Change in Upper Airway Geometry Between Upright and Supine Position During Tidal Nasal Breathing

Abstract

Background:

As the upper airway is the most important limiting factor for the deposition of inhalation medication in the lower airways, it is interesting to assess how its morphology varies between different postures. The goal of this study is to compare the upper airway morphology and functionality of healthy volunteers in the upright and supine positions during tidal nasal breathing and to search for baseline indicators for these changes. This is done by performing three-dimensional measurements on computed tomography (CT) and cone beam computed tomography (CBCT) scans.

Methods:

This prospective study was approved by all relevant institutional review boards. All patients gave their signed informed consent. In this study, 20 healthy volunteers (mean age, 62 years; age range, 37–78 years; mean body mass index, 29.26; body mass index range, 21.63–42.17; 16 men, 4 women) underwent a supine low-dose CT scan and an upright CBCT scan of the upper airway. The (local) average (S_avg) and minimal (S_min) cross-sectional area, the position of the latter, the concavity, and the airway resistance were examined to determine if they changed from the upright to the supine position. If changes were found, baseline parameters were sought that were indicators for these differences.

Results:

There were five dropouts due to movement artifacts in the CBCT scans. S_avg and S_min were 9.76% and 26.90% larger, respectively, in the CBCT scan than in the CT scan, whereas the resistance decreased by 26.15% in the upright position. The S_avg of the region between the hard palate and the bottom of the uvula increased the most (49.85%). In people with a high body mass index, this value changed the least. The airway resistance in men decreased more than in women.

Conclusions:

This study demonstrated that there are differences in upper airway morphology and functionality between the supine and upright positions and that there are baseline indicators for these differences.

Introduction

Small airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are treated with inhaled compounds according to the Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.^(1,2) Delivering the drugs to the inflamed airway regions is critical, as undertreatment can cause exacerbations.^(3,4) However, simply increasing the dosage to counter this issue can cause systemic side effects⁽⁵⁾ and still not guarantee adequate treatment. Computational fluid dynamics (CFD) in patient-specific airway models can predict where the particles of an inhaled compound deposit in a certain patient. This technique has been validated and has promise in assessing patient-specific treatment.^(6–8)

To perform the particle simulations correctly, patient-specific boundary conditions and airway anatomy are needed. Upper airway morphology is the most important factor in assessing particle deposition in the lower airways^(9–11) and is mostly obtained using computed tomography (CT) or magnetic resonance imaging scans, as these scanners are widely available. The problem with these scanning techniques is that the images are taken when the subject or patient is in the supine position. Inhaled medication, however, is mostly administered in an upright position. Posture is thought to be an important determinant of upper airway dimension^(12–14) and can thus have an influence on the CFD results.

Another interesting item is that most oropharyngeal casts and models that are used for in vitro deposition modeling are based on scans in a supine position, such as those by McRobbie et al.⁽¹⁵⁾ A larger insight in posture-dependent differences could possibly help to optimize the throat models currently used by the industry.

A scanning device that has the possibility to scan a subject in an upright position is the cone beam computed tomography (CBCT) scanner. CBCT is nowadays widely used in dentistry and maxillofacial surgery due to its low radiation dose,⁽¹⁶⁾ and has already been used to make upper airway models in an upright position.^(17–19) Also, a phantom study has shown that CBCT is a valid technology for accurately quantifying air volumes.⁽²⁰⁾

As most particle simulations in realistic airway structures are performed on models obtained with a CT scanner,^(6,9,21,22) it is interesting to assess if there is a possibility that these simulations under- or overpredict the lung deposition. The purpose of this prospective open crossover study is to quantify the differences in airway morphology and functionality between the supine and upright positions using CT and CBCT scans of healthy volunteers. The study also investigates which anatomical regions are more prone to possible position-dependent changes, and if there are baseline morphological or clinical parameters that have an influence on these.

Materials and Methods

Subject data

A total of 20 adult healthy volunteers [mean age, 62 years; age range, 37–78 years; mean body mass index (BMI), 29.26; BMI range 21.63–42.17] were included from March 18, 2011 to April 29, 2011. The population consisted of 16 male and four female subjects and was divided in three BMI groups. There were seven subjects with a BMI lower than 25, six subjects with a BMI between 25 and 30, and seven subjects with a BMI higher than 30. The detailed inclusion and exclusion criteria can be found in Table 1. Institutional review board approval was obtained, a written informed consent was signed by all subjects, and the study was submitted to ClinicalTrials.gov (NCT01594164).

