What Is the Size of a Baby Windpipe

INTRODUCTION

Extrathoracic deposition plays an important role in determining the total lung dose (TLD) of pharmaceutical inhalers (Stahlhofen et al. 1989; Borgstrom et al. 2006)^. Because of possible fluid mechanic interactions between the oral cavity and the flow exiting an inhaler (DeHaan and Finlay 2004), geometric mimics of the mouth-throat are useful in aiding inhaler design. Thus, there has been a long-term interest in simplifying the testing of drug delivery devices by having a simple geometry that can be used to mimic average extrathoracic deposition among adults and children.

In vitro methods using physical oral airway models have been successful in mimicking TLD for adult subjects (Ehtezazi et al. 2005; Finlay and Martin 2008; Delvadia et al. 2012). The use of a single geometry, such as the US Pharmacopeia (USP) induction port to mimic throat deposition and thereby measure TLD has been popular for testing inhalers due to its relative simplicity. However, the USP throat is far from resembling a realistic human airway; thus, it has not been successful in replicating mouth-throat deposition of gently delivered aerosols (Srichana et al. 2000; Zhang et al. 2007; Zhou et al. 2011). To address these limitations of the highly simplified USP throat, an idealized adult throat, the "Alberta Idealized Throat," has previously been developed by our group based on the actual geometry of human extrathoracic airways (Stapleton et al. 2000). This throat has been successful in replicating extrathoraic deposition (Grgic et al. 2004a, b; Zhang et al. 2007; Zhou et al. 2011) and is commercially available (Copley Scientific, UK).

Due to recent interest in optimizing pediatric drug delivery, pediatric models are needed for in vitro testing. Studies have been done by our group (Storey-Bishoff et al. 2008; Golshahi et al. 2011a) and others (Janssens et al. 2001; Corcoran et al. 2003; Minocchieri et al. 2008; Laube et al. 2010) to mimic pediatric deposition with airway models, mostly among infants and young children who are nose breathers. However, as for adults, there is a need for a single idealized model to consistently predict average pediatric deposition. Previously, MRI scans of children, younger than five years old, have been used to modify the laryngeal region of the Alberta Idealized Throat to replicate the oral airway of a five-year-old child (Wachtel et al. 2010). This modified idealized throat was used to test Respimat® Soft Mist^TM inhalers (Boehringer Ingelheim, Germany) with and without a holding chamber. The capability of this nonuniformly modified idealized throat to give average deposition among children younger than five years old remains to be examined. Since inhalers are more common among older children, we recently completed a systematic study to examine and reduce the intersubject variability in deposition of micrometer-sized particles in oral airways of children aged 6–14 years (Golshahi et al. 2011b). The present communication examines the possibility of uniformly scaling the Alberta Idealized Throat to replicate average deposition among children with a single simplified geometry. This scaling is based on our recent measurements of the dimensions of children's oropharyngeal airways and deposition of micrometer-sized particles in replicas of these airways (Golshahi et al. 2011b). The development of such a simple geometry can be considered a major advance in the field of pediatric drug delivery since it will provide a standard platform for optimizing the treatment of children with inhaled pharmaceutical aerosols.

An Idealized Child Throat that Mimics Average Pediatric Oropharyngeal Deposition

Published online:

29 February 2012

FIG. 1 Schematic of the Idealized Child Throat. The lengths of the sections a, b, and c (62.7, 40.6, and 38.7 mm, respectively) are the summations of polylines shown in each section.

FIG. 1 Schematic of the Idealized Child Throat. The lengths of the sections a, b, and c (62.7, 40.6, and 38.7 mm, respectively) are the summations of polylines shown in each section.

METHODS

In our recent study with oropharyngeal airway replicas of children, the characteristic diameter that resulted in the most reduction in scatter due to intersubject variability was the ratio of the volume to the surface area of the airway (d _c = V/A _s) (Golshahi et al. 2011b). By examining CT scans of oral airways of children and adults, it appears that the main geometrical features of the child and adult airways are similar. Thus, it would seem logical that scaling the Alberta Idealized Throat by a uniform factor based on the average characteristic diameter would be suitable to mimic average oral deposition among children. The scale factor of 0.62 was thus used for scaling the Adult Idealized Throat in Magics software (Materialise, USA) based on the above reasoning. This scaling was chosen to match the characteristic diameter (V/A _s) of the "Idealized Child Throat" to the average of the nine tested child replicas in our recent study (i.e., 2.7 mm) (Golshahi et al. 2011b). Figure 1 shows our new "Idealized Child Throat" and its main dimensions (i.e., a = 62.7 mm, b = 40.6, and c = 38.7 mm) that are similar to the average of the main dimensions of our nine realistic children replicas (a = 59.4 ± 4.9, b = 45.9 ± 8.1, and c = 46.2 ± 3.9 mm). A 3D printer (Invision SR, 3D Systems, USA) was used to build the Idealized Child Throat using Visijet SR200, which is an acrylic material. A cylindrical shaped adaptor was made to connect the inlet of the throat to the tubing in the experimental setup. The inner diameter of that cylinder was 11 mm.

