pii: sp- 00004-15
http://dx.doi.org/10.5665/sleep.5440
SLEEP DISORDERED BREATHING
Tube Law of the Pharyngeal Airway in Sleeping Patients with Obstructive Sleep Apnea Pedro R. Genta, MD1,2; Bradley A. Edwards, PhD1; Scott A. Sands, PhD1,3; Robert L. Owens, MD1; James P. Butler, PhD1; Stephen H. Loring, MD4; David P. White, MD1; Andrew Wellman, MD, PhD1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA; 2Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil; 3Department of Allergy Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, Australia; 4Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 1
Study Objectives: Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during sleep. However, the dynamics of pharyngeal narrowing and re-expansion during flow-limited breathing are not well described. The static pharyngeal tube law (end-expiratory area versus luminal pressure) has demonstrated increasing pharyngeal compliance as luminal pressure decreases, indicating that the airway would be sucked closed with sufficient inspiratory effort. On the contrary, the airway is rarely sucked closed during inspiratory flow limitation, suggesting that the airway is getting stiffer. Therefore, we hypothesized that during inspiratory flow limitation, as opposed to static conditions, the pharynx becomes stiffer as luminal pressure decreases. Methods: Upper airway endoscopy and simultaneous measurements of airflow and epiglottic pressure were performed during natural nonrapid eye movement sleep. Continuous positive (or negative) airway pressure was used to induce flow limitation. Flow-limited breaths were selected for airway cross-sectional area measurements. Relative airway area was quantified as a percentage of end-expiratory area. Inspiratory airway radial compliance was calculated at each quintile of epiglottic pressure versus airway area plot (tube law). Results: Eighteen subjects (14 males) with OSA (apnea-hypopnea index = 57 ± 27 events/h), aged 49 ± 8 y, with a body mass index of 35 ± 6 kg/m2 were studied. A total of 163 flow limited breaths were analyzed (9 ± 3 breaths per subject). Compliances at the fourth (2.0 ± 4.7 % area/cmH2O) and fifth (0.0 ± 1.7 % area/cmH2O) quintiles were significantly lower than the first (12.2 ± 5.5 % area/cmH2O) pressure quintile (P < 0.05). Conclusions: The pharyngeal tube law is concave (airway gets stiffer as luminal pressure decreases) during respiratory cycles under inspiratory flow limitation. Keywords: flow limitation, obstructive sleep apnea, pharyngeal mechanics Citation: Genta PR, Edwards BA, Sands SA, Owens RL, Butler JP, Loring SH, White DP, Wellman A. Tube law of the pharyngeal airway in sleeping patients with obstructive sleep apnea. SLEEP 2016;39(2):337–343. Significance The mechanical behavior of the pharynx can be described through pharyngeal area vs. luminal pressure plots (tube law). The pharynx becomes more compliant during static conditions when luminal area is measured at end-expiration after step reductions of luminal pressure. Inspiratory flow limitation is a hallmark feature of obstructive sleep apnea (OSA). During flow limitation, despite a substantial decrease in luminal pressure that could lead to collapse, airflow persists and the pharynx remains patent. In the present study, we showed that the pharynx becomes stiffer as luminal pressure decreases during flow limitation in OSA patients. Understanding the mechanisms of pharyngeal stiffening during flow limitation may lead to the development of novel therapeutic approaches for OSA patients.
INTRODUCTION Obstructive sleep apnea (OSA) is characterized by repetitive upper airway narrowing and obstruction during sleep. Inspiratory flow limitation characterizes obstructive hypopneas and can be described as the failure of flow to increase despite increasing effort. Inspiratory effort against upstream resistance results in the reduction of pharyngeal luminal pressure and leads to pharyngeal narrowing.1,2 However, the dynamic behavior of airway narrowing and reexpansion during inspiration is not completely understood. The pharyngeal airway during sleep acts like a floppy tube. The cross-sectional area versus transmural pressure of a floppy tube (tube law) illustrates the stiffness and size of the tube at different pressure regimes. Previous studies have plotted the pharyngeal luminal area versus pressure, which is analogous to the tube law plot if extraluminal pressure is considered to be constant or atmospheric. However, in these studies, crosssectional area measurements were obtained during end-expiration or a prolonged central apnea, and decreases in luminal pressure were achieved by lowering nasal continuous positive airway pressure (CPAP), rather than with inspiratory suction pressure. The authors concluded that these “static” tube law plots demonstrated an increase in pharyngeal compliance as SLEEP, Vol. 39, No. 2, 2016
luminal pressure became more negative.3–5 This progressive increase in pharyngeal compliance suggests that the airway would easily collapse with any further decrease in luminal pressure. However, during inspiratory flow imitation, although flow may decrease (so-called negative effort dependence) after reaching an initial peak, the airway does not close completely despite increasingly negative luminal pressure reaching as low as −20 to −30 cmH2O. This could occur because of the formation of a Starling resistor or wave speed-like choke point whereby changes in downstream pressure do not affect airflow.6,7 Alternatively, contrary to the conventional wisdom about the pharyngeal tube law, the airway may actually be getting stiffer as luminal pressure becomes more negative. If the airway stiffens during inspiration, then the mechanisms that lead to stiffening need to be understood because it may help new therapies to be developed for OSA. The purpose of the current study was to assess the dynamic behavior of the pharynx during inspiratory flow limitation. A method to digitally process the images was developed, allowing the images to be analyzed at a high sampling frequency (30 Hz). Based on our observations of ongoing flow limitation despite very negative luminal pressures, we hypothesized that the pharynx becomes stiffer as luminal pressure decreases 337
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during inspiration. In order to test this hypothesis, subjects with OSA were submitted to upper airway endoscopy and simultaneous measurements of airflow and pharyngeal epiglottic pressure.
