JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 27, Number 3, 2014 ª Mary Ann Liebert, Inc. Pp. 149–169 DOI: 10.1089/jamp.2013.1075

ISAM Congress 2013, Review Papers

Pediatric In Vitro and In Silico Models of Deposition via Oral and Nasal Inhalation

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Nicholas B. Carrigy, BSc,1 Conor A. Ruzycki, BSc,1 Laleh Golshahi, PhD,2 and Warren H. Finlay, PhD1

Abstract

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can be useful for estimating exposure risks to inhaled particulate matter. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, deposition in this region plays an important role in both cases. Compared to adults, much less extrathoracic deposition data are available with pediatric subjects. Recently, progress in magnetic resonance imaging and computed tomography scans to develop pediatric extrathoracic airway replicas has facilitated addressing this issue. Indeed, the use of realistic replicas for benchtop inhaler testing is now relatively common during the development and in vitro evaluation of pediatric respiratory drug delivery devices. Recently, in vitro empirical modeling studies using a moderate number of these realistic replicas have related airway geometry, particle size, fluid properties, and flow rate to extrathoracic deposition. Idealized geometries provide a standardized platform for inhaler testing and exposure risk assessment and have been designed to mimic average in vitro deposition in infants and children by replicating representative average geometrical dimensions. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Computational fluid dynamics simulations allow for the quantification of local deposition patterns and an in-depth examination of aerosol behavior in the respiratory tract. Recent studies have used both in vitro and in silico deposition measurements in realistic pediatric airway geometries to some success. This article reviews the current understanding of pediatric in vitro and in silico deposition modeling via oral and nasal inhalation. Key words: benchtop models, empirical correlations, mathematical models, computational fluid dynamics, inhaled pharmaceutical aerosol, inhalation toxicology, exposure risk assessment, child, infant

Introduction

D

eposition models provide a useful method for estimating the relative risks to pediatric subjects of inhaled particulate matter, as well as aiding in the selection of appropriate inhaled pharmaceutical aerosol delivery devices and doses. Unfortunately, much less research on deposition modeling has been done regarding children and infants as compared to adults. Particulate matter is thought to play a role in the development of asthma and chronic obstructive pulmonary disorder (COPD).(1) The incidence of asthma is higher among children than in any other age group,(2) and epidemiological

observations have suggested chronic particulate matter exposure during childhood may lead to increased vulnerability to COPD in adulthood.(1) Infant mortality rates have been directly associated with ambient fine particulate matter concentration.(3–6) Compared with adults, children, who lack fully developed immune systems, tend to spend more time outdoors in areas of increased particulate matter concentration.(7) Deposition models can be useful for defining exposure limits,(8–10) which may lead to a decrease in negative health effects in the pediatric population, as well as reduced health-care costs.(11) Most inhaled therapies are not approved for young children, and clinicians have limited deposition information to

1 Aerosol Research Laboratory of Alberta, Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada T6G 2G8. 2 Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298.

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150 help them with dose prescriptions.(12) The respiratory tract continues to develop new alveolar airways until around 8 years of age,(13,14) and the geometry and size of the extrathoracic airways continue to change during infancy and childhood.(15) In addition, due to differences in pharmacodynamics and pharmacokinetics between infants, children, and adults, a similar lung dose, whether normalized to height, weight, or body surface area, does not imply a similar treatment efficacy or risk. This can lead to uncertainty in the extrapolation of dose-response measures developed for adults to pediatrics. Pediatric in vivo studies using radiolabeled aerosol(16–31) have illustrated, for example, that aerosol delivery to older patients is generally more effective than to younger patients,(16–19) that facemask leaks(20) and crying(20,21) can reduce lung deposition, and that extrathoracic deposition tends to be higher in younger patients.(22,23) However, in vivo studies are limited by high cost and time requirements, a lack of patient cooperation with aerosol delivery devices,(32–36) radiological exposure concerns,(37) blood sample invasiveness, and difficulties with obtaining timed urine samples.(38) Total deposition studies can be performed in vivo by comparing inhaled to exhaled aerosol concentrations.(39–43) However, regional measurement of deposition with this technique is limited. In vitro benchtop studies avoid some of the limitations associated with in vivo work, and allow for systematic isolation and investigation of parameters believed to influence aerosol deposition from different delivery devices.(44) In vitro extrathoracic airway replicas developed from magnetic resonance imaging (MRI) or computed tomography (CT) scans can be useful for determining extrathoracic particle filtration. Empirical correlations of deposition that can account for various patient, particle, and flow parameters have been developed from aerosol deposition measurements in these replicas. Aside from in vitro models, in silico models, including one-dimensional whole-lung models and threedimensional computational fluid dynamics (CFD) simulations, use mathematical techniques to predict particle behavior in the respiratory tract. In this review, pediatric in vitro benchtop studies of aerosol delivery by pressurized metered dose inhaler (pMDI), nebulizer, dry powder inhaler (DPI), soft mist inhaler (SMI), and nasal spray are discussed first, followed by a summary of empirical extrathoracic deposition correlations. Idealized models designed to mimic average geometrical dimensions in pediatrics are then reviewed briefly. Finally, pediatric in silico mathematical and CFD studies are reviewed. Pediatric In Vitro Modeling: Pharmaceutical Aerosol Benchtop Studies Introduction to pediatric aerosol delivery devices The inhalation technique required to properly use a pMDI can be difficult for young children to learn.(45) The pMDI with valved holding chamber (VHC) and facemask combination is the recommended delivery method for providing asthma maintenance therapy to infants and young children who have demonstrated symptoms of asthma but are too young to use a mouthpiece.(35,45) This delivery method allows the child to inhale the aerosolized medication tidally

CARRIGY ET AL. while limiting extrathoracic deposition and associated side effects. However, a lack of child cooperation may prevent an adequate face–facemask seal with this delivery method.(32–36) A tight facemask seal is necessary to ensure that the inspiration valve opens and the aerosol is not diluted by ambient air; a lack of an adequate facemask seal may result in the requirement of longer administration times to counter aerosol dilution and wasted drug due to increased sedimentation in the VHC. Crying or screaming results in a poor facemask seal, with a potential increase in particle impaction in the extrathoracic region due to higher peak inspiratory flow rates.(32) To encourage cooperation during the aerosol administration process, toys, videos, or making a game out of it,(45,46) as well as sucking on a pacifier,(47,48) have been suggested. Many different types of nebulizers exist, which atomize a drug solution or suspension to allow for aerosol inhalation via a mouthpiece or facemask interface. Nebulizers with an attached facemask are often prescribed to children who cannot tolerate pMDI VHC facemask delivery.(45) A transition from a nebulizer facemask to a mouthpiece can usually take place at the ages of 4 or 5.(45) Alternatives to using a facemask as a nebulizer attachment include hood(49,50) and humidified high-flow nasal cannula (HHFNC).(51,52) Very young children may not be able to generate the inhalation flow rates necessary to entrain and de-agglomerate the powder from a passive DPI, and may blow into the device, moistening the powder.(45) Passive DPIs are often excluded as a delivery method for children under the age of 6, regardless of approval status for younger age groups.(45,53) Active DPIs, on the other hand, use an additional energy source, which can be either electrical or mechanical,(54) to help disperse the powder and allow for more effective treatment in younger children. A relatively new inhaler platform, the Respimat SMI, generates a slowly moving liquid aerosol cloud, with prolonged spray duration, requiring little coordination to operate or inhale from.(55) An SMI can be combined with a VHC and facemask for children under 4 years of age(55) in a similar manner to a pMDI. Nasal sprays can be used for central nervous system (CNS), systemic circulation, or topical treatments. CNS treatment by targeting the olfactory region allows for the blood–brain barrier to be bypassed.(56,57) There is a growing interest in the nasal delivery of vaccines, because children often become distressed by needles.(55) Sinusitis is more prevalent than asthma in the United States, and topical treatment using aerosolized drugs via nasal spray is a noninvasive treatment option.(58) Chronic sinusitis is almost universal among children with cystic fibrosis.(59) Topical treatment of allergic rhinitis and nasal congestion are common. However, compliance with syringes and atomizing spray pump devices that have been developed for nasal drug delivery may be an issue with small children.(55) Pediatric pMDI benchtop studies Everard et al.(60) showed that minimal dead-space volume between the inhalation valve of a holding chamber and the patient is essential for effective drug delivery to infants due to their low tidal volumes. Therefore, in vitro water displacement techniques have been used to determine facemask

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PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS dead-space volume for different applied forces.(61,62) Using a flat plate with a hole to represent the mouth, Chavez et al.(63) found that decreasing facemask dead-space volume, increasing tidal volume, and increasing respiratory rate all increased the inhaled mass of albuterol. Everard et al.(60) showed that the VHC inhalation valve should have a low resistance to opening when treating infants. One difficulty with low-resistance valves is that aerosol leaks are more likely.(53) Everard et al.(60) also showed that chamber agitation can reduce the dose delivered from a holding chamber, and that a single large dose into a holding chamber is preferred over multiple actuations of small doses, which has been confirmed by Barry and O’Callaghan.(64) Delivering the same amount of aerosol into smaller holding chambers generally results in a higher aerosol concentration. This can increase sedimentation rates, thus imposing a lower limit on the time between actuation and inhalation by the child. On the other hand, smaller VHCs allow for the inhalation of a higher aerosol concentration on the first breath, which may be viewed as less intimidating for infants, and are easier for caregivers to handle.(60,65) Over two decades ago, the publication of an in vitro benchtop study(66) showed that an antistatic lining can increase aerosol delivery from spacers by decreasing electrostatic sedimentation rates, and numerous other studies since then have shown that limiting electrostatic effects can substantially increase drug output.(64,67–74) Despite this, the use of antistatic spacers in developing countries is still rare. Creation of realistic airways can now be done using CT scans or MRI instead of postmortem casts. Cadaver airways may incur postmortem shrinkage, and the casting process may cause distortion of the geometry(75); therefore, models created from MRI or CT scans are preferred when possible. CT scans can typically be taken at a finer spatial resolution and can result in higher fidelity and shorter exposure times than MRI. However, ionizing radiation exposure occurs with CT scans and generally increases with finer spatial resolution. The models used for in vitro benchtop studies are typically created from MRI or CT scans of the extrathoracic region. An early CT-derived pediatric extrathoracic replica for benchtop study is the Sophia Anatomical Infant Nose–Throat (SAINT) model, which represents the nasal airways of a 9-month-old Caucasian girl down to the subglottic level.(76) The female infant was scanned for an unrelated injury while under anesthesia and positioned on her back; the scan took around 2 min to complete.(76) The replica was made using a stereolithographical technique out of polymerized resin (Stereocol).(76) This resin was found to interfere with highperformance liquid chromatography (HPLC) chromatograms; therefore, upper airway deposition was not measured directly by chemical assay with this model.(76) However, the model can be cleaned with ethanol without significantly changing the internal geometry, as verified by repeated CT scans and resistance measurements.(76) Coatings to eliminate particle bounce and electrostatics in the SAINT model have been suggested, but there is no consensus in the literature on an appropriate coating procedure, and concerns have been expressed about uneven coating distributions and coating reproducibility between runs.(77) Preliminary lung dose measurements for different particle size fractions were per-

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formed by Janssens et al.(76) using the experimental procedure shown in Figure 1, which is a modified form of the experimental setup developed by Finlay.(78) Using a similar benchtop study methodology, Janssens et al.(79) found that hydrofluoroalkane (HFA) beclomethasone dipropionate (BDP) had a significantly higher proportion of extra-fine particles ( < 2.1 lm) passing through the SAINT model than chlorofluorocarbon (CFC) BDP. The prospect of delivering pharmaceutical aerosol to toddlers by pMDI VHC facemask during sleep was also evaluated using the SAINT model(80); however, an in vivo study found that 69% of children woke up during administration, and they were often distressed.(81) Another benchtop study with the SAINT model, using the same setup shown in Figure 1, found that spacer output increases with tidal volume but is independent of respiratory rate, whereas ‘‘lung dose,’’ which commonly refers to the dose reaching the trachea in benchtop studies, tends to decrease with increasing respiratory rate.(82) An initial increase and then decrease in lung dose was observed with increasing tidal volume.(82) Janssens et al.(82) also observed that upper airway deposition tended to increase with respiratory rate and tidal volume, fine particle dose tended to decrease with respiratory rate and tidal volume, and extra-fine particle dose was not affected by either.(82) Mass median aerodynamic diameter (MMAD) of the aerosol passing through the model decreased with increasing tidal volume or respiratory rate.(82) Putty was used to seal the facemask to the hard SAINT model face, because a facemask leak can drastically reduce aerosol delivery.(82,83) Esposito-Festen et al.(83) systematically quantified the relation between facemask leak size (in the range of 0 and 1.5 cm2) and position of the facemask leak with spacer output and lung dose. A hole was drilled into round facemasks, which were individually sealed to the hard SAINT model face using putty; the facemasks were positioned with the hole location near the nose or near the chin.(83) Spacer output decreased for increasing leak size, but was not related to leak position.(83) Lung dose decreased with increasing leak size,

FIG. 1. The experimental technique used by Janssens et al.(76) to determine the particle size distribution and delivered dose distal to the SAINT model via pMDI with VHC and facemask. Reprinted by permission from Ref. 76.

