Search

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1 ) withdrawal of neural ventilatory drive or 2 ) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness ). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P  < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P  < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

Key Points: •Some patients with obstructive sleep apnoea (OSA) respond well to oral appliance therapy, whereas others do not for reasons that are unclear. •In the present study, we used gold-standard measurements to demonstrate that patients with a posteriorly-located tongue (natural sleep endoscopy) exhibit a preferential improvement in collapsibility (lowered critical closing pressure) with oral appliances. •We also show that patients with both posteriorly-located tongue and less severe collapsibility (predicted responder phenotype) exhibit greater improvements in severity of obstructive sleep apnoea (i.e. reduction in event frequency by 83%, in contrast to 48% in predicted non-responders). •The present study suggests that the structure and severity of pharyngeal obstruction determine the phenotype of sleep apnoea patients who benefit maximally from oral appliance efficacy., Abstract: A major limitation to the administration of oral appliance therapy for obstructive sleep apnoea (OSA) is that therapeutic responses remain unpredictable. In the present study, we tested the hypotheses that oral appliance therapy (i) reduces pharyngeal collapsibility preferentially in patients with posteriorly-located tongue and (ii) is most efficacious (reduction in apnoea-hypopnea index; AHI) in patients with a posteriorly-located tongue and less-severe baseline pharyngeal collapsibility. Twenty-five OSA patients underwent upper airway endoscopy during natural sleep to assess tongue position (type I: vallecula entirely visible; type II: vallecula obscured; type III: vallecula and glottis obscured), as well as obstruction as a result of other pharyngeal structures (e.g. epiglottis). Additional sleep studies with and without oral appliance were performed to measure collapsibility (critical closing pressure; Pcrit) and assess treatment efficacy. Overall, oral appliance therapy reduced Pcrit by 3.9 ± 2.4 cmH 2 O (mean ± SD) and AHI by 69 ± 19%. Therapy lowered Pcrit by an additional 2.7 ± 0.9 cmH 2 O in patients with posteriorly-located tongue (types II and III) compared to those without (type I) (P < 0.008). Posteriorly-located tongue (p = 0.03) and lower collapsibility (p = 0.04) at baseline were significant determinants of (greater-than-average) treatment efficacy. Predicted responders (type II and III and Pcrit < 1 cmH 2 O) exhibited a greater reduction in the AHI (83 ± 9 vs. 48 ± 8% baseline, P < 0.001) and a lower treatment AHI (9 ± 6 vs. 32 ± 15 events h -1 , P < 0.001) than predicted non-responders. The site and severity of pharyngeal collapse combine to determine oral appliance efficacy. Specifically, patients with a posteriorly-located tongue plus less-severe collapsibility are the strongest candidates for oral appliance therapy., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Background: OSA results from the collapse of different pharyngeal structures (soft palate, tongue, lateral walls, and epiglottis). The structure involved in collapse has been shown to impact non-CPAP OSA treatment. Different inspiratory airflow shapes are also observed among patients with OSA. We hypothesized that inspiratory flow shape reflects the underlying pharyngeal structure involved in airway collapse., Methods: Subjects with OSA were studied with a pediatric endoscope and simultaneous nasal flow and pharyngeal pressure recordings during natural sleep. The mechanism causing collapse was classified as tongue-related, isolated palatal, lateral walls, or epiglottis. Flow shape was classified according to the degree of negative effort dependence (NED), defined as the percent reduction in inspiratory flow from peak to plateau., Results: Thirty-one subjects with OSA (mean apnea-hypopnea index score ± SD, 54 ± 27 events/h) who were 50 ± 9 years of age were studied. NED was associated with the structure causing collapse (P < .001). Tongue-related obstruction (n = 13) was associated with a small amount of NED (median, 19; interquartile range [IQR], 14%-25%). Moderate NED was found among subjects with isolated palatal collapse (median, 45; IQR, 39%-52%; n = 8) and lateral wall collapse (median, 50; IQR, 44%-64%; n = 8). The epiglottis was associated with severe NED (median, 89; IQR, 78%-91%) and abrupt discontinuities in inspiratory flow (n = 9)., Conclusions: Inspiratory flow shape is influenced by the pharyngeal structure causing collapse. Flow shape analysis may be used as a noninvasive tool to help determine the pharyngeal structure causing collapse., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: In some patients, obstructive sleep apnea (OSA) can be resolved with improvement in pharyngeal patency by sleeping lateral rather than supine, possibly as gravitational effects on the tongue are relieved. Here we tested the hypothesis that the improvement in pharyngeal patency depends on the anatomical structure causing collapse, with patients with tongue-related obstruction and epiglottic collapse exhibiting preferential improvements., Methods: Twenty-four OSA patients underwent upper airway endoscopy during natural sleep to determine the pharyngeal structure associated with obstruction, with simultaneous recordings of airflow and pharyngeal pressure. Patients were grouped into three categories based on supine endoscopy: Tongue-related obstruction (posteriorly located tongue, N = 10), non-tongue related obstruction (collapse due to the palate or lateral walls, N = 8), and epiglottic collapse (N = 6). Improvement in pharyngeal obstruction was quantified using the change in peak inspiratory airflow and minute ventilation lateral versus supine., Results: Contrary to our hypothesis, patients with tongue-related obstruction showed no improvement in airflow, and the tongue remained posteriorly located while lateral. Patients without tongue involvement showed modest improvement in airflow (peak flow increased 0.07 L/s and ventilation increased 1.5 L/min). Epiglottic collapse was virtually abolished with lateral positioning and ventilation increased by 45% compared to supine position., Conclusions: Improvement in pharyngeal patency with sleeping position is structure specific, with profound improvements seen in patients with epiglottic collapse, modest effects in those without tongue involvement and-unexpectedly-no effect in those with tongue-related obstruction. Our data refute the notion that the tongue falls back into the airway during sleep via gravitational influences., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objectives: Pharyngeal critical closing pressure (Pcrit) or collapsibility is a major determinant of obstructive sleep apnea (OSA) and may be used to predict the success/failure of non-continuous positive airway pressure (CPAP) therapies. Since its assessment involves overnight manipulation of CPAP, we sought to validate the peak inspiratory flow during natural sleep (without CPAP) as a simple surrogate measurement of collapsibility., Methods: Fourteen patients with OSA attended overnight polysomnography with pneumotachograph airflow. The middle third of the night (non-rapid eye movement sleep [NREM]) was dedicated to assessing Pcrit in passive and active states via abrupt and gradual CPAP pressure drops, respectively. Pcrit is the extrapolated CPAP pressure at which flow is zero. Peak and mid-inspiratory flow off CPAP was obtained from all breaths during sleep (excluding arousal) and compared with Pcrit., Results: Active Pcrit, measured during NREM sleep, was strongly correlated with both peak and mid-inspiratory flow during NREM sleep (r = -0.71, p < .005 and r = -0.64, p < .05, respectively), indicating that active pharyngeal collapsibility can be reliably estimated from simple airflow measurements during polysomnography. However, there was no significant relationship between passive Pcrit, measured during NREM sleep, and peak or mid-inspiratory flow obtained from NREM sleep. Flow measurements during REM sleep were not significantly associated with active or passive Pcrit., Conclusions: Our study demonstrates the feasibility of estimating active Pcrit using flow measurements in patients with OSA. This method may enable clinicians to estimate pharyngeal collapsibility without sophisticated equipment and potentially aid in the selection of patients for non- positive airway pressure therapies., (© Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Rationale: Oral appliances (OAs) are commonly used as an alternative treatment to continuous positive airway pressure for patients with obstructive sleep apnea (OSA). However, OAs have variable success at reducing the apnea-hypopnea index (AHI), and predicting responders is challenging. Understanding this variability may lie with the recognition that OSA is a multifactorial disorder and that OAs may affect more than just upper-airway anatomy/collapsibility., Objectives: The objectives of this study were to determine how OA alters AHI and four phenotypic traits (upper-airway anatomy/collapsibility and muscle function, loop gain, and arousal threshold), and baseline predictors of which patients gain the greatest benefit from therapy., Methods: In a randomized crossover study, 14 patients with OSA attended two sleep studies with and without their OA. Under each condition, AHI and the phenotypic traits were assessed. Multiple linear regression was used to determine independent predictors of the reduction in AHI., Measurements and Main Results: OA therapy reduced the AHI (30 ± 5 vs. 11 ± 2 events/h; P < 0.05), which was driven by improvements in upper-airway anatomy/collapsibility under passive (1.9 ± 0.7 vs. 4.7 ± 0.6 L/min; P < 0.005) and active conditions (2.4 ± 0.9 vs. 6.2 ± 0.4 L/min; P < 0.001). No changes were seen in muscle function, loop gain, or the arousal threshold. Using multivariate analysis, baseline passive upper-airway collapsibility and loop gain were independent predictors of the reduction in AHI (r 2  = 0.70; P = 0.001)., Conclusions: Our findings suggest that OA therapy improves the upper-airway collapsibility under passive and active conditions. Importantly, a greater response to therapy occurred in those patients with a mild anatomic compromise and a lower loop gain.