of secretions or if it did not include all the contours of the narrowing pharyngeal site) or if the bronchoscope’s position changed during the sequence. In addition, a sequence was also discarded if the expiratory flow pattern suggested expiratory flow limitation. Airway cross-sectional area was delimited using custom written edge detection software capable of distinguishing the air-tissue border (Image Processing Toolbox, Matlab, Natick, MA). All image sequences had their contrast parameters calibrated in order to optimize the distinction between pharyngeal tissue and lumen. Image distortion caused by the wide-angle endoscopic lens was also digitally corrected before analysis. Cross-sectional area was determined by digitally counting the number of pixels in the airway lumen and expressing the total as a percentage of the number of pixels at end-expiration.2 In order to validate the image distortion correction, the images of black circles of 10 different diameters (0.15–4.4 mm) were recorded at different distances from the tip of the scope (5 to 25 mm). The correlation between known circle area and area measured from the recorded circle images varied from 0.98 to 0.99, according to the various distances between the tip of the scope and the circles. In order to ensemble average all breaths within and between patients, we transformed each inspiration and expiration duration as its duration in percentage as follows. We initially measured the duration of inspiration and expiration for each breath. We then calculated the duration of inspiration and expiration of each breath as a percentage of its duration (0–100%). In addition, we interpolated flow, epiglottic pressure, and area to obtain values at each 1% increment of inspiratory and expiratory duration, using piecewise cubic interpolation. Because subjects were at different levels of CPAP during flow limitation, epiglottic pressure was subtracted from the CPAP level at end-expiration. Airway radial compliance at each quintile of the epiglottic pressure swing (up to peak negative pressure) was calculated as the change in airway area over change in luminal pressure. Sleep was staged according to the latest American Academy of Sleep Medicine criteria.8
METHODS Men and women were recruited from the sleep clinic at the Brigham and Women´s Hospital. All subjects had a previous diagnosis of OSA. The age range was 21 to 70 y. Subjects were excluded if they had heart failure, diabetes, or renal insufficiency, or if they were taking medications that could affect upper airway muscle function. Written, informed consent was given before participation in the study, which was approved by the Human Research Committee at Partners Healthcare. Instrumentation Subjects arrived in the laboratory 2 h before their usual bedtime and were instrumented with electrodes for electroencephalography (C4-A1, O2-A1), left and right electrooculography, and submental electromyography for sleep staging. After topical application of a decongestant (oxymetazoline 0.05%) and anesthetic (lidocaine 4%), a 5-French pressure catheter (Millar Instruments, Houston, TX) and a 2.8 mm-diameter pediatric bronchoscope (model BFXP-160F, Olympus, Tokyo, Japan) were inserted through the left and right nostrils, respectively. The pressure catheter was placed at the level of the epiglottis. The subjects breathed via a nasal mask, which was connected to a pneumotachometer (Hans-Rudolph, Kansas City, MO) and a differential pressure transducer referenced to atmosphere (Validyne, Northridge, CA) to measure airflow and mask pressure, respectively. A modified CPAP device (Philips Respironics, Murrysville, PA) capable of delivering both positive and negative pressures was attached to the mask in order to change the mask pressure to induce flow limitation. A data acquisition system (Power 1401, Cambridge Electronic Design, Cambridge, England) was used to capture and synchronize physiologic signals and endoscopic images. All signals were captured at a sampling frequency of 500 Hz and the images were sampled at 30 frames/sec.
Statistical Analysis Continuous variables are reported as the mean ± standard deviation (SD) or the median (interquartile range) as appropriate. Normal distribution was tested using the Shapiro-Wilk test. In order to compare cross-sectional area at each 10% increase in inspiratory and expiratory time, repeated-measures analysis of variance on ranks was used. Similarly, inspiratory airway radial compliance at each quintile of the epiglottic pressure swing in each patient was compared to test for the stiffening of the airway during inspiration. Pharyngeal hysteresis was defined as the difference between the percentage of airway area at the beginning of inspiration and at the beginning of expiration. In order to compare pharyngeal hysteresis between patients, the difference between airway area at the beginning of inspiration and at the beginning of expiration of each patient was compared using a signed rank test. Cross-correlation between epiglottic pressure and airway area was calculated to test for lags between these variables. A value of P < 0.05 was considered significant.
Protocol After instrumentation, the bronchoscope was placed just above the velopharynx and the subject was allowed to fall asleep in the supine position at his or her prescribed level of CPAP (CPAP was adjusted to eliminate flow limitation, if needed). The position of the scope was adjusted if necessary in order to include a close and clear view of the obstructing segment, while keeping the entire airway lumen in the field of view. After stable nonrapid eye movement (NREM) sleep was achieved, CPAP was reduced to sub-optimum levels for 2- to 3-min intervals in order to induce flow limitation. Data Analysis Flow-limited breath sequences from periods of stable flow limitation (i.e., without arousals) during NREM sleep were analyzed. Endoscopic images during these sequences were then reviewed. Sequences of flow limitation were discarded if the endoscopic image quality was not good (e.g., because SLEEP, Vol. 39, No. 2, 2016
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Table 1—Patient characteristics. Parameter Age (y) Sex (% males) BMI (kg/m2) AHI (events/h)
Values 49 ± 8 78 35 ± 6 57 ± 27
Data are presented as mean ± standard deviation. AHI, apnea-hypopnea index; BMI, body mass index.
RESULTS Eighteen subjects were studied and their characteristics are presented in Table 1. A total of 163 flow limited breaths were analyzed (9 ± 3 breaths per subject). Low levels of CPAP were necessary to provide stable flow limitation (2.6 ± 2.5 cmH2O). An example of flow, epiglottic pressure, and airway area tracings from a representative subject are shown in Figure 1. In all breaths analyzed, the airway narrowed significantly during inspiration. Downstream pressures reached −14.5 ± 5.0 cmH2O below mask pressure, indicating that if the airway is open at the beginning of inspiration, it is fairly resistant to complete closure. A representative recording of the velopharynx, mask and epiglottic pressures, and flow are shown in Video 1.
Figure 1—Tracings of flow, epiglottic pressure, and calculated airway area from a representative patient. Observe that the decrease in epiglottic pressure coincides with inspiratory flow limitation and pharyngeal narrowing.
and at the beginning of expiration of the same breath, was 29.6 (5.5–46.1)%; P = 0.007. No lag between epiglottic pressure and area was observed during inspiratory narrowing (from endexpiration to peak negative epiglottic pressure) (cross-correlation = 0.950) or reexpansion (from peak negative pressure to peak positive epiglottic pressure) (cross-correlation = 0.881).
Behavior of Flow, Epiglottic Pressure, and Airway Crosssectional Area During Flow Limitation Ensemble-averaged flow, epiglottic pressure, and airway crosssectional area plots using all analyzed breaths from all subjects are shown in Figure 2. Inspiratory airway narrowing and reexpansion tracked the change in epiglottic pressure. However, airway area showed minimal changes at mid-inspiration under flow limitation, despite increasingly negative luminal pressures, suggesting stiffening of the airway (Figure 2). Individual epiglottic pressure versus area plots for all subjects are shown in Figure 3A and demonstrate progressive airway stiffening as luminal pressure decreases in all patients. Ensemble averaged inspiratory area versus driving pressure and compliance at each pressure quintile are shown in Figure 3B. The pharynx became progressively stiffer as luminal pressure became more negative during inspiration. Compliances at the fourth and fifth quintiles were significantly lower than the first pressure quintile (P < 0.05). Pronounced inspiratory airway narrowing was observed at peak negative airway pressure (airway area = 11.4 ± 16.3% of the area at end-expiration). In addition, mucosal folding and apposition of the airway walls was observed in all subjects in association with inspiratory flow limitation (Figure 4).
