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. 2020 Apr 13;15(4):e0231262. doi: 10.1371/journal.pone.0231262

The effect of nasal and oral breathing on airway collapsibility in patients with obstructive sleep apnea: Computational fluid dynamics analyses

Masaaki Suzuki 1,*,#, Tadashi Tanuma 2,#
Editor: Pei-Lin Lee3
PMCID: PMC7153879  PMID: 32282859

Abstract

Objective

The purpose of this study was to investigate the effect of breathing route on the collapsibility of the pharyngeal airway in patients with obstructive sleep apnea by using computational fluid dynamics technology.

Methods

This study examined Japanese men with obstructive sleep apnea. Computed tomography scans of the nose and pharynx were taken during nasal breathing with closed mouth, nasal breathing with open mouth, and oral breathing while they were awake. Three-dimensional reconstructed stereolithography models and digital unstructured grid models were created and airflow simulations were performed using computational fluid dynamics software.

Results

Airflow velocity was significantly higher during oral breathing than during nasal breathing with open or closed mouth. No significant difference in maximum velocity was noted between nasal breathing with closed and open mouth. However, airflow during nasal breathing with open mouth was slow but rapidly sped up at the lower level of the velopharynx, and then spread and became a disturbed, unsteady stream. In contrast, airflow during nasal breathing with closed mouth gradually sped up at the oropharyngeal level without spreading or disturbance. Negative static pressure during oral breathing was significantly decreased; however, there were no significant differences between nasal breathing with closed or open mouth.

Conclusions

Computational fluid dynamics results during nasal and oral breathing revealed that oral breathing is the primary condition leading to pharyngeal airway collapse based on the concept of the Starling Resistor model. Airflow throughout the entirety of the breathing route was smoother during nasal breathing with closed mouth than that with open mouth.

Introduction

Mouth opening and oral breathing during sleep are thought to be associated with narrowing of the pharyngeal lumen and decreases in retroglossal diameter, which increase upper airway collapsibility and may lead to airway obstruction. It has been reported that upper airway collapsibility and resistance during sleep are significantly higher in people who breath through the mouth than in those who breath through the nose, which is different from what is seen in the conscious state. Meurice et al. demonstrated that mouth opening increased upper airway collapsibility during sleep [1]. Fitzpatrick et al. confirmed that during sleep, upper airway resistance during oral breathing was 2.5 times higher than that during nasal breathing [2]. Ayuse et al. examined upper airway critical pressure (Pcrit) in closed mouths, mouths opened moderately, and mouths opened maximally during sedation [3]. They reported that maximal mouth opening increased Pcrit to −3.6 ± 2.9 cmH2O, whereas Pcrit in moderate mouth opening was −7.2 ± 4.1 cmH2O and Pcrit in closed mouths was −8.7 ± 2.8 cmH2O, suggesting that maximal mouth opening increases upper airway collapsibility, which contributes to upper airway obstruction.

Although several physiological studies have been reported, the aerodynamics of nasal and oral breathing remain unclear. The purpose of this study was to investigate the effect of breathing route on the collapsibility of the pharyngeal airway, represented by airflow velocity and static pressure calculated using computational fluid dynamics (CFD) technology, in patients with obstructive sleep apnea (OSA).

Methods

Participants

Participants were 14 Japanese men with OSA and no nasal obstruction (age, 42.6 ± 7.7 years; body mass index, 28.4 ± 5.5 kg/m2; apnea–hypopnea index, 43.7 ± 21.6/h; nasal resistance, 0.27 ± 0.11 Pa/cm3/s). The following procedures were conducted for all participants: standard type 1 in-laboratory overnight polysomnography (PSG) (Alice 6, Philips Respironics, Pittsburgh, PA) in accordance with the American Academy of Sleep Medicine (AASM) scoring manual ver. 2.5, [4] and total inspiratory nasal resistance (NR) at −100 Pa with an anterior rhinomanometer (HI-801, Chest M.I., Inc., Tokyo, Japan) in the supine position. Those with OSA had AHI ≥ 15/h, and those without nasal obstruction had total nasal resistance ≤ 0.50 Pa/cm3/s. We measured volumetric flow rates in a steady breathing state as a substitute marker for ventilatory drive. We used a Fleisch pneumotachometer (Laminar Flow Meter LFM-317; Metabo, Lausanne, Switzerland) along with a pressure sensor during nasal breathing with closed mouth, nasal breathing with open mouth, and oral breathing.