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/m(2) 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., (© 2016 Associated Professional Sleep Societies, LLC.)

The human pharyngeal airway during sleep is conventionally modeled as a Starling resistor. However, inspiratory flow often decreases with increasing effort (negative effort dependence, NED) rather than remaining fixed as predicted by the Starling resistor model. In this study, we tested a major prediction of the Starling resistor model--that the resistance of the airway upstream from the site of collapse remains fixed during flow limitation. During flow limitation in 24 patients with sleep apnea, resistance at several points along the pharyngeal airway was measured using a pressure catheter with multiple sensors. Resistance between the nose and the site of collapse (the upstream segment) was measured before and after the onset of flow limitation to determine whether the upstream dimensions remained fixed (as predicted by the Starling resistor model) or narrowed (a violation of the Starling resistor model). The upstream resistance from early to mid inspiration increased considerably during flow limitation (by 35 ± 41 cmH2O · liter(-1) · s(-1), P < 0.001). However, there was a wide range of variability between patients, and the increase in upstream resistance was strongly correlated with the amount of NED (r = 0.75, P < 0.001). Therefore, patients with little NED exhibited little upstream narrowing (consistent with the Starling model), and patients with large NED exhibited large upstream narrowing (inconsistent with the Starling model). These findings support the idea that there is not a single model of pharyngeal collapse, but rather that different mechanisms may dominate in different patients. These differences could potentially be exploited for treatment selection., (Copyright © 2014 the American Physiological Society.)