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152 and decreased slightly more for leaks near the nose than for leaks near the chin.(83) Smaldone et al.(84) confirmed that facemask leakage significantly decreases the delivered dose for pMDI VHC facemask aerosol delivery, and observed that the decrease in delivered dose was greater than for facemask leakage with nebulizer-facemask aerosol delivery. Producing a suitable aerosol is only the first step of the aerosol delivery device development process(85); designing a well-fitting facemask is crucial.(86) Therefore, studies using soft face models with the goal of better representing the face– facemask interface have recently become more common. Louca et al.(87) designed a soft face model using silicone where the facemask contacts the face to measure orally inhaled particle mass for different VHC facemask combinations. Soft face models are often made using soft, pliable silicone.(88–90) More recent experimental procedures involve cradles or shuttles to apply the VHC to a soft face model with a known force.(44,91,92) These studies may be useful for comparing different VHC facemasks, assuming a representative variety of faces are used. They can also be useful for determining the effect of facemask leakage on inhaled mass or lung dose in a more clinically relevant manner in vitro.(93,94) It should be noted that a recent adult study found that N95 masks that fit well ex vivo did not fit well on soft face models.(95) Therefore, even these soft facial materials may not be sufficient to mimic ex vivo facemask fit in vitro. However, a comparison of ex vivo–in vitro pharmaceutical aerosol facemask fit has not yet been published to the authors’ knowledge. Pediatric nebulizer benchtop studies An early pediatric jet nebulizer benchtop study was performed by Everard et al.(96) using a Starling ventilator and a facemask applied to a rubber flange ‘‘face.’’ Drug delivery was reduced 85% when the facemask was held 2 cm from the face as compared with a closely fitting facemask. For a doubling in driving gas flow from 4 L min - 1 to 8 L min - 1, with an infant tidal volume of 50 mL, the rate of drug delivery increased by 34%, whereas for an older child tidal volume of 400 mL the doubling in driving gas flow increased inhaled dose rate to a greater extent, 79%.(96) MMAD decreased, whereas fine-particle fraction (FPF) increased, for increasing driving gas flow.(96) The rate of inhaled drug delivery was thought to increase with tidal volume, whereas the rate of drug delivery per kilogram of body weight using this type of nebulizer was suggested to decrease with increasing tidal volume.(96) In vitro studies comparing inhaled mass and droplet size distributions for many nebulizer/compressor combinations using simulated pediatric breathing patterns have since been performed.(97,98) The more recent study used a cooled impactor method to limit hygroscopic-driven changes in particle size, as first suggested by Finlay and Stapleton,(99) and showed that infants may inhale a lower dose (as a percentage of nebulizer charge) than older children.(98) In a benchtop study using an MRI-derived model of the mouth, throat, and upper airways of a 5-year-old boy, Corcoran et al.(100) observed that using aerosol reservoirs to capture exhaled aerosol increased total delivered dose, and that using heliox (a mixture of helium and oxygen) as the delivery gas increased the delivered dose.

CARRIGY ET AL. Schu¨epp et al.(101) measured budesonide delivery through the SAINT model from a perforated vibrating membrane nebulizer with facemask and found that MMAD tended to decrease with increasing tidal volume. Recently, Lin et al.(102) found that breath-synchronized nebulization (manual or breath-actuated) delivered less aerosol to the trachea than continuous nebulization in a simulated 2–4-year-old model regardless of the facemask used, which was noted to be in contrast to studies with adults. It was suggested that this may be due to shorter inspiratory times, smaller tidal volumes, greater proportional anatomical dead space, and more variable inspiratory flow patterns observed in infants and toddlers as compared with adults.(102) Minocchieri et al.(103) developed the premature infant nose–throat (pr-INT) model based on MRI data rather than CT scans due to radiation concerns with the latter. The feasibility of using the pr-INT model to measure aerosol deposition by performing budesonide lung dose measurements with a perforated vibrating membrane nebulizer and facemask was illustrated.(103) A decrease in lung dose with increasing flow rate was observed in these preliminary measurements.(103) Using a gamma camera and the SAINT model, with the facemask lightly pressed to the hard SAINT model face rather than sealed, Laube et al.(77) quantified the deposition of nebulized, radiolabeled albuterol in the nose, through the model nasal airways, on the corrugated tube and facemask of the delivery device, and to the environment (measured using a bag surrounding the model). Similar lung deposition and losses in the corrugated tube and facemask were found for 50-, 100-, and 200-mL tidal volumes, but nasal deposition increased with tidal volume.(77) Aerosol losses to the environment were high at all tidal volumes ( > 50%, but less at 200 mL than at 50 mL), which indicated that caregiver exposure to aerosol escaping past the face of the child may be of concern.(77) The blow-by technique (providing a high flow rate of aerosol with the facemask held away from the face) has been discouraged for pediatrics(45) due to the low in vivo and in vitro dose it has been shown to provide,(20,96) including a decreased lung to facial deposition ratio.(20) However, it has been shown that a sufficient dose may be provided with this aerosol delivery technique with certain nebulizer systems.(104) Using a continuously operating jet nebulizer, Sangwan et al.(105) observed that a tighter, but incomplete, facemask seal increased facial and eye deposition on an in vitro model. This increase in facial deposition for a tighter facemask seal was believed to be associated with increased droplet inertia (associated with higher velocity leaks for tighter fitting facemasks).(106) Smaldone et al.(106) designed a prototype, vented facemask with an increased distance between the facemask and face, and eyecuts to lower the droplet inertia in the facemask and at leaks. A reduction in eye deposition relative to the Salter facemask has been observed with this design.(106,107) Lin et al.(102) later found that the commercial version of this facemask delivered more inhaled mass than other facemasks while tending to reduce facial deposition. Amirav et al.(108) showed, using both an in vitro benchtop study and CFD modeling, that eye deposition of nebulized aerosol emitted from a nebulizer by hood inhaler may not be of great concern provided that the funnel is not directed at

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PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS the eyes. Facial deposition may be higher for infants lying face up rather than on their side during hood therapy, and may be higher for nasal rather than oronasal breathing.(109) Bhashyam et al.(51) measured aerosol dose and size output at different locations within an HHFNC circuit to illustrate the potential of this nebulized aerosol delivery method. Ari et al.(52) found that at 6 L min - 1 inhaled dose could be more than doubled when heliox was used as the HHFNC carrier gas as compared with oxygen, possibly due to less turbulence for heliox. However, at the more efficient flow rate of 3 L min - 1, differences in inhaled dose were not significant between the two gas types.(52) Other in vitro studies have illustrated decreases in inhaled dose from HHFNC circuits at higher flow rates.(110–112) One method of reducing line losses in the HHFNC circuits is to streamline the nebulizer-aerosol line T-adaptor and the nasal cannula interface.(113) To improve the dose reaching the lungs, one can deliver submicrometer-sized particles through one nostril and heated and humidified air through the other nostril, termed the enhanced condensational growth (ECG) technique, which may limit hygroscopic growth prior to the nasopharynx.(114) In addition, it has been demonstrated that the use of different hygroscopic excipients and excipient:drug ratios may be useful for allowing particles to develop to larger sizes once reaching the lungs, a technique termed excipient enhanced growth (EEG).(115) However, the use of ECG and EEG for optimizing nebulized aerosol delivery via nasal cannula to pediatrics has not yet been studied.(114) Pediatric DPI benchtop studies Everard et al.(116) showed that a chamber can reduce the coarse, nonrespirable fraction of particles from the Turbuhaler DPI at 60 L min - 1. No in vitro studies with a Turbuhaler and spacer using a realistic upper airway model have been published to the authors’ knowledge. Bennett et al.(117) used an impactor in conjunction with an infant breathing pattern to evaluate the emitted dose and FPF from the PuffHaler, which is an active DPI equipped with a detachable plastic reservoir with facemask or mouthpiece, designed to deliver live-attenuated measles vaccine. Miller et al.(118) developed a novel DPI for delivering porous nanoparticle aggregate particle vaccines to newborn infants by using a small air-bulb type pump with a spinning capsule and found that the emitted dose did not change significantly until 2 hr of climate zone IV (24C £ temperature £ 32C; 50% £ relative humidity (RH) £ 80%) exposure in vitro. In the active Solovent DPI, a capsule containing the dry powder is ruptured and dispersed upon actuation.(119) Powell et al.(120) showed that temperature and RH can affect the particle size distribution and dose delivered from this device using the SAINT model. Chan et al.(121) found that a nonvalved spacer delivered a higher dose through the SAINT model than a commercial valved spacer.(121) In additional experiments using the SAINT model, Laube et al.(122) further demonstrated the feasibility of using the active Solovent DPI with a spacer and facemask to deliver aerosol therapy to infants. However, it was suggested that improvements to the spacer and facemask should be made.(122) Below et al.(123) found greater upper airway deposition in an idealized 5-year-old child throat from the Salbu Novolizer as compared with the SalbuHexal Easyhaler.

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Different flow rates were used to account for different device resistances; however, it should be noted that high-resistance DPIs tend to open up the oral cavity, oropharynx, and larynx cross-sectional areas during inhalation,(75,124) factors that were not directly considered using this rigid airway model. Pediatric SMI benchtop studies Bickmann et al.(125) compared aerosol delivery by Respimat SMI through an idealized 5-year-old mouth–throat model and the adult Alberta Idealized Throat, finding greater deposition in the child throat. For the idealized 5-year-old mouth–throat model, excellent agreement between CFD predictions and in vitro results were obtained for low flow rate conditions (5 and 10 L min - 1), although agreement was worsened at higher flow rates (20 and 30 L min - 1).(125,126) Wachtel et al.(127) showed using the 5-year-old idealized mouth–throat model and realistic breathing patterns that children may receive up to 51% of the label claim from the Respimat SMI alone, or 33% from the Respimat SMI with VHC and mouthpiece. Pediatric nasal spray benchtop studies Dalby et al.(128) used a load cell and linear displacement transducer to measure and record Flonase actuator displacement for 20 adults and 20 pediatrics, finding lower attained forces and prolonged force application for the pediatrics. Spray weights for pediatrics were found to be more variable and significantly less than for adults.(128) Laube et al.(88) showed that the mean deposition of nasal spray from the Accuspray device anterior to the nasal valve in a 2-year-old face model was significantly greater than in 5- or 12-year-old face models. The angle of insertion was suggested to play a role in aerosol deposition using this device.(88) This is consistent with the CFD simulations performed by Xi et al.,(129) who presented ideal release points for targeted delivery of particles via the nostrils to different nasal-laryngeal regions, for different particle sizes under constant flow conditions. Conclusions regarding pediatric pharmaceutical aerosol benchtop studies A reasonable amount of research into pediatric aerosol delivery by pMDI VHC facemask has been performed due to the widespread use of these devices. This research has highlighted the importance of a tight facemask seal, minimal facemask dead-space volume, an antistatic VHC design, properly operating valves, and the need for delivering small particles. Despite this research, however, the most important factor affecting aerosol delivery by pMDI VHC facemask is patient cooperation.(33,35) Therefore, the importance of designing facemasks and VHCs that are acceptable for use by the pediatric patient, which differs between infants and older children,(46) as well as between individuals, must be emphasized. Pediatric nebulizer benchtop studies have compared different brand-name devices, determined the effect of breathing pattern on aerosol delivery, evaluated caregiver exposure associated with a facemask leak, and evaluated facial and eye deposition. Little research is available in the literature regarding nebulizer-hood and nebulizer-HHFNC aerosol delivery to pediatrics.

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154 Designing DPIs specifically for infants and young children is important, because these patients cannot properly use DPIs designed for adults or older children. Active DPIs are an alternative requiring less coordination on the part of the patient, but little research into pediatric aerosol delivery using active DPIs is present in the literature. The Respimat SMI is an alternative to a pMDI that can minimize coordination requirements in older children. A VHC can be used with the Respimat SMI to deliver therapeutic aerosol to younger patients. Nasal sprays are a promising aerosol delivery method for providing topical, systemic circulation, and CNS treatments to pediatrics. However, there is considerable onus on the caregiver to ensure cooperation from the child. For certain nasal spray devices, the angle of insertion may be crucial in determining the location and therapeutically-relevant quantity of the delivered dose.

CARRIGY ET AL. (3–18 months old), Golshahi et al.(134) measured the extrathoracic deposition of 13–100-nm particles in CT-derived infant nasal airway replicas and developed empirical deposition correlations that account for the effect of cyclic breathing. The age-related correlations developed by Cheng et al.(133) did not accurately predict deposition in these younger infants.(134) Storey-Bishoff et al.(135) measured the deposition of micrometer-sized (0.8–5.3 lm) particles during simulated tidal breathing in CT-derived extrathoracic nasal airway geometries of 10 infants (age 3–18 months), and the SAINT model. The developed infant nasal airway geometries are shown in Figure 2. Considerable intersubject variability in nasal airway deposition was found, and empirical deposition correlations were created based on the nondimensional Stokes and Reynolds numbers for different characteristic diameters.

