Pediatric Pulmonology 50:276–283 (2015)
Nasal Versus Oral Aerosol Delivery to the “Lungs” in Infants and Toddlers Israel Amirav, MD,1,2* Azadeh A. T. Borojeni, MSc,2 Asaf Halamish,3 Michael T. Newhouse, MD, MSc, FRCP(C),4 and Laleh Golshahi, PhD5 Summary. Objectives: The oral route has been considered superior to the nasal route for aerosol delivery to the lower respiratory tract (LRT) in adults and children. However, there are no data comparing aerosol delivery via the oral and nasal routes in infants. The aim of this study was to compare nasal and oral delivery of aerosol in anatomically correct replicas of infants’ faces containing both nasal and oral upper airways. Methods: Three CT-derived upper respiratory tract (“URT”) replicas representing infants/toddlers aged 5, 14 and 20 months were studied and aerosol delivery to the “lower respiratory tract” (LRT) by either the oral or nasal route for each of the replicas was measured at the “tracheal” opening. A radio-labeled (99mDTPA) normal saline solution aerosol was generated by a soft-mist inhaler (SMIRespimat1 Boehringer Ingelheim, Germany) and aerosol was delivered via a valved holding chamber (Respichamber1 TMI, London, Canada) and an air-tight mask (Unomedical, Inc., McAllen, TX). A breath simulator was connected to the replicas and an absolute filter at the “tracheal” opening captured the aerosol representing “LRT” dose. Age-appropriate mask dimensions and breathing patterns were employed for each of the airway replicas. Two different tidal volumes (Vt) were used for comparing the nasal versus oral routes. Results: Nasal delivery to the LRTexceeded that of oral delivery in the 5- and 14-month models and was equivalent in the 20-month model. Differences between nasal and oral delivery diminished with “age”/size. Similar findings were observed with lower and higher tidal volumes (Vt). Conclusion: Nasal breathing for aerosol delivery to the “LRT” is similar to, or more efficient than, mouth breathing in infant/toddler models, contrary to what is observed in older children and adults. Pediatr Pulmonol. 2015;50:276–283. ß 2014 Wiley Periodicals, Inc. Key words: aerosol delivery; airway models; pediatric; leak; inhaled dose. Funding source: none reported.
1
Pediatric Department, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. 2
University of Alberta, Edmonton, Alberta, Canada.
3
Technosaf, Karkur, Israel.
4 Firestone Institute for Respiratory Health, St. Joseph’s Hospital, McMaster University, Hamilton, Ontario, Canada. 5
Virginia Commonwealth University, Richmond, Virginia.
Financial Disclosure: Dr. Newhouse is the consulting Chief Medical Officer of InspiRx Inc, developer of the SootherMask1. All other authors have indicated they have no financial relationships relevant to this article to disclose. Conflicts of interest: Israel Amirav and Michael Newhouse have patents rights for devices for delivering aerosols to infants. The other authors have no conflicts of interest relevant to this article to disclose. Contributors’ Statement: Israel Amirav: Dr. Amirav conceptualized and designed the study, carried out the data analyses, drafted the initial manuscript, and approved the final manuscript as submitted. Azadeh A. T. Borojeni: Measured the pressure drop and airway “dead volume” of the models. Asaf Halamish: Mr. Halamish designed the data collection system, and coordinated and supervised data collection, critically reviewed the
ß 2014 Wiley Periodicals, Inc.
manuscript, and approved the final manuscript as submitted. Michael T. Newhouse: Dr. Newhouse conceptualized and designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted. Laleh Golshahi: Dr. Golshahi carried out the statistical analyses, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr Amirav wrote the first draft of the manuscript. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. What’s known on This Subject: For aerosol delivery to the LRT, the oral route has been considered superior due to greater nasal resistance. Evidence exists to support this notion in adults and children. However, no data comparing these routes exist for infants. What This Study Adds: Nasal aerosol delivery may be superior to oral delivery in infants/toddlers, in contrast to older children and adults.
Correspondence to: Dr Israel Amirav, MD, Respiratory Medicine, Department of Pediatrics, University of Alberta, 4-527 Edmonton Clinic Health Academy (ECHA), 11405 87 Avenue, Edmonton AB T6G 1C9, Canada. E-mail: [email protected] Received 31 August 2013; Accepted 5 January 2014. DOI 10.1002/ppul.22999 Published online 31 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
Nasal vs. Oral Aerosol Delivery to Infants
INTRODUCTION
Aerosol delivery to the “LRT” is commonly used in children for various indications (e.g., asthma) and can be accomplished using either the oral or nasal route. The oral route has long been considered superior and more effective due to greater nasal turbulence and resistance. This has been particularly emphasized in children older than 3 years of age who can use a mouthpiece. Some evidence exists to support this notion in adults and children. Chua et al.1 have shown that if the “URT” aerodynamic filter is bypassed by aerosol inhalation through the mouth, delivery of medication to the lungs of children (>6 years of age) is two- to three-fold greater. Bennett et al.2 have shown that compared to adults, the nasal component of breathing both during rest and exercise in children aged 6–10 years was slightly lower. They also showed less efficient nasal filtering for large particles and higher flow in these children compared to adults.2 While oral delivery of aerosol therapy has therefore become the standard for adults and older children, there are no data to determine the optimal route of administration in infants and toddlers. Furthermore, there are no studies comparing nasal and oral inhalation by means of face masks in these children. In particular, there are few data that describe LRT aerosol deposition in suckling and thus nasal-breathing infants. This is partly due to a common assumption that infants younger than 18 months are obligate nasal breathers; however, there are studies, showing that newborn infants may use oral breathing spontaneously or in response to nasal occlusion.3 In vivo determination of LRT aerosol delivery in infants is difficult due to compliance and safety concerns. A commonly used approach has therefore been the use of anatomically derived airway models of infants.4–9 Given that, in children, nasal airway cross sections do not change noticeably during the breathing cycle,10 creating CTderived images of such airway models is an alternative that avoids the complexities of subject recruitment and in vivo studies in infants and toddlers. Recently, anatomically appropriate URT model studies comparing LRT aerosol delivery via nasal and oral “inhalation” in age groups from 4 to 14 were undertaken by Golshahi et al.11–14 However, none of the existing models has been used to compare “LRT” aerosol delivery by the nasal and oral route in infants and toddlers. Infants breathe at lower tidal volumes (Vt), depending on their activity level,15,16 and this may influence LRT aerosol