Rationale: Body habitus is a major determinant of obstructive sleep apnea (OSA). However, many individuals do not have OSA despite being overweight/obese (body mass index > 25 kg/m(2)) for reasons that are not fully elucidated., Objectives: To determine the key physiologic traits (upper-airway anatomy/collapsibility, upper-airway muscle responsiveness, chemoreflex control of ventilation, arousability from sleep) responsible for the absence of OSA in overweight/obese individuals., Methods: We compared key physiologic traits in 18 overweight/obese subjects without apnea (apnea-hypopnea index < 15 events per hour) with 25 overweight/obese matched patients with OSA (apnea-hypopnea index ≥ 15 events per hour) and 11 normal-weight nonapneic control subjects. Traits were measured by repeatedly lowering continuous positive airway pressure to subtherapeutic levels for 3 minutes during non-REM sleep., Measurements and Main Results: Overweight/obese subjects without apnea exhibited a less collapsible airway than overweight/obese patients with apnea (critical closing pressure: -3.7 ± 1.9 vs. 0.6 ± 1.2 cm H2O; P = 0.003; mean ± 95% confidence interval), but a more collapsible airway relative to normal-weight control subjects (-8.8 ± 3.1 cm H2O; P < 0.001). Notably, overweight/obese subjects without apnea exhibited a threefold greater upper-airway muscle responsiveness than both overweight/obese patients with apnea (Δgenioglossus EMG/Δepiglottic pressure: -0.49 [-0.22 to -0.79] vs. -0.15 [-0.09 to -0.22] %max/cm H2O; P = 0.008; mean [95% confidence interval]) and normal-weight control subjects (-0.16 [-0.04 to -0.30] %max/cm H2O; P = 0.02). Loop gain was elevated (more negative) in both overweight/obese groups and normal-weight control subjects (P = 0.02). Model-based analysis demonstrated that overweight/obese individuals without apnea rely on both more favorable anatomy and collapsibility and enhanced upper-airway dilator muscle responses to avoid OSA., Conclusions: Overweight/obese individuals without apnea have a moderately compromised upper-airway structure that is mitigated by highly responsive upper-airway dilator muscles to avoid OSA. Elucidating the mechanisms underlying enhanced muscle responses in this population may provide clues for novel OSA interventions.

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patient's physiology and guide therapy based on the traits.

Increasing either genioglossus muscle activity (GG) or end-expiratory lung volume (EELV) improves airway patency but not sufficiently for adequate treatment of obstructive sleep apnea (OSA) in most patients. The mechanisms by which these variables alter airway collapsibility likely differ, with increased GG causing airway dilation, whereas increased EELV may stiffen the airway walls through caudal traction. We sought to determine whether the airway stabilizing effect of GG activation is enhanced when EELV is increased. To investigate this aim, 15 continuous positive airway pressure (CPAP)-treated OSA patients were instrumented with an epiglottic catheter, intramuscular GG-EMG electrodes, magnetometers, and a nasal mask/pneumotachograph. Subjects slept supine in a sealed, head-out plastic chamber in which the extra-thoracic pressure could be lowered (to raise EELV) while on nasal CPAP with a variable deadspace to allow CO(2) stimulation (and GG activation). The pharyngeal critical closing pressure (P(CRIT)) was measured by sudden reduction of CPAP for three to five breaths each minute during non-rapid eye movement (NREM) sleep in 4 conditions: a) baseline, b) 500 ml increased EELV, c) 50% increased GG, and d) conditions b and c combined. P(CRIT) was found to be reduced from 2.2 + or - 0.7 cmH(2)O at baseline to -1.0 + or - 0.5 with increased EELV, 0.6 + or - 0.7 with increased GG and -1.6 + or - 0.7 when both variables were raised (P < 0.001). The slope of the P(CRIT) curves remained unchanged in all conditions (P = 0.05). However, the CPAP level at which flow limitation developed was lower in both increased EELV conditions (P = 0.001). These findings indicate that while both increased GG and EELV improve airway collapsibility, the combination of both variables has little additional effect over increasing EELV alone.

