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Obstructive Sleep Apnea

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Abstract

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the pharyngeal airway during sleep. Control of pharyngeal patency is a complex process relating primarily to basic anatomy and the activity of many pharyngeal dilator muscles. The control of these muscles is regulated by a number of processes including respiratory drive, negative pressure reflexes, and state (sleep) effects. In general, patients with OSA have an anatomically small airway the patency of which is maintained during wakefulness by reflex‐driven augmented dilator muscle activation. At sleep onset, muscle activity falls, thereby compromising the upper airway. However, recent data suggest that the mechanism of OSA differs substantially among patients, with variable contributions from several physiologic characteristics including, among others: level of upper airway dilator muscle activation required to open the airway, increase in chemical drive required to recruit the pharyngeal muscles, chemical control loop gain, and arousal threshold. Thus, the cause of sleep apnea likely varies substantially between patients. Other physiologic mechanisms likely contributing to OSA pathogenesis include falling lung volume during sleep, shifts in blood volume from peripheral tissues to the neck, and airway edema. Apnea severity may progress over time, likely due to weight gain, muscle/nerve injury, aging effects on airway anatomy/collapsibility, and changes in ventilatory control stability. © 2012 American Physiological Society. Compr Physiol 2:2541‐2594, 2012.

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Figure 1. Figure 1.

Shown is a one minute recording of rapid eye movement (REM) sleep demonstrating an approximately 30 s obstructive apnea with arterial oxygen desaturation and arousal at the termination. The channels recorded are: electroencephalography (EEG) (C4A1 and 01A2), eye movement [right occulogram (ROC) and left occulogram (LOC)], Chin EMG, electrocardiography (EKG), sound (snore), thermister flow (FLOW), nasal pressure (NAF), thoracic and abdominal motion (THO and ABD), and oxygen saturation (SAO2).

Figure 2. Figure 2.

Estimated mean apnea‐hypopnea index (AHI) reduction (as a percentage of baseline AHI) associated with mean weight loss (as a percentage of baseline weight) from clinical studies of dietary weight loss (triangles), surgical weight loss (circles), and one population‐based observational study of weight change (fitted regression line). Note that the regression line is fitted to individual observations from Peppard and co‐workers and is not fitted to the points (representing other studies) in the figure. Adapted, with permission, from reference .

Figure 3. Figure 3.

Smoothed plot (5‐year moving average) of the prevalence of an apnea‐hypopnea index (AHI) of 15 or greater by age. Adapted, with permission, from reference .

Figure 4. Figure 4.

(A) Midsagittal MRI in a normal subject, highlighting the four upper airway regions: the nasopharynx, which is defined from the nasal turbinates to the hard palate; the retropalatal (RP) oropharynx, extending from the hard palate to the caudal margin of the soft palate; the retroglossal (RG) region from the caudal margin of the soft palate to the base of the epiglottis; and the hypopharynx, which is defined from the base of the tongue to the larynx. (B) The diagram demonstrates important midsagital upper airway, soft tissue, and bone structures. Adapted, with permission, from reference .

Figure 5. Figure 5.

The nose and nasal cavities are illustrated. The nasal value, the highest resistance portion of the upper airway, lies just inside the external nares shown in the figure.

Figure 6. Figure 6.

Illustrated are the extrensic muscles of the tongue. The primary protruders are the genioglossus and geniohyoid, while the primary retractors are the myoglossus and styloglossus.

Figure 7. Figure 7.

The group mean relationships between negative pressure at the epiglottis (Pepi) and genioglossal electromyogram (EMG) (GG EMG) are shown. In each condition there is a highly significant relationship between Pepi and GG EMG throughout inspiration. This can be seen both in the plot of both signals against time (upper panels) and in the x‐y plots (lower panels). The mean slopes of the relationships between negative Pepi and GG EMG were very similar among conditions within each experiment. Nonetheless, there was invariably some degree of “hysteresis”, whereby GG EMG changed relatively more for a given change in Pepi early in inspiration. Adapted, with permission, from reference .

Figure 8. Figure 8.