ABBREVIATIONS: CT Computed tomography LRT Lower respiratory tract URT Upper respiratory tract
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delivery by either route. Furthermore, URT and LRT anatomical differences in infant airways may also be relevant. The aim of this study was to compare, using various tidal volumes (Vt), nasal versus oral delivery of aerosol passing through replicas of infants’ faces containing both nasal and oral upper airways to the level of the “tracheal orifice.” The dose obtained at the “tracheal orifice” being assumed to represent the dose that would be delivered to the “LRT.” METHODS In Vitro Aerosol Delivery; Experimental Design
Aerosol was delivered to three infant models representing the “URT” of infants aged 5 (small), 14 (medium), and 20 (large) months. Each of the models was “linked” to the “URT” via either the oral or the nasal route and a RespiChamber VHC, connected to a the tightly-fitting face mask. A breathing simulator (Harvard Pump, South Natick, MA) was programmed to appropriately mimic the breathing patterns of the infants. By labeling aerosol with 99m technetium (99mTc) and collecting the aerosol at the “tracheal orifice” using bacterial filters (Pari GMBH, Munich, Germany), the delivered dose was quantified for each case study using either the nasal airway (with oral opening occluded) or the oral airway (with nasal openings occluded). The system setup is depicted in Figure 1. Face and URT Models
We quantified aerosol deposition to the LRT in the three face and upper airway models, which were created from CT scans of the URT and LRT to the level of the tracheal orifice. Models were fabricated using previously established methods.5,7 In brief, CT scans were obtained for medical indications in individual infants aged 5 (small), 14 (medium), and 20 (large) months with no craniofacial anomalies. The scans were reconstructed and stored in stereolithography (STL) format from which each model was then printed using rapid prototype development techniques. Both the nasal and oral airways were reproduced in these replicas. For “oral” aerosol delivery, the “nostrils” were sealed with putty. For nasal administration putty sealed the “mouth.” Aerosol Generation
Aerosol was generated by a Respimat1 soft mist inhaler (SMI). This aerosol generator is powered by compressed air using a spring-driven piston within an 8 ml canister in which ambient air is compressed to produce a metered dose output of 15 ml. The Respimat SMI was chosen because the medication solution is contained in a readily accessible, removable plastic canister that Pediatric Pulmonology
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Fig. 1. In vitro aerosol delivery setup.
facilitates radiolabelling with 99mTc and produces an aerosol of an aerodynamic “size” at the mouthpiece/mask similar to that of many current pressurized metered dose inhalers attached to valved holding chambers. For each trial, the SMI canister was filled with 4.0 ml of 99m Tclabeled normal saline with a total activity of 31,400 microcuries (mCi). Two “puffs” from the Respimat were fired into the VHC for each run. Each puff was separated by a 30 sec interval during the infant’s tidal breathing. Aerosol Delivery Interfaces
Respimat-generated aerosol was delivered through a RespiChamber static-reduced VHC equipped with an “anesthesia“mask (Unomedical, Inc., McAllen, TX). These masks have an air cushion and were selected to ensure an optimal and reproducible seal. An infant mask (# 585U-E) was used for the small model whereas a child mask (# 586U-E) was used for the other two models. Masks completely sealed around both the nasal and oral openings. Breathing Waveforms
A computer-operated breathing simulator (Harvard Pump) generated a standard waveform at a pre-set frequency (f) and tidal volume (Vt) appropriate for the “size” of the “infant” (i.e., small, medium, and large). Two tidal volumes (Vt) (high and low) were used for each study: Pediatric Pulmonology
(1) Small: Vt ¼ 50 or 80 ml at 40 breaths/min; (2) Medium: Vt ¼ 50 or 80 ml at 40 breaths/min; (3) Large: Vt ¼ 80 or 120 ml at 30 breaths/min; The Vt and f was chosen based upon age-appropriate values reported in the recent literature.17,18 The breathing patterns were generated by the breathing simulator at the inlet of the face and URT models. The breathing frequency is not affected by the site of the evaluation and the same breathing frequency is expected at the entrance of the aerosol stream into the models. However, the tidal volume changes with the pressure drop across the models. Additionally, the volume of the models’ airways, so-called “dead volume,” is also useful in predicting the fate of the inhaled aerosol in terms of reaching the collection filter at the ‘tracheal’ orifice. Trans-nasal and trans–oral pressure drops were measured (in triplicate) by a low range (0–2 inches of water) digital manometer (HHP 103, Omega Engineering, Inc., Stamford, CT). The pressure tap was positioned in the tubing that connected the outlet of the models to a vacuum pump. The flow of 4 and 6.4 L/min, which is the average flow corresponding to 50 and 80 ml tidal volumes, 40 breaths/min, and a duty cycle (inspiratory time/total breathing period) of 0.5 was generated by the vacuum pump through the small and medium models. The average flow through the large model was 4.8 and 7.2 L/
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Fig. 2. Images of the in vitro small infant model in STL format.
min, based on tidal volumes of 80 and 120 ml at a respiratory rate of 30 breaths/min. The “dead volume” of the models, that is the volume of the air path (nasal vs oral) in the models was also measured using the corresponding STL files in conjunction with SolidWorks (Education Edition, Dassault Systemes, Waltham, MA) software. Figure 2 shows an example of these files. A duty cycle of 0.5 was considered. However, the relative differences between nasal and oral deposition are expected to be valid for other duty cycles since the differences are proportional to the average flow through the models. A digital mass flow meter (Model 4140, TSI, Inc., St. Paul, MN) was placed between the breath simulator and the model. Actual values of breaths/min and tidal volume for each test were measured by analyzing recorded flow patterns versus time, given that the tidal volume is the area under the curve.