Changes in end-expiratory lung volume (EELV) affect upper airway stability. The passive pharyngeal critical pressure (Pcrit), a measure of upper airway collapsibility, is determined using airway pressure drops. The EELV change during these drops has not been quantified and may differ between obese obstructive sleep apnea (OSA) patients and controls. Continuous positive airway pressure (CPAP)-treated OSA patients and controls were instrumented with an epiglottic catheter, magnetometers (to measure change in EELV), and a nasal mask/pneumotachograph. Subjects slept supine in a head-out plastic chamber in which the extrathoracic pressure could be lowered (to raise EELV) while on nasal CPAP. The magnitude of EELV change during Pcrit measurement (sudden reductions of CPAP for 3-5 breaths each minute) was assessed at baseline and with EELV increased approximately 500 ml. Fifteen OSA patients and 7 controls were studied. EELV change during Pcrit measurement was rapid and pressure dependent, but similar in OSA and control subjects (74 +/- 36 and 59 +/- 24 ml/cmH(2)O respectively, P = 0.33). Increased lung volume (mean +521 ml) decreased Pcrit by a similar amount in OSA and control subjects (-3.1 +/- 1.7 vs. -3.9 +/- 1.9 cmH(2)O, P = 0.31). Important lung volume changes occur during passive Pcrit measurement. However, on average, there is no difference in lung volume change for a given CPAP change between obese OSA subjects and controls. Changes in lung volume alter Pcrit substantially. This work supports a role for lung volume in the pathogenesis of OSA, and lung volume changes should be a consideration during assessment of pharyngeal mechanics.

Background: Aging increases vulnerability to obstructive sleep apnea (OSA), but the underlying mechanisms remain unclear. Recent data in awake healthy volunteers show a decrease in the genioglossus negative pressure reflex and anatomic compromise with increasing age, suggesting an age-related predisposition to pharyngeal collapse. However, aging effects on pharyngeal collapsibility have not been studied extensively during sleep. We tested the hypotheses that upper airway closing pressure (PCLOSE) and the increase in pharyngeal resistance during sleep (primary outcomes) as well as measures of arousal threshold (secondary outcomes) increase with age., Methods: We studied 21 healthy individuals (8 women [mean (+/- SD) age, 36 +/- 18 years] and 13 men [mean age, 41 +/- 23 years]) who were between 18 and 75 years of age. During overnight polysomnography, we measured nasal pressure (PMASK) and epiglottic pressure (Pepi) during stage 2 sleep before and after airway occlusion (external valve) until arousal. PCLOSE was defined as the pressure at which PMASK plateaued despite further decreases in PEPI., Results: Increasing age was correlated with both pharyngeal collapsibility ([PCLOSE] r = 0.69; p < 0.01) and an increase in pharyngeal resistance during sleep (r = 0.56; p < 0.01) independent of body mass index (BMI) and gender. There was no evidence for an effect of age on arousal threshold after airway occlusion during stage 2 sleep., Conclusions: Older age is associated with increased pharyngeal airway collapsibility during sleep independent of gender and BMI. These data may at least partially explain the mechanisms underlying the predisposition for pharyngeal collapse in the elderly.

Considerable progress has been made over the last several decades in our understanding of the pathophysiology of both central and obstructive sleep apnea. Central sleep apnea, in its various forms, is generally the product of an unstable ventilatory control system (high loop gain) with increased controller gain (high hypercapnic responsiveness) generally being the cause. High plant gain can contribute under certain circumstances (hypercapnic patients). On the other hand, obstructive sleep apnea can develop as the result of a variety of physiologic characteristics. The combinations of these may vary considerably between patients. Most obstructive apnea patients have an anatomically small upper airway with augmented pharyngeal dilator muscle activation maintaining airway patency awake, but not asleep. However, individual variability in several phenotypic characteristics may ultimately determine who develops apnea and how severe the apnea will be. These include: (1) upper airway anatomy, (2) the ability of upper airway dilator muscles to respond to rising intrapharyngeal negative pressure and increasing Co(2) during sleep, (3) arousal threshold in response to respiratory stimulation, and (4) loop gain (ventilatory control instability). As a result, patients may respond to different therapeutic approaches based on the predominant abnormality leading to the sleep-disordered breathing.

Obstructive sleep apnea (OSA) is two to three times more common in men as in women. The mechanisms leading to this difference are currently unclear but could include gender differences in respiratory stability [loop gain (LG)] or upper airway collapsibility [pharyngeal critical closing pressure (Pcrit)]. The aim of this study was to compare LG and Pcrit between men and women with OSA to determine whether the factors contributing to apnea are similar between genders. The first group of 11 men and 11 women were matched for OSA severity (mean +/- SE apnea-hypopnea index = 43.8 +/- 6.1 and 44.1 +/- 6.6 events/h). The second group of 12 men and 12 women were matched for body mass index (BMI; 31.6 +/- 1.9 and 31.3 +/- 1.8 kg/m2, respectively). All measurements were made during stable supine non-rapid eye movement sleep. LG was determined using a proportional assist ventilator. Pcrit was measured by progressively dropping the continuous positive airway pressure level for three to five breaths until airway collapse. Apnea-hypopnea index-matched women had a higher BMI than men (38.0 +/- 2.4 vs. 30.0 +/- 1.9 kg/m2; P = 0.03), but LG and Pcrit were similar between men and women (LG: 0.37 +/- 0.02 and 0.37 +/- 0.02, respectively, P = 0.92; Pcrit: 0.35 +/- 0.62 and -0.18 +/- 0.87, respectively, P = 0.63). In the BMI-matched subgroup, women had less severe OSA during non-rapid eye movement sleep (30.9 +/- 7.4 vs. 52.5 +/- 8.1 events/h; P = 0.04) and lower Pcrit (-2.01 +/- 0.62 vs. 1.16 +/- 0.83 cmH2O; P = 0.005). However, LG was not significantly different between genders (0.38 +/- 0.02 vs. 0.33 +/- 0.03; P = 0.14). These results suggest that women may be protected from developing OSA by having a less collapsible upper airway for any given degree of obesity.