Pediatric In Vitro Modeling: Empirical Correlations of Extrathoracic Deposition Introduction to pediatric empirical extrathoracic deposition modeling Empirical deposition correlations are algebraic equations that can be used for selecting pharmaceutical aerosol treatment doses or for the development of exposure limits. For estimating aerosol deposition in pediatrics, the International Commission on Radiological Protection (ICRP) model(130) suggested age-related scaling factors to modify empirical deposition correlations developed for adult males. However, it was noted that validation of the ICRP model was required, which was due to the lack of morphometric and deposition information in pediatrics.(130) Recent empirical correlations have been developed based on aerosol deposition studies in modest numbers of MRI- or CT-derived airway replicas of the extrathoracic region. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, these empirical deposition correlations are of particular importance. Pediatric empirical extrathoracic deposition modeling studies Swift(131) showed that 1–10-lm particle deposition was greater in an MRI-derived nasal airway replica of a 6-weekold female as compared with a 53-year-old male replica at the same flow rate. Distinct impaction parameter curves were found between the two. By plotting deposition efficiency against the Stokes number (based on a characteristic diameter defined by the square root of the area of minimum cross-section), the states of congestion (by histamine spray) and decongestion (by xylometazoline spray) were modeled.(131) In another study, Swift et al.(132) developed a diffusional deposition equation based on in vitro measurements of 0.6–200-nm ultrafine particle deposition in nasal airway replicas of three adults and one child (1.5 years old). Cheng et al.(133) expanded on this diffusional deposition equation by performing 4.6–200-nm particle deposition measurements in MRI-derived nasal replicas of a 1.5-year-old, 2.5-year-old, and 4-year-old, and found decreasing deposition with increasing age. However, intersubject variability was not considered in the development of this equation. To address the issue of intersubject variability and to study younger infants

FIG. 2. CT scan reconstructions of realistic infant nasal airways created by Storey-Bishoff et al.(135) Realistic replicas created from these geometries have been used for micrometer(135) and ultrafine(134) particle deposition measurements. Reprinted by permission from Ref. 135.

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PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS Golshahi et al.(136) measured the deposition of inhaled micrometer-sized (0.5–5.3 lm) particles in the nasal airways of children (age 4–14 years) during simulated tidal breathing, and compared the results to deposition measurements with nasal breathing in infant and adult replicas. When plotted against the impaction parameter, infants tended to have greater extrathoracic deposition than children or adults.(136) It was found that the developed empirical correlations did not accurately model deposition for one congested patient, and its use in this regard was not recommended.(136) In a different study, Golshahi et al.(137) created oropharyngeal airway replicas, shown in Figure 3, from CT scan data of children age 6–14 years imaged while inhaling at a constant flow rate. The deposition of 0.5–5.3-lm particles in these airways was measured for constant flow rates ranging from 30 to 150 L min - 1. These replicas have also been used to measure the deposition of micrometer-sized particles (0.5– 6.3 lm) during simulated tidal breathing.(138) Caution against comparing studies taken at constant flow rates with those simulating tidal breathing was advised.(138) Age-scaled factors suggested by the ICRP model(130) were applied to estimate particle deposition in the oral airways of children, and the results were inconsistent with in vitro measurements, indicating the insufficiency of the diameter of the trachea as a scaling parameter.(138) Zhou et al.(139) compared regional and total deposition of 1–20-lm particles inhaled at constant flow rates of 10 and 20 L min - 1 both in vitro and in silico, in an MRI-derived nasal airway geometry of a 5-year-old child. At the lower flow rate, CFD overestimated deposition in the anterior region and underestimated deposition in the turbinate region.(139) At the higher flow rate, agreement was found in the anterior region, but the underestimation of deposition in the turbinate region remained.(139) Differences in surface properties (e.g., roughness) between the replica and the idealized smooth surface of the CFD model may partially explain this discrepancy.(139) Empirical correlations were developed, which provided similar deposition estimates to those suggested by Golshahi

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et al.(136) for particle sizes smaller than 5.3 lm. The deposition predictions were inaccurate regarding larger particle sizes, indicating that extrapolating particle deposition correlations to outside their validated range is not advisable.(139) In a continuation study, Zhou et al.(140) used nasal replicas of a 10-day-old, 7-month-old, 3-year-old, 5-year-old, and adult to suggest that 2–28-lm-sized aerosol deposition in the nasal airways may be higher in small children and infants than adults for similar breathing conditions (sitting awake). Comparisons were made to the empirical deposition correlations developed by Golshahi et al.(136) and Javaheri et al.,(141) but extrapolations were made outside of the intended age and particle size range for which these correlations were developed. It should be noted that intersubject variability was not addressed in the two recent studies by Zhou et al.(139,140) Pediatric empirical extrathoracic deposition modeling correlations Swift et al.(132) suggested the use of the equation g ¼ 1  exp (  fQ  1=8 D1=2 )

(1)

to model ultrafine particle deposition in nasal airways of any age group. Here, the fitting parameter f = 12.65 – 0.17, the volumetric flow rate Q has units of L min - 1, and the particle diffusion coefficient D has units of cm2 sec - 1. This equation is based on a simplified theoretical turbulent flow deposition model shown to collapse deposition data in adults,(142) but with a different value of f than shown here. Cheng et al.(133) suggested modifying the parameter f to include age effects according to the equation f ¼ 13:8 þ

2:96 7:48 þ 2 t t

(2)

where t has the unit years. Decreasing deposition efficiency with increasing age was suggested for the same flow rate and diffusion coefficient.(133)

FIG. 3. Images of realistic oral airway replicas of children age 6–14 years, including the attached mouthpiece from which they inhaled from at a constant flow rate during the CT scans.(137) These replicas have been used to measure micrometer-sized particle deposition during constant flow(137) and tidal(138) inhalation. Reprinted by permission from Ref. 137. Color images available online at www.liebertpub.com/jamp

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CARRIGY ET AL.

For evaluating the deposition of micrometer-sized particles in the extrathoracic region of pediatrics, empirical correlations of the form 

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a g¼1 a þ bRec Stkd

e (3)

have been suggested in many recent studies.(135–138,143,144) The constants a–e represent fitting parameters, Re represents the Reynolds number (which determines the fluid mechanics regime), and Stk represents the Stokes number (which determines the importance of particle inertia). The Reynolds number is defined for Equation 3 based on Equation 4. The Stokes number is defined for Equation 3 based on Equation 5. Re ¼

4qf Q plf dc

(4)

k

Stk ¼

2qx d2a (1 þ 2:52 dfa )Q

(5)

9plf d3c

In Equations 4 and 5, qf is the fluid density, Q is the average inhalation flow rate, lf is the fluid viscosity, qw is a standard reference density similar to water (1,000 kg m - 3), da is the particle aerodynamic diameter, and kf is the mean free k path length of the fluid. The term (1 þ 2:52 daf ) represents a simple form of the Cunningham correction factor, which can be used to correct for noncontinuum interactions between small particles and fluid molecules. A crucial parameter in Equations 4 and 5 is dc, which is a characteristic length scale. In this section, twop characteristic ffiffiffiffiffiffiffiffiffiffiffi diameters are considered, the first being dc, 1 ¼ V=L, where

V is the airway volume and L is the centerline length of the airway. The advantage of this characteristic diameter is that it can be determined from acoustic rhinometry (for the nasal airways)(135) or acoustic pharyngometry (for the oral airways). Thus, no radiation imaging is required. The second characteristic diameter considered usually provides a slightly better fit and is given by dc,2 = V/As, where As is the airway surface area, which can be determined from MRI or CT scan postprocessing techniques. Table 1 summarizes the average characteristic diameters (dc,1 and dc,2) and fitting parameters (a–e) for use in Equation 3 to estimate extrathoracic nonhygroscopic micrometer-sized particle deposition in pediatrics. Values for adults are also given for convenience. These empirical correlations can be useful for predicting differences in extrathoracic deposition fractions between different age groups. For example, using Equation 3 with typical air properties (qf = 1.2 kg m - 3, lf = 1.8 · 10 - 5 Pa sec, kf = 67 nm) and the average characteristic diameters dc,2 with its corresponding coefficients given in Table 1, differences in extrathoracic deposition fraction can be estimated for da = 2.5 lm aerodynamic diameter particles, as shown in Figure 4. At this particle size, nasally breathing infants tend to have the highest extrathoracic deposition fraction, due to their smaller airway geometries. Orally and nasally breathing children tend to have similar extrathoracic deposition fractions for this particle size, and adults tend to have the lowest extrathoracic deposition fraction. Extrathoracic deposition fractions are observed to be stronger functions of flow rate in infants and children than in adults. Again using Equation 3, one can consider a comparison of 1–5-lm aerodynamic diameter particle deposition for average resting inhalation flow rates of Q = 100 mL sec - 1 for an infant, Q = 200 mL sec - 1 for a child, and Q = 300 mL sec - 1 for an adult, which represent typical flow rates as approximated

Table 1. Average Characteristic Diameters and Fitting Parameters for Use In Equation 3 To Estimate the Extrathoracic Deposition of Nonhygroscopic Micrometer-Sized Particles in Pediatric Subjects 3–18 months(135)

4–14 years(136)

6–14 years(137)

6–14 years(138)

Adults(143)a

Adults(144)

Airway

Nasal

Nasal

Oral

Oral

Oral

Oral

Breathing mode

Tidal

Tidal

Constant flow

Tidal

Constant flow

Tidal

0.0146 m 1 2.45 0.58 1.33 1

0.0146 m 1 1.27 · 107 - 0.74 2.18 1

0.020 m 1 8.381b 0.707 1.912 1

— — — — — —

0.0027 m 1 0.000335 0.69 1.5 1

0.0027 m 1 4.99 - 0.17 2.41 1

— — — — — —

0.01824 md 1 1.51 · 105 0.25 3.03 1

Age

pffiffiffiffiffiffiffiffiffi Average dc, 1 ¼ V=L a1 b1 c1 d1 e1 Average dc, 2 ¼ V=As a2 b2 c2 d2 e2 a

0.0103 m 10.4 0.5659b 1.201 1.156 0.5201

0.011 m 119.4 1 1.28 1.23 0.57 0.090 mc 4.21 · 10 - 3 1 1.32 1.25 0.55

0.0012 m 2.164 · 105 0.5913b 1.118 1.057 0.851 k

The Cunningham correction factor (1 þ 2:52 daf ) was neglected in the study of Grgic et al.(143) due to the larger particle sizes tested and, hence, was not included in the calculation of the Stokes number in Equation 5. b Note that the Reynolds and Stokes numbers were defined differently in the studies of Golshahi and colleagues(136–138,144) than in these studies and, hence, the b fitting parameters have been adjusted accordingly. The factor dc/dc,avg in the equations given by Storey-Bishoff et al.(135) was assumed to equal 1. c (136) Here the characteristic diameter dc,2 = Aps/L ffiffiffiffiffiffi was instead used as it better fit the experimental data. d Here the characteristic diameter dc, 2 ¼ Ac , where Ac is the average cross-sectional area, was instead used as it better fit the experimental data.(144)

PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS

157 g ¼ 1  exp (  (3:69Stkz )2:20 )

(7)

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where Stkz ¼ d2a U=18ldc . Here, U is the flow velocity and the characteristic diameter dc ¼ (0:0181Lnose =Rnose )4=19 , which was developed by Garcia et al.(145) based on theoretical considerations of turbulent pressure drop in a circular pipe under standard conditions for air. In this equation, Lnose is the centerline length of the nasal airways including the laryngeal region, and the nasal resistance is given by Rnose ¼ Dp=Q1:75 . In their continuation study, Zhou et al.(140) suggested the following correlation, similar to Equation 6, for fitting nasal airway deposition data across all age groups for similar breathing conditions (sitting awake): FIG. 4. Extrathoracic deposition fraction of 2.5-lm aerodynamic diameter particles as a function of flow rate for infants, children, and adults. Color images available online at www.liebertpub.com/jamp from Xi et al.(15) Using Equation 3 with the same typical fluid properties, average characteristic diameters, and fitting parameters, a comparison of extrathoracic deposition fraction as a function of particle size among different age groups can be made, as shown in Figure 5. It is seen that for typical resting, tidal breathing conditions, a nasally breathing infant is expected to receive a slightly greater extrathoracic deposition fraction than a nasally breathing child, whereas an orally breathing child is expected to receive a greater extrathoracic deposition fraction than an orally breathing adult. To best collapse nasal airway deposition data in a 5-yearold replica, Zhou et al.(139) suggested the equation g ¼ 1  exp (  (0:00214d2a Dp 2=3 )2:21 )

(6)

where Dp is the pressure drop across the model and da is the particle aerodynamic diameter.(139) Equation 6 uses a modified impaction parameter with pressure drop instead of flow rate to take into account the geometry of the nasal airways, which was previously suggested by Golshahi et al.(136) As noted by Zhou et al.,(140) transnasal pressure drop can be measured in vivo using rhinomanometry. Zhou et al.(139) also suggested an empirical correlation given by

FIG. 5. Extrathoracic deposition fraction as a function of particle aerodynamic diameter for resting inhalation flow rates typical of an infant (Q = 100 mL sec - 1), a child (Q = 200 mL sec - 1), and an adult (Q = 300 mL sec - 1). Color images available online at www.liebertpub.com/jamp

g ¼ 1  exp (  (0:0019d2a Dp2=3 )1:285 )

(8)

For an even better fit, the following correlation was suggested(140): g ¼ 1  exp (  (2:76Stkz )1:29 )

(9)