the average radioactive dose was taken as the emitted dose. Aerosol Delivery Measurements
Radiolabeled aerosol was delivered during four runs with each of the three models via the two routes. Thus, 12 runs were carried out by each of the nasal and oral routes. Studies were repeated for two Vt for a total of 48 runs. The breathing simulator ran continuously at the preset variables. For each run, the Respimat mouthpiece was inserted into the back of the VHC and the mask was tightly sealed to the surface of the “face.” Two successive puffs of aerosol, separated by a 30 sec interval, were discharged into the VHC and “tidal breathing” continued for 30 sec. This period of time, spanning 15–20 breaths, ensured complete evacuation of the aerosol from the VHC.19 The mask was then removed from the “face.” Evaluation of Aerosol Deposition
Evaluation of the Respimat Emitted Dose
Prior to the study with the URT models, total emitted dose from the Respimat was determined by means of a filter tightly affixed to the orifice of the device. After two successive emitted doses total radioactivity was measured using a dose calibrator (Capintec, Inc., Ramsey, NJ). The emitted dose was quantified by measuring the number of microcuries of technetium at the outlet of the Respimat SMI following two successive puffs. Radioactivity was measured by two techniques. 1. Radioactivity in the SMI reservoir was measured with the dose calibrator both before and immediately after firing two puffs. 2. Radioactivity in the filter that covered the outlet of the MDI was also determined by the dose calibrator. The two techniques were employed for five runs each and
Aerosol was captured on an absolute non-absorbent filter (Pari GMBH) covering the tracheal opening (representing “LRT” deposition). The drug dose in the filter was quantified by means of a dose calibrator (Capintec, Inc.) and expressed as percent of the emitted dose. The dose measured was corrected for decay. The standard deviation is shown as the error bars in the Figures. Statistical Analysis
Two-way ANOVA followed by Tukey HSD post hoc test for the size of the model (i.e., small, medium, and large) and the student t-test post hoc for the difference between nasal and oral routes were performed to compare the filter’s radiolabelled aerosol deposition for each tidal volume. In case of interaction between the variables (age Pediatric Pulmonology
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and route of delivery) the reported P-values are the results of a Tukey HSD post hoc including the full factorial effects of both variables instead of each individual effect. All statistical tests were performed using JMP1 Pro 10.0.2, (Cary, NC), with a P-value of 0.05). This again emphasizes the reduction in the difference in lung dose delivered by the nasal compared with the oral route with increasing age. The trans-nasal and trans-oral pressure drop values across the three in vitro infant models are given in Table 1. Both trans-nasal and trans-oral pressure drop decreased with increasing age. The trans-nasal pressure drop values were significantly (P < 0.05) lower than the trans-oral for the small and medium models with all flow velocities and were comparable (P > 0.05) between nasal and oral airways in the large model (Table 1). The dead space volume of the nasal and oral airways in the models were, respectively: “nasal” versus “oral”: 9.27 and 7.12, (P > 0.05) ml for the small model, 10.31 and 10.96 (P > 0.05) ml for the medium model, and 26.80 and 16.45, (P < 0.05) ml for the large model. These dead space volumes were not related to the filter deposition doses in any of the test combinations.
TABLE 1— Mean (Standard Deviation) of Trans-Nasal/Oral Pressure Drop Across the Three In Vitro Infant Models
Fig. 3. Lung doses as a percentage of the emitted dose delivered through the nasal and oral airways of the three small, medium, and large replicas during simulation of the breathing waveforms at low (a) and high (b) tidal volumes. Asterisk indicating significantly higher nasal delivery compared to oral delivery, t-test, P < 0.05.
Pediatric Pulmonology
Name of model
Flow rate (L/min)
Small
6.4 4 6.4 4 7.2 4.8
Medium Large
Trans-nasal pressure drop (Pa) 31.52 15.50 30.31 18.58 9.22 4.68
(1.03) (0.58) (1.95) (1.23) (0.16) (0.16)
Trans-oral pressure drop (Pa) 61.13 28.32 50.46 23.76 9.26 4.88
(3.14) (2.21) (1.30) (1.48) (0.07) (0.10)
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DISCUSSION
In our in vitro model simulation of the URT and LRT, nasal aerosol delivery to the LRT exceeded that of oral aerosol delivery in infants and toddlers younger than 20 months of age, in contrast to that seen in older children and adults.20–22 This in vitro study suggests that in infants up to the age of about 18 months, nasal breathing of aerosolized medication would result in better lung delivery compared to oral breathing. Previous studies in older children have demonstrated that the nasal airway has the highest resistance and turbulence in the respiratory tract as well as very efficient aerodynamic filtration as reflected in the relatively high Reynolds number.23 Thus, it is reasonable to assume that nasal breathing would be inferior to oral breathing with regard to targeting aerosols to the LRT. In line with this assumption, Chua et al.1 demonstrated that children (6 years of age and above) have significantly greater LRT aerosol delivery when they breathe through the mouth. In recent pediatric guidelines it is also recommended that aerosol treatment should, as much as possible, be through the mouth and not through the nose. For instance, Levin24 suggests that patients breathe slowly and deeply through the mouth instead of the nose, regardless of the use of a mask or a mouthpiece, a suggestion that could not be implemented in tidal breathing infants and toddlers as well as many children to age 3–4. However, for aerosol delivery in infants, these routes of aerosol administration have not been compared previously. In view of the previous results in older children, the outcome of the present study was somewhat unexpected and again emphasizes the fact that “infants are not merely small adults.” The mechanism by which nasal delivery is greater than oral in these URT model simulations of infants and toddlers is not fully understood. However, we can speculate that it may be related to the anatomical differences in the URT between oral and nasal airways of infants and older children compared to adults as shown in Figure 4. As Figure 4 shows, the oro-pharyngeal passages in infants appear somewhat more convoluted than the nasopharyngeal airways. This may explain why oral inhalation might result in relatively high local airflow velocity and turbulence, which in turn could result in greater URT particle impaction and consequently reduced LRT aerosol deposition. The narrower the airways the greater the flow velocity and friction and consequently the resulting URT pressure drop.25 Thus, the smaller cross sectional diameter of the airways in the young infants is associated with greater pressure drop compared to the older children. This is in line with our in vitro pressure drop measurements (Table 1), showing significantly greater trans-oral compared to trans-nasal pressure drops in the small and medium models, which, in turn, supports the greater aerosol delivery through the nose in these age groups. Furthermore, a close look at the URT cross
Fig. 4. Comparison of the upper airways of adults (on the left) with the similar regions in infants (on the right). (A) pharynx and supraglottic region: less rigid; (B) epiglottis: narrow, floppy and closer to palate; (C) larynx: higher and very close to the base of the tongue. Reprinted with permission from Ref.26
