Pathophysiology of Adult Obstructive Sleep Apnea

Danny J. Eckert1 and Atul Malhotra1,2
1
Division of Sleep Medicine, Sleep Disorders Program, Brigham and Women’s Hospital, and Harvard Medical School; and 2Division of
Pulmonary/Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Obstructive sleep apnea (OSA) is a common disorder characterized disease (4). Further, the prevalence of OSA is two to three
by repetitive narrowing or collapse of the pharyngeal airway during times greater in men than in women (3, 5, 6) and in older
sleep. The disorder is associated with major comorbidities including individuals (>65 yr) compared with middle-aged individuals
excessive daytime sleepiness and increased risk of cardiovascular (30–64 yr) (7).
disease. The underlying pathophysiology is multifactorial and may The pathophysiological causes of OSA likely vary consid-
vary considerably between individuals. Important risk factors in- erably between individuals. Important components likely in-
clude obesity, male sex, and aging. However, the physiological clude upper airway anatomy, the ability of the upper airway
mechanisms underlying these risk factors are not clearly understood. dilator muscles to respond to respiratory challenge during
This brief review summarizes the current understanding of OSA
sleep, the propensity to wake from increased respiratory drive
pathophysiology in adults and highlights the potential mechanisms
during sleep (arousal threshold), the stability of the respiratory
underlying the principal risk factors. In addition, some of the
control system (loop gain), and the potential for state-related
pathophysiological characteristics associated with OSA that may
modulate disease severity are illustrated. Finally, the potential for changes in lung volume to influence these factors. These vari-
novel treatment strategies, based on an improved understanding of ous physiological traits and the potential for each to influence
the underlying pathophysiology, is also discussed with the ultimate sleep apnea pathophysiology have been described in detail in
aim of stimulating research ideas in areas where knowledge is review articles (8–10). The focus of the current article is to (1)
lacking. briefly review the key physiological factors, discuss how they
may interact with one another, and highlight advances in our
Keywords: arousal; genioglossus; lung volume; upper airway; ventilatory understanding of OSA pathogenesis; (2) discuss the potential
control stability physiological mechanisms underlying the key epidemiologic
risk factors for OSA; (3) highlight some of the physiological
factors associated with OSA that may modulate disease sever-
Obstructive sleep apnea (OSA) is characterized by recurrent
ity; and (4) briefly discuss potential treatment strategies ac-
collapse of the pharyngeal airway during sleep, resulting in
cording to the various underlying physiological causes of OSA.
substantially reduced (hypopnea) or complete cessation (apnea)
of airflow despite ongoing breathing efforts. These disruptions
to breathing lead to intermittent blood gas disturbances (hy- PATHOPHYSIOLOGY
percapnia and hypoxemia) and surges of sympathetic activation.
Loud snoring is a typical feature of OSA and in most cases the Upper Airway Anatomy
culmination of a respiratory event is associated with a brief The human upper airway is a unique multipurpose structure
awakening from sleep (arousal). These events result in a cyclical involved in performing functional tasks such as speech, swal-
breathing pattern and fragmented sleep as the patient oscillates lowing of food/liquids, and the passage of air for breathing. The
between wakefulness and sleep. In severe cases respiratory anatomy and neural control of the upper airway have evolved to
events can occur more than 100 times per hour and typically enable these various functions. The airway, therefore, is com-
each event lasts 20–40 seconds (see Figure 1 for an example). posed of numerous muscles and soft tissue but lacks rigid or
OSA is associated with major comorbidities including day- bony support. Most notably, it contains a collapsible portion
time somnolence, impaired cognition, poor quality of life, and that extends from the hard palate to the larynx. Although the
increased risk of motor vehicle accidents. There is emerging ability of the upper airway to change shape and momentarily
evidence to suggest that OSA is an independent risk factor for close is essential for speech and swallowing during wakefulness,
a variety of adverse cardiovascular outcomes (1, 2). The clinical this feature also provides the opportunity for collapse at inop-
disorder, defined as more than five abnormal breathing dis- portune times such as during sleep.
turbances (hypopneas or apneas) per hour of sleep combined From a purely anatomic perspective, a narrow upper airway
with symptoms of daytime sleepiness, affects at least 2–4% of is generally more prone to collapse than a larger one. Accord-
the adult population (3). Although nonobese individuals may ingly, on the whole, the cross-sectional area of the upper airway
suffer from OSA, obesity is the main epidemiologic risk factor. as measured by computed tomography and magnetic resonance
Indeed, increases in body mass index, central accumulation of imaging during wakefulness is reduced in patients with OSA
adipose tissue, and neck circumference are strong predictors of compared with subjects without OSA (11–13). Further, the
arrangement of the surrounding soft tissues appears to be
altered in patients with OSA, which may place the upper
(Received in original form July 31, 2007; accepted in final form August 22, 2007) airway at risk for collapse (11). Imaging studies during wake-
Supported by the Thoracic Society of Australia and by a New Zealand/Allen and fulness, however, are complicated to interpret because ongoing
Hanbury’s respiratory research fellowship (D.J.E.) and by NIH grants P50 upper airway dilator muscle activity may lead to potential
HL060292-09, AG024837-01, and RO1-HL73146 (A.M.). differences between groups, due to factors other than anatomy.