The same Stokes number, characteristic diameter, and nasal resistance definitions for use in Equation 7 are used in Equation 9. Conclusions regarding pediatric empirical extrathoracic deposition modeling Recently developed empirical models of extrathoracic deposition have taken into account intersubject variability within infant and child age groups. An online calculator, available at www.mece.ualberta.ca/arla/deposition_ calculator.html, allows for predictions of extrathoracic deposition in pediatric and adult subjects.(146) A methodology for providing dose adjustments has recently been presented by Finlay et al.(147) In vitro empirical deposition data for pediatrics are still lacking for more distal lung airways, nonrigid models, and disease-state geometries. Pediatric In Vitro Modeling: Idealized Geometries for Measuring Extrathoracic Deposition Although commonly used for inhaler testing, the 90 bend United States Pharmacopeia (USP) port does not replicate the average mouth–throat deposition measured in adults.(148) To better capture extrathoracic deposition in various age groups, idealized geometries have been developed that incorporate simplified analogues of important geometrical features measured in a given patient population. The simplified geometry of these idealized models allows for reproducible high-precision manufacturing out of metal, which prevents issues associated with localized electrostatic charge, material extraction during HPLC, and fragility.(148) Impactor connections can be used at the distal end of these models for analyzing particle size distributions. As with impactors, a proper airway surface coating should be used with these idealized airways to eliminate particle bounce/rebound. Proper electrical grounding procedures should also be used. Javaheri et al.(141) recently developed an idealized geometry of the nasal airways of an infant that captures average deposition of 10 subjects in the 3–18-month range, based on average geometrical features measured from CT scan reconstructions. An idealized geometry of a 3-year-old child

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158 has been used for CFD study.(149) Bickmann et al.(125) developed an idealized geometry of an orally breathing 5-year-old child by adjusting several dimensions of the adult Alberta Idealized Throat based on MRI data in children, and estimated particle deposition with this throat from DPIs.(123) Golshahi and Finlay(150) developed an idealized geometry of an orally breathing child based on scaling the Alberta Idealized Throat by a uniform factor determined from the average value of dc,2 (Table 1) in nine children age 6–14 years, and validations have since been performed in vitro.(137,138,151) These idealized models can be useful for evaluating the effectiveness of pediatric aerosol delivery device and formulation modifications. A device developer may wish to modify a VHC design developed for children to be suitable for infants by decreasing facemask size and increasing valve flexibility, whereas a formulation developer may be required to modify the excipients in a pMDI designed for adults to be safe for and tolerated by pediatrics. These idealized models can be used to compare the original and modified designs in terms of dose and particle size distribution when used in conjunction with an impactor. Pediatric In Silico Modeling: One-Dimensional Whole-Lung Models Introduction to whole-lung models Whole-lung models estimate particle deposition efficiencies in regions of the respiratory tract under specific flow conditions for deposition mechanisms including, but not limited to, diffusion, impaction, interception, and gravitation. Lung morphology definitions range in complexity from single-path models consisting of symmetric bifurcating airways to more complicated and variable asymmetric models that are generated stochastically. Although lacking the capability to predict hot-spot formation, whole-lung deposition models offer a computationally inexpensive method for predicting regional and total deposition in the human respiratory tract, which may be more appealing in the study and design of aerosol drug delivery platforms for the general patient population than more intensive CFD simulations.(152) Further reviews of whole-lung models are given elsewhere(54,152–158). Deterministic and stochastic models Deterministic and stochastic whole-lung deposition models use simplifying assumptions regarding airflow conditions and airway geometries to calculate deposition based on aerosol physics.(159–163) Deterministic models can provide information on particle deposition in predetermined lung morphologies, such as single airways, bifurcations, or larger branching networks. In the simplest of these models, each airway in a given airway generation has identical linear dimensions, resulting in equal path lengths from the trachea.(156) To better represent the lung, stochastic models use statistical distributions to define variable lung morphologies, including airway diameters, lengths, and branching angles. The resulting morphologies consist of highly variable path lengths from the trachea to a given airway generation, resulting in varying particle trajectories and deposition. Many of the early whole-lung deposition studies were deterministic,(164–173) often applying previously-derived equations describing aerosol physics to lung morphologies

CARRIGY ET AL. representative of children; more recent studies have built upon these initial analyses. Isaacs and Martonen(174) presented an age-dependent deposition model based on earlier work,(162,175) using scaled versions of the commonly used symmetric lung morphology developed by Weibel.(176) The authors found consistent agreement between model predictions and in vivo deposition, and concluded that children are likely to receive larger particle doses than adults due to the increased doseper-surface area in the respiratory tract of younger patients. Musante and Martonen(177) used the deposition model of Martonen et al.(173) to show that children may receive higher tracheobronchial and pulmonary deposition than adults. A considerable increase in dosing was noted for children when accounting for ventilation rate and airway surface area; children were estimated to receive a localized dose up to three times higher than adults. Similarly, a lobar-specific multiplepath particle deposition model used by Asgharian et al.(178) and Ginsberg et al.(179) predicted higher deposition in younger patients, with doses decreasing with increasing age. Compared with deterministic models, relatively few studies have used stochastic methods in analyzing particle deposition in pediatric subjects. Horva´th et al.(180) applied the stochastic lung deposition model IDEAL(181,182) in a study examining airway deposition of intact and fragmented pollen in patients of various ages. Results showed that small and fragmented pollen could avoid the filtering effects of the extrathoracic region, leading to deposition in the thoracic airways. Bronchial deposition fractions, when normalized by unit time and surface area, were consistently higher in children than in adults, suggesting that youth may receive higher normalized doses of pollen. Sturm(183) also used the stochastic model of Koblinger and Hofmann(181) in a study on carcinogenic particle deposition in the lungs of children. The highest deposition fractions were observed in adolescents (15 years old) and adults, with the lowest deposition occurring in infants (1 year old). For younger patients, deposition accumulated primarily in the extrathoracic region and upper bronchi, whereas for adolescents and adults significant fractions of particles deposited in the lower bronchi and alveoli. These results were attributed to the complex interactions between various deposition mechanisms (Brownian diffusion, inertial impaction, interception, and gravitational settling) and the age-dependent nature of breathing parameters and lung morphologies. Although results were not quantifiably normalized by surface area, Sturm(183) did note that particle concentrations per lung tissue area (equivalent to surface area) could reach dangerously high values in young patients. Conclusions regarding mathematical modeling Whole-lung models have been used to characterize particle deposition in the general patient population, with agedependent models providing information on particle behavior in infants, children, and adolescents. Many of the aforementioned studies predicted that increased particle deposition concentrations would occur in younger patients, with important implications in airborne particulate risk assessments and aerosol drug delivery. Although a great deal of work in the latter half of the past century led to a variety of methods and approaches to whole-lung modeling, as of late there have been a relatively limited number of investigations using deterministic or stochastic pediatric deposition models.

PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS This may be due in part to a general lack of experimental data for validation purposes; advances in imaging techniques and expanded data sets will be required for validations of model predictions at generation-specific levels.(152,157,184) As such, further work is required for wholelung model predictions to be adequately validated in infants and children. Pediatric In Silico Modeling: Computational Fluid Dynamics

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Introduction to CFD CFD has been used to great effect in the analysis of fluid flows in many branches of science and engineering. CFD involves solving the dynamic equations governing fluid motion numerically over a physical region of interest. Various approaches to CFD are available, including direct numerical simulation (DNS), large eddy simulation (LES), and Reynolds-averaged Navier-Stokes (RANS) equations, each suited to different situations. In the examination of particle deposition, Lagrangian methods have proven useful in tracking particle trajectories and predicting the point of interception with walls or surfaces. Particles that intercept these surfaces can be considered to have deposited, allowing for a quantification of deposition efficiency for a given airway geometry. It should be noted that the literature on CFD theory and application is extensive, and a number of texts(185–188) and best practice guides(189,190) are available. Computational methods and technologies continue to improve in terms of ability and sophistication, leading to an increased use of CFD in applications related to pulmonary drug delivery, as highlighted in a number of recent reviews.(157,191–193) However, despite these advances, relatively little work has been performed in modeling pharmaceutical aerosol deposition in pediatric subjects. Studies have occurred primarily in the past decade, beginning with rudimentary CFD simulations of fluid flow in pediatric airways and leading to more complicated modeling of aerosol deposition and behavior in extrathoracic airways. Here, studies using CFD in the examination of aerosol behavior in infants, children, and adolescents are discussed, and important considerations are identified. Pediatric CFD deposition studies Initial applications of CFD in the area of pediatric drug delivery examined airflow characteristics without considering particle deposition. In a pair of complementary studies, Segal et al.(194) and Guan et al.(195) examined the effects of tumors and breathing parameters on airflow in a symmetric lung model representative of the upper airways of a 4-year-old child. Segal et al.(194) found that tumor size and location had considerable effects on localized airway velocity profiles and the bulk flow distribution of air within the lungs. Guan et al.(195) similarly observed that varying breathing frequencies and tidal volumes influenced flow patterns in the presence of tumors. More recently, Allen et al.(196) compared airflow in a realistic 5-year-old male upper airway model with airflow in adults. Simulations showed strong regions of recirculation forming downstream of the glottis in response to the laryngeal jet, which forced flow toward the anterior wall of the throat. Abnormally high turbulent kinetic energy and maximum jet

159

velocities were observed in the child model compared with adults, despite having relatively low tracheal Reynolds numbers, which was hypothesized to result in increased particle deposition in pediatric airways. Although these initial studies provided insight into airflow in pediatric airways, none provided quantitative information regarding particle transport and deposition, thereby limiting their utility. More recent studies have begun to explicitly simulate the transport and deposition of particles in pediatric airways. Longest et al.(197) investigated the effects of asthma-induced airway constriction on deposition in symmetric double bifurcating models representing the upper and central airways of a 4-year-old child. A diameter reduction of 30%, chosen conservatively, was used to simulate the effects of bronchoconstriction and inflammation during an acute asthma attack, and particles ranging from 1 to 7 lm were introduced to the models under various activity conditions. Under a steady inhalation flow rate, deposition was quantified both regionally as branch-averaged deposition and locally with a microdosimetry factor, indicative of cellular-level deposition hot spots. Results showed that airway constrictions significantly increased axial and secondary velocities, causing enhanced deposition via impaction and interception. Airway constriction increased branch-average filtering efficiencies by a factor of 1.5 to 10 and local cellular-level deposition by one to two orders of magnitude. Based on these results, the authors stressed the importance of accounting for highly localized deposition (microdosimetry) in evaluating the potential health risks of particulate matter. A more recent study by Longest and Vinchurkar(198) used the same airway geometries in a study of inertial deposition during steady expiratory flow. Results indicated that deposition occurred predominantly through secondary motion of the velocity field, with hot spots forming on the top and bottom surfaces of bifurcations, in agreement with past experimental(199) and numerical(200) results. Both secondary motion and particle inertia were concluded to play important roles in expiratory deposition. However, Longest and Vinchurkar(198) found that deposition efficiency could not be captured with correlations based on the Stokes number and bifurcation angle, as suggested by Kim et al.(199) in an earlier in vitro study on single bifurcations. Rather, a new correlation was presented based on the Stokes number (representative of a particle’s ability to follow streamlines) and Dean number (representative of secondary motion intensity). Although the study provided insight into expiratory deposition, the choice of pediatric airway was relatively arbitrary, and conditions were limited to steady flow in simplified, symmetric geometries. More recent studies have examined aerosol deposition in realistic airway models. Xi et al.(129) examined aerosol deposition of particles with diameters ranging from 0.5 to 30 lm in a realistic nasal airway model of a 5-year-old boy, reconstructed from MRI. Simulations showed that airflow in the pediatric nasal airway was predominantly laminar and transitional at moderate breathing conditions, with turbulence occurring further downstream in the pharynx and larynx. Significantly increased deposition occurred in the pediatric nasal airway compared with adults at similar flow rates, although when scaled to age-appropriate equivalent activity conditions, differences in deposition were less pronounced. Local deposition was dependent on flow conditions and particle size, and the flow-deposition response

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160 varied among the different subregions of the nose. For example, at moderate and high breathing conditions, most particles greater than 10 lm deposited in or before the nasal turbinates, leading to less deposition in the larynx and pharynx. Deposition in the nasal turbinates was lowest for light-activity breathing conditions, as inertial deposition and sedimentation of particles were likely minimized. Deposition hot spots were identified based on activity levels; upstream of the pharynx, sedentary conditions saw particles accumulating on the nasal floor and inferior turbinate, whereas under light activity particles deposited primarily on the vestibule and middle turbinate. Based on these areas of local accumulation, Xi et al.(129) determined that inhalation toxicology studies based on regional deposition alone could considerably underestimate exposure health risks. It was also demonstrated that by tracing particle trajectories, drugs could be effectively targeted to specific regions of the nasal airways by controlling the point of release in the nostril, potentially allowing for optimal delivery of nasal sprays in various patient groups. Unfortunately, the realism of the model was limited by the assumptions of steady flow, a smooth and rigid airway surface, constant nasal valve and glottal apertures, and the use of only a single subject. Given that intersubject variability can cause large differences in deposition, a broader population group is needed to determine average properties and develop more general predictive correlations. Following a similar methodology, Xi et al.(15) examined ultrafine (1 to 100 nm) particle deposition in realistic extrathoracic models of a 10-day-old newborn, a 7-month-old infant, a 5-year-old child, and a 53-year-old adult, constructed using MRI and CT scans. Simulations of airflow under quiet conditions showed that the small airway diameters in the three youngest patients prevented the formation of recirculating zones in the nasopharynx, in contrast to the observable recirculation in the adult model. Total deposition fractions were similar among the various models, in agreement with the in vitro study by Golshahi et al.,(134) and particle deposition patterns displayed much less heterogeneity(15) than that observed with micrometer-sized particles.(129) The high diffusivity of 1- to 10-nm particles caused a large fraction of these particles to deposit throughout the models, predominantly in the nasal turbinates and the pharynx–larynx region. In contrast, 20- to 100-nm particles, with a significantly lower diffusivity, deposited much less frequently and tended to accumulate in the turbulence-laden pharynx–larynx region,(15) as shown in Figure 6. Whereas total deposition was remarkably consistent across the various models, subregional deposition varied considerably, likely as a result of competing mechanisms including turbulent dispersion, upstream particle depletion, and secondary fluid motion. Xi et al.(15) concluded that differences in subregional deposition would lead to varying levels of burden in a given region of interest among different age groups when exposed to the same environment. In an additional study, Xi et al.(201) analyzed the deposition of ultrafine and fine particles with diameters ranging from 1 to 1,000 nm in realistic models of the nasal airways of a 9-month-old girl, 5-year-old boy, and 53-year-old male. Similar trends to the aforementioned study by Xi et al.(15) were observed, with relatively consistent total deposition and variable subregional deposition occurring among the