DISCUSSION The main finding of the current study is that the tube law of the pharyngeal airway during inspiratory flow limitation is concave upward (the airway gets stiffer as luminal pressure decreases). Furthermore, we demonstrated that the tube law of the pharynx exhibited significant hysteresis, as exemplified by lack of full airway reexpansion during late inspiration. This study is the first to show highly sampled airway images as luminal pressure is decreased during inspiration, which provide new insights on the dynamic behavior of the pharynx during flow limitation. Previous studies have plotted the pharyngeal tube law by measuring airway area at end-expiration or during a central apnea. In the studies measuring airway area at end-expiration, the area was determined after dropping CPAP from therapeutic pressure to different lower levels.3,5 In another study that measured the area during central apnea, Isono et al.4 analyzed OSA patients and normal adults under general anesthesia and complete paralysis. After interrupting mechanical ventilation, the airway pressure was lowered during a prolonged central apnea from +20 cmH2O until the airway collapsed. Again, low compliance at high pressures and high compliance at low pressures was reported.4 Isono et al.9 also studied normal children and those with OSA under general anesthesia and paralysis. Most children exhibited the same exponential tube law reported in adults. However, some normal children could tolerate more negative airway pressures (−20 cmH2O) without airway collapse. These children were modeled with a sigmoidal, rather
Hysteresis Ensemble averaged epiglottic pressure and area plots for the entire respiratory cycle shows that the airway area does not fully recover by the end of inspiration. In addition, there is separation between the descending and ascending inspiratory and expiratory loops, compatible with hysteresis (Figure 5). Hysteresis, calculated as the difference between the percentage of airway area at the beginning of inspiration SLEEP, Vol. 39, No. 2, 2016
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Figure 2—Ensemble-averaged flow, epiglottic pressure, and airway area (± 95% confidence interval) plots from all subjects. Inspiratory airway narrowing and reexpansion largely follow the swing in epiglottic pressure. However, little or no change in airway area occurs at midinspiration despite the continued decrease in driving pressure, suggesting stiffening of the airway. *P < 0.05 (compared to beginning of inspiration). # P < 0.05 (compared to beginning of expiration).
A B
Figure 3—(A) Individual area versus pressure plots showing a more compliant airway at early inspiration, but stiffening as luminal pressure decreases in all subjects studied. (B) Ensemble averaged area versus driving pressure plot (continuous line) and pharyngeal compliance (◊) at each quintile of pressure. Pharyngeal compliance (mean ± 95% confidence interval) decreases as luminal pressure decreases (*P < 0.05 compared to first pressure quintile).
than exponential, curve (i.e., airway stiffening at low airway pressures, as we report in the current study). Our study was performed under different conditions and using different techniques than in previous studies, which may explain the different findings. In particular, luminal pressures tested in these previous studies were usually significantly SLEEP, Vol. 39, No. 2, 2016
higher than in our study.3–5,9 Moreover, in previous studies a single image was analyzed manually at each step of CPAP at end expiration or prolonged central apneas. In the current study, the images were analyzed continuously at a high sampling rate (30 Hz). In addition, previous studies assumed an exponential fit to the data, which could impair the identification 340
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Figure 5—Ensemble averaged epiglottic pressure versus airway area plot showing that the tube law is different during airway narrowing and reexpansion (hysteresis). The symbol (*) is pointing the beginning of inspiration. Airway area does not fully recover by the end of inspiration.
Figure 4—Endoscopic views of the velopharynx at end-expiration (left) and peak negative epiglottic pressure (right) taken from two different patients. The pressure catheter is passing through the airway (white). Observe the sulci on the mucosa (white arrows) denoting mucosal folding, which increase in number with pharyngeal narrowing. There is extensive surface contact of the pharyngeal walls and the formation of small luminal channels (black arrows) in the crevices of the folds but without complete collapse.
The tracheal lumen buckled but did not fully collapse.16 Kozlovsky et al.17 submitted floppy tubes to negative luminal pressures under simultaneous ultrasonography to observe tube folding. A sudden decrease in tube compliance was observed as soon as the tube walls touched in the center, forming two side channels.17 Although we did not quantify airway mucosal folding, it was evident in all patients during airway narrowing (Figure 4). It has been shown that OSA patients are subject to several structural changes of the pharyngeal mucosa such as extracellular matrix composition, increased fat, and inflammation that could potentially change mucosal elasticity, thickness and folding behavior.18–20 In addition, when the airway narrowed, the downstream structures were subjected to negative pressures that subsequently pulled them into the airway, possibly lengthening the region of collapse. This increased lengthening could add to the airflow resistance without further airway narrowing. Recognizing pharyngeal stiffening during flow limitation opens the opportunity to explore local pharyngeal mucosa characteristics that could be involved in this process. This could lead not only to a better understanding of the mechanisms of pharyngeal collapse but also potentially to novel treatment approaches for OSA. Phasic activation of the pharyngeal muscles could also be an additional mechanism that could explain stiffening of the airway during inspiration.10 However, tracheal traction, lung volume increases, and phasic muscle activation are not needed to explain the stiffening of the tube/airway in bench models and isolated animal preparations.13,16,17 Moreover, stiffening was observed in all individuals studied, some of whom are likely to have negligible pharyngeal dilator muscle activity during sleep (many OSA patients have reduced electromyographic responsiveness and ineffective muscles during sleep).21–23 Therefore, the progressive stiffening with decreasing luminal pressure we observed in human patients with OSA may be, at least in part, a mechanical property of the pharyngeal tissue.
of pharyngeal stiffening at more negative luminal pressures. Furthermore, by measuring airway area during expiration or central apnea, it was necessary to lower the luminal pressure by decreasing the CPAP, as opposed to our study, which lowered luminal pressure by using the patients’ own inspiratory effort (as occurs during OSA). Taken together, it is likely that the pharyngeal airway stiffens at the extremes, i.e., at high pressures3–5 as well as during flow limitation at more negative luminal pressures. The pharynx may become stiffer when luminal pressure is decreased by inspiratory effort via effects of tracheal tug and increasing lung volume.10–12 This is the opposite of what happens during a reduction of CPAP; when luminal pressure falls, lung volume decreases and pharyngeal collapsibility increases.11 Consistent with this mechanism, Amatoury et al.13 exposed Penrose tubes to different levels of wall strain. The area versus downstream pressure curves reported were similar to our results and suggested a significant contribution of wall strain as a cause of tube stiffening.13 Extraluminal tissue pressure has been shown to decrease during inspiration and after an increase in lung volume, suggesting that it may be involved in the stiffening of the pharynx during inspiratory flow limitation.14,15 Another potential mechanism making the airway stiffer during inspiration is folding of the airway walls. Amatoury et al.13 also showed that Penrose compliance decreased in association with buckling as luminal pressure was decreased, especially when three lobes were formed.13 In another study, Jones et al.16 used dog tracheas to plot area versus transmural pressure curves and showed that tracheal compliance decreased progressively as driving pressure increased. SLEEP, Vol. 39, No. 2, 2016
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Regarding the hysteresis observed in the collapse and reexpansion of the airway, mucosal surface tension is a potential mechanism. Mucosal surface tension has been listed as a potential contributor to pharyngeal collapse in OSA. Experiments that were able to reduce pharyngeal surface tension led to improvement in upper airway collapsibility and to a modest reduction in OSA severity.24–26 In the current study, significant pharyngeal hysteresis was found during respiratory cycles under inspiratory flow limitation through direct endoscopic visualization. Condos et al.27 showed that a higher CPAP was necessary to abolish flow limitation during an ascending CPAP titration as compared to a descending CPAP titration, indicating pharyngeal hysteresis. Bijaoui et al.28 reported pharyngeal hysteresis during inspiratory flow limitation from the analysis of flow versus pressure plots of OSA patients. Another study assessing the pharyngeal critical closing pressure (Pcrit) during inspiration and expiration using a single breath method showed that Pcrit during inspiration was lower than expiration, and the difference became greater if the airway was allowed to collapse during inspiration.29 The increased pressure necessary to reexpand a severely narrowed or collapsed airway may be explained by surface tension forces. During our studies, we observed significant luminal narrowing during inspiratory flow limitation, promoting extensive contact of the mucosal surface (Figure 4). Although we were not able to measure surface tension, this could be a possible mechanism to explain the observed pharyngeal hysteresis. We acknowledge some limitations of our study. First, area calculations from endoscopic images can be subjected to image distortion and amplification of the wide view lenses. In addition, longitudinal movement of the pharyngeal structures during the respiratory cycle and difficulty defining the plane of measurements may also influence luminal area calculations. We corrected lens distortion and calibrated image contrast to minimize these issues. Second, we did not measure extraluminal tissue pressure but considered it constant. A decrease of extraluminal tissue pressure during inspiration could have mitigated the resulting transmural pressure. Third, we did not monitor pharyngeal muscle activity. Although tube stiffening during an increase in driving pressure is found in isolated animal and bench models,13,16,30 it is not possible to rule out the contribution of tissue pressure and muscle activation to the inspiratory airway stiffening we observed. In conclusion, the pharyngeal tube law is concave (airway gets stiffer as luminal pressure decreases) during respiratory cycles under inspiratory flow limitation. In addition, significant hysteresis was observed. Further understanding of the mechanisms of pharyngeal stiffening and hysteresis may lead to novel interventions to facilitate airway patency in patients with OSA.