The top panel shows the instantaneous frequency plots for 2 motor units recorded on the same electrode before and after alpha to theta and theta to alpha transitions. Also shown are the raw electromyogram (EMG), airflow, and the electroencephalogram (EEG) recordings. Vertical lines indicate state transitions. The figure illustrates the differential effects of the alpha to theta transition on inspiratory phasic (top tracing) and tonic (second tracing) motor units and shows that the cessation of the inspiratory phasic unit was not a consequence of electrode movement. The bottom panel shows typical individual spikes for the 2 motor units illustrated in the top panel at points A, B, and C (a is the inspiratory phasic unit and b, the tonic unit). Adapted, with permission, from reference .

Figure 9. Figure 9.

Demonstrated are the muscles of the soft palate: (2) levator palatini; (3) tensor palatini; (4) musculus uvula; and (5) palatopharyngeus. The palatoglossus is not shown. Also shown is: (1) external pterygoid. Adapted, with permission, from reference .

Figure 10. Figure 10.

Depicted in this figure are the multiple muscles that attach to the hyoid bone and influence its position. Adapted, with permission, from reference .

Figure 11. Figure 11.

Many upper airway structures are shown on this figure. It is shown here primarily to demonstrate the superior, middle, and inferior constrictor muscles of the pharynx. Adapted, with permission, from reference .

Figure 12. Figure 12.

Upper airway cross‐sectional area plotted as a function of tidal volume in an apneic patient over four anatomic levels. In this apneic subject, the upper airway at all four anatomic levels enlarges in early inspiration and then remains relatively constant during the rest of inspiration, enlarges significantly in early expiration, and then narrows significantly toward the end of expiration. (A) Nasopharynx, (B) retropalatal high, (C) retropalatal low, and (D) retroglossal. (Solid line with open squares = inspiration, dashed line with closed triangles = expiration, dotted line = extrapolation between end of inspiration and the beginning of expiration, and between end of expiration and the beginning of inspiration.) Adapted, with permission, from reference .

Figure 13. Figure 13.

Box plots illustrating observed closing pressures (Pc). Distribution of sites of primary closure was provided for each of three groups: normal, sleep‐disordered breathing (SDB)‐1, and SDB‐2. Mean values are indicated by horizontal bar within each box; bars above and below each box represent SE. Ends of vertical lines denote SD. O or + symbols, outliers. VP, velopharynx; OP, oropharynx. **P < 0.01 versus normal group. Adapted, with permission, from reference .

Figure 14. Figure 14.

(A) Relation between external airway pressure and minimum pharyngeal cross‐sectional area in four subjects, representing the spectrum of passive mechanical properties of the pharynx. PClose, pressure at which the pharynx is closed. Constructed, with permission, from data in reference . (B) Relation between external airway pressure and maximum flow conducted by the upper airway (MAX). Lines A to F provide the spectrum seen in patients with obstructive sleep disorders (constructed, with permission, from data in reference ). The dashed line represents a subject who would have no obstructive abnormality during sleep. MAX0, maximum flow that can be conducted in the absence of pharyngeal dilator activity in the subject breathing with no external pressure applied. Modified, with permission, from reference .

Figure 15. Figure 15.

Pressure/flow relationships during a single respiratory event. The x‐axis shows time in seconds. Breaths with normal, intermediate, and flattened flow contours are labeled and a plot of the driving pressure/flow relationship is shown. As illustrated in the third small panel below, flow within each of the inspiratory phases beyond 5 s decreases as glottic pressure becomes more negative. This negative effort dependence is seen in some, but not all, flow limited breaths. Adapted, with permission, from reference .

Figure 16. Figure 16.

Apnea‐hypopnea index (AHI) in 82 patients with varying degrees of passive mechanical abnormalities (maximum flow at near atmospheric pressure). In 61 patients, the relation was determined in two body positions, resulting in 143 patient‐position combinations. Note that in patients with complete obstruction at atmospheric pressure (abscissa value = 0) AHI varies between 0 and 160 h−1 and that some patients with mild mechanical abnormalities have high AHI values. Adapted, with permission, from reference .

Figure 17. Figure 17.

Scatter plot of the relationship between minimum flow observed at near atmospheric pressure and the fraction of sleep time in stable breathing in the same patient‐body position combination during polysomnography. Adapted, with permission, from reference .

Figure 18. Figure 18.

Continuous polysomnography tracings showing spontaneous transition from cyclic obstructions (OSA) to stable breathing in a patient with a highly collapsible pharynx. C4/A1 is the electroencephalogram.

Figure 19. Figure 19.