sections (Figure 4) indicates that in the infant, not only are the turbinates rudimentary, providing a relatively larger and smoother nasal airway,26 but in addition it appears that the naso-pharyngeal angle is much less acute than in the adult. The difference favoring nasal breathing was most apparent in the “youngest” infant model, and progressively diminishes with age. Per-oral and per-nasal “LRT” deposition becomes similar in the large model representing a child aged 20 months. Interestingly, this is approximately the age at which most small children stop suckling and go from “obligate”/preferential nasal to oral breathing. The change to equivalent LRT aerosol delivery via the “nasal airway” at 20 months, although arbitrary in our study, is of considerable interest and needs to be confirmed in vivo. It is certainly possible that this coincides with the stage of respiratory tract development, where oral inhalation supercedes nasal as the preferential mode of breathing in infants due to the lower resistance of the oral over the nasal route. The mechanism by which this occurs is not well understood, yet the results of our study appear to coincide with this previously described trend in children aged above about 18 months.6,27,28 The average “tracheal orifice” filter dose in the present study is greater than reported in previous in vitro studies5,29 utilizing infant airway models and pMDIs. We attribute this to the highly effective mask to face seal achieved using anesthesia masks with air cushions combined with a non electrostatic chamber, as well as, perhaps, to the soft-mist aerosol produced by the inhaler used in this study resulting in reduced impaction of aerosol within the VHC and thus greater targeting to the LRT. From a clinical perspective, dosage recommendations with different inhalers may vary and additional pharmacokinetic studies may be required to address these issues. Pediatric Pulmonology
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We acknowledge the limitations of our study. The models used were rigid models constructed from the CT scans of single relatively healthy children at each age, that may not be entirely representative of that age group. They may also fail to account for physiological variations in the diameter and volume of the airways with respiration. On the other hand it is known that, at least with respect to the nasal airways, the respiration-related variation in diameter and volume are negligible The fact that the scans were obtained during quiet tidal breathing lends support to this idea. Additionally, the aerosol produced by the Respimat device produces aerosol clouds that are ejected with a lower velocity than pMDIs, are more prolonged and contain, on average, smaller particles than those produced by pMDIs,30 Thus, our results may be limited to this delivery device or quality of aerosol. However, since infants in this age range almost always inhale medication from valved holding chambers that function as aerosol reservoirs rather than directly from a pMDI, these limitations may be clinically less relevant under “real life” conditions. Chua et al.1 noted that no radiolabeled aerosol was found in the oral airways of tidal breathing infants aged 0.3–1.4 years, strongly supporting the concept that infants are preferential nose-breathers; an activity that would stand them in good stead while suckling. Ideally, the results of this study should be confirmed in vivo. However, such a study would be almost impossible to carry out because of the natural preference of the majority of infants to breathe nasally most of the time as noted by Chua et al.1 The results of the present study are clinically important despite the fact that most infants and toddlers are generally preferential nasal breathers,31,32 and are unlikely to breathe orally unless they are crying, breathless due to lung or airway disease, hypoxemia, hypercapnia or have an obstructed nasal airway. The fact that in the upper airway infant models used in this study, the nasally inhaled aerosol dose targeted to the “LRT” equaled or exceeded that of oral inhalation, should be somewhat reassuring to pediatricians and infants’ caregivers since they can be reasonably confident that, at least up to about 20 months of age, a similar aerosol dose inhaled nasally is likely to be as effective as if it were inhaled orally. The results of the present study, as well as our recent scintigraphic deposition study in infants under age 12 months,33 confirm that, also in vivo, infants can use a pacifier or feed while receiving inhaled treatments with no decrease in drug delivery to the lungs. In conclusion, contrary to what is observed in older children and adults, the present study suggests that nasal breathing for aerosol delivery to the LRT is as or more efficient than mouth breathing in infants/toddlers. Pediatric Pulmonology
REFERENCES 1. Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD, Le Souef PN. The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J 1994;7:2185–2191. 2. Bennett WD, Zeman KL, Jarabek AM. Nasal contribution to breathing and fine particle deposition in children versus adults. J Toxicol Environ Health A 2008;71:227–237. 3. Miller MJ, Martin RJ, Carlo WA, Fouke JM, Strohl KP, Fanaroff AA. Oral breathing in newborn infants. J Pediatr 1985;107:465–469. 4. Cheng YS, Smith SM, Yeh HC, Kim DB, Cheng KH, Swift DL. Deposition of ultrafine aerosols and thoron progeny in replicas of nasal airways of young children. Aerosol Sci Technol 1995;23: 541–552. 5. Janssens HM, De Jongste JC, Fokkens WJ, Robben SGF, Wouters K, 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. 6. Swift PGF, Emery JL. Clinical observations on response to nasal occlusion in infancy. Arch Dis Child 1973;48:947–951. 7. Minocchieri S, Burren JM, Bachmann MA, Stern G, Wildhaber J, Buob S, Schindel R, Kraemer R, Frey UP, Nelle M. Development of the premature neonate for the study of aerosol delivery. Pediatr Res 2008;64:141–146. 8. Storey-Bishoff J, Noga M, Finlay WH. Deposition of micrometersized aerosol particles in infant nasal airway replicas. J Aerosol Sci 2008;39:1055–1065. 9. Javaheri E, Golshahi L, Finlay WH. An idealized geometry that mimics average infant nasal airway deposition. J Aerosol Sci 2013;55:137–148. 10. Arens R, Sin S, McDonough JM, Palmer JM, Dominguez T, Meyer H, Wootton DM, Pack AI. Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2005;171:1298–1304. 11. Golshahi L, Noga ML, Thompson RB, 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. 12. Golshahi L, Noga ML, 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. 13. Golshahi L, Vehring R, Noga ML, 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. 14. Finlay WH, Golshahi L, Noga M. New validated extrathoracic and pulmonary deposition models for infants and children. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, editors. Respiratory Drug Delivery 2012. May 13–17, Scottsdale, Arizona. River Grove, IL: Davis Healthcare Int’l Publishing; 2012. pp 325–334. 15. Janssens HM, Van der Wiel EC, Verbraak AFM, de Jongste JC, Merkus PJFM, Tiddens HAWM. Aerosol therapy and the fighting toddler: is administration during sleep an alternative? J Aerosol Med 2003;16:395–400. 16. Bergeson PS, Shaw JC. Are infants really obligatory nasal breathers? Clin Pediatr 2001;10:567–569. 17. Fleming S, Thompson M, Stevens R, Heneghan C, Plu¨ddemann A, Maconochie I, Tarassenko L, Mant D. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet 2011;377: 1011–1018. 18. Stick S. Measurements during tidal breathing. In: S J, Sly P, Tepper R, Morgan W, editors. Infant respiratory function testing. New York, NY: Wiley-Liss; 1996. p 134. 19. Schultz A, Le Soue¨f TJ, Venter A, Zhang G, Devadason SG, Le Soue¨f PN. Aerosol inhalation from spacers and valved holding
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chambers requires few tidal breaths for children. Pediatrics 2010;126:e1493–e1498. Everard ML, Hardy JG, Milner AD. Comparison of nebulised aerosol deposition in the lungs of healthy adults following oral and nasal inhalation. Thorax 1993;48:1045–1046. Schwab JA, Zenkel M. Filtration of particulates in the human nose. Laryngoscope 1998;108:120–124. Becquemin MH, Swift DL, Bouchikhi A, Roy M, Teillac A. Particle deposition and resistance in the noses of adults and children. Eur Respir 1991;4:694–702. Wang DY, Lee HP, Gordon BR. Impacts of fluid dynamic simulation in study of nasal airflow physiology in realistic human three-dimensional nose models. Clin Exp Otorhinolaryngol 2012;5:181–187. Levin ME. Optimal aerosol delivery. Curr Allergy Clin Immunol 2011;24:27–30. White FM. Fluid mechanics, 4th edition. Boston, MA: McGrawHill; 1999. Amirav I, Newhouse MT. Deposition of small particles in the developing lung. Pediatr Resp Rev 2012;13:73–78.
