0031-3998/05/5801-0010
`PEDIATRIC RESEARCH
`Copyright © 2005 International Pediatric Research Foundation, Inc.
`
`Vol. 58, No. 1, 2005
`Printed in U.S.A.
`
`ARTICLES
`
`Aerosol Deposition in Neonatal Ventilation
`
`JEAN C. DUBUS, LAURENT VECELLIO, MICHELE DE MONTE, JAMES B. FINK,
`DANIEL GRIMBERT, JEROME MONTHARU, CHANTAL VALAT, NEIL BEHAN, AND PATRICE DIOT
`
`INSERM U618 [J.C.D., L.V., M.d.M., D.G., J.M., C.V., P.D.], 37044, Tours, France; Department of
`Pediatrics [J.C.D.], Timone-Enfants Hospital, 13385, Marseille, France; and Aerogen, Inc. [J.B.F., N.B.],
`Mountain View, California 94043
`
`ABSTRACT
`
`Lung deposition of inhaled drugs in ventilated neonates has
`been studied in models of questionable relevance. With conven-
`tional nebulizers, pulmonary deposition has been limited to 1%
`of the total dose. The objective of this study was to assess lung
`delivery of aerosols in a model of neonatal ventilation using a
`conventional and novel electronic micropump nebulizer. Aerosol
`deposition studies with 99mTc diethylenetriamine pentaacetate
`(99mTc-DTPA) were performed in four macaques (2.6 kg) that
`were ventilated through a 3.0-mm endotracheal tube (with neo-
`natal settings (peak inspiratory pressure 12–14 mbar, positive
`end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate
`40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8
`␮m), an electronic micropump nebulizer operating continuously
`[Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6
`␮m], and another synchronized with inspiration [Aeroneb Pro-
`fessional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8
`␮m]. The amount of radioactivity deposited into lungs and
`connections and remaining in the nebulizer was measured by a
`gamma counter. Despite similar amounts of 99mTc-DTPA in the
`
`respiratory circuit with all nebulizers, both APN-S and APN-C
`delivered more drug to the lungs than MistyNeb (14.0, 12.6, and
`0.5% in terms of percentage of nebulizer charge, respectively; p
`⫽ 0.006). Duration of delivery was shorter with APN-C than
`with the two other nebulizers (2 versus 6 and 10 min for the
`APN-S and the MistyNeb, respectively; p ⬍ 0.001). Electronic
`micropump nebulizers are more efficient to administer aerosols in
`an animal model of ventilated neonates. Availability of Aero-
`gen’s electronic micropump nebulizers offers new opportunities
`to study clinical efficacy and risks of aerosol therapy in ventilated
`neonates. (Pediatr Res 58: 10–14, 2005)
`
`Abbreviations
`APN-C, Aeroneb Professional Nebulizer operating
`continuously
`APN-S, Aeroneb Professional Nebulizer Synchronized
`ETT, endotracheal tube
`PCA, principal components of analysis
`99mTC-DTPA, 99mTc diethylenetriamine pentaacetate
`
`Treatment of lung diseases with inhaled medications is a
`challenge for mechanically ventilated patients, especially for
`the youngest ones. Therapeutic effects are thought to be limited
`by the combination of small endotracheal tube (ETT) diameter,
`low vital capacity, and mechanical ventilator settings, reducing
`drug delivery to the lungs (1,2). However, deposition pattern of
`inhaled drugs in ventilated neonates and young children re-
`mains largely unknown because the usual approach in older
`children and adults, based on studying radiolabeled aerosol
`distribution, has been contained to isolated investigations be-
`cause of concern of ethical issues in this age range. When
`
`Received May 10, 2004; accepted November 10, 2004.
`Correspondence: Patrice Diot, M.D., Ph.D, INSERM U618, Service de Pneumologie, CHU
`Bretonneau, 2 Boulevard Tonnellé, 37044 Tours, France; e-mail: diot@med.univ-tours.fr.
`This study was funded in part by Aerogen, Inc. (Mountain View, CA).
`
`DOI: 10.1203/01.PDR.0000156244.84422.55
`
`infants (10 ventilated and 13 nonintubated) who ranged from 1
`to 4 kg were administered a mixture of 100 ␮g of albuterol and
`99mTc diethylenetriamine pentaacetate (99mTc-DTPA) over 5
`min with a conventional jet nebulizer, the proportion of dose
`delivered to the lungs was 0.22 ⫾ 0.08% for ventilated and
`0.28 ⫾ 0.014% in the nonintubated infants (3).