Tracings from a patient to show how an increase in the fraction of time spent with inspiratory flow can make it possible to tolerate maximum flows that are well below peak flow in the unobstructed state. C3/A2, central electroencephalogram showing a continuous sleep pattern; ABD, abdomen; RC, ribcage; PMASK, mask pressure; PF; peak flow; TI/TTOT, fraction of time spent with inspiratory flow; MAX; maximum flow; RR, respiratory rate. (Left panel) Upon dial‐down of CPAP, the patient immediately developed an obstructive hypopnea where flow was less than 40% peak flow on CPAP and tidal volume (VT) was only 43% of VT requirement. With time (right panel, 5 min later), and despite no change in MAX, VT and ventilation returned to near baseline as a result of marked increase in the duration of inspiratory flow (note interval between vertical lines). There were only modest changes in end‐tidal PCO2 (PETCO2) and O2 saturation, making a steady state possible. Inset: diagram showing how an increase in the amplitude of inspiratory efforts (more negative intrathoracic pressure) can increase TI/TTOT and the time during which flow is maximum even in the absence of any prolongation in neural inspiratory time. PMAX, intrathoracic pressure at which MAX is reached. The faster rate of reduction in intrathoracic pressure results in an earlier flow crossing from expiration to inspiration and MAX is reached sooner (point c vs. point a). Likewise, intrathoracic pressure remains below PMAX for much of the declining phase of inspiratory effort (rising intrathoracic pressure), resulting in a delay in onset of expiratory flow and continued presence of MAX well beyond the point at which flow would have started to decline at the lower effort (point d vs. point b). Adapted, with permission, from reference .

Figure 20. Figure 20.

Peak phasic genioglossal electromyogram (EMG). Cumulative data from all subjects and patients demonstrating that in the basal state, the genioglossus functions at a higher percentage of maximum in OSA patients than controls. *P < 0.05 versus controls. Adapted, with permission, from reference .

Figure 21. Figure 21.

Response of genioglossus activity to an induced severe hypopnea in the absence of cortical arousal. C3/A2, C4/A1, and O2/A1 are three electroencephalography leads; PAW, airway pressure; MA GG, moving average of genioglossus activity; GG opening threshold, increase in GG activity level at which the airway opened. Note the progressive increase in both tonic and phasic GG activities and that both activities remained higher than at the beginning of the obstruction well beyond upper airway opening. The second obstructive event is milder than the first.

Figure 22. Figure 22.

Tracings illustrating an example of the response to increasing chemical drive on continuous positive airway pressure (CPAP) and immediately following induced obstruction. C3/A2: electroencephalogram. PETCO2: airway PCO2. MA‐GG: moving average of genioglossus activity, expressed as percent of maximum activity. (A) Patient breathing room air. CPAP was reduced to 1.0 cmH2O (dial‐down) inducing a severe hypopnea (arrow in flow tracing). Note that there was no increase in genioglossus activity during the obstructed breath. (B) In the same patient, inspired CO2 was increased for 30 s prior to dial‐down. Note that genioglossus activity increased little on CPAP despite doubling of ventilation (VE). However, there was a large increase in genioglossus activity following dial‐down. Adapted, with permission, from reference .

Figure 23. Figure 23.

Tracing from a patient showing failure of genioglossus activity to increase appreciably during the first obstructed breath despite a 3‐fold increase in ventilation prior to dial‐down (compare last breath in panels A and B). This patient had only mild hypopnea during dial‐down from air breathing (A), indicating mild abnormalities in pharyngeal mechanics (PCRIT was −10 cmH2O). His apnea‐hypopnea index was 68 h−1. Adapted, with permission, from reference .

Figure 24. Figure 24.

Tracings illustrating strong short‐term potentiation (STP) in a patient with obstructive apnea. C3/A2, electroencephalogram; MA GG, moving average of genioglossus activity. An apnea was induced by lowering CPAP pressure at arrow (dial‐down). Ventilation was stimulated prior to the dial‐down to advance GG recruitment. The obstruction was relieved by reinstituting optimum CPAP prior to arousal. Ventilation returned within a few breaths to or below the levels observed prior to the dial‐down (period covered by the solid horizontal bar). Note the increase in tonic activity during the obstruction. Also note that both phasic and tonic GG activities remained higher than activities prior to dial‐down despite comparable or lower ventilation. Unpublished observations.