Computational fluid dynamics analyses

Computed tomography (CT) scans of the nose, sinuses, and pharynx were taken at 0.5-mm intervals (Toscaner-32251μhd; Toshiba IT & Control Systems, Tokyo, Japan) during nasal breathing with closed mouth, nasal breathing with open mouth, and oral breathing while the participants were awake. We controlled each participant’s breathing in a steady state with volumetric flow rates. Individual three-dimensional (3D) reconstructed stereolithography (STL) models were created using image analysis software (Intage Volume Editor; Cybernet Systems, Ann Arbor, MI). These 3D reconstructed STL models included the nasal cavity, paranasal sinuses, pharynx, and soft tissue surrounding the airway (Fig 1). The digital unstructured grid models were meshed with 8 million hexahedral cells using the Intage Volume Editor and Hexpress/Hybrid (Numeca International, Brussels, Belgium). Geometrical modeling from medical image data and CFD analyses were conducted using a methodology described in our previous study [5, 6]. In brief, the surfaces were highly corrugated due to artifacts of digitization and were therefore smoothed to facilitate computational meshing. For inspiratory flow CFD analysis, the inlet boundary was set at a cross-section of the nostrils and an outlet boundary was set at a cross-section of the bottom of the hypopharynx. Inlet boundary conditions were set with atmospheric pressure conditions, and the inlet velocity distributions were approximated as flat, neglecting the boundary layer. The outlet boundary conditions were set with static pressures that corresponded to the volume flow conditions for the current cases. For expiratory flow analysis, these conditions were reversed.

Fig 1. 3D reconstructed STL model.

Fig 1

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Airflow simulations were conducted using Navier–Stokes equations in CFD software (Fine/Open, ver. 2.10.4; Numeca, Brussels, Belgium). Simulations were run over a 24-hour period on a 64-bit workstation with 24 GB of memory and 6 CPUs. Atmospheric pressure at 20°C was applied to the inlet boundary (101.325 kPa = 1033.26 cmH2O), with volumetric flow rates for inspiration and expiration of 320 mL/s in cases with nasal breathing, 45 mL/s in cases with oral breathing at the nostrils, and 560 mL/s in cases with oral breathing in front of the mouth. Air density was 1.204 kg/m3. Air mass flow rate was 3.853 × 10−4 kg/s in cases with nasal breathing and 7.285 × 10−4 kg/s in cases with oral breathing. Nasal wall boundary conditions were heat-insulated walls with viscosity and turbulence taken into consideration. A no-slip boundary condition was applied on all nasal airway surfaces. Simulation models were confirmed to agree with measured airflow values.

All calculations were steady-state calculations using the maximum instantaneous flow rates measured during inspiration. The averaged Reynolds number in this study was around 3500. The Spalart-Allmaras one-equation turbulence model was used with the extended wall function for all cases in this study. The inlet turbulence boundary conditions were set with turbulence viscosity of 0.0001 m2/s in our empirical models. The convergence of the CFD calculations was determined on the assumption that the average residual of CFD iterations should be less than 10−6 or the mass flow rate difference between inlet and outlet boundaries should be less than 0.5%.

Airflow velocity, wall shear stress, and static pressure in the nasal cavities and pharynx were analyzed in patients with OSA during nasal breathing with closed mouth, nasal breathing with open mouth, and oral breathing.

Ethics and statistics

The Ethics Committee of Teikyo University approved this study (approval number 14–063) and written informed consent was obtained from all participants.

All descriptive statistics calculated for each variable are presented as the mean ± standard deviation. Variables were evaluated by one-way analysis of variance (ANOVA) among the three breathing conditions. A p value less than 0.01 was considered to indicate statistical significance. For multiple comparisons (post hoc test), variables were analyzed using the Bonferroni test. For comparisons between two conditions, variables were evaluated by Wilcoxon signed-rank test. Difference in airflow volume between inspiration and expiration was analyzed using a 2 × 2 Chi-square test. A p value less than 0.05 was considered to indicate statistical significance.