A three-element, pressure- and state (sleep and wake) -dependent contraction model of the genioglossal muscle was developed based on the microstructure of skeletal muscle and the cross-bridge theory. This model establishes a direct connection between the contractile forces generated in muscle fibers and the measured electromyogram signals during various upper airway conditions. This effectively avoids the difficulty of determining muscle shortening velocity during complex pharyngeal conditions when modeling the muscle's contractile behaviors. The activation of the genioglossal muscle under different conditions was then simulated. A sensitivity analysis was performed to determine the effects of varying each modeled parameter on the muscle's contractile behaviors. This muscle contraction model was then incorporated into our anatomically correct, two-dimensional computational model of the pharyngeal airway to perform a finite-element analysis of air flow, tissue deformation, and airway collapse. The model-predicted muscle deformations are consistent with previous observations regarding upper airway behavior in normal subjects.

Obstructive sleep apnea (OSA) is a common disease with important neurocognitive and cardiovascular sequelae. Existing therapies are unsatisfactory, leading investigators to seek alternative forms of anatomic manipulation to influence pharyngeal mechanics. We have developed a two-dimensional computational model of the normal human upper airway based on signal averaging of MRI. Using the finite element method, we can perform various anatomic perturbations on the structure in order to assess the impact of these manipulations on pharyngeal mechanics and collapse. By design, the normal sleeping upper airway model collapses at -13 cm H2O. This closing pressure becomes more negative (ie, less collapsible) when we perform mandibular advancement (-21 cm H2O), palatal resection (-18 cm H2O), or palatal stiffening (-17 cm H2O). Where clinical data are available in the literature, the results of our model correspond reasonably well. Furthermore, our model provides information regarding the site of obstruction and provides hypotheses for clinical studies that can be undertaken in the future (eg, combination therapies). We believe that, in the future, finite element modeling will provide a useful tool to help advance our understanding of OSA and its response to various therapies.

Ventilatory instability may play an important role in the pathogenesis of obstructive sleep apnea. We hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, we correlated loop gain with apnea-hypopnea index during supine, nonrapid eye movement sleep in three groups of patients with obstructive sleep apnea based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure less than -1 cm H(2)O), atmospheric pressure group (between -1 and +1 cm H(2)O), and positive pressure group (greater than +1 cm H(2)O). Loop gain was measured by sequentially increasing proportional assist ventilation until periodic breathing developed, which occurred in 24 of 25 subjects. Mean loop gain for all three groups was 0.37 +/- 0.11. A significant correlation was found between loop gain and apnea-hypopnea index in the atmospheric group only (r = 0.88, p = 0.0016). We conclude that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric.

Study Objectives: Previous studies in both awake and sleeping humans have demonstrated that lung-volume changes substantially affect upper-airway size and pharyngeal resistance and, thus, may influence pharyngeal patency. We sought to systematically investigate the isolated effects of lung-volume changes on pharyngeal collapsibility and mechanics and genioglossus muscle activation during stable non-rapid eye movement sleep. We hypothesized that lower lung volumes would lead to increased pharyngeal collapsibility, airflow resistance, and, in compensation, augmented genioglossus muscle activation., Design: Nineteen normal individuals (age, 30.4 +/- 0.5 years; body mass index: 24.5 +/- 0.4 kg/m2) were studied during stable non-rapid eye movement sleep in a rigid head-out shell equipped with a variable positive/negative pressure attachment for manipulations of extrathoracic pressure and, thus, lung volume., Setting: Sleep physiology laboratory., Participants: Normal healthy volunteers., Interventions: N/A., Measurements and Results: We measured change in end-expiratory lung volume (EELV) (magnetometers), genioglossus electromyogram (GGEMG) (intramuscular electrodes), pharyngeal pressure, and collapsibility of the pharynx in response to a brief pulse of negative pressure (-8 to -15 cm H2O) under the following conditions: (1) baseline, (2) increased EELV (+1 liter), and (3) decreased EELV (-0.6 liter). Reduced lung volumes led to increased inspiratory airflow resistance (7.54 +/- 2.80 cm H2O x L(-1) x s(-1) vs 4.53 +/- 1.05 cm H2O x L(-1) x s(-1), mean +/- SEM, P = 0.02) and increased genioglossus muscle activation (GGEMG peak 14.6% +/- 1.5% of maximum vs 8.6% +/- 1.5% of maximum, maximum P = 0.001) compared to baseline. The pharynx was also more collapsible at low lung volumes (4.3 +/- 0.5 cm H2O vs 5.4 +/- 0.6 cm H2O, P = 0.04)., Conclusions: We conclude that upper-airway muscles respond to changes in lung volumes but not adequately to prevent increased collapsibility. These results suggest that lung volume has an important influence on pharyngeal patency during non-rapid eye movement sleep in normal individuals.