Correspondence and requests for reprints should be addressed to Danny Eckert, In addition to these imaging measures, a methodology to
Ph.D., Brigham and Women’s Hospital, Division of Sleep Medicine, Sleep Disorders determine the pressure at which the upper airway collapses
Program, BIDMC, 75 Francis Street, Boston, MA 02115. E-mail: deckert@rics.bwh.
during sleep (Pcrit) as a gauge of passive upper airway anatomy
harvard.edu
is also in concordance with reduced upper airway caliber in
Proc Am Thorac Soc Vol 5. pp 144–153, 2008
DOI: 10.1513/pats.200707-114MG patients with OSA (14, 15). Perhaps the most definitive data
Internet address: www.atsjournals.org come from Isono and colleagues, who observed increased

As is discussed tective reflexes which increase upper airway dilator muscle below. Thus. In support of this hypothesis. upper airway dilator muscle activity believed to be important in the pathogenesis of OSA relates to (21). slow wave sleep is associated with with OSA compared with control subjects. patients with OSA appear to compensate OSA. Thus. airway during sleep (17). SaO2 5 arterial blood oxygen saturation measured via pulse oximetry at the finger. the transition from wakefulness to sleep in OSA. Flow 5 airflow mea- sured via nasal mask and pneumo- tachograph. were not sufficient to restore flow without arousal in this in- stance. Note the repeated oxy- gen desaturations as a result of severely impaired (hypopnea) or absent (apnea) airflow despite con- tinual breathing efforts (Pepi) and the cyclical breathing pattern that ensues as the patient oscillates be- tween sleep and arousal (down- ward pointing arrows). muscle gies have shown that patients with OSA have anatomic tone measured via multiunit EMG intramuscular electrodes of compromise making these individuals susceptible to pharyngeal the genioglossus is reduced at sleep onset in healthy individuals collapse during sleep. the largest and most extensively studied upper sleep. hypopneas and apneas commonly occur at for an anatomically compromised upper airway through pro. and patients with OSA (18. in aggregate. although occur- ring. Upper Airway Dilator Muscle Activity and an individual reliant on muscle tone due to an anatomic Reflex Responsiveness vulnerability will be particularly susceptible to developing During wakefulness. during which the patient is experiencing sleep-disordered breathing. (B) An expanded segment during an ob- structive event. airway dilator muscle in humans. each event is typically associated with a cortical arousal activity to maintain airway patency (17). whereas healthy individ- uals experience a loss of upper airway muscle tone at sleep onset and experience some degree of breathing instability (20). Accordingly. EEG 5 electroencephalogram (C3– A2). Thus. (A) An 8-minute segment during stage 2 sleep. not decreased. Note: Evidence of snoring on the flow tracing. EMGgg 5 Electromyo- gram of the genioglossus muscle (intramuscular). and progressive increases in EMGgg activity throughout the obstructive event. making it difficult to achieve deeper stages of sleep. quan- tification of the arousal threshold. . the such that the patient with OSA cycles between wakefulness and genioglossus. closing pressure (more collapsible) in OSA as compared with the interaction between pharyngeal anatomy and a diminished control subjects under conditions of general anesthesia and ability of the upper airway dilator muscles to maintain a patent muscle paralysis (16). One mechanism increased. when patients are able to achieve slow wave sleep.Eckert and Malhotra: Pathophysiology of Adult OSA 145 Figure 1. 19). Accordingly. Pepi 5 pressure at the level of the epiglottis. EMGsub 5 EMG of the submental muscle (surface). has higher activity in patients Unlike the transition to sleep. Polysomnographic trac- ings of obstructive sleep apnea from a detailed experimental study of a patient with severe disease (apnea–hypopnea index 5 56 events/h). multiple methodolo.