Results

The STL models revealed that the tongue touched the hard palate during nasal breathing with closed mouth, whereas a low tongue position that did not touch the hard palate was observed during nasal and oral breathing with open mouth.

The inspiratory airflow velocity was higher during oral breathing (as high as 9.37 ± 1.07 mL/s) than during nasal breathing with open or closed mouth (p = 0.04) (Fig 2, Table 1). No significant difference was noted between nasal breathing with closed mouth (8.30 ± 1.07 mL/s) and nasal breathing with open mouth (7.93 ± 1.16 mL/s) (Figs 2 and 3, Table 1). During nasal breathing with open mouth, the inspiratory airflow in the nasal cavity and pharynx was relatively slow; it rapidly sped up at the lower level of the velopharynx, the junction of the nasal and oral breathing routes, then spread and became a disturbed, unsteady stream (Figs 2 and 3). A small amount of stream flowed into the mouth, and certain components of the inhaled air passed through the ostia into the maxillary sinuses before moving to the pharynx (Figs 2 and 3). In contrast, during nasal breathing with closed mouth, the inspiratory airflow was smooth throughout the breathing route, without spreading, disturbance, or instability; it gradually sped up to the maximum velocity at the oropharyngeal level without flowing into the oral cavity or the maxillary sinuses (Figs 2 and 3). CFD analyses showed that patients breathed 100% via the nose both in inspiration and expiration during nasal breathing, even with open mouth (Figs 2 and 4). In contrast, during oral breathing, patients breathed 28.7% ± 3.3% via the nose and 71.3 ± 5.1% via the mouth during inspiration, and breathed 20.4% ± 2.5% via the nose and 79.6% ± 4.4% via the mouth during expiration (p = 0.17) (Figs 2 and 4).

Fig 2. Airflow imaging and velocity contours during inspiration, side view.

Fig 2

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(A) Nasal breathing with closed mouth, (B) Nasal breathing with open mouth, (C) Oral breathing.

Table 1. Summary of CFD results.

A: nasal breathing with closed mouth B: nasal breathing with open mouth C: oral breathing
Inspiratory airflow velocity (mL/s) (95% confidence interval) 8.30 ± 1.07
(7.69 to 8.92)		 7.93 ± 1.16
(7.27 to 8.60)		 9.37 ± 1.07
(8.75 to 9.98)		 * p = 0.04
† p = 0.04
‡ p = 0.04
# N.S.
Negative static pressure (Pa) (95% confidence interval) −66.2 ± 7.55
(−61.8 to −70.5)		 −58.2 ± 7.97
(−53.6 to −62.8)		 −121.8 ± 13.9
(−113.7 to −129.8)		 * p < 0.01
† p < 0.01
‡ p < 0.01
# N.S.
Wall shear stress (Pa) (95% confidence interval) 2.18 ± 0.37
(1.97 to 2.38)		 2.41 ± 0.28
(2.26 to 2.57)		 Unparsable # p = 0.024
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* among the three conditions (ANOVA test);

† between nasal breathing with closed mouth and oral breathing (Bonferroni test);

‡ between nasal breathing with open mouth and oral breathing (Bonferroni test);

# between nasal breathing with closed and open mouth (Bonferroni test among the three conditions, Wilcoxon signed-rank test between the two conditions)

Fig 3. Airflow imaging and velocity contours during inspiration, top and rear view.

Fig 3

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(A) Nasal breathing with closed mouth, (B) Nasal breathing with open mouth.

Fig 4. Airflow imaging and velocity contours during expiration, side view.

Fig 4

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(B) Nasal breathing with open mouth, (C) Oral breathing.

Next, the wall shear stress and static pressure distribution during inspiration were calculated. Wall shear stress during nasal breathing with closed mouth was 2.18 ± 0.37 Pa, and during nasal breathing with open mouth was 2.41 ± 0.28 Pa, showing a significant difference (p = 0.024) (Fig 5, Table 1). We were unable to perform CFD analyses of the wall shear stress during oral breathing, because we found it difficult to analyze wall shear stress during inspiration at the junction of nasal and oral flow.