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27. Polgar G, Kong GP. The nasal resistance of newborn infants. J Pediatr 1965;67:557–567. 28. Nathan CA, Seid AB. Neonatal rhinitis. Int J Pediatr Otorhinolaryngol 1997;39:59–65. 29. Janssens HM, Krijgsman A, Verbraak TFM, Hop WCJ, de Jongste JC, 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. 30. Hochrainer D, Holz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. Comparison of the aerosol velocity and spray duration of Respimat soft mist inhaler and pressurized metered dose inhaler. J Aerosol Med 2005;18:273–282. 31. Moss ML. The veloepiglottic sphincter and obligate. Nose breathing in the neonate. J Pediatr 1965;67:330–333. 32. Sasaki CT, Levine PA, Laitman JT, Crelin ES, Jr. Postnatal descent of the epiglottis in man. A preliminary report. Arch Otolaryngol 1977;103:169–171. 33. Amirav I, Luder A, Chleechel A, Newhouse MT, Gorenberg M. Lung aerosol deposition in suckling infants. Arch Dis Child 2012;97:497–501.
Pediatric Pulmonology
Nasal Versus Oral Aerosol Delivery to the “Lungs” in Infants and Toddlers Israel Amirav, MD,1,2* Azadeh A. T. Borojeni, MSc,2 Asaf Halamish,3 Michael T. Newhouse, MD, MSc, FRCP(C),4 and Laleh Golshahi, PhD5 Summary. Objectives: The oral route has been considered superior to the nasal route for aerosol delivery to the lower respiratory tract (LRT) in adults and children. However, there are no data comparing aerosol delivery via the oral and nasal routes in infants. The aim of this study was to compare nasal and oral delivery of aerosol in anatomically correct replicas of infants’ faces containing both nasal and oral upper airways. Methods: Three CT-derived upper respiratory tract (“URT”) replicas representing infants/toddlers aged 5, 14 and 20 months were studied and aerosol delivery to the “lower respiratory tract” (LRT) by either the oral or nasal route for each of the replicas was measured at the “tracheal” opening. A radio-labeled (99mDTPA) normal saline solution aerosol was generated by a soft-mist inhaler (SMIRespimat1 Boehringer Ingelheim, Germany) and aerosol was delivered via a valved holding chamber (Respichamber1 TMI, London, Canada) and an air-tight mask (Unomedical, Inc., McAllen, TX). A breath simulator was connected to the replicas and an absolute filter at the “tracheal” opening captured the aerosol representing “LRT” dose. Age-appropriate mask dimensions and breathing patterns were employed for each of the airway replicas. Two different tidal volumes (Vt) were used for comparing the nasal versus oral routes. Results: Nasal delivery to the LRTexceeded that of oral delivery in the 5- and 14-month models and was equivalent in the 20-month model. Differences between nasal and oral delivery diminished with “age”/size. Similar findings were observed with lower and higher tidal volumes (Vt). Conclusion: Nasal breathing for aerosol delivery to the “LRT” is similar to, or more efficient than, mouth breathing in infant/toddler models, contrary to what is observed in older children and adults. Pediatr Pulmonol. 2015;50:276–283. ß 2014 Wiley Periodicals, Inc. Key words: aerosol delivery; airway models; pediatric; leak; inhaled dose. Funding source: none reported.
1
Pediatric Department, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. 2
University of Alberta, Edmonton, Alberta, Canada.
3
Technosaf, Karkur, Israel.
4 Firestone Institute for Respiratory Health, St. Joseph’s Hospital, McMaster University, Hamilton, Ontario, Canada. 5
Virginia Commonwealth University, Richmond, Virginia.
Financial Disclosure: Dr. Newhouse is the consulting Chief Medical Officer of InspiRx Inc, developer of the SootherMask1. All other authors have indicated they have no financial relationships relevant to this article to disclose. Conflicts of interest: Israel Amirav and Michael Newhouse have patents rights for devices for delivering aerosols to infants. The other authors have no conflicts of interest relevant to this article to disclose. Contributors’ Statement: Israel Amirav: Dr. Amirav conceptualized and designed the study, carried out the data analyses, drafted the initial manuscript, and approved the final manuscript as submitted. Azadeh A. T. Borojeni: Measured the pressure drop and airway “dead volume” of the models. Asaf Halamish: Mr. Halamish designed the data collection system, and coordinated and supervised data collection, critically reviewed the
ß 2014 Wiley Periodicals, Inc.
manuscript, and approved the final manuscript as submitted. Michael T. Newhouse: Dr. Newhouse conceptualized and designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted. Laleh Golshahi: Dr. Golshahi carried out the statistical analyses, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr Amirav wrote the first draft of the manuscript. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. What’s known on This Subject: For aerosol delivery to the LRT, the oral route has been considered superior due to greater nasal resistance. Evidence exists to support this notion in adults and children. However, no data comparing these routes exist for infants. What This Study Adds: Nasal aerosol delivery may be superior to oral delivery in infants/toddlers, in contrast to older children and adults.