`Animal models have been used for mimicking such patients
`but with limited relevance because of differences in anatomy
`and the absence of underlying lung disease (4 –9). Nonetheless,
`lung deposition has been consistently found to be low in these
`studies. In a model of anesthetized rabbits that were intubated
`with a 3.0-mm ETT, deposition of an aerosol administered via
`a spacer placed on the ventilator’s inspiratory line or directly
`into the ETT ranged from 0.2 to 0.4% of the emitted dose (6,7).
`In conditions of uncontrolled ventilation in nonparalyzed rab-
`bits, deposition reached a maximum of 5% of the emitted dose
`
`10
`
`IPR2021-00406
`United Therapeutics EX2082
`
`

`

`AEROSOL DEPOSITION IN NEONATAL VENTILATION
`
`11
`
`(7,9). The use of a jet nebulizer resulted in ⬍1% of the charge
`deposited into the lungs of rabbits with a 3.5-mm ETT (4,5,8).
`Lung deposition was slightly improved by using an ultrasonic
`nebulizer with a small 10-mL cup (8) or by using nebulizers
`that were jet synchronized with ventilation rather than operat-
`ing continuously (10).
`A new generation of electronic micropump nebulizers was
`developed recently (11). One such nebulizer, the Aeroneb
`Professional Nebulizer System (Aeroneb Pro. Aerogen, Inc.,
`Mountain View, CA), incorporates the OnQ aerosol generator,
`which consists of a membrane with ~1000 funnel-shaped
`apertures, in contact with a reservoir of fluid, vibrating at
`ultrasonic frequencies. This action extrudes fluid through the
`holes in the membrane, where surface tension and hydrody-
`namic effects result in breaking the extruded fluid into a stream
`of precisely controlled droplets. The size of the droplets is
`controlled primarily by the exit diameter of the apertures. This
`technology can produce precise particle sizes, with residual
`volume as low as microliters.
`The aim of this study was to test the hypothesis that the
`Aeroneb Professional Nebulizer, an electronic micropump neb-
`ulizer developed by Aerogen, Inc., improves aerosol delivery
`in critical conditions such as neonatal ventilation, when com-
`pared with conventional nebulizers. The study was conducted
`in macaques that were chosen for their relevance in terms of
`anatomy and physiology to model ventilation in neonates.
`99mTc-DTPA was used as tracer to assess aerosol deposition.
`Three different nebulizers were compared: a standard jet neb-
`ulizer (MistyNeb; Airlife) used in previous studies (12,13) and
`two electronic micropump nebulizers, the Aeroneb Profes-
`sional Nebulizer operating continuously (APN-C) and a pro-
`totype Aeroneb Professional Nebulizer synchronized with re-
`gards to inspiration (APN-S).
`
`METHODS
`
`Animal model. Four healthy macaque monkeys (two male) that weighed
`2.5–2.8 kg and were a mean age of 44 mo were studied. Anesthesia was
`administered initially with an i.m. injection of xylazine (1 mg/kg) and ket-
`amine (5 mg/kg). Macaques were intubated with a 3.0-mm internal diameter
`Portex uncuffed ETT and ventilated with a Draeger Babylog 2 ventilator
`(respiratory rate 40/min, peak inspiratory pressure 12–14 mbar, positive end-
`expiratory pressure 2 mbar, I/E ratio 1/2). The gas delivered into the circuit
`was neither heated nor humidified. Anesthesia was maintained with repeated
`injections of ketamine when necessary to suppress spontaneous respiration.
`Macaques were placed in the supine position on the gamma camera during all
`of the experiments. At the end of the experiments, macaques were awakened
`with Dopram (1 drop by nostril). They were extubated and then housed in their
`cages for a minimum of 2 d before a new experiment was initiated. The
`macaques were housed under conventional conditions in our laboratory and
`maintained in accordance with the Guide for the Care and the Use of
`Laboratory Animals.