3. Isono S, Morrison DL, Launois SH, Feroah TR, Whitelaw WA, Remmers JE. Static mechanics of the velopharynx of patients with obstructive sleep apnea. J Appl Physiol 1993;75:148–54. 4. Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319–26. 5. Oliven A, Kaufman E, Kaynan R, et al. Mechanical parameters determining pharyngeal collapsibility in patients with sleep apnea. J Appl Physiol 2010;109:1037–44. 6. Dawson SV, Elliott EA. Use of the choke point in the prediction of flow limitation in elastic tubes. Fed Proc 1980;39:2765–70. 7. Smith PL, Wise RA, Gold AR, Schwartz AR, Permutt S. Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol 1988;64:789–95. 8. Berry RB, Brooks R, Gamaldo CE, et al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Version 2.0. www.aasmnet.org. Darien, IL: American Academy of Sleep Medicine, 2012. 9. Isono S, Shimada A, Utsugi M, Konno A, Nishino T. Comparison of static mechanical properties of the passive pharynx between normal children and children with sleep-disordered breathing. Am J Respir Crit Care Med 1998;157:1204–12. 10. Jordan AS, White DP, Owens RL, et al. The effect of increased genioglossus activity and end-expiratory lung volume on pharyngeal collapse. J Appl Physiol 2010;109:469–75. 11. Owens R, Malhotra A, Eckert D, White D, Jordan A. The influence of end-expiratory lung volume on measurements of pharyngeal collapsibility. J Appl Physiol 2010;108:445–51. 12. Thut DC, Schwartz AR, Roach D, Wise RA, Permutt S, Smith PL. Tracheal and neck position influence upper airway airflow dynamics by altering airway length. J Appl Physiol 1993;75:2084–90. 13. Amatoury J, Kairaitis K, Wheatley JR, Bilston LE, Amis TC. Onset of airflow limitation in a collapsible tube model: impact of surrounding pressure, longitudinal strain, and wall folding geometry. J Appl Physiol 2010;109:1467–75. 14. Kairaitis K, Verma M, Amatoury J, Wheatley JR, White DP, Amis TC. A threshold lung volume for optimal mechanical effects on upper airway airflow dynamics: studies in an anesthetized rabbit model. J Appl Physiol 2012;112:1197–205. 15. Kairaitis K, Parikh R, Stavrinou R, et al. Upper airway extraluminal tissue pressure fluctuations during breathing in rabbits. J Appl Physiol 2003;95:1560–6. 16. Jones JG, Fraser RB, Nadel JA. Prediction of maximum expiratory flow rate from area-transmural pressure curve of compressed airway. J Appl Physiol 1975;38:1002–11. 17. Kozlovsky P, Zaretsky U, Jaffa AJ, Elad D. General tube law for collapsible thin and thick-wall tubes. J Biomech 2014;47:2378–84. 18. Stauffer JL, Buick MK, Bixler EO, et al. Morphology of the uvula in obstructive sleep apnea. Am Rev Respir Dis 1989;140:724–8. 19. Sériès F, Chakir J, Boivin D. Influence of weight and sleep apnea status on immunologic and structural features of the uvula. Am J Respir Crit Care Med 2004;170:1114–9. 20. Sériès F, Côté C, St Pierre S. Dysfunctional mechanical coupling of upper airway tissues in sleep apnea syndrome. Am J Respir Crit Care Med 1999;159:1551–5. 21. Genta PR, Owens RL, Edwards BA, et al. Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway. Respir Physiol Neurobiol 2014;201:55–9. 22. McGinley B, Schwartz A, Schneider H, Kirkness J, Smith P, Patil S. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol 2008;105:197–205. 23. Sands SA, Eckert DJ, Jordan AS, et al. Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med 2014;190:930–7. 24. Jokic R, Klimaszewski A, Mink J, Fitzpatrick MF. Surface tension forces in sleep apnea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial. Am J Respir Crit Care Med 1998;157:1522–5.
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SUBMISSION & CORRESPONDENCE INFORMATION
25. Kirkness JP, Christenson HK, Garlick SR, et al. Decreased surface tension of upper airway mucosal lining liquid increases upper airway patency in anaesthetised rabbits. J Physiol 2003;547:603–11. 26. Kirkness JP, Madronio M, Stavrinou R, Wheatley JR, Amis TC. Relationship between surface tension of upper airway lining liquid and upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome. J Appl Physiol 2003;95:1761–6. 27. Condos R, Norman RG, Krishnasamy I, Peduzzi N, Goldring RM, Rapoport DM. Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea. Am J Respir Crit Care Med 1994;150:475–80. 28. Bijaoui EL, Champagne V, Baconnier PF, Kimoff RJ, Bates JH. Mechanical properties of the lung and upper airways in patients with sleep-disordered breathing. Am J Respir Crit Care Med 2002;165:1055–61. 29. Kirkness JP, Schwartz AR, Patil SP, et al. Dynamic modulation of upper airway function during sleep: a novel single-breath method. J Appl Physiol 2006;101:1489–94. 30. Bertram CD. Flow phenomena in floppy tubes. Contemp Phys 2004;45:45–60.
Submitted for publication January, 2015 Submitted in final revised form June, 2015 Accepted for publication September, 2015 Address correspondence to: Pedro Rodrigues Genta, MD, 221 Longwood Avenue BLI 036, Boston, MA 02115; Email: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. Funding was provided by CAPES (Coordination for the Improvement of Higher Education Personnel), American Heart Association (13POST14770069), National Health and Medical Research Council (NHMRC) of Australia’s CJ Martin Overseas Biomedical Fellowship (1035115), NHMRC Early Career Fellowship (1053201) and R.G. Menzies award and NIH Grants R01 HL102321 and P01 NIH HL095491. Dr. Wellman has received research support from Philips Respironics. Dr. White is Chief Scientific Officer for Apnicure and a consultant for Philips Respironics. Dr. Owens is a paid consultant for Philips Respironics. The other authors have indicated no financial conflicts of interest. The research was conducted at the Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital.
ACKNOWLEDGMENTS The authors acknowledge Lauren Hess and Alison Foster for technical assistance with the studies.