CARRIGY ET AL. various models. In these ultrafine and fine particle deposition studies,(15,201) correlations for predicting deposition were presented, but with only one patient in each age group the effects of intersubject variability could not be examined. Additionally, a selective validation to geometries only with similar dimensions by Xi et al.(15) further limits the applicability of these correlations to the general population. Recently, Kim et al.(202) examined the growth and deposition of hygroscopic aerosols in the same 5-year-old nasal airway replica analyzed in earlier studies by Xi et al.(15,129,201) Simulations of monodisperse 200-nm particles inhaled at steady flow rates under four temperature and RH conditions, ranging from warm and dry (23C, 30% RH) to hot and saturated (47C, 100% RH), were performed. Figure 7 illustrates the effect of hygroscopic growth on particle size within different subregions of the extrathoracic nasal airway representative of a 5year-old child. In the absence of a saturated environment, hygroscopic growth and evaporation had a negligible effect on total deposition, but a considerable impact on local deposition. For the hot and saturated condition, considerable hygroscopic growth was observed; the average particle growth rate (ratio of final to initial particle MMAD) was 17.5, resulting in significantly enhanced total deposition. Under this hot and saturated condition, deposition in the whole nasal airway increased by a factor of 2.5, in the turbinate region by a factor of 6, and in the olfactory region by a factor of 11 relative to the control case of no particle growth. As noted by Kim et al.,(202) the considerable increase in deposition observed in the olfactory region carries implications in both environmental health risk assessments and therapeutic aerosol delivery, with a potential application in direct nose-to-brain drug delivery for CNS treatment. In addition, it was demonstrated that airflow approached the ambient airway RH and surface temperature prior to exiting the nasopharynx regardless of inhalation condition, meaning condensational growth occurred mostly in the vestibule and turbinate region. With these insights in mind, certain limitations of the study were noted. Two-way coupling effects of hygroscopic growth were neglected, meaning the impact of droplet evaporation and condensation on air temperature and saturation were not simulated. Furthermore, the study did not account for intersubject variability, as only one subject model was analyzed, and thus results may not apply to the general pediatric population. In a different study, Kim et al.(109) studied the effect of head direction and breathing mode on particle behavior within a nebulizer hood and the respiratory tract of a realistic 7-month-old infant face-airway geometry that included both the oral and nasal extrathoracic routes, building upon the insights provided in previous studies with regard to particle behavior in the hood and total inhaled drug dose.(108,203,204). Deposition of particles 1 to 5 lm in size, released with zero initial velocity and constant concentration in a spherical boundary encompassing the infant geometry, was examined under a steady inhalation flow rate of 5 L min - 1 for nasal and oronasal breathing modes and various head directions, including face up, face side, and upright (face forward). Results showed that the lung delivery efficiency, defined as the fraction of dose exiting the trachea of the infant geometry to the initial administered dose, was heavily dependent on both head direction and breathing mode. Increased lung delivery efficiency was demonstrated for oronasal breathing (22.5%) compared with the nasal route (18.5%) with

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FIG. 6. A comparison of a newborn, infant, child, and adult with respect to (a) airflow streamtraces, (b) deposition of 1–10nm particles, and (c) deposition of 20–100-nm particles, for typical resting steady inhalation flow rates initiated through the right nostril.(15) Reprinted by permission from Ref. 15. Color images available online at www.liebertpub.com/jamp corresponding differences in regional extrathoracic deposition: oronasal breathing resulted in increased deposition in the pharynx and larynx compared with nasal breathing (30% versus 12%), whereas nasal breathing resulted in higher deposition in the turbinates (8% versus 3% oronasally). Comparable lung delivery efficiencies were observed between face-side and face-forward head directions, with a slight decrease for the face-up direction. From these results, Kim et al.(109) suggested that the face-side position was advantageous over the face-up position for administration of aerosolized medications to infants via nebulizer hood. Certain limitations of the numerical study were noted, however, including the use of steady inhalation flow rates, rigid airway surfaces, and the use of only a single subject. Conclusions regarding CFD The application of CFD to the investigation of particle deposition in pediatric airways has been relatively limited. As

discussed by Hofmann,(156) the use of CFD in predicting pediatric pulmonary deposition is made difficult both by a lack of morphometric data describing the lower respiratory tract and by the extreme complexity of aerosol dynamics. Limitations in current medical scanning technologies have prevented thorough in vivo validation of computational models in the distal airways. To date, studies involving CFD in simulating pediatric pulmonary deposition have made use of the relatively computationally-inexpensive RANS methods, often using the low Reynolds number j-x turbulence model with various study-dependent modifications to, for example, provide improved predictions of deposition locations or account for hygroscopic growth. The standard models for predicting particle behavior in turbulence require careful modification to replicate deposition in the upper airways, and proper setup and execution of CFD simulations require thorough validation and significant effort on the part of trained personnel. One potential area of in silico development lies in combining whole-lung models and CFD simulations. As noted

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FIG. 7. Smoke particle droplet trajectories, colored according to transient particle size, illustrating hygroscopic condensation and evaporation effects for different inhalation temperatures and RH levels.(202) The initial particle diameter is 0.2 lm, the constant inhalation flow rate is 5 L min - 1, and the nasal airway is representative of a 5-year-old child. Reprinted by permission from Ref. 202. Color images available online at www.liebertpub.com/jamp

by Byron et al.(152) and Longest and Holbrook,(157) wholelung models could be developed to incorporate the results of CFD simulations, improving the quality of predictions while avoiding large increases in computational costs. This approach may incorporate the best of both techniques, relying on whole-lung models to estimate regional deposition and CFD to resolve local deposition patterns. Additionally, recent work(205–208) has seen the development of a stochastic individual path (SIP) CFD model, which provides an efficient method for calculating regional and local deposition in the conducting airways. In this SIP CFD model, aerosol transport and deposition are calculated throughout a computational model of the airways to the third bifurcation, including the inhaler, after which individual pathways that are generated stochastically are selectively continued at each subsequent bifurcation. By continuing one path at each bifurcation, instead of both, the exponential increase in pathways observed within deeper generations of the lungs is avoided, allowing for more efficient computational model-

ing. At present, however, the SIP CFD model has been applied only to geometries representative of adults, and thus the utility of the model in describing pediatric pharmaceutical aerosol deposition is untested. CFD holds the potential to vastly improve the understanding of aerosol transport and deposition in pulmonary airways at a fundamental level, and as computational technologies improve, the use of numerical methods in this area will inevitably increase. At present, CFD should not be viewed as a replacement but rather as a complement to existing measurement techniques. Joint in silico, in vitro, and in vivo experiments may yet reveal important insights into pediatric aerosol deposition to aid in the development of new formulations and delivery devices. Conclusions In vitro benchtop studies of pMDI VHC facemask aerosol delivery have highlighted the importance of a facemask seal,

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PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS minimal facemask dead-space volume, properly operating valves, antistatic VHCs, and delivering small particles. The realistic, CT-derived SAINT extrathoracic airway model has been used to illustrate, for example, the importance of delivering extra-fine particles to treat infants, the importance of a tight facemask seal, as well as the effect of respiratory rate and tidal volume on aerosol delivery. Nebulizer benchtop studies have compared many brand-name devices and have been used to design and evaluate new facemasks. The effect of breathing pattern on aerosol delivery, as well as caregiver exposure to aerosol escaping at facemask leaks, has also been evaluated. The blow-by technique may decrease facial and eye deposition, but with an associated decrease in lung dose. Benchtop studies have also been used to aid the development of active DPIs and their add-on devices, to demonstrate that SMIs can be used effectively with a VHC, and to reveal the importance of nasal spray angle and location of insertion on deposition location and therapeutically-relevant dose. Pediatric asthma prevalence is on the rise, and deposition models may prove useful for defining exposure limits for inhaled particulate matter and for estimating the dose a patient is likely to receive from an inhaled pharmaceutical aerosol delivery device prior to experimental or clinical study. A recent study has found that the ICRP methodology for evaluating particle deposition in pediatrics did not match in vitro deposition measurements.(138) Recently developed empirical correlations may prove useful in revising the ICRP methodology and, as illustrated in this review, for providing patient-specific or age group–averaged dose estimates. An online deposition calculator using many of these empirical correlations is available online at www.mece.ualberta.ca/ arla/deposition_calculator.html. Idealized geometries have been designed to capture pertinent, average in vitro geometrical factors for infant and child age groups. Designing aerosol delivery devices and formulations specifically for children is of interest, and these idealized models may provide a useful and standardized platform in this regard. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Recently, CFD models have allowed for a quantification of localized deposition and hot-spot formation in models of the extrathoracic region, while demonstrating the impact of hygroscopic growth on particle deposition. Limitations of current medical scanning technologies have prevented sufficient in vivo morphometric knowledge of the bronchial and more distal airways for input to CFD models, while a general lack of pediatric deposition data for validation further hinders the adoption of these methods. With advancements in computing power, CFD software, and user training, the use of CFD as an analytical tool for estimating aerosol deposition is expected to rise in the near future. Further studies quantifying aerosol deposition in the same pediatric airway geometries using CFD and experimental techniques can provide a partial validation of these methods until more in vivo data become available. Acknowledgments W.H.F. gratefully acknowledges continuing financial support from the Natural Sciences and Engineering Research

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Council of Canada and the Canadian Institutes of Health Research. Author Disclosure Statement W.H.F. and L.G. may receive future royalties from sales of the Idealised Alberta Child Throat by Copley Scientific Ltd. (UK). References 1. Kelly FJ, and Fussell JC: Air pollution and airway disease. Clin Exp Allergy. 2011;41:1059–1071. 2. Research and Health Education Division, Epidemiology and Statistics Unit, American Lung Association: Trends in asthma morbidity and mortality. American Lung Association. Available at: www.lung.org/finding-cures/ourresearch/trend-reports/asthma-trend-report.pdf. Accessed June 3, 2013. 3. Woodruff TJ, Grillo J, and Schoendorf KC: The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environ Health Perspect. 1997;105:608–612. 4. Loomis D, Castillejos M, Gold DR, McDonnell W, and Borja-Aburto VH: Air pollution and infant mortality in Mexico City. Epidemiology. 1999;10:118–123. 5. Bobak M, and Leon DA: The effect of air pollution on infant mortality appears specific for respiratory causes in the postneonatal period. Epidemiology. 1999;10:666–670. 6. Ha E-H, Lee J-T, Kim H, Hong Y-C, Lee B-E, Park H-S, and Christiani DC: Infant susceptibility of mortality to air pollution in Seoul, South Korea. Pediatrics. 2003;111:284–290. 7. Schwartz J: Air pollution and children’s health. Pediatrics. 2004;113:1037–1043. 8. Jarabek AM: The application of dosimetry models to identify key processes and parameters for default dose-response assessment approaches. Toxicol Lett. 1995;79:171–184. 9. Lippmann M, Frampton M, Schwartz J, Dockery D, Schlesinger R, Koutrakis P, Froines J, Nel A, Finkelstein J, Godleski J, Kaufman J, Koenig J, Larson T, Luchtel D, Liu L-JS, Oberdo¨rster G, Peters A, Sarnat J, Sioutas C, Suh H, Sullivan J, Utell M, Wichmann E, and Zelikoff J: The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report on status, progress, and plans. Environ Health Perspect. 2003;111:1074–1092. 10. Ginsberg G, Foos B, Dzubow RB, and Firestone M: Options for incorporating children’s inhaled dose into human health risk assessment. Inhal Toxicol. 2010;22:627–647. 11. Norris G, YoungPong SN, Koenig JG, Larson TV, Sheppard L, and Stout JW: An association between fine particles and asthma emergency department visits for children in Seattle. Environ Health Perspect. 1999;107:489–493. 12. Fink JB: Delivery of inhaled drugs for infants and small children: a commentary on present and future needs. Clin Ther. 2012;34:S36–S45. 13. Reid L: 1976 Edward B.D. Neuhauser lecture: the lung: its growth and remodeling in health and disease. AJR Am J Roentgenol. 1977;129:777–788. 14. Dunhill MS: Postnatal growth of the lung. Thorax. 1962; 17:329–333. 15. Xi J, Berlinski A, Zhou Y, Greenberg B, and Ou X: Breathing resistance and ultrafine particle deposition in nasal-laryngeal airways of a newborn, an infant, a child, and an adult. Ann Biomed Eng. 2012;40:2579–2595.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