Table 1.

Inclusion and Exclusion Criteria

Inclusion criteria	• Written informed consent obtained
	• Male or female subject aged ≥18 years
	• BMI<25 kg/m² (group 1), BMI≥25 kg/m² and <30 kg/m² (group 2), and BMI≥30 kg/m² (group 3)
	• Female subject of childbearing potential who confirms that a contraception method was used at least 2 months before scan
Exclusion criteria	• Subject is under the age of legal consent
	• Subject who is pregnant or is breast-feeding
	• Subject with a history of surgery of the upper airway
	• Subject with a history of any illness that, in the opinion of the investigator, might confound the results of the study or poses an additional risk to the subject by participation in the study
	• Subject is unlikely to comply with the protocol or unable to understand the nature, scope, and possible consequences of the study
	• Subject who received any investigational new drug within the last 4 weeks prior to scan
	• Subject who has claustrophobia

CT and CBCT

All subjects underwent one low-dose CT scan in the supine position and one CBCT scan in the upright position on the same day. Both scans were taken during tidal nose-breathing to prevent any patient-induced occlusion of the glottis. A pneumotach device was used to make sure that the subject breathed consistently and to detect if the subject swallowed during the scan. The scanning region started at the beginning of the palatum and extended down to the sternum.

A Lightspeed VCT scanner (GE Healthcare, Milwaukee, WI) was used to obtain supine images. The images had a pixel size of approximately 0.5 mm² and were reconstructed with a slice thickness of 0.3 mm. The scan took around 1 sec and was triggered to start at the beginning of the inspiration. The subject received a radiation dose around 0.1 mSv.

An i-CAT CBCT scanner (Imaging Sciences International, Hatfield, PA) was used for the upright images. The images had a voxel size of approximately 0.4 mm². The scan took around 9 sec, and the effective dose was approximately 68 μSv.

Every volunteer in this study was thus exposed to a total radiation dose around 0.2 mSv.

Airway segmentation

Both CT and CBCT scans were loaded into the Mimics 13.1 (Materialise, Leuven, Belgium) software suite. This validated package (U.S. Food and Drug Administration, K073468; Conformité Européenne certificate, BE 05/1191.CE.01) allowed the anatomical region of interest to be segmented and a three-dimensional representation of it to be generated. The scans were first resliced so that the central sagittal slice of the hard palate was positioned horizontally. This enabled the same region of interest to be taken for both CT and CBCT, which was important for a correct comparison. The region of interest was chosen as the space of air posterior to the tongue, from the hard palate to the larynx (Fig. 1), as this region is most prone to airway collapse due to the weight of the surrounding tissue.⁽²³⁾ The segmented region consisted of pixels in a Hounsfield units region between −1,024 and −400.⁽²⁴⁾ Subsequently, the segmented mask was converted to a three-dimensional object using a contour interpolation algorithm.

FIG. 1.

Sagittal slice of a CT scan (left) and a CBCT scan (right), taken without contrast material. The region of interest is indicated in white.

Computational fluid dynamics

CFD simulations were performed on the three-dimensional objects in order to generate extra functional data. A hexahedral dominant computational grid was created using SnappyHexMesh 2.0.1 (OpenCFD Ltd., Bracknell, UK). A sensitivity study showed that a computational grid between 300,000 and 1,400,000 cells was sufficient for reaching mesh convergence. This convergence was obtained using differences in mass flow and total pressure drop for increasing mesh refinement levels. The final flow simulations were performed using the mesh size based on a difference of less than 1% between the coarse and fine grids. The computations were performed using a custom-made Navier–Stokes solver based on the OpenFOAM 2.0.1 library (OpenCFD Ltd.). As the air velocity in the upper airways is smaller than a Mach number of 0.2, an incompressible solver could be used.⁽²⁵⁾ Also, the flow in the upper airways was considered adiabatic. Second-order discretization schemes were used for the pressure and momentum equations, and the pressure–velocity coupling was solved using the SIMPLE scheme. To enable proper comparison between the models, the boundary conditions were set equally for all models. At the inlet, a total pressure of 0 Pa was set, and at the outlet, a static pressure of −20 Pa was applied. Sensitivity analyses on turbulence showed that no inaccuracies were introduced by employing a laminar flow approach. The mass flow and the total pressure drop were similar between laminar and k-ω SST turbulence boundary conditions (considering 5% turbulence intensity at the inlet), with a maximum difference of less than 1% for the model with the highest Reynolds number. Pressure boundary conditions were chosen for realistic interpatient comparison, as morphology changes in the upper airway will not change the pressure difference between atmosphere and lungs, but will restrict the airflow. The resulting flows were between 6.5 L/min and 50 L/min.