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http://dx.doi.org/10.5665/sleep.5440
SLEEP DISORDERED BREATHING
Tube Law of the Pharyngeal Airway in Sleeping Patients with Obstructive Sleep Apnea Pedro R. Genta, MD1,2; Bradley A. Edwards, PhD1; Scott A. Sands, PhD1,3; Robert L. Owens, MD1; James P. Butler, PhD1; Stephen H. Loring, MD4; David P. White, MD1; Andrew Wellman, MD, PhD1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA; 2Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil; 3Department of Allergy Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, Australia; 4Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 1
Study Objectives: Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during sleep. However, the dynamics of pharyngeal narrowing and re-expansion during flow-limited breathing are not well described. The static pharyngeal tube law (end-expiratory area versus luminal pressure) has demonstrated increasing pharyngeal compliance as luminal pressure decreases, indicating that the airway would be sucked closed with sufficient inspiratory effort. On the contrary, the airway is rarely sucked closed during inspiratory flow limitation, suggesting that the airway is getting stiffer. Therefore, we hypothesized that during inspiratory flow limitation, as opposed to static conditions, the pharynx becomes stiffer as luminal pressure decreases. Methods: Upper airway endoscopy and simultaneous measurements of airflow and epiglottic pressure were performed during natural nonrapid eye movement sleep. Continuous positive (or negative) airway pressure was used to induce flow limitation. Flow-limited breaths were selected for airway cross-sectional area measurements. Relative airway area was quantified as a percentage of end-expiratory area. Inspiratory airway radial compliance was calculated at each quintile of epiglottic pressure versus airway area plot (tube law). Results: Eighteen subjects (14 males) with OSA (apnea-hypopnea index = 57 ± 27 events/h), aged 49 ± 8 y, with a body mass index of 35 ± 6 kg/m2 were studied. A total of 163 flow limited breaths were analyzed (9 ± 3 breaths per subject). Compliances at the fourth (2.0 ± 4.7 % area/cmH2O) and fifth (0.0 ± 1.7 % area/cmH2O) quintiles were significantly lower than the first (12.2 ± 5.5 % area/cmH2O) pressure quintile (P < 0.05). Conclusions: The pharyngeal tube law is concave (airway gets stiffer as luminal pressure decreases) during respiratory cycles under inspiratory flow limitation. Keywords: flow limitation, obstructive sleep apnea, pharyngeal mechanics Citation: Genta PR, Edwards BA, Sands SA, Owens RL, Butler JP, Loring SH, White DP, Wellman A. Tube law of the pharyngeal airway in sleeping patients with obstructive sleep apnea. SLEEP 2016;39(2):337–343. Significance The mechanical behavior of the pharynx can be described through pharyngeal area vs. luminal pressure plots (tube law). The pharynx becomes more compliant during static conditions when luminal area is measured at end-expiration after step reductions of luminal pressure. Inspiratory flow limitation is a hallmark feature of obstructive sleep apnea (OSA). During flow limitation, despite a substantial decrease in luminal pressure that could lead to collapse, airflow persists and the pharynx remains patent. In the present study, we showed that the pharynx becomes stiffer as luminal pressure decreases during flow limitation in OSA patients. Understanding the mechanisms of pharyngeal stiffening during flow limitation may lead to the development of novel therapeutic approaches for OSA patients.
INTRODUCTION Obstructive sleep apnea (OSA) is characterized by repetitive upper airway narrowing and obstruction during sleep. Inspiratory flow limitation characterizes obstructive hypopneas and can be described as the failure of flow to increase despite increasing effort. Inspiratory effort against upstream resistance results in the reduction of pharyngeal luminal pressure and leads to pharyngeal narrowing.1,2 However, the dynamic behavior of airway narrowing and reexpansion during inspiration is not completely understood. The pharyngeal airway during sleep acts like a floppy tube. The cross-sectional area versus transmural pressure of a floppy tube (tube law) illustrates the stiffness and size of the tube at different pressure regimes. Previous studies have plotted the pharyngeal luminal area versus pressure, which is analogous to the tube law plot if extraluminal pressure is considered to be constant or atmospheric. However, in these studies, crosssectional area measurements were obtained during end-expiration or a prolonged central apnea, and decreases in luminal pressure were achieved by lowering nasal continuous positive airway pressure (CPAP), rather than with inspiratory suction pressure. The authors concluded that these “static” tube law plots demonstrated an increase in pharyngeal compliance as SLEEP, Vol. 39, No. 2, 2016
luminal pressure became more negative.3–5 This progressive increase in pharyngeal compliance suggests that the airway would easily collapse with any further decrease in luminal pressure. However, during inspiratory flow imitation, although flow may decrease (so-called negative effort dependence) after reaching an initial peak, the airway does not close completely despite increasingly negative luminal pressure reaching as low as −20 to −30 cmH2O. This could occur because of the formation of a Starling resistor or wave speed-like choke point whereby changes in downstream pressure do not affect airflow.6,7 Alternatively, contrary to the conventional wisdom about the pharyngeal tube law, the airway may actually be getting stiffer as luminal pressure becomes more negative. If the airway stiffens during inspiration, then the mechanisms that lead to stiffening need to be understood because it may help new therapies to be developed for OSA. The purpose of the current study was to assess the dynamic behavior of the pharynx during inspiratory flow limitation. A method to digitally process the images was developed, allowing the images to be analyzed at a high sampling frequency (30 Hz). Based on our observations of ongoing flow limitation despite very negative luminal pressures, we hypothesized that the pharynx becomes stiffer as luminal pressure decreases 337
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during inspiration. In order to test this hypothesis, subjects with OSA were submitted to upper airway endoscopy and simultaneous measurements of airflow and pharyngeal epiglottic pressure.