164 16. Wildhaber JH, Janssens HM, Pie´rart F, Dore ND, Devadason SG, and LeSoue¨f PN: High-percentage lung delivery in children from detergent-treated spacers. Pediatr Pulmonol. 2000;29:389–393. 17. Roller CM, Zhang G, Troedson RG, Leach CL, Le Soue¨f PN, and Devadason SG: Spacer inhalation technique and deposition of extrafine aerosol in asthmatic children. Eur Respir J. 2007;29:299–306. 18. Tal A, Golan H, Grauer N, Aviram M, Albin D, and Quastel MR: Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J Pediatr. 1996;128:479–484. 19. Wildhaber JH, Dore ND, Wilson JM, Devadason SG, and LeSoue¨f PN: Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in children. J Pediatr. 1999;135:28–33. 20. Erzinger S, Schueepp KG, Brooks-Wildhaber J, Devadason SG, and Wildhaber JH: Facemasks and aerosol delivery in vivo. J Aerosol Med. 2007;20:S78–S84. 21. Schueepp KG, Devadason SG, Roller C, Minnocchieri S, Moeller A, Hamacher J, and Wildhaber JH: Aerosol delivery of nebulised budesonide in young children with asthma. Respir Med. 2009;103:1738–1745. 22. Bennett WD, Zeman KL, Kang CW, and Schechter MS: Extrathoracic deposition of inhaled, coarse particles (4.5lm) in children vs adults. Ann Occup Hyg. 1997;41:497–502. 23. Diot P, Palmer LB, Smaldone A, DeCelie-Gernana J, Grimson R, and Smaldone GC: RhDNase I aerosol deposition and related factors in cystic fibrosis. Am J Crit Care Med. 1997;156:1662–1668. 24. Smaldone GC, Diot P, Groth M, and Ilowite J: Respirable mass: vague and indefinable in disease. J Aerosol Med. 1998;11:S-105–S-111. 25. Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD, and Le Souef PN: The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J. 1994;7:2185–2191. 26. Ilowite JS, Gorvoy JD, and Smaldone GC: Quantitative deposition of aerosolized gentamicin in cystic fibrosis. Am Rev Respir Dis. 1987;136:1445–1449. 27. Mallol J, Rattray S, Walker G, Cook D, and Robertson CF: Aerosol deposition in infants with cystic fibrosis. Pediatr Pulmonol. 1996;21:276–281. 28. Alderson PO, Secker-Walker RH, Strominger DB, Markham J, and Hill RL: Pulmonary deposition of aerosols in children with cystic fibrosis. J Pediatr. 1974;84:479–484. 29. O’Doherty MJ, Thomas SHL, Gibb D, Page CJ, Harrington C, Duggan C, Nunan TO, and Bateman NT: Lung deposition of nebulised pendamidine in children. Thorax. 1993;48:220–226. 30. Devadason SG, Everard ML, MacEarlan C, Roller C, Summers QA, Swift P, Borgstrom L, and Le Soue¨f PN: Lung deposition from the Turbuhaler in children with cystic fibrosis. Eur Respir J. 1997;10:2023–2028. 31. Devadason SG, Huang T, Walker S, Troedson R, and Le Soue¨f PN: Distribution of technetium-99m-labelled Qvar delivered using an Autohaler device in children. Eur Respir J. 2003;21:1007–1011. 32. Amirav I, and Newhouse MT: Deposition of small particles in the developing lung. Paediatr Respir Rev. 2012;13:73–78. 33. Janssens HM, Heijnen EMEW, de Jong VM, Hop WCJ, Holland WPJ, de Jongste JC, and Tiddens HAWM: Aerosol

CARRIGY ET AL.

34.

35.

36. 37. 38.

39.

40.

41.

42.

43.

44.

45.

46. 47.

48.

49.

50.

51.

delivery from spacers in wheezy infants: a daily life study. Eur Respir J. 2000;16:850–856. Esposito-Festen J, Ates B, van Vliet F, Hop W, and Tiddens H: Aerosol delivery to young children by pMDI-spacer: is facemask design important? Pediatr Allergy Immunol. 2005;16:348–353. Janssens HM, and Tiddens HAWM: Aerosol therapy: the special needs of young children. Paediatr Respir Rev. 2006;7 Suppl 1:S83–S85. Amirav I: Infant aerosol holding chamber face masks: not all are born equal! Respir Care. 2006;51:123–125. Everard ML: Studies using radiolabelled aerosols in children. Thorax. 1994;49:1259–1266. Salmon B, Wilson NM, and Silverman M: How much aerosol reaches the lungs of wheezy infants and toddlers? Arch Dis Child. 1990;65:401–403. Becquemin MH, Swift DL, Bouchikhi A, Roy M, and Teillac A: Particle deposition and resistance in the noses of adults and children. Eur Respir J. 1991;4:694–702. Schiller-Scotland CF, Hlawa R, Gebhart J, Wo¨nne R, and Heyder J: Total deposition of aerosol particles in the respiratory tract of children during spontaneous and controlled mouth breathing. J Aerosol Sci. 1992;23:S457–S460. Schiller-Scotland CF, Hlawa R, and Gebhart J: Experimental data for total deposition in the respiratory tract of children. Toxicol Lett. 1994;72:137–144. Bennett WD, and Zeman KL: Effect of body size on breathing pattern and fine-particle deposition in children. J Appl Physiol. 2004;97:821–826. Bennett WD, Zeman KL, and Jarabek AM: Nasal contribution to breathing and fine particle deposition in children versus adults. J Toxicol Environ Health A. 2008;71:227–237. Hsu W, Bai T, von Hollen D, Nikander K, and Dalby R: Realistic evaluation of a valved holding chamber with facemask—using a soft anatomical model face to evaluate aerosol output under simulated conditions. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2010. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 835–838, 2010. Geller P, and Berlinski A: Aerosol delivery of medication. In: American Academy of Pediatrics Section on Pediatric Pulmonology, (eds). Pediatric Pulmonology. American Academy of Pediatrics, Elk Grove Village, IL; pp. 913–932, 2011. Everard ML: Inhalation therapy for infants. Adv Drug Delivery Rev. 2003;55:869–878. Amirav I: Elements of mask design for successful aerosol delivery. [Abstract only]. O-22. ISAM 19th International Congress. International Society for Aerosols in Medicine, Chapel Hill, NC. April 6–10, 2013. Amirav I, Luder A, Chleechel A, Newhouse MT, and Gorenberg M: Lung aerosol deposition in suckling infants. Arch Dis Child. 2012;97:497–501. Amirav I, Balanov I, Gorenberg M, Groshar D, and Luder AS: Nebuliser hood compared to mask in wheezy infants: aerosol therapy without tears! Arch Dis Child. 2003;88:719–723. Amirav I, Oron A, Tal G, Cesar K, Ballin A, Houri S, Naugolny L, and Mandelberg A: Aerosol delivery in respiratory syncytial virus bronchiolitis: hood or face mask? J Pediatr. 2005;147:627–631. Bhashyam AR, Wolf MT, Marcinkowski AL, Saville A, Thomas K, Carcillo JA, and Corcoran TE: Aerosol delivery through nasal cannulas: an in vitro study. J Aerosol Med Pulm Drug Deliv. 2008;21:181–188.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS 52. Ari A, Harwood R, Sheard M, Dailey P, and Fink JB: In vitro comparison of heliox and oxygen in aerosol delivery using pediatric high flow nasal cannula. Pediatr Pulmonol. 2011;46:795–801. 53. Bisgaard H, Anhøj J, and Wildhaber JH: Spacer devices. In: H Bisgaard, C O’Callaghan, and GC Smaldone, (eds). Drug Delivery to the Lung. Marcel Dekker, Inc., New York, NY; pp. 389–420, 2002. 54. Finlay WH: The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press, London, UK; 2001. 55. Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M, on behalf of the European Paediatric Formulation Initiative (EuPFI): Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm. 2011;415: 221–231. 56. Hanson LR, and Frey WHF II: Strategies for intranasal delivery of therapeutics for the prevention and treatment of NeuroAIDS. J Neuroimmune Pharmacol. 2007;2:81–86. 57. Lochhead JJ, and Thorne RG: Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;15:614–628. 58. Laube BL: Sinus drug delivery: science versus anecdotes. In: RN Dalby, PR Byron, JP Peart, and JD Suman, (eds). RDD Europe 2007. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 159–168, 2007. 59. Schechter MS, and O’Sullivan BP: Cystic fibrosis. In: American Academy of Pediatrics Section on Pediatric Pulmonology, (eds). Pediatric Pulmonology. American Academy of Pediatrics, Elk Grove Village, IL; pp. 717–743, 2011. 60. Everard ML, Clark AR, and Milner AD: Drug delivery from holding chambers with attached facemask. Arch Dis Child. 1992;67:580–585. 61. Shah SA, Berlinski AB, and Rubin BK: Force-dependent static dead space of face masks used with holding chambers. Respir Care. 2006;51:140–144. 62. Amirav I, and Newhouse MT: Dead space variability of face masks for valved holding chambers. Isr Med Assoc J. 2008;10:224–225. 63. Chavez A, McCracken A, and Berlinksi A: Effect of face mask dead volume, respiratory rate, and tidal volume on inhaled albuterol delivery. Pediatr Pulmonol. 2010;45:224– 229. 64. Barry PW, and O’Callaghan C: The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler. Br J Clin Pharmacol. 1995;40:76–78. 65. Kamin W, and Ehlich H: In vitro comparison of output and particle size distribution of budesonide from metered-dose inhaler with three spacer devices during pediatric tidal breathing. Treat Respir Med. 2006;5:503–508. 66. O’Callaghan C, Lynch J, Cant M, and Robertson C: Improvement in sodium cromoglycate delivery from a spacer device by use of an antistatic lining, immediate inhalation, and avoiding multiple actuations of drug. Thorax. 1993; 48:603–606. 67. Bisgaard H: A metal aerosol holding chamber devised for young children with asthma. Eur Respir J. 1995;8:856–860. 68. Bisgaard H, Anhøj J, Klug B, and Berg E: A non-electrostatic spacer for aerosol delivery. Arch Dis Child. 1995;73:226–230. 69. Bisgaard H: A metal aerosol holding chamber devised for young children with asthma. Eur Respir J. 1995;8:856–860. 70. Wildhaber JH, Devadason SG, Hayden MJ, James R, Dufty AP, Fox RA, Summers QA, and LeSoue¨f PN: Electrostatic

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

165 charge on a plastic spacer device influences the delivery of salbutamol. Eur Respir J. 1996;9:1943–1946. Kenyon CJ, Thorsson L, Borgstro¨m L, and Newman SP: The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J. 1998;11:606–610. Wildhaber JH, Devadason SG, Eber E, Hayden MJ, Everard ML, Summers QA, and LeSoue¨f PN: Effect of electrostatic charge, flow, delay, and multiple actuations on the in vitro delivery of salbutamol from different small volume spacers for infants. Thorax. 1996;51:985–988. Dewsbury NJ, Kenyon CJ, and Newman SP: The effect of handling techniques on electrostatic charge on spacer devices: a correlation with in vitro particle size analysis. Int J Pharm. 1996;137:261–264. Lipworth BJ, Lee DKC, Anhøj J, and Bisgaard H: Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol. 2002;54:544–547. McRobbie DW, Pritchard S, and Quest RA: Studies of the human oropharyngeal airspaces using magnetic resonance imaging. I. Validation of a three-dimensional MRI method for producing ex vivo virtual and physical casts of the oropharyngeal airways during inspiration. J Aerosol Med. 2003;16:401–415. Janssens HM, de Jongste JC, Fokkens WJ, Robben SGF, Wouters K, and Tiddens HAWM: The Sophia Anatomical Infant Nose-Throat (Saint) model: a valuable tool to study aerosol deposition in infants. J Aerosol Med. 2001;14:433–441. Laube BL, Sharpless G, Shermer C, Nasir O, Sullivan V, and Powell K: Deposition of albuterol aerosol generated by pneumatic nebulizer in the Sophia Anatomical Infant NoseThroat (Saint) model. Pharm Res. 2010;27:1722–1729. Finlay WH: Inertial sizing of aerosol inhaled during pediatric tidal breathing from an MDI with attached holding chamber. Int J Pharm. 1998;168:147–152. Janssens HM, de Jonste JC, Hop WCJ, and Tiddens HAWM: Extra-fine particles improve lung delivery of inhaled steroids in infants: a study in an upper airway model. Chest. 2003;123:2083–2088. Janssens HM, van der Wiel EC, Verbraak AFM, de Jongste JC, Merkus PJFM, and Tiddens HAWM: Aerosol therapy and the fighting toddler: is administration during sleep an alternative? J Aerosol Med. 2003;16:395–400. Esposito-Festen J, Ijsselstijn H, Hop W, van Vliet F, de Jongste J, and Tiddens H: Aerosol therapy by pressurized metered-dose inhaler-spacer in sleeping young children: to do or not to do? Chest. 2006;130:487–192. Janssens HM, Krijgsman A, Verbraak TFM, Hop WCJ, de Jongste JC, and Tiddens HAWM: Determining factors of aerosol deposition for four pMDI-spacer combinations in an infant upper airway model. J Aerosol Med. 2004;17:51–61. Esposito-Festen JE, Ates B, van Vliet FJM, Verbraak AFM, de Jongste JC, and Tiddens HAWM: Effect of facemask leak on aerosol delivery from a pMDI-spacer system. J Aerosol Med. 2004;17:1–6. Smaldone GC, Berg E, and Nikander K: Variation in pediatric aerosol delivery: importance of facemask. J Aerosol Med. 2005;18:354–363. Everard ML: Playing the game: designing inhalers for pediatric use. In: RN Dalby, PR Byron, JP Peart, and JD Suman, (eds). RDD Europe 2007. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 71–78, 2007. Amirav I, Mansour Y, Mandelberg A, Bar-Ilan I, and Newhouse MT: Redesigned face mask improves ‘‘real life’’

166

87.