Correspondence to: Dr Israel Amirav, MD, Respiratory Medicine, Department of Pediatrics, University of Alberta, 4-527 Edmonton Clinic Health Academy (ECHA), 11405 87 Avenue, Edmonton AB T6G 1C9, Canada. E-mail: [email protected] Received 31 August 2013; Accepted 5 January 2014. DOI 10.1002/ppul.22999 Published online 31 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
Nasal vs. Oral Aerosol Delivery to Infants
INTRODUCTION
Aerosol delivery to the “LRT” is commonly used in children for various indications (e.g., asthma) and can be accomplished using either the oral or nasal route. The oral route has long been considered superior and more effective due to greater nasal turbulence and resistance. This has been particularly emphasized in children older than 3 years of age who can use a mouthpiece. Some evidence exists to support this notion in adults and children. Chua et al.1 have shown that if the “URT” aerodynamic filter is bypassed by aerosol inhalation through the mouth, delivery of medication to the lungs of children (>6 years of age) is two- to three-fold greater. Bennett et al.2 have shown that compared to adults, the nasal component of breathing both during rest and exercise in children aged 6–10 years was slightly lower. They also showed less efficient nasal filtering for large particles and higher flow in these children compared to adults.2 While oral delivery of aerosol therapy has therefore become the standard for adults and older children, there are no data to determine the optimal route of administration in infants and toddlers. Furthermore, there are no studies comparing nasal and oral inhalation by means of face masks in these children. In particular, there are few data that describe LRT aerosol deposition in suckling and thus nasal-breathing infants. This is partly due to a common assumption that infants younger than 18 months are obligate nasal breathers; however, there are studies, showing that newborn infants may use oral breathing spontaneously or in response to nasal occlusion.3 In vivo determination of LRT aerosol delivery in infants is difficult due to compliance and safety concerns. A commonly used approach has therefore been the use of anatomically derived airway models of infants.4–9 Given that, in children, nasal airway cross sections do not change noticeably during the breathing cycle,10 creating CTderived images of such airway models is an alternative that avoids the complexities of subject recruitment and in vivo studies in infants and toddlers. Recently, anatomically appropriate URT model studies comparing LRT aerosol delivery via nasal and oral “inhalation” in age groups from 4 to 14 were undertaken by Golshahi et al.11–14 However, none of the existing models has been used to compare “LRT” aerosol delivery by the nasal and oral route in infants and toddlers. Infants breathe at lower tidal volumes (Vt), depending on their activity level,15,16 and this may influence LRT aerosol
ABBREVIATIONS: CT Computed tomography LRT Lower respiratory tract URT Upper respiratory tract
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delivery by either route. Furthermore, URT and LRT anatomical differences in infant airways may also be relevant. The aim of this study was to compare, using various tidal volumes (Vt), nasal versus oral delivery of aerosol passing through replicas of infants’ faces containing both nasal and oral upper airways to the level of the “tracheal orifice.” The dose obtained at the “tracheal orifice” being assumed to represent the dose that would be delivered to the “LRT.” METHODS In Vitro Aerosol Delivery; Experimental Design
Aerosol was delivered to three infant models representing the “URT” of infants aged 5 (small), 14 (medium), and 20 (large) months. Each of the models was “linked” to the “URT” via either the oral or the nasal route and a RespiChamber VHC, connected to a the tightly-fitting face mask. A breathing simulator (Harvard Pump, South Natick, MA) was programmed to appropriately mimic the breathing patterns of the infants. By labeling aerosol with 99m technetium (99mTc) and collecting the aerosol at the “tracheal orifice” using bacterial filters (Pari GMBH, Munich, Germany), the delivered dose was quantified for each case study using either the nasal airway (with oral opening occluded) or the oral airway (with nasal openings occluded). The system setup is depicted in Figure 1. Face and URT Models
We quantified aerosol deposition to the LRT in the three face and upper airway models, which were created from CT scans of the URT and LRT to the level of the tracheal orifice. Models were fabricated using previously established methods.5,7 In brief, CT scans were obtained for medical indications in individual infants aged 5 (small), 14 (medium), and 20 (large) months with no craniofacial anomalies. The scans were reconstructed and stored in stereolithography (STL) format from which each model was then printed using rapid prototype development techniques. Both the nasal and oral airways were reproduced in these replicas. For “oral” aerosol delivery, the “nostrils” were sealed with putty. For nasal administration putty sealed the “mouth.” Aerosol Generation
Aerosol was generated by a Respimat1 soft mist inhaler (SMI). This aerosol generator is powered by compressed air using a spring-driven piston within an 8 ml canister in which ambient air is compressed to produce a metered dose output of 15 ml. The Respimat SMI was chosen because the medication solution is contained in a readily accessible, removable plastic canister that Pediatric Pulmonology
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Fig. 1. In vitro aerosol delivery setup.
