Fig. 1), which may serve as a reservoir, and are delivered to the lung model or the expiratory limb (flow analyzer 3) (Figs. 1 and 3). Thus, the similar delivery efficiency between the 2 settings may be explained by the closed exhalation port of the Phasitron 5 and a possible reservoir effect of the in-line adapter and the Y-piece for IPV–invasive ventilation.
We have shown that albuterol delivery by using the Phasitron 5 is increased at the hard mode (low frequency) for IPV–invasive ventilation (Fig. 2). For IPV alone, this is explained by increased entrainment of gas from the IPV device at the hard mode.9,22 Whereas 
delivered from IPV is shown to correlate with drug delivery for IPV alone (Fig. 4B),9 the relationship between 
and albuterol delivery is reported to be neutral for IPV–invasive ventilation with a pediatric ventilator model.12 In our study with an adult model, 
seemed to have no effect on albuterol delivery (Fig. 4A), which is different from the positive relationship for IPV alone (Fig. 4B). The lack of dependence of albuterol delivery on 
is in agreement with albuterol delivery via IPV and other nebulizers in a pediatric ventilator model.12,23
Elshafei et al24 recently reported albuterol delivery efficiency during invasive ventilation via continuous high-frequency oscillation, showing that factors, including the nebulizer type and its position, substantially influence albuterol delivery. In particular, delivery efficiency was markedly improved when a vibrating mesh nebulizer was used at the ETT–Y-piece junction with continuous high-frequency oscillation on. Berlinski and Willis14 reported using the in-line adapter in a pediatric model that adapter opening and IPV percussion frequency influence albuterol delivery, whereas lung conditions, ventilator mode, IPV operational pressure, and the ETT size have no effect. In contrast, the present study showed the influence of the lung conditions on albuterol delivery (Fig. 2). The difference between these studies14 may be explained by the use of a pediatric lung model in their study, in which the same 
(20 cm H2O/L/s) is used in the normal and the ARDS conditions, whereas, in our adult model, 
was higher for the diseased lung conditions versus the normal conditions (20 cm H2O/L/s vs 5 cm H2O/L/s).
To our knowledge, this study is the first to examine the degree of deposition of nebulized aerosols via IPV in the ventilator circuit. The amount of albuterol retained in the nebulizer bowl was the highest (35.0 ± 5.3% of the loaded dose) among the measurement positions (Fig. 5). Thomas et al25 previously reported the nebulizer retention of ∼50% as well as the lung deposition of 2.2% when using a jet nebulizer.26 A reduction in this drug retention in the nebulizer bowl could increase the drug output, which may be possible by increasing the volume of nebulizer solution or by washing out the nebulizer bowl with small volumes of saline solution during IPV. In fact, increased volumes of a nebulization solution are shown to increase drug deposition to the lung.27 In addition, the location of the nebulizer in the ventilator circuit is known to influence drug delivery, possibly because the ventilator tubing acts as a reservoir where aerosols accumulate between breaths.28
It seems likely that placing a nebulizer farther away from the ETT improves drug delivery, depending on the nebulizer type. Changing the position of the IPV device from the Y-piece to the humidifier or ventilator in the inspiratory limb may improve drug delivery as shown with jet nebulizers.27,29 Furthermore, heated and/or humidified conditions and bias flow are shown to negatively influence drug delivery via jet and vibrating mesh nebulizers during mechanical ventilation.29,30 Higher humidity may increase aerosol deposition in the circuit, and higher bias flow may decrease aerosol density in inspired gas or increase the washout of aerosol into the expiratory limb. However, the effects of these factors on drug delivery individually or in combination have not been reported for IPV–invasive ventilation. Further studies may provide novel insights into optimization of aerosol delivery via IPV–invasive ventilation.
Limitations
This study was an in vitro experiment and can not be translated to humans without caution because trachea and lung models mimic human lungs imperfectly. In addition, other types of ventilators may generate different results.11,13 This study used pressure controlled continuous mandatory ventilation but not volume controlled continuous mandatory ventilation because the latter mode has the risk of volutrauma and hyperinflation.13 A humidifier was not operated to exclude possible effects of temperature and humidity, and bias flow was set to off as in a previous study.13
Conclusions
When IPV was superimposed on invasive ventilation with pressure controlled mode, the amount of albuterol delivered to an adult lung model was influenced by percussion frequency and lung mechanics. Although albuterol delivery efficiency was similar between IPV alone and IPV–invasive ventilation, it was not sufficiently high for clinical use, and further optimization is required by reduction of nebulizer retention and extrapulmonary deposition.
Footnotes
- Correspondence: Yusuke Mimura MD, Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, 685 Higashikiwa, Ube, 755–0241, Japan. E-mail: mimura.yusuke.qy{at}mail.hosp.go.jp
Policy-Based Medical Services Foundation (Japan) provided research funding.
Supplementary material related to this paper is available at http://www.rcjournal.com.
The authors have disclosed no conflicts of interest.
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