`99mTc-DTPA labeling. The 99mTc-DTPA was prepared from a commer-
`cially available kit (Pentacis; CIS Bio International, France). This kit, which is
`under nitrogen atmosphere, contains a lyophilized, sterile, and apyogenous
`mixture of 9.10 mg of DTPA-CaNa3, 0.45 mg of SnCl2, and 2 H2O. Addition
`of sterile pyrogen-free Na-99mTcO4 from a commercial generator in 5 mL of
`0.9% NaCl yielded an injectable solution of 99mTC-DTPA-CaNa3. The
`solution was mixed and allowed to stand for 5 min before use.
`Aerosol administration. The order of the nebulizers to be tested was
`randomized for each monkey. The nebulizers were tested with the fill volumes
`recommended by the manufacturers and based on the drug residual at the end
`of nebulization (determined gravimetrically). The MistyNeb (residual volume
`of 1.1 mL) was charged with 3-mL volume 99mTc-DTPA, whereas the APN-C
`and the APN-S (residual volume 0.1 mL) were charged with 0.5-mL volume.
`
`The 3-mL dose for the MistyNeb was selected as a representative median dose
`actually used with standard jet nebulizers during infant ventilation (most
`commonly albuterol sulfate, 2.5 mg in 3 mL). Each nebulizer was tested in
`every monkey (one nebulization with the three different nebulizers, respec-
`tively, for each monkey), resulting in 12 experiments for the four monkeys
`(three nebulizations ⫻ four monkeys). The same nebulizers (MistyNeb,
`APN-C, and APN-S) were used with the four monkeys.
`The nebulizer charges (1110 MBq of 99m-DTPA in all cases) were
`controlled by counting the radioactivity in the syringe that contained 99mTc-
`DTPA in a gamma counter (Capintec, France) before and after charging the
`nebulizers. Then, the nebulizers were connected to the inspiratory line via a
`T-piece 10 cm from the Y-piece. Ventilator settings were adjusted to maintain
`constant delivery parameters as needed when the nebulizer was inserted and
`operated in the ventilator circuit. The MistyNeb was driven by oxygen at a flow
`of 6 L/min. The VMD produced by MistyNeb was 4.6 ␮m (Spraytech,
`Malvern, UK). Maintenance of ventilator parameters required substantial
`adjustments during the use of the MistyNeb. The APN-C produced aerosol
`continuously. The VMD produced by APN-C was 4.8 ␮m. The APN-S was
`synchronized to generate aerosol
`immediately before and during part of
`inspiration. The VMD produced by APN-S was 2.8 ␮m. Particle size distri-
`bution of the aerosol that reached the end of the ETT was also measured under
`experimental conditions and found to be 1.4 ␮m with each of the three
`nebulizers. Time for delivery was recorded for each experiment.
`Gamma camera imaging. Immediately after the end of the aerosol delivery,
`the animals were scanned with a gamma camera (Orbiter 75; Siemens). Static
`acquisition was made during 60 s on a 128 ⫻ 128 matrix. The amount of
`radiolabeled DTPA deposited in the lungs and in the circuit components
`(T-piece, inspiratory limbs, Y-piece, ETT, expiratory limbs, and expiratory
`filter) was determined from the digitized images and using tissue attenuation
`coefficients derived from pertechnetate-macroaggregated albumin perfusion
`scanning of each macaque lung. The total body outline was determined by a
`rectangular region of interest, and the lungs were delineated using the perfu-
`sion scan regions of interest. The amount of radioactivity that remained in ETT
`and circuit components was determined using the same method with a 120-s
`static acquisition imaging. Corrections for decay of technetium were made on
`all measurements.
`Statistical analysis. A multivariate descriptive analysis was used to com-
`pare the three nebulizers according to their performances in terms of aerosol
`deposition into the lungs. The radioactivity deposited into the animal’s lungs
`(one variable) and the radioactivity that remained in the nebulizer (one
`variable) were expressed as a percentage of the nebulizer charge. The radio-
`activity deposited into the different parts of the experimental settings—T-
`piece, inspiratory limb, Y-piece, ETT, expiratory limb and expiratory filter (six
`variables, corresponding to the circuit)—was expressed as the percentage of
`the nebulized activity (the nebulized activity was defined by the difference in
`the countings of the nebulizer before beginning nebulization and at the end of
`nebulization).