Figure 25. Figure 25.

Tracings illustrating lack of short‐term potentiation (STP) in a patient with obstructive apnea. C3/A2, electroencephalogram; MA GG, moving average of genioglossus activity. An obstructive hypopnea was induced by lowering CPAP pressure at arrow (dial‐down). Ventilation was stimulated prior to the dial‐down to advance GG recruitment. The obstruction was relieved by reinstituting optimum CPAP prior to arousal. Ventilation returned within a few breaths to or below the levels observed prior to the dial‐down (period covered by the solid horizontal bar). Note minimal increase in tonic activity during the obstruction and lack of sustained increase in either tonic or phasic GG activity post obstruction at comparable levels of ventilation. Unpublished observations.

Figure 26. Figure 26.

Sequence of events following the onset of an obstructive event. At eupneic drive, dilator activity during sleep is less than the level required to keep the airway open. A hypopnea or apnea develops. Chemical drive increases. At a certain chemical drive (recruitment threshold), which varies greatly from patient to patient, the dilators begin responding to further increases in drive. The rate at which activity increases beyond the recruitment threshold is also highly variable. Activity increases until the level required to open the airway (dilator opening threshold) is reached. This threshold varies from 1% to 37% of GGMAX among patients. Activity increases for one or two breaths beyond the point of opening and then begins declining as chemical drive decreases. In the declining phase activity is higher than at the same drive in the rising phase as a result of short‐term potentiation (STP). Both the dilator opening threshold and the gain of STP are highly variable. The chemical drive at which dilator activity reaches Dilator Opening Threshold is referred to as effective recruitment threshold (TER). This sequence can be interrupted if the arousal threshold (TA) is less than TER.

Figure 27. Figure 27.

Schematic illustration of the events that lead to mixed or obstructive apneas. There are two chemical drive thresholds, the central apnea threshold (central AT) below which there are no respiratory efforts, and an obstructive apnea/hypopnea threshold below which there are efforts but the airway is obstructed and flow is unresponsive to chemical drive (i.e. effective recruitment threshold; TER). In the first sequence, the efforts increase, but with no ventilatory response, as chemical drive increases in the range between the two thresholds. Finally, as TER is crossed, the airway opens. A large overshoot develops that forces chemical drive below the central AT. A central apnea develops followed by a number of obstructed breaths as chemical drives cross between the two threshold (mixed apnea; M). In the second and third sequences, the ventilatory overshoot was not as pronounced and chemical drive decreases into the range between the two thresholds. An obstructive apnea/hypopnea develops (O).

Figure 28. Figure 28.

Frequency of observations having different intervals between upper airway opening and arousal. Type 1, no arousal before or after opening. Type 2, opening occurred before arousal. Type 3, opening occurred at or after arousal. Adapted, with permission, from reference .

Figure 29. Figure 29.

Average genioglossus (GG) opening threshold, expressed as % maximum GG activity, in 32 patients arranged in order of threshold values. Bars are standard deviation. Open bars are patients with closing pressure less than −1 cmH2O. Adapted, with permission, from reference .

Figure 30. Figure 30.

Relationship between genioglossus opening threshold and closing pressure (PCRIT) in patients with PCRIT more than −1 cmH2O. Adapted, with permission, from reference .

Figure 31. Figure 31.

Response of phasic genioglossus activity to increasing chemical drive on CPAP (solid lines) and during the first obstructed breath in six patients representing the three response types. Type A response (panels A and D): mechanoreceptor effect (difference between the two lines) is evident beginning with baseline (lowest) drive. Type B response (panels B and E): mechanoreceptor effect appears only after a threshold increase in chemical drive. Type C response (panels C and F): no mechanoreceptor effect across the entire range of chemical drive permitted by the arousal threshold. Adapted, with permission, from reference .

Figure 32. Figure 32.

Two examples illustrating the importance of control mechanisms in determining the apnea‐hypopnea index (AHI). Patient MO had a very high AHI despite a very low critical closing pressure (PCRIT) and a very low genioglossus opening threshold. In this patient, the problem was that the dilators were not responsive to chemical drive up to five times the eupneic drive (i.e. very high dilator recruitment threshold). By contrast, patient SI had a low AHI despite very high PCRIT and dilator opening threshold. In this patient, there was a vigorous dilator response, with activity reaching the opening threshold with a modest increase in drive. Unpublished observations.