albeit to a lesser extent than raised the possibility that more pronounced reflex inhibition healthy individuals. These findings suggest that OSA (e. Indeed. is measured as the minimal esophageal pressure (or pressure at lighted the heterogeneity of the genioglossus muscle and pro.e. (CPAP) reductions in patients with OSA. as is discussed below. is likely to be the key trigger for inducing arousal from to gain insight into their unique characteristics and regulation. Although such approaches may lead to reduced to have an impaired arousal response to airway occlusion (more severity of OSA for some patients. hypoxia. However. and repeated airway obstruction) exercises of upper airway muscles may lead to some improve. In studying the response to experimen- Mechanistically. the level of the epiglottis. although genioglossus muscle responsiveness may be respiratory stimuli to restore pharyngeal patency (31. for exam- effectiveness of these compensatory responses to restore airflow ple. it is clear this be the case. hypercapnia. they have high.. similar between patients with OSA and healthy individuals. of negative pharyngeal pressure during sleep and a brisk ventilatory response (48) (Figure 1B). REM sleep in healthy individuals (24. the stimulus (e. given negative pressure required or a higher arousal threshold) than the heterogeneity of OSA pathogenesis such an approach will control subjects (46). events result in longer arousals (40). Consistent with the nature minutes resulted in increases in genioglossus muscle activity and of OSA being a state-related disease. there is evidence to suggest that novel training sleep fragmentation. airway reopening (41).. 39). severity (49). It is hoped that. Although these changes are beneficial in rapidly restoring airflow and reversing oxygen Arousal from Sleep desaturation/hypercapnia. the genioglossus negative changes in duty cycle. in addition to central respiratory drive. generated by respiratory effort regardless of muscle activity in humans. and respiratory load- frequency sampling and allows sorting of individual motor units ing). hypoxia. on the responsible for the impaired arousal responses in patients with basis of the state dependence of OSA. posture when gravitational collapsing effects on the upper The findings that patients with OSA are able to restore airway are maximal (26. Although muscle activity may ultimately be identified for some patients there is wide interindividual variability. patients with OSA were less able to restore ventila- recent data have demonstrated maintenance of genioglossus tion without cortical arousal than were healthy individuals given reflex activation in non-REM sleep.g. muscle training during OSA. arousals may be beneficial if it allows sufficient accumulation of less. Figure 1B depicts knowledge from animal models with sensitive neurophysiolog.. the tally induced transient continuous positive airway pressure genioglossus is importantly modulated by locally mediated (i..e. wakefulness is unlikely to have major effects on airway patency When initiated. because combinations negative pressure reflex and hypoglossal motor nucleus inputs of stimuli such as carbon dioxide and negative pressure can from rat studies have highlighted the extensive presence of activate upper airway dilator muscles during sleep. arousal from sleep is associated with height- during sleep unless the increased muscle activity/efficiency is ened upper airway dilator muscle activity for an equivalent level maintained during sleep. single motor unit– Most of the available evidence suggests that the level of recording techniques have been employed to assess genioglossus pleural pressure. Nonetheless. quantification of the arousal threshold. be deleterious because of worsening of blood gas abnormalities To further advance our understanding of pharyngeal muscle (43). These compensatory responses were pressure reflex has been shown to be diminished during non. Should impaired during sleep compared with wakefulness. 25). particularly in the supine stimuli of similar magnitude (32). the arousal threshold Although these studies are in their infancy. 41). The identification of a secondary ventilation in the face of respiratory loading without cortical state-dependent suppression component to this reflex arc has arousal at least some of the time. pressures that are subatmo. increasing the arousal threshold appears to be substantial interindividual variability in the in patients with a preexisting high arousal threshold. 45). In fact. particularly when who awaken easily (low arousal threshold) to respiratory loads combinations of stimuli are provided (31–33). Younes noted that in the upper airway) mechanoreceptive reflex mechanisms that inspiratory flow increased in 22% of instances before arousal respond to negative pharyngeal pressure (22). delaying of inhibitory inputs to the genioglossus muscle (28–30).g. One such mech. However. This technique is based on high. strategies to prevent arousal from sleep (increase that the muscle does respond to sustained negative pressure the arousal threshold) are likely to be most beneficial in patients (Figure 1) and potentially hypercapnia. However. may during respiratory loading in sleep (32). For example. patients with OSA tend with OSA. they can also destabilize breathing and perpetuate apnea has long been believed to be an important protective mecha. Treating OSA with CPAP tends to lower likely not resolve sleep-disordered breathing for all patients. Jordan and colleagues conducted a study to muscle is activated in response to rapid changes in negative examine the mechanisms underlying these arousal-free restora- intrapharyngeal pressure (i. . advances are able to remain asleep for a