Study Objectives: While obesity is the most common risk factor for the development of obstructive sleep apnea, the correlation between measures of obesity and apnea severity is only moderate. We thus attempted to identify anatomic and physiologic predictors of apnea severity., Design: We combined a careful assessment of upper airway anatomy, upper airway physiology, and ventilatory control in a group of obese individuals to identify predictors of apnea severity., Setting: Tertiary care academic medical center., Patients: 14 morbidly obese subjects being evaluated for weight-reduction surgery., Interventions: N/A MEASUREMENT AND RESULTS: We found no relationship between obesity (weight or body mass index) and apnea severity (respiratory disturbance index, RDI). However, those with severe apnea (RDI > 30) were found to have higher peak genioglossus EMG (GGEMG) (23.5 +/- 1.9 vs. 14.1 +/- 3.7 %max, p = 0.05) and greater airway collapsibility during pulses of negative pressure (7.6 +/- 0.9 vs. 4.4 -/+/-0.7 cmH2O, p =0.02). Airway collapsibility was significantly associated with RDI (r = 0.62, p < 0.01) as was peak GGEMG (r = 0.55, p < 0.05). Of the anatomic variables airway shape (A-P/lateral ratio) and volume change of the pharyngeal airway between total lung capacity and residual volume were different between those with and without severe apnea. Both correlated with RDI (A-P/lateral ratio: r = 0.70, p < 0.01 and volume change: r = 0.77, p < 0.01)., Conclusions: We believe these findings suggest that specific anatomic and physiologic properties of the airway interact with obesity to predispose to the development of airway collapse during sleep.

Study Objectives: Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during sleep. Several techniques have been proposed to assess the collapsibility of the upper airway in awake humans, but sleep-wake comparisons have rarely been attempted and there are few studies comparing OSA patients to control subjects. We sought to compare two collapsibility measurement techniques between normal and apneic subjects, and between wakefulness and sleep., Design: We conducted three studies. First, we examined whether collapsibility assessed by negative pressure pulses (NPPs) during wakefulness reflected values during sleep in 21 normal subjects. Second, we determined in these normal subjects whether collapsibility during sleep assessed by NPPs was predictive of collapsibility measured by inspiratory resistive loading (IRL). Finally, we compared upper-airway collapsibility between apnea patients (n = 22) and normal volunteers (n = 38) during wakefulness by NPPs., Setting: Clinical and research laboratories at the Brigham and Women's Hospital., Participants: Two populations of normal subjects (n = 21 and n = 38) and OSA patients (n = 22)., Measurements and Results: Collapsibility during wakefulness, as measured by NPPs, correlated significantly with collapsibility during sleep (r = 0.62; p = 0.003). There was also a significant correlation between the two measures of collapsibility (IRL and NPP) during sleep (r = 0.53; p = 0.04). Both measures revealed a significant increase in pharyngeal collapsibility during sleep as compared to wakefulness. Finally, apnea patients had significantly greater pharyngeal collapsibility than control subjects during wakefulness (p = 0.017)., Conclusions: These data suggest that upper-airway collapsibility measured during wakefulness does provide useful physiologic information about pharyngeal mechanics during sleep and demonstrates clear differences between individuals with and without sleep apnea.

Although pharyngeal muscles respond robustly to increasing PCO(2) during wakefulness, the effect of hypercapnia on upper airway muscle activation during sleep has not been carefully assessed. This may be important, because it has been hypothesized that CO(2)-driven muscle activation may importantly stabilize the upper airway during stages 3 and 4 sleep. To test this hypothesis, we measured ventilation, airway resistance, genioglossus (GG) and tensor palatini (TP) electromyogram (EMG), plus end-tidal PCO(2) (PET(CO(2))) in 18 subjects during wakefulness, stage 2, and slow-wave sleep (SWS). Responses of ventilation and muscle EMG to administered CO(2) (PET(CO(2)) = 6 Torr above the eupneic level) were also assessed during SWS (n = 9) or stage 2 sleep (n = 7). PET(CO(2)) increased spontaneously by 0.8 +/- 0.1 Torr from stage 2 to SWS (from 43.3 +/- 0.6 to 44.1 +/- 0.5 Torr, P < 0.05), with no significant change in GG or TP EMG. Despite a significant increase in minute ventilation with induced hypercapnia (from 8.3 +/- 0.1 to 11.9 +/- 0.3 l/min in stage 2 and 8.6 +/- 0.4 to 12.7 +/- 0.4 l/min in SWS, P < 0.05 for both), there was no significant change in the GG or TP EMG. These data indicate that supraphysiological levels of PET(CO(2)) (50.4 +/- 1.6 Torr in stage 2, and 50.4 +/- 0.9 Torr in SWS) are not a major independent stimulus to pharyngeal dilator muscle activation during either SWS or stage 2 sleep. Thus hypercapnia-induced pharyngeal dilator muscle activation alone is unlikely to explain the paucity of sleep-disordered breathing events during SWS.