Figure 33. Figure 33.

Flow chart showing how different polysomnographic features (boxed terms) can arise following sleep‐induced obstructive events. FL, flow limitation; LG, loop gain; OSA, obstructive sleep apnea; PUF, peak unloaded flow rate; SS, steady state; TA, increase in chemical drive required to cause arousal; TER, increase in chemical drive required to open the airway without arousal; UARS, upper airway resistance syndrome; MAX0, maximum flow at atmospheric pressure in the absence of pharyngeal dilator activity. See text. Adapted, with permission, from reference .

Figure 34. Figure 34.

Pclose as a function of age. Mean values from 18 persons. Multiple regression analysis revealed that Pclose became less negative with age (r = 0.75; P = 0.011). Adapted, with permission, from reference .



Figure 1.

Shown is a one minute recording of rapid eye movement (REM) sleep demonstrating an approximately 30 s obstructive apnea with arterial oxygen desaturation and arousal at the termination. The channels recorded are: electroencephalography (EEG) (C4A1 and 01A2), eye movement [right occulogram (ROC) and left occulogram (LOC)], Chin EMG, electrocardiography (EKG), sound (snore), thermister flow (FLOW), nasal pressure (NAF), thoracic and abdominal motion (THO and ABD), and oxygen saturation (SAO2).



Figure 2.

Estimated mean apnea‐hypopnea index (AHI) reduction (as a percentage of baseline AHI) associated with mean weight loss (as a percentage of baseline weight) from clinical studies of dietary weight loss (triangles), surgical weight loss (circles), and one population‐based observational study of weight change (fitted regression line). Note that the regression line is fitted to individual observations from Peppard and co‐workers and is not fitted to the points (representing other studies) in the figure. Adapted, with permission, from reference .



Figure 3.

Smoothed plot (5‐year moving average) of the prevalence of an apnea‐hypopnea index (AHI) of 15 or greater by age. Adapted, with permission, from reference .



Figure 4.

(A) Midsagittal MRI in a normal subject, highlighting the four upper airway regions: the nasopharynx, which is defined from the nasal turbinates to the hard palate; the retropalatal (RP) oropharynx, extending from the hard palate to the caudal margin of the soft palate; the retroglossal (RG) region from the caudal margin of the soft palate to the base of the epiglottis; and the hypopharynx, which is defined from the base of the tongue to the larynx. (B) The diagram demonstrates important midsagital upper airway, soft tissue, and bone structures. Adapted, with permission, from reference .



Figure 5.

The nose and nasal cavities are illustrated. The nasal value, the highest resistance portion of the upper airway, lies just inside the external nares shown in the figure.



Figure 6.

Illustrated are the extrensic muscles of the tongue. The primary protruders are the genioglossus and geniohyoid, while the primary retractors are the myoglossus and styloglossus.



Figure 7.

The group mean relationships between negative pressure at the epiglottis (Pepi) and genioglossal electromyogram (EMG) (GG EMG) are shown. In each condition there is a highly significant relationship between Pepi and GG EMG throughout inspiration. This can be seen both in the plot of both signals against time (upper panels) and in the x‐y plots (lower panels). The mean slopes of the relationships between negative Pepi and GG EMG were very similar among conditions within each experiment. Nonetheless, there was invariably some degree of “hysteresis”, whereby GG EMG changed relatively more for a given change in Pepi early in inspiration. Adapted, with permission, from reference .



Figure 8.

The top panel shows the instantaneous frequency plots for 2 motor units recorded on the same electrode before and after alpha to theta and theta to alpha transitions. Also shown are the raw electromyogram (EMG), airflow, and the electroencephalogram (EEG) recordings. Vertical lines indicate state transitions. The figure illustrates the differential effects of the alpha to theta transition on inspiratory phasic (top tracing) and tonic (second tracing) motor units and shows that the cessation of the inspiratory phasic unit was not a consequence of electrode movement. The bottom panel shows typical individual spikes for the 2 motor units illustrated in the top panel at points A, B, and C (a is the inspiratory phasic unit and b, the tonic unit). Adapted, with permission, from reference .



Figure 9.

Demonstrated are the muscles of the soft palate: (2) levator palatini; (3) tensor palatini; (4) musculus uvula; and (5) palatopharyngeus. The palatoglossus is not shown. Also shown is: (1) external pterygoid. Adapted, with permission, from reference .