of secretions or if it did not include all the contours of the narrowing pharyngeal site) or if the bronchoscope’s position changed during the sequence. In addition, a sequence was also discarded if the expiratory flow pattern suggested expiratory flow limitation. Airway cross-sectional area was delimited using custom written edge detection software capable of distinguishing the air-tissue border (Image Processing Toolbox, Matlab, Natick, MA). All image sequences had their contrast parameters calibrated in order to optimize the distinction between pharyngeal tissue and lumen. Image distortion caused by the wide-angle endoscopic lens was also digitally corrected before analysis. Cross-sectional area was determined by digitally counting the number of pixels in the airway lumen and expressing the total as a percentage of the number of pixels at end-expiration.2 In order to validate the image distortion correction, the images of black circles of 10 different diameters (0.15–4.4 mm) were recorded at different distances from the tip of the scope (5 to 25 mm). The correlation between known circle area and area measured from the recorded circle images varied from 0.98 to 0.99, according to the various distances between the tip of the scope and the circles. In order to ensemble average all breaths within and between patients, we transformed each inspiration and expiration duration as its duration in percentage as follows. We initially measured the duration of inspiration and expiration for each breath. We then calculated the duration of inspiration and expiration of each breath as a percentage of its duration (0–100%). In addition, we interpolated flow, epiglottic pressure, and area to obtain values at each 1% increment of inspiratory and expiratory duration, using piecewise cubic interpolation. Because subjects were at different levels of CPAP during flow limitation, epiglottic pressure was subtracted from the CPAP level at end-expiration. Airway radial compliance at each quintile of the epiglottic pressure swing (up to peak negative pressure) was calculated as the change in airway area over change in luminal pressure. Sleep was staged according to the latest American Academy of Sleep Medicine criteria.8
METHODS Men and women were recruited from the sleep clinic at the Brigham and Women´s Hospital. All subjects had a previous diagnosis of OSA. The age range was 21 to 70 y. Subjects were excluded if they had heart failure, diabetes, or renal insufficiency, or if they were taking medications that could affect upper airway muscle function. Written, informed consent was given before participation in the study, which was approved by the Human Research Committee at Partners Healthcare. Instrumentation Subjects arrived in the laboratory 2 h before their usual bedtime and were instrumented with electrodes for electroencephalography (C4-A1, O2-A1), left and right electrooculography, and submental electromyography for sleep staging. After topical application of a decongestant (oxymetazoline 0.05%) and anesthetic (lidocaine 4%), a 5-French pressure catheter (Millar Instruments, Houston, TX) and a 2.8 mm-diameter pediatric bronchoscope (model BFXP-160F, Olympus, Tokyo, Japan) were inserted through the left and right nostrils, respectively. The pressure catheter was placed at the level of the epiglottis. The subjects breathed via a nasal mask, which was connected to a pneumotachometer (Hans-Rudolph, Kansas City, MO) and a differential pressure transducer referenced to atmosphere (Validyne, Northridge, CA) to measure airflow and mask pressure, respectively. A modified CPAP device (Philips Respironics, Murrysville, PA) capable of delivering both positive and negative pressures was attached to the mask in order to change the mask pressure to induce flow limitation. A data acquisition system (Power 1401, Cambridge Electronic Design, Cambridge, England) was used to capture and synchronize physiologic signals and endoscopic images. All signals were captured at a sampling frequency of 500 Hz and the images were sampled at 30 frames/sec.
Statistical Analysis Continuous variables are reported as the mean ± standard deviation (SD) or the median (interquartile range) as appropriate. Normal distribution was tested using the Shapiro-Wilk test. In order to compare cross-sectional area at each 10% increase in inspiratory and expiratory time, repeated-measures analysis of variance on ranks was used. Similarly, inspiratory airway radial compliance at each quintile of the epiglottic pressure swing in each patient was compared to test for the stiffening of the airway during inspiration. Pharyngeal hysteresis was defined as the difference between the percentage of airway area at the beginning of inspiration and at the beginning of expiration. In order to compare pharyngeal hysteresis between patients, the difference between airway area at the beginning of inspiration and at the beginning of expiration of each patient was compared using a signed rank test. Cross-correlation between epiglottic pressure and airway area was calculated to test for lags between these variables. A value of P < 0.05 was considered significant.
Protocol After instrumentation, the bronchoscope was placed just above the velopharynx and the subject was allowed to fall asleep in the supine position at his or her prescribed level of CPAP (CPAP was adjusted to eliminate flow limitation, if needed). The position of the scope was adjusted if necessary in order to include a close and clear view of the obstructing segment, while keeping the entire airway lumen in the field of view. After stable nonrapid eye movement (NREM) sleep was achieved, CPAP was reduced to sub-optimum levels for 2- to 3-min intervals in order to induce flow limitation. Data Analysis Flow-limited breath sequences from periods of stable flow limitation (i.e., without arousals) during NREM sleep were analyzed. Endoscopic images during these sequences were then reviewed. Sequences of flow limitation were discarded if the endoscopic image quality was not good (e.g., because SLEEP, Vol. 39, No. 2, 2016
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Table 1—Patient characteristics. Parameter Age (y) Sex (% males) BMI (kg/m2) AHI (events/h)
Values 49 ± 8 78 35 ± 6 57 ± 27
Data are presented as mean ± standard deviation. AHI, apnea-hypopnea index; BMI, body mass index.
RESULTS Eighteen subjects were studied and their characteristics are presented in Table 1. A total of 163 flow limited breaths were analyzed (9 ± 3 breaths per subject). Low levels of CPAP were necessary to provide stable flow limitation (2.6 ± 2.5 cmH2O). An example of flow, epiglottic pressure, and airway area tracings from a representative subject are shown in Figure 1. In all breaths analyzed, the airway narrowed significantly during inspiration. Downstream pressures reached −14.5 ± 5.0 cmH2O below mask pressure, indicating that if the airway is open at the beginning of inspiration, it is fairly resistant to complete closure. A representative recording of the velopharynx, mask and epiglottic pressures, and flow are shown in Video 1.
Figure 1—Tracings of flow, epiglottic pressure, and calculated airway area from a representative patient. Observe that the decrease in epiglottic pressure coincides with inspiratory flow limitation and pharyngeal narrowing.
and at the beginning of expiration of the same breath, was 29.6 (5.5–46.1)%; P = 0.007. No lag between epiglottic pressure and area was observed during inspiratory narrowing (from endexpiration to peak negative epiglottic pressure) (cross-correlation = 0.950) or reexpansion (from peak negative pressure to peak positive epiglottic pressure) (cross-correlation = 0.881).
Behavior of Flow, Epiglottic Pressure, and Airway Crosssectional Area During Flow Limitation Ensemble-averaged flow, epiglottic pressure, and airway crosssectional area plots using all analyzed breaths from all subjects are shown in Figure 2. Inspiratory airway narrowing and reexpansion tracked the change in epiglottic pressure. However, airway area showed minimal changes at mid-inspiration under flow limitation, despite increasingly negative luminal pressures, suggesting stiffening of the airway (Figure 2). Individual epiglottic pressure versus area plots for all subjects are shown in Figure 3A and demonstrate progressive airway stiffening as luminal pressure decreases in all patients. Ensemble averaged inspiratory area versus driving pressure and compliance at each pressure quintile are shown in Figure 3B. The pharynx became progressively stiffer as luminal pressure became more negative during inspiration. Compliances at the fourth and fifth quintiles were significantly lower than the first pressure quintile (P < 0.05). Pronounced inspiratory airway narrowing was observed at peak negative airway pressure (airway area = 11.4 ± 16.3% of the area at end-expiration). In addition, mucosal folding and apposition of the airway walls was observed in all subjects in association with inspiratory flow limitation (Figure 4).