Fig 5. Wall shear stress distribution during inspiration.

Fig 5

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(A) Nasal breathing with closed mouth, (B) Nasal breathing with open mouth.

Negative static pressure was also similar during nasal breathing with closed mouth (−66.2 ± 7.55 Pa) and nasal breathing with open mouth (−58.2 ± 7.97 Pa), showing no significant difference (Fig 6, Table 1). In contrast, negative static pressure during oral breathing decreased the most significantly, down to −121.8 ± 13.9 Pa (p < 0.01) (Fig 6). CFD results are summarized in Table 1.

Fig 6. Static pressure distribution during inspiration.

Fig 6

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(A) Nasal breathing with closed mouth, (B) Nasal breathing with open mouth, (C) Oral breathing.

Discussion

Two novel findings were obtained in this CFD study. First, airflow velocity and static pressure were highest during oral breathing, suggesting that oral breathing is the primary condition leading to pharyngeal collapse in the three breathing conditions. Second, the airflow during nasal breathing with closed mouth was smooth throughout the whole breathing route—without spreading, disturbance, or instability—whereas that during nasal breathing with open mouth became a spreading and disturbed, unsteady stream.

Although several physiological studies have shown that mouth opening increases upper airway collapsibility, no reports to date have used CFD technology to investigate the effect of nasal and oral breathing route on upper airway collapsibility. Some studies, including our previous study, have evaluated the efficacy of OSA treatments by using CFD simulations with parameters such as velocity and static pressure; improvements in these CFD parameters after OSA treatment have been reported [6–8]. This is the first report to use CFD technology for investigating the effect of nasal and oral breathing route on upper airway collapsibility.

Airflow velocity, static pressure, and collapsibility

Maintenance of upper airway patency is a primary physiologic condition during sleep; failure leads to collapse of the upper airway. Dynamic alterations in patency in patients with OSA are modeled as a function of transmural pressure across collapsible segments. Collapsibility of the upper airway is based on the Starling resistor model, a theoretical model related to Bernoulli’s theory, whereby maximal airflow through the collapsible segment is dependent on the resistance of the upstream and downstream rigid segment and the pressure surrounding the collapsible segment [9–10]. In this model, the upper airway is considered to contain a compressible segment with a smaller cross-sectional area than the two rigid segments of the upper airway that it connects, so that the airflow velocity is greater through it than through the rigid segments. When the upstream and downstream pressures are lower than the critical pressure surrounding the collapsible segment, the negative intraluminal pressure (negative static pressure) decreases and the velocity of inspiratory airflow increases. Thus, obstruction occurs, the airway closes, and airflow ceases. This model postulates the oropharynx as a collapsible segment. Static pressure changes are amplified dynamically in this segment via the Bernoulli effect, and the airflow velocity through the upper airway is proportional to the static pressure gradient across the entire airway.

Based on the concept of the Starling resistor model, collapsibility is dependent on the airflow velocity and the static pressure through the oropharynx. Detailed values for airflow velocity and static pressure through the pharyngeal airway can be calculated using CFD. Our results showed that airflow velocity and static pressure were significantly increased during oral breathing, indicating that airflows with different velocities merged to generate friction and swirl, which led to loss of pressure and an increase in entropy that facilitated collapse.

Oral breathing, nasal obstruction, and pharyngeal collapse

During sleep, the physiology of the upper and lower airways and respiratory control encourage nasal breathing rather than oral breathing. However, in nasal diseases such as nasal septum deviation or inferior turbinate hypertrophy, nasal obstruction can be bypassed by opening the mouth and allowing a greater volume of air to be inspired and expired. McLean et al. showed that oral breathing during sleep is induced by increased nasal resistance [11]. Our previous study showed that oral flow can be divided into three main patterns [12]. In these three patterns, spontaneous arousal-related oral flow was associated with nasal obstruction, typically seen in patients with mild to moderate sleep-disordered breathing. Increased nasal resistance leads to mouth opening and oral breathing. If nasal airway obstruction is severe, with high inspiratory resistive loads, nasal resistance exceeds a certain threshold and nasal breathing switches to oral breathing to bypass nasal airway obstruction. The results of this study are in agreement with those of the above-mentioned physiological studies. In patients susceptible to airway collapse or habitual oral breathing, oral breathing leads to mouth opening and sustained oral breathing; consequently, post-event or during-event oral flows would occur and induce respiratory events such as apnea or hypopnea.