`The principal components of analysis (PCA; SPAD software, Decisia
`96 –99, France) constructs an eight-dimensional space corresponding to the
`eight variables. Each observation is positioned in this space according to its
`score for each variable. Consequently, observations that have very similar
`scores in the different variables are closely related. One observation per
`macaque was made with each nebulizer, leading to four observations per
`nebulizer. Observations were named A1–A4 for the APN-S (category of
`observation A), B1–B4 for the APN-C (category of observation B), and C1–C4
`for the MistyNeb (category of observation C). For a condensed display, the
`observations were also described using the center of gravity of all observations
`that belonged to the same category (A, B, and C).
`The eight variables were placed on the graph, and their correlations with
`each axis were calculated. For example, on the graph, each observation has a
`coordinate on F1; each observation also has a score for the variable “lungs” so
`that the linear correlation between “lungs” and F1 can be calculated and
`represented as a vector on the graph. The vector is placed in a correlation
`circle, its direction and its length being determined by the correlation’s value.
`This vector, representing the variable “lungs,” will be close to F1, long and
`directed toward the positive direction of F1 if the score of the linear correlation
`between “lungs” and F1 is positive and close to 1. The vector also points at
`observations on the graph in which the scores for the variable “lungs” are high.
`Each variable is positioned on the graph as a vector according to the values of
`its correlation with each of the two factors F1 and F2. These vectors, or
`“artificial variables,” are the PCA.
`The three categories of observations—APN-C, APN-S, and MistyNeb—
`were also subjected to the DEMOD (DEscription of MODalities) procedure of
`SPAD that displays the statistical links between categories of observations and
`active variables. Differences between the three nebulizers (APN-S, APN-C,
`and MistyNeb) in radioactivity deposited into the lungs (expressed in percent-
`age of the nebulizer charge) were tested by the nonparametric Kruskal-Wallis
`
`

`

`12
`
`DUBUS ET AL.
`
`ANOVA. Differences between the Aeroneb Pro nebulizers (APN-S and
`APN-C) in radioactivity deposited into the lungs and in the nebulizer (ex-
`pressed in percentage of the nebulizer charge), in different parts of the circuit
`connections (expressed in percentage of the nebulized activity), were tested by
`the nonparametric permutation test with general scores. Correlations between
`the variables “lung” and “nebulizer” were tested by the Spearman’s rank-order
`correlation test. The different nonparametric tests were performed with the
`StatXact software. A p ⬍ 0.05 was considered statistically significant.
`
`RESULTS
`
`All animals were submitted to the whole study without any
`incident. Deposition in the lungs in this model of intubated and
`ventilated macaques was significantly different between the
`nebulizers (Fig. 1) with an ~25-fold greater lung deposition of
`99mTc-DTPA with both Aeroneb Pro nebulizers than with
`MistyNeb (14.0% of the nebulizer charge with APN-S, 12.6%
`with APN-C, and 0.5% with MistyNeb; p ⫽ 0.006; Table 1).
`With APN-S, the volume deposited into the lung ranged be-
`tween 61 and 119 ␮L (median 70 ␮L) in 6 min of nebulization
`time; with APN-C, the volume deposited in the lung ranged
`between 48 and 103 ␮L (median 63 ␮L) in 2 min of nebuli-
`zation time; and with MistyNeb, the volume deposited in the
`lung ranged between 12 and 39 ␮L (median 15 ␮L) in 10 min
`of nebulization time. APN-C delivered four times more aerosol
`into the lungs than MistyNeb in one fifth of the time.
`Figure 2 summarizes the results as analyzed by the PCA.
`The three categories of observations (A for APN-S, B for
`APN-C, and C for MistyNeb) were clearly separated from each
`other. The principal opposition on F1 was between the obser-
`vations related to the MistyNeb nebulizer (circles C1–C4 on
`Fig. 2) that clearly clustered by their gravity center (square
`MistyNeb on Fig. 2) on the right and the observations related
`to the APN-S nebulizer (circles A1–A4 on Fig. 2) whose
`gravity center (square APN-S on Fig. 2) was on the left. The
`vector corresponding to the variable nebulizer was directed to
`the right toward MistyNeb observations, indicating that the
`C1–C4 observations were mainly characterized by high resid-
`ual radioactivity in the MistyNeb nebulizer (positive correla-
`tion between F1 and the nebulizer active variable, r ⫽ 0.92).