Study Objective: To assess the effect of high local oral nicotine administration on the upper airway (UA) of normal males during wakefulness., Design: Nonrandomized study., Setting: Brigham & Women's Hospital General Clinical Research Center., Participants: Two groups of 13 and 12 normal male subjects were evaluated., Interventions: A "Fast acting" or "Intermediate acting" 2 mg transmucosal nicotine patch was attached to an upper molar tooth of study participants during wakefulness., Measurements: All data were collected prior to, and at several time points after, patch placement. Data measured included serum nicotine levels, genioglossal EMG, and pharyngeal resistance during basal breathing as well as the UA muscle response and UA collapsibility during negative UA pressure pulses., Results: None of the variables measured showed a statistically significant change with either nicotine patch despite a significant rise (p<0.05) in nicotine serum levels post patch placement in both groups. In several subjects, muscle activity and responsiveness to negative pressure increased after application of both patches and returned to near baseline levels at the last time point measured, a response consistent with the time course of nicotine release in both patches., Conclusions: Oral nicotine administration failed to consistently increase GG muscle activation which may be a problem of local bioavailability of nicotine in the muscle.

Obstructive sleep apnea is generally recognized as more common in men than in women. This could relate to gender differences in either ventilatory control mechanisms or the structure and function of the pharyngeal airway. Most studies suggest that women have a structurally smaller pharyngeal airway than men, which would likely predispose rather than protect them from airway collapse. However, pharyngeal airway patency is actually a dynamic interaction between anatomy and pharyngeal muscle activity. We therefore hypothesized that females may have increased pharyngeal dilator muscle activity, thereby protecting them from airway collapse during sleep. To test this hypothesis, we compared genioglossal EMG (GG-EMG, measured as a percentage of maximal muscle activity) and upper airway resistance in 22 healthy subjects, 11 males and 11 females, during wakefulness. No significant difference in pharyngeal resistance could be found between the genders. However, inspiratory peak phasic and expiratory tonic GG-EMG activity were both significantly greater in females (GG-EMG peak phasic; 24.3 +/- 3.8 versus 13.1 +/- 4.5% of maximum, p < 0.02; GG-EMG tonic; 12.2 +/- 2.8 versus 4.7 +/- 1.2% of maximum, p < 0.01). In addition, females demonstrated a significant EMG response to inspiratory loading that was not observed in men. We conclude that women have, under basal conditions during wakefulness, augmented genioglossal muscle activity compared with men. To the extent that this augmented muscle activity is maintained across states, the female airway may be more stable and less collapsible.

Pharyngeal collapse in obstructive sleep apnea patients is likely a product of a sleep-related decrement in pharyngeal dilator muscle activity superimposed upon abnormal airway anatomy. We postulate that during wakefulness, increased pharyngeal dilator muscle activity in apnea patients compensates for diminished airway size thus maintaining patency. We studied the waking genioglossus (GG) electromyogram (EMG) activity in 11 OSA patients and 14 age-matched controls to determine if GG activity is higher in the awake state in apnea patients than controls. To make this determination, we developed a reproducible methodology whereby true maximal GG EMG could be defined and thus basal activity quantitated as a percentage of this maximal value. Therefore, direct comparisons of basal activity between individuals was possible. We observed apnea patients to have significantly greater basal genioglossal activity compared to controls (40.6 +/- 5.6% vs. 12.7 +/- 1.7% of maximum). This difference persisted when size-matched subsets were compared. This augmented GG activity in apnea patients could be reduced with positive airway pressure. We speculate that this neuromuscular compensation present during wakefulness in apnea patients may be lost during sleep leading to airway collapse.

Reduction in the size of the pharynx and increased pharyngeal airflow resistance have been demonstrated in patients with obstructive sleep apnea (OSA). We evaluated 15 men with severe OSA and 10 nonapneic control subjects matched for age and weight in order to determine if PCSA, inspiratory pharyngeal airflow resistance, and abnormal breathing events during sleep were associated with alterations in the flow-volume relationship and other awake PFTs. Pharyngeal cross-sectional area was determined by CT, and pharyngeal resistance between choanae and epiglottis was measured during quiet awake breathing. In patients with OSA, there was an inverse relationship between the mean cross-sectional area of the oropharynx and the ratio of FEF50%/FIF50% (rs = -0.54; p = 0.03). In all subjects, pharyngeal resistance was inversely related to percentage of predicted values for FEF25-75% (rs = -0.56; p = 0.01). The frequency of apneas during sleep was significantly (p less than 0.05) related to the percentage of predicted values for MVV, TLC, FVC, and PIF. Obesity appears to account for the strength of these relationships. Flow-volume loops and other PFTs did not distinguish patients with OSA from controls.