Outcome parameters

All measurements on the upper airways were done on the three-dimensional objects that were extracted from the CT and CBCT scans. In this way, it was possible to detect morphological differences. The anatomical parameters that were measured were:

• The average cross-sectional area of the upper airway (S_avg)

• The minimal cross-sectional area of the upper airway (S_min)

• The position of S_min, measured from the hard palate (PosS_min)

To see if the potential differences between CT and CBCT are due to very local movements or due to global movements, the S_avg was also measured in three anatomical zones:

• In the region between the hard palate and the end of the uvula (S_{avg_top})

• In the region between the end of the uvula and the epiglottis (S_{avg_central})

• In the region between the epiglottis and the larynx (S_{avg_bottom})

The different zones and cross-sectional areas are shown in Figure 2. The ratio S_min/S_avg was defined as the concavity and has been calculated, as it was to be investigated whether upper airways with a uniform area distribution react differently from airways that are more concave and thus have a lower S_min/S_avg.

FIG. 2.

The different airway zones and the definition of the cross-sectional areas.

From the CFD simulations, the upper airway resistance R was extracted. The resistance was defined as the ratio of the total pressure drop over the upper airway and the mass flow rate through it.^(26,27)

Finally, it was investigated if men and women respond differently to the change in posture.

Statistics

The data were tested for normality using the Shapiro–Wilk W test. Depending on the outcome of these tests, parametric or nonparametric statistical techniques were used. In this study, correlations were calculated using the Spearman rank test, and differences between CT and CBCT were analyzed using the Wilcoxon matched pairs test. Differences between sexes were investigated using the Mann-Whitney U test. Statistical analysis was performed using Statistica 10 (Statsoft, Tulsa, OK), and the significance level was set at 0.05.

Results

Dropouts

From the 20 healthy volunteers that were included, only 15 valid CBCT scans could be analyzed, as the rotating gantry of the CBCT touched the shoulders of the broad-shouldered subjects, causing motion artifacts. These subjects were especially found in the highest BMI group (one male with a BMI lower than 25, one male with a BMI between 25 and 30, three males with BMIs above 30).

Differences between CBCT and CT

Values of S_avg and S_min were significantly larger in the CBCT scan than the same parameters in the CT scan (9.76% and 26.90%, respectively), whereas the concavity and the PosS_min did not change significantly. A good example can be seen in Figure 3. Also, the resistance R was found to be 26.45% smaller in the upright posture than when lying down.

FIG. 3.

These two images show the same upper airway: CT scan (left), and CBCT scan (right). It can be seen that the cross-sectional areas are much larger in the CBCT airway scan.

When looking more in detail at the diameter distribution, it can be seen that there was a very significant increase (49.85%) in S_{avg_top} when the subject changed from the supine position to the upright position. However, the values of S_{avg_central} and S_{avg_bottom} were not influenced by this action. Detailed statistical results can be found in Table 2.

Table 2.

Differences Between CT and CBCT

Wilcoxon matched pairs test: CT versus CBCT
	Median CT	Lower/upper quartile CT	Median CBCT	Lower/upper quartile CBCT	Median difference (%)	p value
S_avg (mm²)	196.55	126.84/216.91	216.44	170.01/378.69	+9.76	0.005
S_{avg_top} ( mm²)	135.53	94.45/202.50	230.34	154.35/364.53	+49.85	<0.001
S_{avg_central} ( mm²)	178.52	107.06/248.65	195.88	125.22/285.31	−14.16	0.820
S_{avg_bottom} (mm²)	193.45	178.66/270.28	223.32	192.02/382.69	+4.25	0.112
S_min (mm²)	57.31	35.49/84.91	78.70	60.66/173.06	+26.90	0.027
PosS_min (mm)	27	23/57	41	24/61	+6.67	0.177
S_min/S_mean (−)	0.326	0.270/0.418	0.388	0.336/0.463	+15.98	0.100
R (kPa.sec/L)	0.084	0.055/0.116	0.054	0.025/0.071	−26.45	0.004