88.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

89.

90.

91.

92.

93.

94.

95.

96. 97.

98.

CARRIGY ET AL. aerosol delivery for Nebuchamber. Pediatr Pulmonol. 2004; 37:172–177. Louca E, Leung K, Coates AL, Mitchell JP, and Nagel MW: Comparison of three valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face model. J Aerosol Med. 2006;19:160–167. Laube BL, Sharpless G, Harrand V, Zinreich J, Sedberry K, Przekwas A, Knaus D, Barry J, and Papania M: Intranasal deposition of liquid aerosol in anatomically-correct models of 2, 5 and 12 year-old children. [Abstract only]. P-084. ISAM 18th International Congress. International Society for Aerosols in Medicine, Rotterdam, The Netherlands. June 18–22, 2011. Liberman EA, Sousa NM, and von Hollen D: In vitro techniques for evaluating eye deposition of aerosolized drug associated with nebulizer facemasks. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 731–734, 2008. Mitchell JP, Wiersema KJ, MacKay HA, Nagel MW, Pischel SM, and Cripps AL: Novel approach for evaluating medication delivered via valved holding chambers (VHCs) with facemask using a face model for infants and small children. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 785–788, 2008. Xu Z, Hsu W, von Hollen D, Viswanath A, Nikander K, and Dalby R: Delivery efficiency from valved holding chambers with facemasks: a comparative study using soft anatomical models. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2012. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 809–813, 2012. Mitchell JP, Finlay JB, Nutall JM, Limbrick MR, Nagel MW, Avvakoumova VI, MacKay HA, Ali RS, and Doyle CC: Validation of a new model infant face with nasopharynx for the testing of valved holding chambers (VHCs) with facemask as a patient interface. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2010. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 777–780, 2010. Mitchell JP: Appropriate face models for evaluating drug delivery in the laboratory: the current situation and prospects for future advances. J Aerosol Med Pulm Drug Deliv. 2008;21:97–111. Mitchell J, and Dolovich MB: Clinically relevant test methods to establish in vitro equivalence for spacers and valved holding chambers used with pressurized metered dose inhalers (pMDIs). J Aerosol Med Pulm Drug Deliv. 2012;25:217–242. Golshahi L, Telidetzki K, King B, Shaw D, and Finlay WH: A pilot study on the use of geometrically accurate face models to replicate ex vivo N95 mask fit. Am J Infect Control. 2013;41:77–79. Everard ML, Clark AR, and Milner AD: Drug delivery from jet nebulisers. Arch Dis Child. 1992;67:586–591. Smaldone GC, Cruz-Rivera MC, and Nikander K: In vitro determination of inhaled mass and particle distribution for budesonide nebulizing suspension. J Aerosol Med. 1998;11:113–125. Berg EB, and Picard RJ: In vitro delivery of budesonide from 30 jet nebulizer/compressor combinations using infant and child breathing patterns. Respir Care. 2009;54: 1671–1678.

99. Finlay WH, and Stapleton KW: Undersizing of droplets from a vented nebulizer caused by aerosol heating during transit through an Andersen impactor. J Aerosol Sci. 1999;30:105–109. 100. Corcoran TE, Shortall BP, Kim IK, Meza MP, and Chigier N: Aerosol drug delivery using heliox and nebulizer reservoirs: results from an MRI-based pediatric model. J Aerosol Med. 2003;16:263–271. 101. Schu¨epp KG, Jauernig J, Janssens HM, Tiddens HAWM, Straub DA, Stangl R, Keller M, and Wildhaber JH: In vitro determination of the optimal particle size for nebulized aerosol delivery to infants. J Aerosol Med. 2005;18:225– 235. 102. Lin HL, Wan GH, Chen YH, Fink JB, Liu WQ, and Liu KY: Influence of nebulizer type with different pediatric aerosol masks on drug deposition in a model of a spontaneously breathing small child. Respir Care. 2012;57:1894–1900. 103. Minocchieri S, Burren JM, Bachmann MA, Stern G, Wildhaber J, Buob S, Schindel R, Kraemer R, Frey UP, and Nelle M: Development of the premature infant nose throat-model (Pr-INT-Model)—an upper airway replica of a premature neonate for the study of aerosol delivery. Pediatr Res. 2008;64:141–146. 104. Mansour MM, and Smaldone GC: Blow-by as potential therapy for uncooperative children: an in-vitro study. Respir Care. 2012;57:2004–2011. 105. Sangwan S, Gurses BK, and Smaldone GC: Facemasks and facial deposition of aerosols. Pediatr Pulmonol. 2004;37: 447–452. 106. Smaldone GC, Sangwan S, and Shah A: Facemask design, facial deposition, and delivered dose of nebulized aerosols. J Aerosol Med. 2007;20:S66–S77. 107. Harris KW, and Smaldone GC: Facial and ocular deposition of nebulized budesonide: effects of face mask design. Chest. 2008;133:482–488. 108. Amirav I, Shakked T, Broday DM, and Katoshevski D: Numerical investigation of aerosol deposition at the eyes when using a hood inhaler for infants—a 3D simulation. J Aerosol Med Pulm Drug Deliv. 2008;21:207–214. 109. Kim J, Xi J, Si X, Berlinksi A, and Su WC: Hood nebulization: effects of head direction and breathing mode on particle inhalability and deposition in a 7-month-old infant model. J Aerosol Med Pulm Drug Deliv. 2013. [Epub ahead of print] 110. Dailey PA, Walsh K, Fink JB, Harwood R, and Ari A: Aerosol delivery through adult high flow nasal cannula: an in vitro comparison with heliox and oxygen. Baystate Health. Available at: www.aerogen.com/uploads/Publications/ Aerosol%20Delivery%20Through%20Adult%20High%20 Flow%20Nasal%20Cannula%20An%20In%20Invitro%20 Comparison%20with%20Heliox%20and%20Oxygen%202 .pdf. Accessed August 12, 2013. 111. MacLoughlin R, Power P, Wolny M, and Duffy C: Evaluation of vibrating mesh nebulizer performance during nasal high flow therapy. [Abstract only]. P-091. ISAM 19th International Congress. International Society for Aerosols in Medicine, Chapel Hill, NC. April 6–10, 2013. 112. Perry SA, Kesser KC, Geller DE, Selhorst DM, Rendle JK, and Hertzog JH: Influence of cannula size and flow rate on aerosol drug delivery through the Vapotherm humidified high-flow nasal cannula system. Pediatr Crit Care Med. 2013;14:e250–e256. 113. Longest PW, Golshahi L, and Hindle M: Improving pharmaceutical aerosol delivery during noninvasive ventilation:

PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS

114.

115.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

effects of streamlined components. Ann Biomed Eng. 2013;41:1217–1232. Longest PW, Tian G, and Hindle M: Improving the lung delivery of nasally administered aerosols during noninvasive ventilation—an application of enhanced condensational growth (ECG). J Aerosol Med Pulm Drug Deliv. 2011;24:103–118. Golshahi L, Tian G, Azimi M, Son Y-J, Walenga R, Longest PW, and Hindle M: The use of condensational growth methods for efficient drug delivery to the lungs during noninvasive ventilation high flow therapy. Pharm Res. 2013; 30:2917–2930. Everard ML, Devadason SG, and Le Souef: Particle size selection device for use with the Turbohaler. Thorax. 1996; 51:537–539. Bennett DJ, Sievers RE, Cape SP, Best JA, Morin AL, Pelzmann CA, Quinn BP, Rebits LG, Evans S, Threadgill RD, and McAdams DH: The PuffHaler: a simple active DPI with a pressure release valve disperser. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 345–349, 2008. Miller RL, Plourde R, Bovet J-M, Howell KR, and Boyce CM: Designing a novel dry powder inhaler for the delivery of porous nanoparticle aggregate particle (PNAP) vaccines to infants. In: RN Dalby, PR Byron, JP Peart, and JD Suman, (eds). RDD Europe 2007. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 291–294, 2007. Shermer CD, Krayer JD, Chan L, and Powell KG: Development of a disposable dry powder delivery device platform. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 405–408, 2008. Powell KG, Chan L, Shermer CD, and Krayer JD: Environmental effects on the performance of a novel disposable pulmonary delivery device. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 399–403, 2008. Chan L, Shermer CD, Powell KG, and Krayer JD: Spacer considerations in pulmonary delivery to young children. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 395–398, 2008. Laube BL, Sharpless G, Shermer C, Sullivan V, and Powell K: Deposition of dry powder generated by Solovent in Sophia Anatomical Infant Nose-Throat (Saint) model. Aerosol Sci Technol. 2012;46:514–520. Below A, Bickmann D, and Breitkreutz J: Assessing the performance of two dry powder inhalers in preschool children using an idealized pediatric upper airway model. Int J Pharm. 2013;444:169–174. Ehtezazi T, Horsfield MA, Barry PW, Goodenough P, and O’Callaghan C: Effect of device inhalational resistance on the three-dimensional configuration of the upper airway. J Pharm Sci. 2005;94:1418–1426. Bickmann D, Wachtel H, Kro¨ger R, and Langguth P: Examining inhaler performance using a child’s throat model. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 565–569, 2008. Bickmann D: Combining imaging techniques and CFD to model lung deposition in various age classes of the pae-

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

167 diatric population: lung imaging in product development. Boehringer Ingelheim. Available at: www.apsgb.org/ drugsinthelungs2011/10.00_Dr_Deborah_Bickmann.pdf. Accessed May 15, 2013. Wachtel H, Bickmann D, Breitkreutz J, and Langguth P: Can pediatric throat models improve our dose finding strategy? In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2010. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 195–204, 2010. Dalby RN, Doughty D, and Kundoor V: New approaches to nasal spray evaluation: pediatric versus adult actuation profiles and anatomically based spray pattern tests. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2010. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 101–110, 2010. Xi J, Si X, Kim JW, and Berlinski A: Simulation of airflow and aerosol deposition in the nasal cavity of a 5-year-old child. J Aerosol Sci. 2011;42:156–173. International Commission on Radiological Protection: ICRP Publication 66: Human Respiratory Tract Model for Radiological Protection. Permagon Press, Oxford, UK; 1994. Swift DL: Inspiratory inertial deposition of aerosols in human nasal airway replicate casts: implication for the proposed NCRP lung model. Radiat Prot Dosimetry. 1991; 38:29–34. Swift DL, Montassier N, Hopke PK, Karpen-Hayes K, Cheng Y-S, Su YF, Yeh HC, and Strong JC: Inspiratory deposition of ultrafine particles in human nasal replicate cast. J Aerosol Sci. 1992;23:65–72. Cheng Y-S, Smith SM, Yeh H-C, Kim D-B, Cheng H-H, and Swift DL: Deposition of ultrafine aerosols and thoron progeny in replicas of nasal airways of young children. Aerosol Sci Technol. 1995;23:541–552. Golshahi L, Finlay WH, Olfert JS, Thompson RB, and Noga ML: Deposition of inhaled ultrafine aerosols in replicas of nasal airways of infants. Aerosol Sci Technol. 2010;44:741– 752. Storey-Bishoff J, Noga M, and Finlay WH: Deposition of micrometer-sized aerosol particles in infant nasal airway replicas. J Aerosol Sci. 2008;39:1055–1065. Golshahi L, Noga ML, Thompson RB, and Finlay WH: In vitro deposition measurement of inhaled micrometer-sized particles in extrathoracic airways of children and adolescents during nose breathing. J Aerosol Sci. 2011;42:474–488. Golshahi L, Noga ML, and Finlay WH: Deposition of inhaled micrometer-sized particles in oropharyngeal airway replicas of children at constant flow rates. J Aerosol Sci. 2012;49:21–31. Golshahi L, Vehring R, Noga ML, and Finlay WH: In vitro deposition of micrometer-sized particles in the extrathoracic airways of children during tidal oral breathing. J Aerosol Sci. 2013;57:14–21. Zhou Y, Xi J, Simpson J, Irshad H, and Cheng Y-S: Aerosol deposition in a nasopharyngolaryngeal replica of a 5-yearold child. Aerosol Sci Technol. 2013;47:275–282. Zhou Y, Guo M, Xi J, Irshad H, and Cheng Y-S: Nasal deposition in infants and children. J Aerosol Med Pulm Drug Deliv. 2013. [Epub ahead of print] Javaheri E, Golshahi L, and Finlay WH: An idealized geometry that mimics average infant nasal airway deposition. J Aerosol Sci. 2013;55:137–148. Cheng Y-S, Yeh H-C, and Swift DL: Aerosol deposition in human nasal airway for particles 1 nm to 20 lm: a model study. Radiat Prot Dosimetry. 1991;38:41–47.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