Apnea during sleep has been associated with both increased pharyngeal resistance and nasal obstruction. Alcohol can worsen obstructive sleep apnea, but its influence on pharyngeal resistance and nasal patency has not been evaluated. Accordingly, we determined the effects of alcohol on pharyngeal and nasal resistances in 11 normal awake subjects on 2 separate days. Baseline pharyngeal resistance prior to placebo and alcohol was not significantly different. After placebo, pharyngeal resistance did not change significantly. However, after alcohol, pharyngeal resistance increased from 1.9 +/- 0.5 (SEM) to 3.3 +/- 0.8 cm H2O/L/s at 45 min (p less than 0.05) and returned to near baseline level by 90 min. Baseline nasal resistance varied considerably within subjects on the 2 days, but the mean values for baseline nasal resistance on alcohol and placebo days were not significantly different. Nasal resistance did not change after placebo, but after alcohol, nasal resistance increased from 2.4 +/- 0.9 at baseline to 3.7 +/- 0.8 at 45 min (NS) and to 4.3 +/- 1.2 cm H2O/L/s at 90 min (p less than 0.05). We conclude that a decrease in pharyngeal airway size and an increase in nasal resistance may account for alcohol's ability to worsen obstructive sleep apnea.

Although anatomic and physiologic abnormalities of the upper airway are thought to be important in the pathogenesis of obstructive sleep apnea (OSA), the relative contributions of these factors have not been elucidated. We therefore measured pharyngeal cross-sectional area (PCSA) and pharyngeal air-flow resistance (Rp) in 12 overweight men with severe symptomatic OSA (mean apnea plus hypopnea index [AHI], 66.9 +/- 6.0 events per hour) and in 17 age- and weight-matched control subjects without spontaneous complaints of OSA symptoms (mean AHI, 4.9 +/- 1.6 events per hour). During wakefulness, PCSA was assessed during breath cessation at FRC by computed tomography (CT) and Rp by measuring inspiratory air-flow resistance between the choanae and epiglottis. No measure of PCSA differed significantly between patients and control subjects, and only 1 measure of PCSA, minimal pharyngeal area, correlated with AHI in all subjects (r = -0.38, p less than 0.05). In contrast, Rp was significantly higher (p less than 0.05) in patients (6.9 +/- 1.0 cm H2O/L/s) than in all control subjects (4.2 +/- 0.5 cm H2O/L/s) and correlated significantly with AHI (r = 0.53, p less than 0.01). We conclude that increased inspiratory resistance to air flow in the naso-oropharynx is present during wakefulness in overweight men with OSA, when compared with matched control subjects without symptomatic OSA, and is associated with disordered breathing during sleep. This occurs even though computed tomography is unable to demonstrate that pharyngeal size during wakefulness at FRC is significantly different between patients and control subjects. These observations suggest that the ability to dilate the pharynx during inspiration may be defective in patients with OSA.

Investigation into the etiology of obstructive sleep apnea is beginning to focus increasing attention on upper airway anatomy and physiology (patency and resistance). Before conclusions concerning upper airway resistance in these patients can be made, the normal range of supraglottic and, more specifically, pharyngeal resistance needs to be better defined. We measured supraglottic and pharyngeal resistances during nasal breathing in a normal population of 35 men and women. Our technique measured epiglottic pressure with a balloon-tipped catheter, choanal pressure using anterior rhinometry, and flow with a sealed face mask and pneumotachograph. Resistance was measured at a flow rate of 300 ml/s during inspiration. Men had a mean pharyngeal resistance (choanae to epiglottis) of 4.6 +/- 0.8 (SE) cmH2O X l-1 X s, whereas women demonstrated a significantly (P less than 0.01) lower value, 2.3 +/- 0.3 cmH2O X l-1 X s. Supraglottic resistance was also higher in men (P = 0.01). Age (r = 0.73, P less than 0.01) correlated closely with pharyngeal resistance in men, but no such correlations could be found in women. These results may have implications in the epidemiology of obstructive sleep apnea.

Nasal obstruction has been shown to increase the number of apneas during sleep in normal subjects and in some may actually cause the sleep apnea syndrome. We postulated that the pharynx may act as a Starling resistor, where increases in negative inspiratory pressure result in elevated resistance across a collapsible pharyngeal segment. To test this theory in normal subjects we studied 10 men and 10 women during wakefulness. Pharyngeal resistance (the resistance across the airway segment between the choanae and the epiglottis) was determined in the normal state and with three inspiratory loads added externally. Flow was measured using a pneumotachometer and a sealed face mask; epiglottic pressure by a latex balloon placed just above the epiglottis and choanal pressure by anterior rhinometry. Pharyngeal resistance (measured at 300 ml/s) could thus be determined. Base-line inspiratory pharnygeal resistance was 1.6 +/- 0.2 cmH2O . l-1 . s. This increased to 2.3 +/- 0.3, 2.8 +/- 0.4, and 2.9 +/- 0.4 cmH2O . l-1 . s, respectively, with the addition of 1.3, 2.7, and 6.7 cmH2O . l-1 . s inspiratory load. The resistance at each level of load was significantly different from the base-line resistance determination (P less than 0.05) but not different from each other. We conclude that added nasal resistive loads during inspiration cause an increase in pharyngeal resistance during wakefulness but that this resistance does not increase further with additional increments of load.