DISCUSSION The main finding of the current study is that the tube law of the pharyngeal airway during inspiratory flow limitation is concave upward (the airway gets stiffer as luminal pressure decreases). Furthermore, we demonstrated that the tube law of the pharynx exhibited significant hysteresis, as exemplified by lack of full airway reexpansion during late inspiration. This study is the first to show highly sampled airway images as luminal pressure is decreased during inspiration, which provide new insights on the dynamic behavior of the pharynx during flow limitation. Previous studies have plotted the pharyngeal tube law by measuring airway area at end-expiration or during a central apnea. In the studies measuring airway area at end-expiration, the area was determined after dropping CPAP from therapeutic pressure to different lower levels.3,5 In another study that measured the area during central apnea, Isono et al.4 analyzed OSA patients and normal adults under general anesthesia and complete paralysis. After interrupting mechanical ventilation, the airway pressure was lowered during a prolonged central apnea from +20 cmH2O until the airway collapsed. Again, low compliance at high pressures and high compliance at low pressures was reported.4 Isono et al.9 also studied normal children and those with OSA under general anesthesia and paralysis. Most children exhibited the same exponential tube law reported in adults. However, some normal children could tolerate more negative airway pressures (−20 cmH2O) without airway collapse. These children were modeled with a sigmoidal, rather
Hysteresis Ensemble averaged epiglottic pressure and area plots for the entire respiratory cycle shows that the airway area does not fully recover by the end of inspiration. In addition, there is separation between the descending and ascending inspiratory and expiratory loops, compatible with hysteresis (Figure 5). Hysteresis, calculated as the difference between the percentage of airway area at the beginning of inspiration SLEEP, Vol. 39, No. 2, 2016
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Figure 2—Ensemble-averaged flow, epiglottic pressure, and airway area (± 95% confidence interval) plots from all subjects. Inspiratory airway narrowing and reexpansion largely follow the swing in epiglottic pressure. However, little or no change in airway area occurs at midinspiration despite the continued decrease in driving pressure, suggesting stiffening of the airway. *P < 0.05 (compared to beginning of inspiration). # P < 0.05 (compared to beginning of expiration).
A B
Figure 3—(A) Individual area versus pressure plots showing a more compliant airway at early inspiration, but stiffening as luminal pressure decreases in all subjects studied. (B) Ensemble averaged area versus driving pressure plot (continuous line) and pharyngeal compliance (◊) at each quintile of pressure. Pharyngeal compliance (mean ± 95% confidence interval) decreases as luminal pressure decreases (*P < 0.05 compared to first pressure quintile).
than exponential, curve (i.e., airway stiffening at low airway pressures, as we report in the current study). Our study was performed under different conditions and using different techniques than in previous studies, which may explain the different findings. In particular, luminal pressures tested in these previous studies were usually significantly SLEEP, Vol. 39, No. 2, 2016
higher than in our study.3–5,9 Moreover, in previous studies a single image was analyzed manually at each step of CPAP at end expiration or prolonged central apneas. In the current study, the images were analyzed continuously at a high sampling rate (30 Hz). In addition, previous studies assumed an exponential fit to the data, which could impair the identification 340
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Figure 5—Ensemble averaged epiglottic pressure versus airway area plot showing that the tube law is different during airway narrowing and reexpansion (hysteresis). The symbol (*) is pointing the beginning of inspiration. Airway area does not fully recover by the end of inspiration.
Figure 4—Endoscopic views of the velopharynx at end-expiration (left) and peak negative epiglottic pressure (right) taken from two different patients. The pressure catheter is passing through the airway (white). Observe the sulci on the mucosa (white arrows) denoting mucosal folding, which increase in number with pharyngeal narrowing. There is extensive surface contact of the pharyngeal walls and the formation of small luminal channels (black arrows) in the crevices of the folds but without complete collapse.
The tracheal lumen buckled but did not fully collapse.16 Kozlovsky et al.17 submitted floppy tubes to negative luminal pressures under simultaneous ultrasonography to observe tube folding. A sudden decrease in tube compliance was observed as soon as the tube walls touched in the center, forming two side channels.17 Although we did not quantify airway mucosal folding, it was evident in all patients during airway narrowing (Figure 4). It has been shown that OSA patients are subject to several structural changes of the pharyngeal mucosa such as extracellular matrix composition, increased fat, and inflammation that could potentially change mucosal elasticity, thickness and folding behavior.18–20 In addition, when the airway narrowed, the downstream structures were subjected to negative pressures that subsequently pulled them into the airway, possibly lengthening the region of collapse. This increased lengthening could add to the airflow resistance without further airway narrowing. Recognizing pharyngeal stiffening during flow limitation opens the opportunity to explore local pharyngeal mucosa characteristics that could be involved in this process. This could lead not only to a better understanding of the mechanisms of pharyngeal collapse but also potentially to novel treatment approaches for OSA. Phasic activation of the pharyngeal muscles could also be an additional mechanism that could explain stiffening of the airway during inspiration.10 However, tracheal traction, lung volume increases, and phasic muscle activation are not needed to explain the stiffening of the tube/airway in bench models and isolated animal preparations.13,16,17 Moreover, stiffening was observed in all individuals studied, some of whom are likely to have negligible pharyngeal dilator muscle activity during sleep (many OSA patients have reduced electromyographic responsiveness and ineffective muscles during sleep).21–23 Therefore, the progressive stiffening with decreasing luminal pressure we observed in human patients with OSA may be, at least in part, a mechanical property of the pharyngeal tissue.
of pharyngeal stiffening at more negative luminal pressures. Furthermore, by measuring airway area during expiration or central apnea, it was necessary to lower the luminal pressure by decreasing the CPAP, as opposed to our study, which lowered luminal pressure by using the patients’ own inspiratory effort (as occurs during OSA). Taken together, it is likely that the pharyngeal airway stiffens at the extremes, i.e., at high pressures3–5 as well as during flow limitation at more negative luminal pressures. The pharynx may become stiffer when luminal pressure is decreased by inspiratory effort via effects of tracheal tug and increasing lung volume.10–12 This is the opposite of what happens during a reduction of CPAP; when luminal pressure falls, lung volume decreases and pharyngeal collapsibility increases.11 Consistent with this mechanism, Amatoury et al.13 exposed Penrose tubes to different levels of wall strain. The area versus downstream pressure curves reported were similar to our results and suggested a significant contribution of wall strain as a cause of tube stiffening.13 Extraluminal tissue pressure has been shown to decrease during inspiration and after an increase in lung volume, suggesting that it may be involved in the stiffening of the pharynx during inspiratory flow limitation.14,15 Another potential mechanism making the airway stiffer during inspiration is folding of the airway walls. Amatoury et al.13 also showed that Penrose compliance decreased in association with buckling as luminal pressure was decreased, especially when three lobes were formed.13 In another study, Jones et al.16 used dog tracheas to plot area versus transmural pressure curves and showed that tracheal compliance decreased progressively as driving pressure increased. SLEEP, Vol. 39, No. 2, 2016
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Regarding the hysteresis observed in the collapse and reexpansion of the airway, mucosal surface tension is a potential mechanism. Mucosal surface tension has been listed as a potential contributor to pharyngeal collapse in OSA. Experiments that were able to reduce pharyngeal surface tension led to improvement in upper airway collapsibility and to a modest reduction in OSA severity.24–26 In the current study, significant pharyngeal hysteresis was found during respiratory cycles under inspiratory flow limitation through direct endoscopic visualization. Condos et al.27 showed that a higher CPAP was necessary to abolish flow limitation during an ascending CPAP titration as compared to a descending CPAP titration, indicating pharyngeal hysteresis. Bijaoui et al.28 reported pharyngeal hysteresis during inspiratory flow limitation from the analysis of flow versus pressure plots of OSA patients. Another study assessing the pharyngeal critical closing pressure (Pcrit) during inspiration and expiration using a single breath method showed that Pcrit during inspiration was lower than expiration, and the difference became greater if the airway was allowed to collapse during inspiration.29 The increased pressure necessary to reexpand a severely narrowed or collapsed airway may be explained by surface tension forces. During our studies, we observed significant luminal narrowing during inspiratory flow limitation, promoting extensive contact of the mucosal surface (Figure 4). Although we were not able to measure surface tension, this could be a possible mechanism to explain the observed pharyngeal hysteresis. We acknowledge some limitations of our study. First, area calculations from endoscopic images can be subjected to image distortion and amplification of the wide view lenses. In addition, longitudinal movement of the pharyngeal structures during the respiratory cycle and difficulty defining the plane of measurements may also influence luminal area calculations. We corrected lens distortion and calibrated image contrast to minimize these issues. Second, we did not measure extraluminal tissue pressure but considered it constant. A decrease of extraluminal tissue pressure during inspiration could have mitigated the resulting transmural pressure. Third, we did not monitor pharyngeal muscle activity. Although tube stiffening during an increase in driving pressure is found in isolated animal and bench models,13,16,30 it is not possible to rule out the contribution of tissue pressure and muscle activation to the inspiratory airway stiffening we observed. In conclusion, the pharyngeal tube law is concave (airway gets stiffer as luminal pressure decreases) during respiratory cycles under inspiratory flow limitation. In addition, significant hysteresis was observed. Further understanding of the mechanisms of pharyngeal stiffening and hysteresis may lead to novel interventions to facilitate airway patency in patients with OSA.