`On the opposite, the vectors corresponding to the active vari-
`ables ETT, lungs, and filter were negatively correlated with F1
`(respectively, r ⫽ ⫺0.83, r ⫽ ⫺0.79, and r ⫽ ⫺0.66) and were
`directed toward the APN-S observations (A1–A4). This sug-
`gests that these observations are characterized by high levels of
`radioactivity in the lungs, in the ETT, and in the filter.
`A secondary effect appeared on F2, allowing another cate-
`gorization separating the APN-C observations (B1–B4), in
`
`Figure 1. Lung scintigraphy after inhalation of 99mTc-DTPA aerosol with
`MistyNeb jet nebulizer (A), APN-C (B), and APN-S (C).
`
`Table 1. Deposition of 99mTc-DTPA using APN-S, APN-C, and the
`MistyNeb in a macaque model of neonatal ventilation
`
`Nebulizer
`T-piece
`
`Inspiratory limb
`
`Y-piece
`
`ETT
`
`Lungs
`Expiratory limb
`
`Expiratory filter
`
`APN-S
`
`APN-C
`
`MistyNeb
`
`2.7 (1.8 –3.7)*
`0.9 (0.7–2.0)*
`0.9 (0.7–2.1)†
`8.2 (0.5–9.5)*
`8.4 (0.6 –9.8)†
`3.3 (1.9 –5.7)*
`3.4 (2.0 –5.9)†
`9.0 (3.1–9.8)*
`9.3 (3.1–14.0)†
`14.0 (12.2–23.7)*
`3.0 (1.4 – 4.2)*
`3.1 (1.4 – 4.3)†
`20.1 (19.0 –22.3)*
`20.6 (19.7–22.8)†
`
`22.4 (19.7–23.7)*
`9.9 (8.7–11.3)*
`6.5 (2.1–10.0)*
`9.8 (2.3–15.9)*
`8.4 (2.0 –12.5)†
`9.8 (2.6 –18)†
`7.9 (3.7–11.3)*
`8.4 (0.7–17.3)*
`9.3 (0.8 –19.0)† 10.2 (3.6 –14.1)†
`10.5 (5.6 –17.1)*
`3.5 (0.0 – 6.9)*
`11.6 (6.3–19.3)†
`4.4 (0.0 – 6.7)†
`4.4 (2.1– 6.8)*
`1.0 (0.5–2.1)*
`4.8 (2.4 –7.7)†
`1.3 (0.5–2.8)
`12.6 (9.6 –20.6)*
`0.5 (0.4 –1.3)*
`3.3 (2.7– 4.8)*
`1.6 (0.6 –2.3)*
`3.7 (3.1–5.2)†
`1.9 (0.7–2.6)†
`9.5 (7.7–11.1)*
`10.6 (8.2–12.7)*
`10.5 (8.5–12.4)†
`12.0 (10.2–16.4)†
`
`Results are expressed in percentage of the nebulizer charge (median and
`range)* and in percentage of the aerosol nebulized (median and range)† in the
`case of the circuit components.
`
`Figure 2. PCA characterizing the three types of nebulizers according to the
`radioactivity deposited in the animals’ lungs and the radioactivity remaining in
`the different parts of the experimental settings. The eight vectors representing
`active variables are underlined. The 12 observations (three experiments by
`monkey) are in bold circles and italic characters: A1–A4, observations of
`monkeys that were treated with the APN-S; B1–B4, observations of monkeys
`that were treated with the APN-C; C1–C4, observations of monkeys that were
`treated with the MistyNeb. The gravity centers for the three nebulizers are in
`bold squares and straight characters. The percentage of variance explained by
`each factor F1 and F2 is indicated in italics.
`
`positive coordinates of F2, from the two others. The vectors
`corresponding to the Y tube and the expiratory tubes were
`directed toward the observations B1–B4 and did correlate with
`F2 (r ⫽ 0.74 and 0.76, respectively), indicating greater loss of
`aerosol in those locations.
`These categorizations were characterized statistically by
`DEMOD. Observations with the APN-S nebulizer were statis-
`tically characterized by the variables filter (p ⫽ 0.001), ETT (p
`⫽ 0.01), and lungs (p ⫽ 0.03), whereas observations with the
`APN-C nebulizer were characterized by Y-piece (p ⫽ 0.005)
`and expiratory limb (p ⫽ 0.03). Observations with the
`MistyNeb nebulizer correlated only with the variable nebulizer
`(p ⫽ 0.002).