Figure 10.

Depicted in this figure are the multiple muscles that attach to the hyoid bone and influence its position. Adapted, with permission, from reference .



Figure 11.

Many upper airway structures are shown on this figure. It is shown here primarily to demonstrate the superior, middle, and inferior constrictor muscles of the pharynx. Adapted, with permission, from reference .



Figure 12.

Upper airway cross‐sectional area plotted as a function of tidal volume in an apneic patient over four anatomic levels. In this apneic subject, the upper airway at all four anatomic levels enlarges in early inspiration and then remains relatively constant during the rest of inspiration, enlarges significantly in early expiration, and then narrows significantly toward the end of expiration. (A) Nasopharynx, (B) retropalatal high, (C) retropalatal low, and (D) retroglossal. (Solid line with open squares = inspiration, dashed line with closed triangles = expiration, dotted line = extrapolation between end of inspiration and the beginning of expiration, and between end of expiration and the beginning of inspiration.) Adapted, with permission, from reference .



Figure 13.

Box plots illustrating observed closing pressures (Pc). Distribution of sites of primary closure was provided for each of three groups: normal, sleep‐disordered breathing (SDB)‐1, and SDB‐2. Mean values are indicated by horizontal bar within each box; bars above and below each box represent SE. Ends of vertical lines denote SD. O or + symbols, outliers. VP, velopharynx; OP, oropharynx. **P < 0.01 versus normal group. Adapted, with permission, from reference .



Figure 14.

(A) Relation between external airway pressure and minimum pharyngeal cross‐sectional area in four subjects, representing the spectrum of passive mechanical properties of the pharynx. PClose, pressure at which the pharynx is closed. Constructed, with permission, from data in reference . (B) Relation between external airway pressure and maximum flow conducted by the upper airway (MAX). Lines A to F provide the spectrum seen in patients with obstructive sleep disorders (constructed, with permission, from data in reference ). The dashed line represents a subject who would have no obstructive abnormality during sleep. MAX0, maximum flow that can be conducted in the absence of pharyngeal dilator activity in the subject breathing with no external pressure applied. Modified, with permission, from reference .



Figure 15.

Pressure/flow relationships during a single respiratory event. The x‐axis shows time in seconds. Breaths with normal, intermediate, and flattened flow contours are labeled and a plot of the driving pressure/flow relationship is shown. As illustrated in the third small panel below, flow within each of the inspiratory phases beyond 5 s decreases as glottic pressure becomes more negative. This negative effort dependence is seen in some, but not all, flow limited breaths. Adapted, with permission, from reference .



Figure 16.

Apnea‐hypopnea index (AHI) in 82 patients with varying degrees of passive mechanical abnormalities (maximum flow at near atmospheric pressure). In 61 patients, the relation was determined in two body positions, resulting in 143 patient‐position combinations. Note that in patients with complete obstruction at atmospheric pressure (abscissa value = 0) AHI varies between 0 and 160 h−1 and that some patients with mild mechanical abnormalities have high AHI values. Adapted, with permission, from reference .



Figure 17.

Scatter plot of the relationship between minimum flow observed at near atmospheric pressure and the fraction of sleep time in stable breathing in the same patient‐body position combination during polysomnography. Adapted, with permission, from reference .



Figure 18.

Continuous polysomnography tracings showing spontaneous transition from cyclic obstructions (OSA) to stable breathing in a patient with a highly collapsible pharynx. C4/A1 is the electroencephalogram.



Figure 19.