3. Isono S, Morrison DL, Launois SH, Feroah TR, Whitelaw WA, Remmers JE. Static mechanics of the velopharynx of patients with obstructive sleep apnea. J Appl Physiol 1993;75:148–54. 4. Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319–26. 5. Oliven A, Kaufman E, Kaynan R, et al. Mechanical parameters determining pharyngeal collapsibility in patients with sleep apnea. J Appl Physiol 2010;109:1037–44. 6. Dawson SV, Elliott EA. Use of the choke point in the prediction of flow limitation in elastic tubes. Fed Proc 1980;39:2765–70. 7. Smith PL, Wise RA, Gold AR, Schwartz AR, Permutt S. Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol 1988;64:789–95. 8. Berry RB, Brooks R, Gamaldo CE, et al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Version 2.0. www.aasmnet.org. Darien, IL: American Academy of Sleep Medicine, 2012. 9. Isono S, Shimada A, Utsugi M, Konno A, Nishino T. Comparison of static mechanical properties of the passive pharynx between normal children and children with sleep-disordered breathing. Am J Respir Crit Care Med 1998;157:1204–12. 10. Jordan AS, White DP, Owens RL, et al. The effect of increased genioglossus activity and end-expiratory lung volume on pharyngeal collapse. J Appl Physiol 2010;109:469–75. 11. Owens R, Malhotra A, Eckert D, White D, Jordan A. The influence of end-expiratory lung volume on measurements of pharyngeal collapsibility. J Appl Physiol 2010;108:445–51. 12. Thut DC, Schwartz AR, Roach D, Wise RA, Permutt S, Smith PL. Tracheal and neck position influence upper airway airflow dynamics by altering airway length. J Appl Physiol 1993;75:2084–90. 13. Amatoury J, Kairaitis K, Wheatley JR, Bilston LE, Amis TC. Onset of airflow limitation in a collapsible tube model: impact of surrounding pressure, longitudinal strain, and wall folding geometry. J Appl Physiol 2010;109:1467–75. 14. Kairaitis K, Verma M, Amatoury J, Wheatley JR, White DP, Amis TC. A threshold lung volume for optimal mechanical effects on upper airway airflow dynamics: studies in an anesthetized rabbit model. J Appl Physiol 2012;112:1197–205. 15. Kairaitis K, Parikh R, Stavrinou R, et al. Upper airway extraluminal tissue pressure fluctuations during breathing in rabbits. J Appl Physiol 2003;95:1560–6. 16. Jones JG, Fraser RB, Nadel JA. Prediction of maximum expiratory flow rate from area-transmural pressure curve of compressed airway. J Appl Physiol 1975;38:1002–11. 17. Kozlovsky P, Zaretsky U, Jaffa AJ, Elad D. General tube law for collapsible thin and thick-wall tubes. J Biomech 2014;47:2378–84. 18. Stauffer JL, Buick MK, Bixler EO, et al. Morphology of the uvula in obstructive sleep apnea. Am Rev Respir Dis 1989;140:724–8. 19. Sériès F, Chakir J, Boivin D. Influence of weight and sleep apnea status on immunologic and structural features of the uvula. Am J Respir Crit Care Med 2004;170:1114–9. 20. Sériès F, Côté C, St Pierre S. Dysfunctional mechanical coupling of upper airway tissues in sleep apnea syndrome. Am J Respir Crit Care Med 1999;159:1551–5. 21. Genta PR, Owens RL, Edwards BA, et al. Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway. Respir Physiol Neurobiol 2014;201:55–9. 22. McGinley B, Schwartz A, Schneider H, Kirkness J, Smith P, Patil S. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol 2008;105:197–205. 23. Sands SA, Eckert DJ, Jordan AS, et al. Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med 2014;190:930–7. 24. Jokic R, Klimaszewski A, Mink J, Fitzpatrick MF. Surface tension forces in sleep apnea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial. Am J Respir Crit Care Med 1998;157:1522–5.
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SUBMISSION & CORRESPONDENCE INFORMATION
25. Kirkness JP, Christenson HK, Garlick SR, et al. Decreased surface tension of upper airway mucosal lining liquid increases upper airway patency in anaesthetised rabbits. J Physiol 2003;547:603–11. 26. Kirkness JP, Madronio M, Stavrinou R, Wheatley JR, Amis TC. Relationship between surface tension of upper airway lining liquid and upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome. J Appl Physiol 2003;95:1761–6. 27. Condos R, Norman RG, Krishnasamy I, Peduzzi N, Goldring RM, Rapoport DM. Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea. Am J Respir Crit Care Med 1994;150:475–80. 28. Bijaoui EL, Champagne V, Baconnier PF, Kimoff RJ, Bates JH. Mechanical properties of the lung and upper airways in patients with sleep-disordered breathing. Am J Respir Crit Care Med 2002;165:1055–61. 29. Kirkness JP, Schwartz AR, Patil SP, et al. Dynamic modulation of upper airway function during sleep: a novel single-breath method. J Appl Physiol 2006;101:1489–94. 30. Bertram CD. Flow phenomena in floppy tubes. Contemp Phys 2004;45:45–60.
Submitted for publication January, 2015 Submitted in final revised form June, 2015 Accepted for publication September, 2015 Address correspondence to: Pedro Rodrigues Genta, MD, 221 Longwood Avenue BLI 036, Boston, MA 02115; Email: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. Funding was provided by CAPES (Coordination for the Improvement of Higher Education Personnel), American Heart Association (13POST14770069), National Health and Medical Research Council (NHMRC) of Australia’s CJ Martin Overseas Biomedical Fellowship (1035115), NHMRC Early Career Fellowship (1053201) and R.G. Menzies award and NIH Grants R01 HL102321 and P01 NIH HL095491. Dr. Wellman has received research support from Philips Respironics. Dr. White is Chief Scientific Officer for Apnicure and a consultant for Philips Respironics. Dr. Owens is a paid consultant for Philips Respironics. The other authors have indicated no financial conflicts of interest. The research was conducted at the Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital.
ACKNOWLEDGMENTS The authors acknowledge Lauren Hess and Alison Foster for technical assistance with the studies.
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