`The most significant finding of the ACM analysis was the
`opposition between the “lung” vector and the “nebulizer”
`vector (negative correlation of ⫺74%). To calculate the sig-
`
`

`

`AEROSOL DEPOSITION IN NEONATAL VENTILATION
`
`13
`
`nificance for this correlation, we performed a nonparametric
`test with the two variables, showing with this test a ⫺0.80%
`correlation coefficient (p ⫽ 0.003). This indicated that the
`performances of the Aeroneb Pro nebulizers, as defined by
`aerosol lung deposition, are due mainly to the low residual
`volume. When APN-C and APN-S were compared in terms of
`statistical differences,
`the nonparametric tests showed that
`activity in the nebulizer, the T piece, and the Y piece was
`significantly higher with the APN-C than with the APN-S (p ⬍
`0.05 in all cases), whereas activity in the filter was significantly
`higher with the APN-S than with the APN-C (p ⬍ 0.05).
`
`DISCUSSION
`
`This study demonstrated that the two electronic micropump
`nebulizers (APN-S and APN-C) deposit higher amounts of
`aqueous aerosols into the lungs (12.6 and 14.0% of the nebu-
`lizer charge, respectively) than the conventional MistyNeb
`nebulizer (0.5% of the nebulizer charge) in an animal model of
`neonatal ventilation. This high efficiency is due mainly to the
`low residual volume of these devices (ACM analysis).
`Aerosol delivery is influenced by numerous factors, includ-
`ing aerosol characteristics (particle size, shape, density, etc.),
`concentration of the aerosol, ventilating parameters (flow, hu-
`midity, etc.), the device, electrostatic charge, technique of
`using the device, patient interface, and host factors (airway
`geometry, pathology, breathing pattern, etc.). Change in any
`one of these alters the amount of aerosol delivered and depos-
`ited. The ventilator settings were adjusted, as necessary, when
`the jet nebulizer was operated in the ventilator circuit, and all
`experiments were made under similar flow and pressure con-
`ditions. Therefore, physiologic parameters could not interfere
`with the way the aerosol was distributed in the circuit connec-
`tions or in the lungs.
`Despite substantial differences between the airway of the
`macaque and that of humans (14), the macaque is a relevant
`model to predict the aerosol deposition in human lung. The
`morphology of our 2.6-kg mean weight macaques corre-
`sponded to normal-weight human infants at 34 or 35 wk of
`gestation or to low-weight, full-term infants. The main differ-
`ence between our model and the usual circumstances of neo-
`natal ventilation was that our macaques had normal airways
`and lungs. Furthermore, medication delivery in a normal lung may
`differ from a sick lung. Deposition may differ between a sedated
`healthy animal model and active neonates with spontaneous
`breathing and lung or airway disease. However, this study was
`designed as a preclinical assessment of the electronic micropump
`nebulizers to determine their efficiency in conventional ventilator
`settings. Further validation in critical care will need clinical
`studies, which this first step will now make acceptable.
`is
`DTPA was chosen because it
`is a stable tracer that
`unaffected by oxidation and whose dynamics in the respiratory
`tract is similar to any other aqueous aerosol (15). Although
`there were some interindividual differences in aerosol deposi-
`tion, possibly as a result of variable leak associated with the
`uncuffed ETT, APN-C and APN-S nebulizers were consis-
`tently more efficient than MistyNeb and lung deposition was in
`the same range for both Aeroneb Pro nebulizers. The perfor-
`
`mance of these devices pertains only to the specific conditions
`and techniques under which the devices were tested. The study,
`limited to four macaques, provided a sufficient number of
`observations to apply the PCA statistical approach.
`The 0.5% of the nebulizer charge lung deposition and the
`23% of the nebulizer charge residual volume obtained with the
`MistyNeb are consistent with previously reported data in other
`animal models of infants. In a model that simulated 4-kg
`infants, Coleman et al. (12) demonstrated that flow rate
`through the MistyNeb increases the deposition by impaction,
`and that residual volume was ~35% of the dose that remained
`in the MistyNeb. Therapeutic aerosols that are produced with
`these standard jet nebulizers are widely used in intubated
`neonates, particularly in infants who are at high risk for
`developing chronic lung disease. The success of this approach
`has been found variable, especially when compared with other
`delivery systems. A recent meta-analysis (16) concluded that
`the delivery of inhaled steroids to ventilator-dependent infants
`had very small effects on the occurrence of chronic lung
`disease, likely because of an inappropriate mode of delivery.