Tracings from a patient to show how an increase in the fraction of time spent with inspiratory flow can make it possible to tolerate maximum flows that are well below peak flow in the unobstructed state. C3/A2, central electroencephalogram showing a continuous sleep pattern; ABD, abdomen; RC, ribcage; PMASK, mask pressure; PF; peak flow; TI/TTOT, fraction of time spent with inspiratory flow; MAX; maximum flow; RR, respiratory rate. (Left panel) Upon dial‐down of CPAP, the patient immediately developed an obstructive hypopnea where flow was less than 40% peak flow on CPAP and tidal volume (VT) was only 43% of VT requirement. With time (right panel, 5 min later), and despite no change in MAX, VT and ventilation returned to near baseline as a result of marked increase in the duration of inspiratory flow (note interval between vertical lines). There were only modest changes in end‐tidal PCO2 (PETCO2) and O2 saturation, making a steady state possible. Inset: diagram showing how an increase in the amplitude of inspiratory efforts (more negative intrathoracic pressure) can increase TI/TTOT and the time during which flow is maximum even in the absence of any prolongation in neural inspiratory time. PMAX, intrathoracic pressure at which MAX is reached. The faster rate of reduction in intrathoracic pressure results in an earlier flow crossing from expiration to inspiration and MAX is reached sooner (point c vs. point a). Likewise, intrathoracic pressure remains below PMAX for much of the declining phase of inspiratory effort (rising intrathoracic pressure), resulting in a delay in onset of expiratory flow and continued presence of MAX well beyond the point at which flow would have started to decline at the lower effort (point d vs. point b). Adapted, with permission, from reference .



Figure 20.

Peak phasic genioglossal electromyogram (EMG). Cumulative data from all subjects and patients demonstrating that in the basal state, the genioglossus functions at a higher percentage of maximum in OSA patients than controls. *P < 0.05 versus controls. Adapted, with permission, from reference .



Figure 21.

Response of genioglossus activity to an induced severe hypopnea in the absence of cortical arousal. C3/A2, C4/A1, and O2/A1 are three electroencephalography leads; PAW, airway pressure; MA GG, moving average of genioglossus activity; GG opening threshold, increase in GG activity level at which the airway opened. Note the progressive increase in both tonic and phasic GG activities and that both activities remained higher than at the beginning of the obstruction well beyond upper airway opening. The second obstructive event is milder than the first.



Figure 22.

Tracings illustrating an example of the response to increasing chemical drive on continuous positive airway pressure (CPAP) and immediately following induced obstruction. C3/A2: electroencephalogram. PETCO2: airway PCO2. MA‐GG: moving average of genioglossus activity, expressed as percent of maximum activity. (A) Patient breathing room air. CPAP was reduced to 1.0 cmH2O (dial‐down) inducing a severe hypopnea (arrow in flow tracing). Note that there was no increase in genioglossus activity during the obstructed breath. (B) In the same patient, inspired CO2 was increased for 30 s prior to dial‐down. Note that genioglossus activity increased little on CPAP despite doubling of ventilation (VE). However, there was a large increase in genioglossus activity following dial‐down. Adapted, with permission, from reference .



Figure 23.

Tracing from a patient showing failure of genioglossus activity to increase appreciably during the first obstructed breath despite a 3‐fold increase in ventilation prior to dial‐down (compare last breath in panels A and B). This patient had only mild hypopnea during dial‐down from air breathing (A), indicating mild abnormalities in pharyngeal mechanics (PCRIT was −10 cmH2O). His apnea‐hypopnea index was 68 h−1. Adapted, with permission, from reference .



Figure 24.

Tracings illustrating strong short‐term potentiation (STP) in a patient with obstructive apnea. C3/A2, electroencephalogram; MA GG, moving average of genioglossus activity. An apnea was induced by lowering CPAP pressure at arrow (dial‐down). Ventilation was stimulated prior to the dial‐down to advance GG recruitment. The obstruction was relieved by reinstituting optimum CPAP prior to arousal. Ventilation returned within a few breaths to or below the levels observed prior to the dial‐down (period covered by the solid horizontal bar). Note the increase in tonic activity during the obstruction. Also note that both phasic and tonic GG activities remained higher than activities prior to dial‐down despite comparable or lower ventilation. Unpublished observations.



Figure 25.

Tracings illustrating lack of short‐term potentiation (STP) in a patient with obstructive apnea. C3/A2, electroencephalogram; MA GG, moving average of genioglossus activity. An obstructive hypopnea was induced by lowering CPAP pressure at arrow (dial‐down). Ventilation was stimulated prior to the dial‐down to advance GG recruitment. The obstruction was relieved by reinstituting optimum CPAP prior to arousal. Ventilation returned within a few breaths to or below the levels observed prior to the dial‐down (period covered by the solid horizontal bar). Note minimal increase in tonic activity during the obstruction and lack of sustained increase in either tonic or phasic GG activity post obstruction at comparable levels of ventilation. Unpublished observations.



Figure 26.