168 143. Grgic B, Finlay WH, Burnell PKP, and Heenan AF: In vitro intersubject and intrasubject deposition measurements in realistic mouth-throat geometries. J Aerosol Sci. 2004; 35:1025–1040. 144. Golshahi L, Noga ML, Vehring R, and Finlay WH: An in vitro study on the deposition of micrometer-sized particles in the extrathoracic airways of adults during tidal oral breathing. Ann Biomed Eng. 2013;41:979–989. 145. Garcia GJM, Tewksbury EW, Wong BA, and Kimbell JS: Interindividual variability in nasal filtration as a function of nasal cavity geometry. J Aerosol Med Pulm Drug Deliv. 2009;22:139–155. 146. Martin AR, and Finlay WH: An online calculator for predicting respiratory deposition of inhaled aerosols. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2008. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 801–805, 2008. 147. Finlay WH, Golshahi L, and Noga M: New validated extrathoracic and pulmonary deposition models for infants and children. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2012. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 325–336, 2012. 148. Finlay WH, Golshahi L, Noga M, and Flores-Mir C: Choosing 3-D mouth-throat dimensions: a rational merging of medical imaging and aerodynamics. In: RN Dalby, PR Byron, JP Peart, JD Suman, SJ Farr, and PM Young, (eds). RDD 2010. Davis Healthcare International Publishing, LLC, River Grove, IL; pp. 185–193, 2010. 149. Liu Z, Li A, Xu X, and Gao R: Computational fluid dynamics simulation of airflow patterns and particle deposition characteristics in children upper respiratory tracts. Eng Appl Comput Fluid Mech. 2012;6:556–571. 150. Golshahi L, and Finlay WH: An idealized child throat that mimics average pediatric oropharyngeal deposition. Aerosol Sci Technol. 2012;46:i–iv. 151. Ruzycki CA, Golshahi L, and Finlay WH: Estimating deposition of respiratory aerosols from inhalers in school age children using an idealized child extrathoracic geometry. [Abstract only]. P-105. ISAM 19th International Congress. International Society for Aerosols in Medicine, Chapel Hill, NC. April 6–10, 2013. 152. Byron PR, Hindle M, Lange CF, Longest PW, McRobbie D, Oldham MJ, Olsson B, Thiel CG, Wachtel H, and Finlay WH: In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols. J Aerosol Med Pulm Drug Deliv. 2010;23:S59–S69. 153. Hofmann W: Modeling techniques for inhaled particle deposition: the state of the art. J Aerosol Med. 1996;9:369–388. 154. Martonen TB, Musante CJ, Segal RA, Schroeter JD, Hwang D, Dolovich MA, Burton R, Spencer RM, and Fleming JS: Lung models: strengths and limitations. Respir Care. 2000;45:712–736. 155. Phalen RF, and Oldham MJ: Methods for modeling particle deposition as a function of age. Respir Physiol. 2001;128: 119–130. 156. Hofmann W: Modelling inhaled particle deposition in the human lung—a review. J Aerosol Sci. 2011;42:693–724. 157. Longest PW, and Holbrook LT: In silico models of aerosol delivery to the respiratory tract—development and applications. Adv Drug Deliv Rev. 2012;64:296–311. 158. Isaacs K, Rosati J, and Martonen T: Modeling deposition of inhaled particles. In: LS Ruzer, and NH Harley, (eds). Aerosols Handbook. CRC Press, Boca Raton, FL; pp. 83–128, 2012.

CARRIGY ET AL. 159. Bates DV, Fish BR, Hatch TF, Mercer TT, and Morrow PE: Deposition and retention models for internal dosimetry of the human respiratory tract. Health Phys. 1966;12:173–207. 160. Taulbee DB, and Yu CP: A theory of aerosol deposition in the human respiratory tract. J Appl Physiol. 1975;38:77–85. 161. Yeh HC, and Schum GM: Models of human lung airways and their application to inhaled particle deposition. Bull Math Biol. 1980;42:461–480. 162. Martonen TB: Analytical model of hygroscopic particle behavior in human airways. Bull Math Biol. 1982;44:425– 442. 163. Heyder J, and Rudolf G: Mathematical models of particle deposition in the human respiratory tract. J Aerosol Sci. 1984;15:697–707. 164. Hofmann W, Steinhausler F, and Pohl E: Dose calculations for the respiratory tract from inhaled natural radioactive nuclides as a function of age. I. Compartmental deposition, retention and resulting dose. Health Phys. 1979;37:517–532. 165. Hofmann W: Dose calculations for the respiratory tract from inhaled natural radioactive nuclides as a function of age. II. Basal cell dose distributions and associated lung cancer risk. Health Phys. 1982;43:31–44. 166. Crawford DJ: Identifying critical human subpopulations by age groups: radioactivity and the lung. Phys Med Biol. 1982;27:539–552. 167. Crawford DJ, and Eckerman KF: Modifications of the ICRP task group lung model to reflect age-dependence. Radiat Prot Dosimetry. 1982;2:209–220. 168. Xu GB, and Yu CP: Effects of age on deposition of inhaled aerosols in the human lung. Aerosol Sci Technol. 1986;5:349–357. 169. Yu CP, and Xu GB: Predicted deposition of diesel particles in young humans. J Aerosol Sci. 1987;18:419–429. 170. Hofmann W, Martonen TB, and Graham RC: Predicted deposition of nonhygroscopic aerosols in the human lung as a function of subject age. J Aerosol Med. 1989;2:49–68. 171. Martonen TB, and Zhang Z: Deposition of sulfate acid aerosols in the developing human lung. Inhal Toxicol. 1993;5:165–187. 172. Phalen RF, Oldham MJ, Kleinman MT, and Crocker TT: Tracheobronchial deposition predictions for infants, children and adolescents. Ann Occup Hyg. 1988;32:11–21. 173. Martonen TB, Graham RC, and Hofmann W: Human subject age and activity level: factors addressed in a biomathematical deposition program for extrapolation modeling. Health Phys. 1989;57:49–59. 174. Isaacs KK, and Martonen TB: Particle deposition in children’s lungs: theory and experiment. J Aerosol Med. 2005; 18:337–353. 175. Martonen TB: Mathematical model for the selective deposition of inhaled pharmaceuticals. J Pharm Sci. 1993;82: 1191–1199. 176. Weibel ER: Morphometry of the Human Lung. Academic Press, New York, NY; 1963. 177. Musante CJ, and Martonen TB: Computer simulations of particle deposition in the developing human lung. J Air Waste Manag Assoc. 2000;50:1426–1432. 178. Asgharian B, Me´nache MG, and Miller F: Modeling agerelated particle deposition in humans. J Aerosol Med. 2004;17:213–224. 179. Ginsberg GL, Asgharian B, Kimbell JS, Ultman JS, and Jarabek AM: Modeling approaches for estimating the dosimetry of inhaled toxicants in children. J Toxicol Environ Health A. 2008;71:166–195.

Downloaded by University of Connecticut e-journal package NERL from online.liebertpub.com at 12/26/17. For personal use only.

PEDIATRIC IN VITRO AND IN SILICO DEPOSITION MODELS ´ , Sa´rka´ny Z, Hofmann W, 180. Horva´th A, Bala´sha´zy I, Farkas A Czitrovszky A, and Dobos E: Quantification of airway deposition of intact and fragmented pollens. Int J Environ Health Res. 2011;21:427–440. 181. Koblinger L, and Hofmann W: Analysis of human lung morphometric data for stochastic aerosol deposition calculations. Phys Med Biol. 1985;30:541–556. 182. Koblinger L, and Hofmann W: Monte Carlo modeling of aerosol deposition in human lungs. Part I: Simulation of particle transport in a stochastic lung structure. J Aerosol Sci. 1990;21:661–674. 183. Sturm R: Theoretical models of carcinogenic particle deposition and clearance in children’s lungs. J Thorac Dis. 2012;4:368–376. 184. Finlay WH, and Martin AR: Recent advances in predictive understanding of respiratory tract deposition. J Aerosol Med Pulm Drug Deliv. 2008;21:189–206. 185. Wesseling P: Principles of Computational Fluid Dynamics. Springer, New York, NY; 2001. 186. Ferziger JH, and Peric M: Computational Methods for Fluid Dynamics. Springer, New York, NY; 2002. 187. Versteeg HK, and Malalasekera W: An Introduction to Computational Fluid Dynamics: The Finite Volume Method. Pearson Education, Harlow, UK; 2007. 188. Tu J, Yeoh GH, and Liu C: Computational Fluid Dynamics: A Practical Approach. Butterworth-Heinemann, Burlington, MA; 2007. 189. Casey M, on behalf of the European Research Community on Flow, Turbulence and Combustion: Best Practice Guidelines: version 1.0. ERCOFTAC, Lausanne, Switzerland; 2000. 190. Sommerfeld M: Best Practice Guidelines for Computational Fluid Dynamics of Dispersed Multiphase Flows. ERCOFTAC, Brussels, Belgium; 2008. 191. Kleinstreuer C, Zhang Z, and Li Z: Modeling airflow and particle transport/deposition in pulmonary airways. Respir Physiol Neurobiol. 2008;163:128–138. 192. Wong W, Fletcher DF, Traini D, Chan H-K, and Young PM: The use of computational approaches in inhaler development. Adv Drug Deliv Rev. 2012;64:312–322. 193. Ruzycki CA, Javaheri E, and Finlay WH: The use of computational fluid dynamics in inhaler design. Expert Opin Drug Deliv. 2013;10:307–323. 194. Segal RA, Guan X, Shearer M, and Martonen TB: Mathematical model of airflow in the lungs of children. I: Effects of tumor sizes and locations. J Theor Med. 2000; 2:199–213. 195. Guan X, Segal RA, Shearer M, and Martonen TB: Mathematical model of airflow in the lungs of children. II: Effects of ventilatory parameters. J Theor Med. 2000;3:51–62. 196. Allen GM, Shortall BP, Gemci T, Corcoran TE, and Chigier NA: Computational simulations of airflow in an in vitro model of the pediatric upper airways. J Biomech Eng. 2004;126:604–613. 197. Longest PW, Vinchurkar S, and Martonen T: Transport and deposition of respiratory aerosols in models of childhood asthma. J Aerosol Sci. 2006;37:1234–1257. 198. Longest PW, and Vinchurkar S: Inertial deposition of aerosols in bifurcating models during steady expiratory flow. J Aerosol Sci. 2009;40:370–378.

169

199. Kim CS, Iglesias AJ, and Garcia L: Deposition of inhaled particles in bifurcating airway models: II. Expiratory deposition. J Aerosol Med. 1989;2:15–27. 200. Bala´sha´zy I, and Hofmann W: Particle deposition in airway bifurcations: II. Expiratory flow. J Aerosol Sci. 1993;24:773– 786. 201. Xi J, Kim JW, and Si XA: Ultrafine and fine aerosol deposition in the nasal airways of a 9-month-old girl, a 5-yearold boy and a 53-year-old male. In: MG Tyshenko, (ed). The Continuum of Health Risk Assessments. InTech, New York, NY; pp. 47–72, 2012. 202. Kim JW, Xi J, and Si XA: Dynamic growth and deposition of hygroscopic aerosols in the nasal airway of a 5-year-old child. Int J Numer Method Biomed Eng. 2013;29:17–39. 203. Shakked T, Katoshevski D, Broday DM, and Amirav I: Numerical simulation of air flow and medical-aerosol distribution in an innovative nebulizer hood. J Aerosol Med. 2005;18:207–217. 204. Shakked T, Broday DM, Katoshevski D, and Amirav I: Administration of aerosolized drugs to infants by a hood: a three-dimensional numerical study. J Aerosol Med. 2006;19:533–542. 205. Tian G, Longest PW, Su G, and Hindle M: Characterization of respiratory drug delivery with enhanced condensational growth using an individual path model of the entire tracheobronchial airways. Ann Biomed Eng. 2011;39:1136–1153. 206. Tian G, Longest PW, Su G, Walenga RL, and Hindle M: Development of a stochastic individual path (SIP) model for predicting the tracheobronchial deposition of pharmaceutical aerosols: effects of transient inhalation and sampling the airways. J Aerosol Sci. 2011;42:781–799. 207. Longest PW, Tian G, Walenga RL, and Hindle M: Comparing MDI and DPI aerosol deposition using in vitro experiments and a new stochastic individual path (SIP) model of the conducting airways. Pharm Res. 2012;29:1670–1688. 208. Longest PW, Tian G, Delvadia R, and Hindle M: Development of a stochastic individual path (SIP) model for predicting the deposition of pharmaceutical aerosols: effects of turbulence, polydisperse aerosol size, and evaluation of multiple lung lobes. Aerosol Sci Technol. 2012;46:1271–1285.

Received on July 3, 2013 in final form, August 20, 2013 Reviewed by: Israel Amirav P. Worth Longest Deborah Bickmann Address correspondence to: Dr. Warren H. Finlay Department of Mechanical Engineering University of Alberta Edmonton, Alberta Canada T6H 2Y8 E-mail: [email protected]

Pediatric in vitro and in silico models of deposition via oral and nasal inhalation.

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can b...
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