S_avg=average cross-sectional area

S_{avg_top}=S_avg in the region between the hard palate and the end of the uvula

S_{avg_central}=S_avg in the region between the end of the uvula and the epiglottis

S_{avg_bottom}=S_avg in the region between the epiglottis and the larynx

S_min=minimal cross-sectional area

PosS_min=the position of S_min, measured from the hard palate

S_min/S_mean=concavity

R=airway resistance

Indicators for the differences between CBCT and CT

From here on, the symbol “Δ” is used to define the percentage change between the parameter measured with CBCT and the parameter measured with CT. A positive value means that the CBCT value is larger than the CT value. The significant results in the previous section showed that the median values of ΔS_avg, ΔS_min, and ΔS_{avg_top} are positive, whereas the median value of ΔR is negative.

BMI was not found to be an indicator for ΔS_avg, ΔS_min, and ΔR. However, it was found that in people with a higher BMI, ΔS_{avg_top} became smaller (Table 3). There was an inverse correlation between BMI and S_{avg_top} in an upright position (Spearman R, −0.664; p=0.007), but BMI had no relation with S_{avg_top} when lying down (Spearman R, −0.282; p=0.308).

Table 3.

BMI Versus Difference Between CBCT and CT

Spearman rank order correlations: Correlating BMI with the difference between CBCT and CT
Parameters	Spearman R	p value
BMI and ΔS_avg	−0.357	0.191
BMI and ΔS_{avg_top}	−0.625	0.013
BMI and ΔS_min	0.032	0.909
BMI and ΔR	0.111	0.694

BMI=body mass index

ΔS_avg=difference between average cross-sectional area measured with CBCT and CT

ΔS_{avg_top}=difference between average cross-sectional area in the region between the hard palate and the end of the uvula measured with CBCT and CT

ΔS_min=difference between minimal cross-sectional area measured with CBCT and CT

ΔR=difference between resistance calculated with CBCT and CT

There was a significant difference between the sexes for ΔR (Table 4). In males, ΔR decreased 42.98% (p=0.006), whereas this value was not different from zero for women (p=0.715).

Table 4.

Sex Versus Difference Between CBCT and CT

Mann-Whitney U test: By sex: 11 men, 4 women
Parameters	Mean rank men	Mean rank women	Mann-Whitney U	p value
Sex and ΔS_avg	8.55	6.50	16.00	0.489
Sex and ΔS_{avg_top}	7.64	9.00	18.00	0.661
Sex and ΔS_min	9.00	5.25	11.00	0.177
Sex and ΔR	6.55	12.00	6.00	0.040

Sex=sex of the subject

ΔS_avg=difference between average cross-sectional area measured with CBCT and CT

ΔS_{avg_top}=difference between average cross-sectional area in the region between the hard palate and the end of the uvula measured with CBCT and CT

ΔS_min=difference between minimal cross-sectional area measured with CBCT and CT

ΔR=difference between resistance calculated with CBCT and CT

The closer the upright PosS_min was to the hard palate, the more ΔS_min increased and ΔR decreased (Spearman R, 0.611; p=0.016).

Discussion

Particle deposition simulations are mostly performed on airway models that are segmented from CT scans, as this technique results in the best visualization of upper and lower airways. As it is possible to decrease the radiation dose for an upper airway scan to 0.1 mSv, the possible negative side effects can be minimized.⁽²⁸⁾ However, due to the fact that inhalation medication is mostly taken in the upright position, whereas the CT scan is taken in the supine position, there is a possibility that the simulated geometry will not correspond completely to the real geometry.

The first aim of this study was to compare the upper airway morphology in the supine and upright positions in order to see if this is the case. This was done by scanning healthy subjects with a CT scanner while lying down and with a CBCT scanner while sitting straight. As both scanning techniques are known to provide good quantitative results when measuring spaces of air, the segmented voxels of both techniques could be compared. We could demonstrate that there is indeed a difference in airway morphology between these postures: the airway becomes significantly smaller and its resistance increases when lying down. This can be explained by the fact that the gravity vectors of the surrounding tissues are aligned perpendicular to the airway walls in this position, increasing the load on the airway muscles. It seems that the tension in the airway muscles does not increase enough to counter the increased load completely, resulting in a smaller airway lumen. The fact that the average airway diameter only decreased in the part posterior to the uvula suggests that, in a population of healthy subjects, this is the region that is most prone to airway collapse. This is supported by previous findings in healthy subjects and sleep apnea patients^(23,29,30) and is probably due to a posterior displacement of the soft palate and the tongue.^(31,32)

The second aim of this study was to find baseline parameters that are indicators for these morphology changes. The closer the position of the minimal cross-sectional area to the hard palate when upright, the more the minimal cross-sectional area will decrease and the resistance will increase when lying down. This is in line with the fact that the region of collapse is mostly posterior to the uvula.