Sequence of events following the onset of an obstructive event. At eupneic drive, dilator activity during sleep is less than the level required to keep the airway open. A hypopnea or apnea develops. Chemical drive increases. At a certain chemical drive (recruitment threshold), which varies greatly from patient to patient, the dilators begin responding to further increases in drive. The rate at which activity increases beyond the recruitment threshold is also highly variable. Activity increases until the level required to open the airway (dilator opening threshold) is reached. This threshold varies from 1% to 37% of GGMAX among patients. Activity increases for one or two breaths beyond the point of opening and then begins declining as chemical drive decreases. In the declining phase activity is higher than at the same drive in the rising phase as a result of short‐term potentiation (STP). Both the dilator opening threshold and the gain of STP are highly variable. The chemical drive at which dilator activity reaches Dilator Opening Threshold is referred to as effective recruitment threshold (TER). This sequence can be interrupted if the arousal threshold (TA) is less than TER.



Figure 27.

Schematic illustration of the events that lead to mixed or obstructive apneas. There are two chemical drive thresholds, the central apnea threshold (central AT) below which there are no respiratory efforts, and an obstructive apnea/hypopnea threshold below which there are efforts but the airway is obstructed and flow is unresponsive to chemical drive (i.e. effective recruitment threshold; TER). In the first sequence, the efforts increase, but with no ventilatory response, as chemical drive increases in the range between the two thresholds. Finally, as TER is crossed, the airway opens. A large overshoot develops that forces chemical drive below the central AT. A central apnea develops followed by a number of obstructed breaths as chemical drives cross between the two threshold (mixed apnea; M). In the second and third sequences, the ventilatory overshoot was not as pronounced and chemical drive decreases into the range between the two thresholds. An obstructive apnea/hypopnea develops (O).



Figure 28.

Frequency of observations having different intervals between upper airway opening and arousal. Type 1, no arousal before or after opening. Type 2, opening occurred before arousal. Type 3, opening occurred at or after arousal. Adapted, with permission, from reference .



Figure 29.

Average genioglossus (GG) opening threshold, expressed as % maximum GG activity, in 32 patients arranged in order of threshold values. Bars are standard deviation. Open bars are patients with closing pressure less than −1 cmH2O. Adapted, with permission, from reference .



Figure 30.

Relationship between genioglossus opening threshold and closing pressure (PCRIT) in patients with PCRIT more than −1 cmH2O. Adapted, with permission, from reference .



Figure 31.

Response of phasic genioglossus activity to increasing chemical drive on CPAP (solid lines) and during the first obstructed breath in six patients representing the three response types. Type A response (panels A and D): mechanoreceptor effect (difference between the two lines) is evident beginning with baseline (lowest) drive. Type B response (panels B and E): mechanoreceptor effect appears only after a threshold increase in chemical drive. Type C response (panels C and F): no mechanoreceptor effect across the entire range of chemical drive permitted by the arousal threshold. Adapted, with permission, from reference .



Figure 32.

Two examples illustrating the importance of control mechanisms in determining the apnea‐hypopnea index (AHI). Patient MO had a very high AHI despite a very low critical closing pressure (PCRIT) and a very low genioglossus opening threshold. In this patient, the problem was that the dilators were not responsive to chemical drive up to five times the eupneic drive (i.e. very high dilator recruitment threshold). By contrast, patient SI had a low AHI despite very high PCRIT and dilator opening threshold. In this patient, there was a vigorous dilator response, with activity reaching the opening threshold with a modest increase in drive. Unpublished observations.



Figure 33.

Flow chart showing how different polysomnographic features (boxed terms) can arise following sleep‐induced obstructive events. FL, flow limitation; LG, loop gain; OSA, obstructive sleep apnea; PUF, peak unloaded flow rate; SS, steady state; TA, increase in chemical drive required to cause arousal; TER, increase in chemical drive required to open the airway without arousal; UARS, upper airway resistance syndrome; MAX0, maximum flow at atmospheric pressure in the absence of pharyngeal dilator activity. See text. Adapted, with permission, from reference .



Figure 34.

Pclose as a function of age. Mean values from 18 persons. Multiple regression analysis revealed that Pclose became less negative with age (r = 0.75; P = 0.011). Adapted, with permission, from reference .

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David P. White, Magdy K. Younes. Obstructive Sleep Apnea. Compr Physiol 2012, 2: 2541-2594. doi: 10.1002/cphy.c110064