`Indeed, the use of a metered-dose inhaler and a spacer device
`may be more efficient than a conventional jet nebulizer for
`delivering both salbutamol and budesonide in neonates (17,18).
`The design of the electronic micropump nebulizers is such
`that the fill volume required to produce the aerosol is much
`lower than with the MistyNeb (0.5 versus 3 mL). The higher
`efficiency at lower fill volumes means that APN-C deposits to
`the lungs in 30 s a volume of aerosol equivalent to that
`deposited by the MistyNeb after 10 min. The ability of both
`Aeroneb nebulizers to deliver in 2– 6 min 25 times more
`aerosol in the lungs than the MistyNeb can in 10 min may have
`positive implications in the treatment of critically ill infants.
`Although APN-S was a prototype device that was expected
`to be more efficient than APN-C, because aerosol generation
`was synchronized with regards to inspiratory phases of the
`ventilator, both Aeroneb Pro nebulizers delivered similar
`amounts of aerosols in the lungs. They differed in the residual
`volume and in the amount of aerosol deposited in the various
`parts of the circuit. The most relevant way to assess the
`differences was to express the deposition in the circuit as a
`percentage of the activity of aerosol nebulized and not as a
`percentage of the nebulizer charge, which is more relevant to
`quantify lung deposition (Table 1).
`Particle size of the aerosols at the outlet of the nebulizers
`was similar with MistyNeb and APN-C (MMAD 4.6 and 4.8
`␮m, respectively) and smaller for the APN-S (MMAD 2.8
`␮m). At the end of the ETT, particle size distribution was
`similar with the three nebulizers, with a 1.4-␮m MMAD (GS1
`cascade impactor; California Measurement, CA). Residual vol-
`ume was significantly higher with the APN-C than with the
`APN-S, possibly because of increased impaction losses in the
`barrel of the nebulizer connector with continuous aerosol
`generation, which means that the nebulized activity was higher
`with the APN-S than with the APN-C. However, there was no
`significant difference in terms of aerosol deposited in the lung.
`In vitro experiments (data not shown) have revealed an aerosol
`delivery at the end of the ETT two times higher with the
`APN-S than with the APN-C, and the countings in the filter
`
`

`

`14
`
`DUBUS ET AL.
`
`in our in vivo model of
`placed on the expiratory circuit
`ventilation was significantly higher with the APN-S than with
`the APN-C. These data show that the aerosol deposited in the
`lung expressed in percentage of aerosol reaching the extremity
`of the ETT is lower with APN-S in comparison with APN-C.
`This discrepancy may be an effect of greater exhaled aerosol
`with the APN-S, which correlates with high deposition in the
`ETT and which cannot be simulated in vitro. This result can be
`explained by the synchronization between the aerosol produc-
`tion and the ventilator settings, which may not be optimized.
`The higher residual and amount of aerosol deposited in the T
`piece with the APN-C may be because larger aerosol droplets
`produced continuously at a high flow rate have an impact at the
`outlet of the nebulizer and in the T piece. Generally, deposition
`of large particles in the circuit is probably the explanation for
`why VMD of the aerosols generated by the three nebulizers are
`the same at the end of the ETT. In this study, APN-C may be
`considered more efficient than the APN-S as it allows deposi-
`tion of similar amounts of aerosol in a significantly shorter
`period of time. However, insights into the differences in dep-
`osition between the two devices suggest that further adjust-
`ments to the aerosol size and generation pattern may offer
`greater efficiencies. Further work is required in this area.
`The performance of the APN-C and APN-S, if applied to
`generate therapeutic aerosols, should result in much higher
`efficiency than what has been reported with previous genera-
`tions of nebulizers. The primary concern with conventional
`nebulizers in neonatal ventilation has been the risk to under-
`treat patients. In contrast, the more efficient electronic mi-
`cropump nebulizers may lead to concern related to safety
`profile, particularly for medications with dose-related poten-
`tials for adverse effects, such as inhaled corticosteroids in
`extremely premature infants. Pharmacokinetic and clinical
`studies will help to better determine appropriate dosing and
`implications of reduced treatment times and rapidity of drug
`action (19) with these new electronic micropump nebulizers.
`
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