facilitates radiolabelling with 99mTc and produces an aerosol of an aerodynamic “size” at the mouthpiece/mask similar to that of many current pressurized metered dose inhalers attached to valved holding chambers. For each trial, the SMI canister was filled with 4.0 ml of 99m Tclabeled normal saline with a total activity of 31,400 microcuries (mCi). Two “puffs” from the Respimat were fired into the VHC for each run. Each puff was separated by a 30 sec interval during the infant’s tidal breathing. Aerosol Delivery Interfaces
Respimat-generated aerosol was delivered through a RespiChamber static-reduced VHC equipped with an “anesthesia“mask (Unomedical, Inc., McAllen, TX). These masks have an air cushion and were selected to ensure an optimal and reproducible seal. An infant mask (# 585U-E) was used for the small model whereas a child mask (# 586U-E) was used for the other two models. Masks completely sealed around both the nasal and oral openings. Breathing Waveforms
A computer-operated breathing simulator (Harvard Pump) generated a standard waveform at a pre-set frequency (f) and tidal volume (Vt) appropriate for the “size” of the “infant” (i.e., small, medium, and large). Two tidal volumes (Vt) (high and low) were used for each study: Pediatric Pulmonology
(1) Small: Vt ¼ 50 or 80 ml at 40 breaths/min; (2) Medium: Vt ¼ 50 or 80 ml at 40 breaths/min; (3) Large: Vt ¼ 80 or 120 ml at 30 breaths/min; The Vt and f was chosen based upon age-appropriate values reported in the recent literature.17,18 The breathing patterns were generated by the breathing simulator at the inlet of the face and URT models. The breathing frequency is not affected by the site of the evaluation and the same breathing frequency is expected at the entrance of the aerosol stream into the models. However, the tidal volume changes with the pressure drop across the models. Additionally, the volume of the models’ airways, so-called “dead volume,” is also useful in predicting the fate of the inhaled aerosol in terms of reaching the collection filter at the ‘tracheal’ orifice. Trans-nasal and trans–oral pressure drops were measured (in triplicate) by a low range (0–2 inches of water) digital manometer (HHP 103, Omega Engineering, Inc., Stamford, CT). The pressure tap was positioned in the tubing that connected the outlet of the models to a vacuum pump. The flow of 4 and 6.4 L/min, which is the average flow corresponding to 50 and 80 ml tidal volumes, 40 breaths/min, and a duty cycle (inspiratory time/total breathing period) of 0.5 was generated by the vacuum pump through the small and medium models. The average flow through the large model was 4.8 and 7.2 L/
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Fig. 2. Images of the in vitro small infant model in STL format.
min, based on tidal volumes of 80 and 120 ml at a respiratory rate of 30 breaths/min. The “dead volume” of the models, that is the volume of the air path (nasal vs oral) in the models was also measured using the corresponding STL files in conjunction with SolidWorks (Education Edition, Dassault Systemes, Waltham, MA) software. Figure 2 shows an example of these files. A duty cycle of 0.5 was considered. However, the relative differences between nasal and oral deposition are expected to be valid for other duty cycles since the differences are proportional to the average flow through the models. A digital mass flow meter (Model 4140, TSI, Inc., St. Paul, MN) was placed between the breath simulator and the model. Actual values of breaths/min and tidal volume for each test were measured by analyzing recorded flow patterns versus time, given that the tidal volume is the area under the curve.
the average radioactive dose was taken as the emitted dose. Aerosol Delivery Measurements
Radiolabeled aerosol was delivered during four runs with each of the three models via the two routes. Thus, 12 runs were carried out by each of the nasal and oral routes. Studies were repeated for two Vt for a total of 48 runs. The breathing simulator ran continuously at the preset variables. For each run, the Respimat mouthpiece was inserted into the back of the VHC and the mask was tightly sealed to the surface of the “face.” Two successive puffs of aerosol, separated by a 30 sec interval, were discharged into the VHC and “tidal breathing” continued for 30 sec. This period of time, spanning 15–20 breaths, ensured complete evacuation of the aerosol from the VHC.19 The mask was then removed from the “face.” Evaluation of Aerosol Deposition
Evaluation of the Respimat Emitted Dose
Prior to the study with the URT models, total emitted dose from the Respimat was determined by means of a filter tightly affixed to the orifice of the device. After two successive emitted doses total radioactivity was measured using a dose calibrator (Capintec, Inc., Ramsey, NJ). The emitted dose was quantified by measuring the number of microcuries of technetium at the outlet of the Respimat SMI following two successive puffs. Radioactivity was measured by two techniques. 1. Radioactivity in the SMI reservoir was measured with the dose calibrator both before and immediately after firing two puffs. 2. Radioactivity in the filter that covered the outlet of the MDI was also determined by the dose calibrator. The two techniques were employed for five runs each and
Aerosol was captured on an absolute non-absorbent filter (Pari GMBH) covering the tracheal opening (representing “LRT” deposition). The drug dose in the filter was quantified by means of a dose calibrator (Capintec, Inc.) and expressed as percent of the emitted dose. The dose measured was corrected for decay. The standard deviation is shown as the error bars in the Figures. Statistical Analysis
Two-way ANOVA followed by Tukey HSD post hoc test for the size of the model (i.e., small, medium, and large) and the student t-test post hoc for the difference between nasal and oral routes were performed to compare the filter’s radiolabelled aerosol deposition for each tidal volume. In case of interaction between the variables (age Pediatric Pulmonology
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and route of delivery) the reported P-values are the results of a Tukey HSD post hoc including the full factorial effects of both variables instead of each individual effect. All statistical tests were performed using JMP1 Pro 10.0.2, (Cary, NC), with a P-value of 0.05). This again emphasizes the reduction in the difference in lung dose delivered by the nasal compared with the oral route with increasing age. The trans-nasal and trans-oral pressure drop values across the three in vitro infant models are given in Table 1. Both trans-nasal and trans-oral pressure drop decreased with increasing age. The trans-nasal pressure drop values were significantly (P < 0.05) lower than the trans-oral for the small and medium models with all flow velocities and were comparable (P > 0.05) between nasal and oral airways in the large model (Table 1). The dead space volume of the nasal and oral airways in the models were, respectively: “nasal” versus “oral”: 9.27 and 7.12, (P > 0.05) ml for the small model, 10.31 and 10.96 (P > 0.05) ml for the medium model, and 26.80 and 16.45, (P < 0.05) ml for the large model. These dead space volumes were not related to the filter deposition doses in any of the test combinations.
TABLE 1— Mean (Standard Deviation) of Trans-Nasal/Oral Pressure Drop Across the Three In Vitro Infant Models
Fig. 3. Lung doses as a percentage of the emitted dose delivered through the nasal and oral airways of the three small, medium, and large replicas during simulation of the breathing waveforms at low (a) and high (b) tidal volumes. Asterisk indicating significantly higher nasal delivery compared to oral delivery, t-test, P < 0.05.