No correlations were found between the BMI and the global changes in morphological and functional airway parameters. This is an important outcome and implies that, in healthy subjects, no large morphological or functional changes occur due to an increased weight of the surrounding tissue. It was even found that, in people with a high BMI, there is less area change posterior to the uvula. It can be suspected that, in healthy subjects, the airway muscles apply enough force to guarantee a certain airway lumen.

Men and women responded significantly differently to the change in posture. The airway resistance decreases in men, whereas there is no significant change found in women. Although there is a sex imbalance in the included subjects (11 males, four females), this is an interesting finding as will be discussed further.

This study had a number of limitations. There were a significant amount of dropouts in the broad-shouldered subjects due to the small diameter of the CBCT rotating gantry that interfered with the region of interest. As this gave some imbalance in the BMI groups, one has to approach the correlations that were found with BMI carefully. The above-mentioned sex imbalance is also a limitation. A higher number of women would open the possibility to perform more detailed comparisons. A previous study found no significant differences between CT and CBCT when measuring spaces of air in a phantom,⁽²⁰⁾ so in a static context no differences will be observed due to the different imaging modalities. However, it is known that the upper airway geometry changes during tidal breathing,⁽³³⁾ which can introduce movement-related errors. As the CT scan only took 1 sec and was triggered at the start of the inhalation, the breath-induced geometry changes were considered to be very small. However, the long scanning time of the CBCT could have introduced some motion artifacts as the subject performed multiple breaths during the scan. Although there were no visible motion artifacts, the possibility exists that the upright volumes were underestimated, as these artifacts would be excluded from the Hounsfield range. As the significant geometrical percentage changes between CBCT and CT were all positive, it is possible that these are underestimated. The effect of the upstream nasal regions was neglected in the CFD simulations. Although this zone was not a part of our region of interest, the exclusion could have had an influence on the results. It was not possible to quantify this influence, as the field of view of the CBCT was not large enough to scan both the nasal region and the upper airway in one movement. The skewness of the data had the effect that nonparametric tests were used and no multivariate analyses were performed.

In future studies, it would be interesting to perform this methodology in a population of obstructive sleep apnea (OSA) patients. The first reason is that this would open possibilities to gain insights in the pathology and to help with diagnostics. Another reason is the fact that there are a lot of patients that suffer from both OSA and asthma/COPD,^(34,35) and that the conclusions of this study are possibly not valid for them.

The most important insight of the current study is that the largest area changes occur at the region posterior to the uvula. As most inhalation compounds are administered through the mouth, it would be interesting to see if the upper airway behavior changes due to mouth breathing. An open mouth can possibly induce a movement of the uvula, which can influence the local or global airway morphology and functionality. There are plans for a future study where this will be investigated. The insights of the current and future studies can lead to more accurate lung deposition estimates.

The large inter- and intrasubject variation in upper airway morphology shows that there is a need for a subject-specific approach when assessing deposition of inhalation medication. Several predictive models exist, as described in a review by Finlay and Martin,⁽³⁶⁾ that are very valuable, but these are based on statistical models and are not able to tell if an individual subject behaves as the fitted deposition curve predicts.

This study demonstrated that there are differences in upper airway morphology and functionality between the supine and upright positions and that there are baseline indicators for these. The upper airway behavior that was extracted from the CT and CBCT scans is in line with clinical observations and shows the usefulness of these techniques. This is especially true as the large variability within and between the subjects emphasizes the added value of subject-specific models.

Footnotes

Acknowledgments

The authors would like to thank Dr. Marijke De Decker, Ms. Caroline Beckers, and Ms. Heidi De Laet for assistance in editing this document.

Author Disclosure Statement

The authors declare that there are no conflicts of interest.

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