Study limitations

A limitation of this study is that, first, we were unable to perform CFD analyses of the wall shear stress during oral breathing with open mouth, because of computational difficulties in analyzing wall shear stress during inspiration at the junction of nasal and oral flow using the CFD software. Further research to confirm the accuracy of analyses of wall shear stress at the junction are needed. Second, CT scans were performed while patients were conscious. It was difficult to distinguish nasal breathing with open mouth from nasal breathing with closed mouth and oral breathing during sleep under CT scanning conditions; thus, patients could have breathed with different amounts of effort, resulting in a large bias.

Opening the mouth and opening the ostium

Simulation models of the paranasal sinuses have been reported, showing increases of the airflow into the maxillary sinuses after nasal surgeries [13–14]. We showed that increased airflow streamlines passed into the maxillary sinuses during nasal breathing with open mouth compared to nasal breathing with closed mouth. When we open the mouth, the palatal tensor muscle makes the eustachian tube open, and airflow goes into the eustachian tube. However, there is no muscle opening the ostium of the maxillary sinus when the mouth opens. The relationship between opening the mouth and opening the ostium of the maxillary sinus is unknown. This could provide rhinologists with an interesting perspective; further investigations are required.

CFD in the upper airway

The aerodynamics of the nose and airway are complex due to their geometry and wall conditions. Static pressure is considered the key to elucidating pharyngeal collapsibility in patients with OSA. However, our results showed that airflow imaging and velocity contours provided detailed aerodynamics of nasal and oral breathing, demonstrating that airflow imaging is also an essential part of CFD analyses in the nose and airway in patients with OSA.

CFD studies to date have improved our understanding of pathogenesis on airflow and implications on nose and airway physiology. We could understand the pathogenesis of the nose and airway in greater detail by using these CFD assessments.

Data Availability

All relevant data are within the paper.

Funding Statement

There were no funding or sources of support received during this study.

References

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Decision Letter 0

Pei-Lin Lee

31 Dec 2019

PONE-D-19-30629

Comparison between nasal and oral breathing in patients with obstructive sleep apnea: computational fluid dynamics analyses

PLOS ONE

Dear Dr. Masaaki Suzuki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

As the reviewers' concern, the sample size is too small to make solid conclusion and  conditions of experiment should be clarified. Moreover, the illustration of procedure and data should be organized to help readers to understand better. I strongly recommend that  more subjects need to be recruited and the paper needs extensive revision to meet the standard of publication.

==============================

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Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: No

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5. Review Comments to the Author

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Reviewer #1: In the current study, the authors investigated differences of airflow dynamics between three types of breathing, that is, nasal breathing with mouth closed, nasal breathing with mouth opened, and oral breathing, in OSA patients (n=6).

Their major finding includes nasal breathing with mouth closed showed the advantage in terms of upper airway collapsibility.

To this reviewer, the current study looks very interesting, and manuscript is well written and well discussed. However, some issues should be addressed for the acceptable form of publication.

Major comments:

Is there any way to identify or assess the anatomical features such as a position of tongue during three types of breathing? It is just curiosity of this reviewer.

The sample size is just 6 OSA patients, so suggestion would be that assessment of SDB characteristics and computational fluid dynamics in each patient should be performed if possible. Might be interesting.

Minor comment:

The authors looked at only inspiration phase. Did the authors instruct the patients how to exhale, i.e. breath out via mouth or nose, and so forth?

Reviewer #2: This study investigated the differences in parameters of computational fluid dynamics (CFD) between the nasal and oral breathing in patients with obstructive sleep apnea (OSA). According to preliminary data of six adulthood patients with OSA, the authors concluded that oral breathing is the primary condition leading to pharyngeal collapse and the airflow during nasal breathing with the closed mouth was smoother than that with open mouth. Although this study is interested, there are many issues need to be addressed. Please consider revising to improve the quality of this manuscript.