The Idealized Child Throat was then tested in the same setup that we used for measuring deposition of micrometer-sized particles in the oral airway replicas of children. The details of such measurements are given in Golshahi et al. 2011b. In brief, an Electrical Low Pressure Impactor (Dekati, Finland) was used for measuring the size distribution of polydisperse jojoba oil aerosols, generated by a six jet Collison atomizer (BGI Inc., USA). The absolute difference between number concentration in the line with no replica and the line with the replica was defined as the deposition for each particle size, given at the cut sizes of the ELPI, which were 0.5, 0.8, 1.3, 2.0, 3.2, and 5.3 micrometers. The tested flow rates were 30, 60, 90, and 120 L/min, which were generated using two vacuum pumps in parallel and recorded using a digital mass flow meter (TSI Model 4043, USA) for both lines (blank and replica line). At 60 L/min the number concentration of 5.3 μm particles was too low to be considered and at 90 and 120 L/min the number of 3.2 and 5.3 μm were too low; thus, those sizes were excluded at the associated flow rates. The variable dilution air, as a result of the resistance of the replica compared to the blank line, was corrected similar to our previous work (Storey-Bishoff et al. 2008; Golshahi et al. 2011a, b). The replica was also removed and the difference between the number concentration through the blank line and the replica line was measured and defined as the baseline, which was then subtracted from the total deposition. Five measurements were made for each data point. However, the errors were too small to be included in visual presentation of the results. In other words, the sizes of error bars were about the size of the data points.

RESULTS AND DISCUSSION

Figure 2 shows the deposition of particles in the "Idealized Child Throat" versus the impaction parameter (d _a ² Q, where d _a is aerodynamic diameter and Q is inhalation flow rate) compared with the nine children (aged 6–14 years) in our previous study (Golshahi et al. 2011b). It is observed that deposition in the Idealized Child Throat lies in the middle of the data and may be used to mimic average deposition among children in that study.

An Idealized Child Throat that Mimics Average Pediatric Oropharyngeal Deposition

Published online:

29 February 2012

FIG. 2 The deposition of orally inhaled micrometer-sized particles in the Idealized Child Throat versus the impaction parameter compared to that of nine children replicas in our previous study (Golshahi et al. 2011b). (Color figure available online.)

FIG. 2 The deposition of orally inhaled micrometer-sized particles in the Idealized Child Throat versus the impaction parameter compared to that of nine children replicas in our previous study (Golshahi et al. 2011b). (Color figure available online.)

Deposition in the Idealized Child Throat and the replicas of nine children's airways (Golshahi et al. 2011b) is plotted in Figure 3 versus a different deposition parameter, a combination of Stokes (Stk) and Reynolds (Re) numbers, which includes the characteristic diameter of V/A _s. This deposition parameter successfully minimized the scatter of the deposition data among our child airway replicas (Golshahi et al. 2011b). It appears that deposition in the Idealized Child Throat for the deposition parameter in the mid range of 600–2000 is slightly (∼10%) higher than the average predictive correlation given in Golshahi et al. 2011b for nine children 6–14 years old. This is presumably because the Idealized Child Throat is a simplified geometry and does not include all of the complex features of the anatomical airways. Hence, this simplification may affect the dynamics of aerosol and flow in a way that is reflected in the data. This slight overestimation was similarly observed in the data with our Adult Idealized Throat (Grgic et al. 2004a). Despite this overestimation, however, the adult Alberta Idealized Throat was successful in replicating average in vivo deposition (Grgic et al. 2004a, b; Zhang et al. 2007; Zhou et al. 2011).

An Idealized Child Throat that Mimics Average Pediatric Oropharyngeal Deposition

Published online:

29 February 2012

FIG. 3 Deposition in the Idealized Child Throat and children's anatomically accurate replicas (Golshahi et al. 2011b) versus the deposition parameter X = Stk^1.5 × Re^0.69 where Stk and Re are Stokes and Reynolds numbers that use a subject specific length scale V/A _s. (Color figure available online.)

FIG. 3 Deposition in the Idealized Child Throat and children's anatomically accurate replicas (Golshahi et al. 2011b) versus the deposition parameter X = Stk^1.5 × Re^0.69 where Stk and Re are Stokes and Reynolds numbers that use a subject specific length scale V/A _s. (Color figure available online.)

It is worth noting that the Idealized Child Throat has been compared here with 9 morphometrically accurate in vitro replicas and there is room for studying if this model is successful in replicating the average of in vivo data. However, comparative studies have been done with adult subjects and in vitro methods have proven to be reasonable in mimicking the airways of adults (Newhouse et al. 1998; Grgic et al. 2004b; Ehtezazi et al. 2005).

CONCLUSIONS

Uniform scaling of the adult Alberta Idealized Throat by a factor of 0.62 resulted in an Idealized Child Throat with a characteristic diameter V/A _s that is equal to the average characteristic diameter of the children's airways (i.e., 2.7 mm) in our previous study (Golshahi et al. 2011b). This Idealized Child Throat mimics the average deposition during oral inhalation among children 6–14 years old in that study. Thus, this geometry may be useful for substantially simplifying experimental studies involving the design and development of inhalers for oral inhaled aerosol drug delivery to the lungs in child patient populations.

What Is the Size of a Baby Windpipe

Source: https://www.tandfonline.com/doi/full/10.1080/02786826.2012.667170

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