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Name of model
Flow rate (L/min)
Small
6.4 4 6.4 4 7.2 4.8
Medium Large
Trans-nasal pressure drop (Pa) 31.52 15.50 30.31 18.58 9.22 4.68
(1.03) (0.58) (1.95) (1.23) (0.16) (0.16)
Trans-oral pressure drop (Pa) 61.13 28.32 50.46 23.76 9.26 4.88
(3.14) (2.21) (1.30) (1.48) (0.07) (0.10)
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DISCUSSION
In our in vitro model simulation of the URT and LRT, nasal aerosol delivery to the LRT exceeded that of oral aerosol delivery in infants and toddlers younger than 20 months of age, in contrast to that seen in older children and adults.20–22 This in vitro study suggests that in infants up to the age of about 18 months, nasal breathing of aerosolized medication would result in better lung delivery compared to oral breathing. Previous studies in older children have demonstrated that the nasal airway has the highest resistance and turbulence in the respiratory tract as well as very efficient aerodynamic filtration as reflected in the relatively high Reynolds number.23 Thus, it is reasonable to assume that nasal breathing would be inferior to oral breathing with regard to targeting aerosols to the LRT. In line with this assumption, Chua et al.1 demonstrated that children (6 years of age and above) have significantly greater LRT aerosol delivery when they breathe through the mouth. In recent pediatric guidelines it is also recommended that aerosol treatment should, as much as possible, be through the mouth and not through the nose. For instance, Levin24 suggests that patients breathe slowly and deeply through the mouth instead of the nose, regardless of the use of a mask or a mouthpiece, a suggestion that could not be implemented in tidal breathing infants and toddlers as well as many children to age 3–4. However, for aerosol delivery in infants, these routes of aerosol administration have not been compared previously. In view of the previous results in older children, the outcome of the present study was somewhat unexpected and again emphasizes the fact that “infants are not merely small adults.” The mechanism by which nasal delivery is greater than oral in these URT model simulations of infants and toddlers is not fully understood. However, we can speculate that it may be related to the anatomical differences in the URT between oral and nasal airways of infants and older children compared to adults as shown in Figure 4. As Figure 4 shows, the oro-pharyngeal passages in infants appear somewhat more convoluted than the nasopharyngeal airways. This may explain why oral inhalation might result in relatively high local airflow velocity and turbulence, which in turn could result in greater URT particle impaction and consequently reduced LRT aerosol deposition. The narrower the airways the greater the flow velocity and friction and consequently the resulting URT pressure drop.25 Thus, the smaller cross sectional diameter of the airways in the young infants is associated with greater pressure drop compared to the older children. This is in line with our in vitro pressure drop measurements (Table 1), showing significantly greater trans-oral compared to trans-nasal pressure drops in the small and medium models, which, in turn, supports the greater aerosol delivery through the nose in these age groups. Furthermore, a close look at the URT cross
Fig. 4. Comparison of the upper airways of adults (on the left) with the similar regions in infants (on the right). (A) pharynx and supraglottic region: less rigid; (B) epiglottis: narrow, floppy and closer to palate; (C) larynx: higher and very close to the base of the tongue. Reprinted with permission from Ref.26
sections (Figure 4) indicates that in the infant, not only are the turbinates rudimentary, providing a relatively larger and smoother nasal airway,26 but in addition it appears that the naso-pharyngeal angle is much less acute than in the adult. The difference favoring nasal breathing was most apparent in the “youngest” infant model, and progressively diminishes with age. Per-oral and per-nasal “LRT” deposition becomes similar in the large model representing a child aged 20 months. Interestingly, this is approximately the age at which most small children stop suckling and go from “obligate”/preferential nasal to oral breathing. The change to equivalent LRT aerosol delivery via the “nasal airway” at 20 months, although arbitrary in our study, is of considerable interest and needs to be confirmed in vivo. It is certainly possible that this coincides with the stage of respiratory tract development, where oral inhalation supercedes nasal as the preferential mode of breathing in infants due to the lower resistance of the oral over the nasal route. The mechanism by which this occurs is not well understood, yet the results of our study appear to coincide with this previously described trend in children aged above about 18 months.6,27,28 The average “tracheal orifice” filter dose in the present study is greater than reported in previous in vitro studies5,29 utilizing infant airway models and pMDIs. We attribute this to the highly effective mask to face seal achieved using anesthesia masks with air cushions combined with a non electrostatic chamber, as well as, perhaps, to the soft-mist aerosol produced by the inhaler used in this study resulting in reduced impaction of aerosol within the VHC and thus greater targeting to the LRT. From a clinical perspective, dosage recommendations with different inhalers may vary and additional pharmacokinetic studies may be required to address these issues. Pediatric Pulmonology
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We acknowledge the limitations of our study. The models used were rigid models constructed from the CT scans of single relatively healthy children at each age, that may not be entirely representative of that age group. They may also fail to account for physiological variations in the diameter and volume of the airways with respiration. On the other hand it is known that, at least with respect to the nasal airways, the respiration-related variation in diameter and volume are negligible The fact that the scans were obtained during quiet tidal breathing lends support to this idea. Additionally, the aerosol produced by the Respimat device produces aerosol clouds that are ejected with a lower velocity than pMDIs, are more prolonged and contain, on average, smaller particles than those produced by pMDIs,30 Thus, our results may be limited to this delivery device or quality of aerosol. However, since infants in this age range almost always inhale medication from valved holding chambers that function as aerosol reservoirs rather than directly from a pMDI, these limitations may be clinically less relevant under “real life” conditions. Chua et al.1 noted that no radiolabeled aerosol was found in the oral airways of tidal breathing infants aged 0.3–1.4 years, strongly supporting the concept that infants are preferential nose-breathers; an activity that would stand them in good stead while suckling. Ideally, the results of this study should be confirmed in vivo. However, such a study would be almost impossible to carry out because of the natural preference of the majority of infants to breathe nasally most of the time as noted by Chua et al.1 The results of the present study are clinically important despite the fact that most infants and toddlers are generally preferential nasal breathers,31,32 and are unlikely to breathe orally unless they are crying, breathless due to lung or airway disease, hypoxemia, hypercapnia or have an obstructed nasal airway. The fact that in the upper airway infant models used in this study, the nasally inhaled aerosol dose targeted to the “LRT” equaled or exceeded that of oral inhalation, should be somewhat reassuring to pediatricians and infants’ caregivers since they can be reasonably confident that, at least up to about 20 months of age, a similar aerosol dose inhaled nasally is likely to be as effective as if it were inhaled orally. The results of the present study, as well as our recent scintigraphic deposition study in infants under age 12 months,33 confirm that, also in vivo, infants can use a pacifier or feed while receiving inhaled treatments with no decrease in drug delivery to the lungs. In conclusion, contrary to what is observed in older children and adults, the present study suggests that nasal breathing for aerosol delivery to the LRT is as or more efficient than mouth breathing in infants/toddlers. Pediatric Pulmonology
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