1. The study topic is vague. What did you want to compare? The topic should include the examination condition (conscious status or sleep status?)

2. The conclusions of the abstract are not supported by the results (There was no result showing oral breathing increased pharyngeal collapse.) or simply duplication (The airflow during nasal breathing with the closed mouth was smoother than that with open mouth.).

3. In the method section, please illustrate the procedures to control the respiratory force during nasal breathing without the mouth opening, nasal breathing with the mouth opening, and mouth breathing? If the respiratory forces were significantly different, measurements of CFD parameters (such as velocity) might be not objective.

4. Please provide several tables to summarize your results because the readers cannot track your data according to the figures.

5. How did you decide your sample size? Did you evaluate the data distribution (normal or not normal?) and the statistical power? Because the sample size of this study was relatively small, this study was very preliminary and hard to make a conclusion.

6. The discussion section was not well-written and effective. The authors should compare their findings with other studies to explain specific research outcomes. The authors may explain the reasons for these findings are specific to OSA. Please consider writing a more effective discussion.

7. During awake, conscious states, patients could breathe with different efforts resulting in a larger bias and did not mimic to sleep-disturbed breathing events. Please consider to add it to your limitation.

8. Please request for English editing of this manuscript. There were many grammar errors and confusing sentences in the manuscript.

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Reviewer #2: Yes: Li-Ang Lee

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PLoS One. 2020 Apr 13;15(4):e0231262. doi: 10.1371/journal.pone.0231262.r002

Author response to Decision Letter 0

19 Feb 2020

Response to Reviewers

We would like to thank the reviewers for the latest review and apologize for delaying the resubmission of this revised manuscript. We have answered each of the points below. We increased the sample size and reorganized the manuscript to try to improve the logical flow of our argument. We hope that this more substantial reworking of the manuscript is satisfactory.

Reviewer #1:

Major comments:

Is there any way to identify or assess the anatomical features such as a position of tongue during three types of breathing? It is just curiosity of this reviewer.

Thank you for pointing this out. The STL models revealed that the tongue touched the hard palate during nasal breathing with closed mouth, whereas a low tongue position that did not touch the hard palate was observed during nasal and oral breathing with open mouth.

We have added these findings to the Results section.

The sample size is just 6 OSA patients, so suggestion would be that assessment of SDB characteristics and computational fluid dynamics in each patient should be performed if possible. Might be interesting.

Thank you for pointing this out. Statistical power test suggested that sample needs more than 12.14 under the conditions of delta; 0.3, sd; 0.2, sig.level; 0.01, and power; 0.8. Therefore, we added eight patients to make sample size 14. Significant difference was observed between the nasal breathing with closed and open mouth in the wall shear stress, however, other statistical comparisons showed almost the same results as before.

We changed the Result section.

Minor comment:

The authors looked at only inspiration phase. Did the authors instruct the patients how to exhale, i.e. breath out via mouth or nose, and so forth?

Thank you for pointing this out. During oral breathing, patients breathed 28.7% ± 3.3% via the nose and 71.3 ± 5.1% via the mouth during inspiration, and breathed 20.4% ± 2.5% via the nose and 79.6% ± 4.4% via the mouth during expiration (p= 0.17, 2x2 Chi square test). In contrast, patients breathed 100% via the nose both in inspiration and expiration during nasal breathing, even with open mouth.

We have added these findings and CFD figures during expiration (Fig. 4) to the Results section.

Reviewer #2:

1. The study topic is vague. What did you want to compare? The topic should include the examination condition (conscious status or sleep status?)

Thank you for pointing this out. The purpose of this study was to investigate the effect of breathing route on the collapsibility of the pharyngeal airway, represented by airflow velocity and static pressure calculated using CFD technology, in patients with OSA.

We changed the title, Introduction, and objective of the abstract to make this clear.

2. The conclusions of the abstract are not supported by the results (There was no result showing oral breathing increased pharyngeal collapse.)

Thank you for pointing this out. We elucidated the pharyngeal airway collapsibility based on the concept of the Starling Resistor model. Collapsibility is dependent on the airflow velocity and the static pressure through the oropharynx. Detailed values for airflow velocity and static pressure through the pharyngeal airway can be calculated using CFD. Our results showed that airflow velocity and static pressure were significantly increased during oral breathing, indicating that airflows with different velocities merged to generate friction and swirl, which led to loss of pressure and an increase in entropy that facilitated collapse.

We changed the Abstract and have added more detailed explanation of collapsibility to the Discussion section.

simply duplication (The airflow during nasal breathing with the closed mouth was smoother than that with open mouth.).

We have avoided the duplication in the Abstract.

3. In the method section, please illustrate the procedures to control the respiratory force during nasal breathing without the mouth opening, nasal breathing with the mouth opening, and mouth breathing? If the respiratory forces were significantly different, measurements of CFD parameters (such as velocity) might be not objective.

Thank you for pointing this out. We measured volumetric flow rates in a steady breathing state as a substitute marker for ventilatory drive using a pneumotachometer along with a pressure sensor rather than performing diaphragm electromyography during nasal breathing with closed mouth, nasal breathing with open mouth, and oral breathing. Simulation models were confirmed to agree with these measured values.

We have added this explanation to the Methods.

4. Please provide several tables to summarize your results because the readers cannot track your data according to the figures.

Thank you for pointing this out. We have added a summarized table of CFD results (Table 1).

5. How did you decide your sample size? Did you evaluate the data distribution (normal or not normal?) and the statistical power? Because the sample size of this study was relatively small, this study was very preliminary and hard to make a conclusion.

Thank you for pointing this out. Statistical power test suggested that sample needs more than 12.14 under the conditions of delta; 0.3, sd; 0.2, sig.level; 0.01, and power; 0.8. Therefore, we added eight patients to make sample size 14. Significant difference was observed between the nasal breathing with closed and open mouth in the wall shear stress, however, other statistical comparisons showed almost the same results as before.

We changed the Result section.

6. The discussion section was not well-written and effective. The authors should compare their findings with other studies to explain specific research outcomes. The authors may explain the reasons for these findings are specific to OSA. Please consider writing a more effective discussion.

Thank you for pointing this out. We have reorganized the Discussion to try to improve the logical flow of our argument. We have added essential discussion concerning velocity, pressure and collapsibility to the Discussion section, and deleted non-effective sections.

7. During awake, conscious states, patients could breathe with different efforts resulting in a larger bias and did not mimic to sleep-disturbed breathing events. Please consider to add it to your limitation.

Thank you for pointing this out. CT scans were performed while patients were conscious; thus, patients could have breathed with different amounts of effort, resulting in a large bias.

We have added this limitation section in the Discussion.

8. Please request for English editing of this manuscript. There were many grammar errors and confusing sentences in the manuscript.

The paper has been checked by a native English-speaking medical editor.

Attachment

Submitted filename: Response to Reviewers.docx

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Decision Letter 1

Pei-Lin Lee

20 Mar 2020

The effect of nasal and oral breathing on airway collapsibility in patients with obstructive sleep apnea: computational fluid dynamics analyses

PONE-D-19-30629R1

Dear Dr. Masaaki Suzuki

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Pei-Lin Lee, M.D., PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Both reviewers comment that all comments have been addressed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This review paper is a re-submission, and addresses the differences in pharyngeal airway collapsibility between nasal and oral breathing routs.

Overall the paper is improved over the initial submission, and my concerns have been adequately addressed.

Reviewer #2: Dear Dr. Suzuki,

Thanks for your revised manuscript. I find that my previous issues have been significantly addressed. This manuscript is more friendly to the audience and provides a reliable methodology to the peers. Your findings are interesting and provide a deep insight into nasal/oral breathing in obstructive sleep apnea. I have no further comments. Congratulate!

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Li-Ang Lee

Acceptance letter

Pei-Lin Lee

30 Mar 2020

PONE-D-19-30629R1

The effect of nasal and oral breathing on airway collapsibility in patients with obstructive sleep apnea: computational fluid dynamics analyses

Dear Dr. Suzuki:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Pei-Lin Lee

Academic Editor

PLOS ONE

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