sufficient duration to recruit in our understanding of the neuroanatomy of the genioglossus compensatory mechanisms. tions of airflow (32). Experimentally. rather than an inherent abnormality in the arousal threshold is ment in sleep-disordered breathing (36. more However. control and its role in OSA pathogenesis. in patients with severe sleep-disordered breathing. novel therapeutic targets to increase airway occlusion during a naturally occurring apnea. work by Younes Alternatively. Nonethe. whereby the More recently. there during sleep (10. non-REM sleep (44. raises the possibility that some patients rather than a loss of excitation may mediate diminished may be able to maintain a patent airway during sleep if they pharyngeal reflex responses during sleep (26). anism is the genioglossus negative pressure reflex. However. and was restored in 17% of trials in the absence of arousal (41). 37). by combining neuroanatomic during a respiratory load or occlusion. which is likely to be similar during vide a powerful tool for studying the neural control of muscle airway occlusion) generated on the breath preceding arousal activity (34. patients with apnea may be able to enter slow has provided insight into the functional role of arousal from wave sleep only when muscle activity is increased and breathing sleep in OSA and challenged the notion that it is essential for is already stabilized. the arousal threshold (47). in this instance during ical techniques in humans. most respiratory important factor contributing to the improvement in apnea events are associated with cortical arousal and more severe severity that is commonly observed in this sleep stage (21).146 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008 increased upper airway dilator muscle activity may be one nism for airway reopening (38. 42). as is discussed in the following sec- Arousal from sleep at the cessation of a hypopnea or an apnea tion. 35). However. Transient pressure reductions for up to 5 spheric or suction pressure) (23). 27).

e. by increased anatomic compromise. Obstructive or central apnea could and obesity although the underlying mechanisms remain un- then occur depending on the prevailing upper airway mechan. gain system (i.. upper airway and stable state (no arousals).. which of these nisms that are likely to be important. whereby the patient oscillates between believed to be an important contributor to OSA pathogenesis.. the lung volume dependence appears to be more a term used to describe the stability of a system controlled by pronounced in patients with OSA compared with control feedback loops. hypoxic and hypercapnic ventilatory responses). The physical sepa.g. dampened ventilatory response to an equiva- lent respiratory stimulus). In the context of ventilatory control. airway. tory delays may make mixing gain more clinically relevant in This movement results in a loss of caudal traction on the upper patients with congestive heart failure (51).e. 67). A third factor. One would predict that pharyngeal obstruction occurs when ventilatory motor output is at its nadir (i. to increase oscillations from the brainstem central pattern generator. when PHYSIOLOGICAL MECHANISMS UNDERLYING neural output to the upper airway muscles is low). Thus. upper airway mechanics can be modulated by changes (Figure 1A). but is a function of caudal traction on upper airway structures during decreased of circulatory delay as well as hemoglobin binding of O2 and lung volume. Second. However. Studies using linkage loop gain of the respiratory system. EPIDEMIOLOGIC RISK FACTORS elevated loop gain may also increase the ventilatory response to arousal. loop gain can be considered as the muscles behaviorally as well. further work is re- Debate exists regarding how elevated loop gain may affect quired to determine by which physiological mechanisms genes the propensity for apnea. A schematic been discussed. halation to total lung capacity is likely to activate upper airway arousal). Techniques have been developed to measure and nonobese patients with OSA (73–75). perpetuating cyclical breathing is currently beyond the scope of and respiratory responses to resistive loading during sleep may this technique. capacity there is a lung volume dependence on upper airway Ventilatory control stability can be described using the cross-sectional area measured during wakefulness (62). obstructive breathing events (sleep) and arousal (wakefulness) Indeed. male sex.e. which may drive PaCO2 below the apnea threshold The major risk factors for OSA include aging. such as the proportional analysis have provided initial insight into the potential link assist ventilation (PAV) technique (53. . ventilatory control abnormalities (85). ventilatory control individuals (57–61). Briefly. Hoffstein and colleagues demon- stability is believed to be an important contributor to OSA strated that across the range from residual volume to total lung pathogenesis. Thus. also have a genetic basis (86). and/or reduced lung volume pathogenesis are illustrated in Figure 2. although circula. information in this regard (79. Essentially. Future studies using genome-wide association analyses elevated loop gain and suggest that ventilatory instability is an and other novel technologies may also provide important important mechanism contributing to sleep-disordered breath. Moreover. In engineering concept loop gain (50). end-expiratory lung volume decreases airway collapsibility in healthy control subjects and improves sleep-disordered breath- ing). upper airway re- propensity for the ventilatory control system to develop cyclical sistance increases as lung volume is reduced (64. Increasing fluctuations in ventilatory output (as seen in periodic breath. An inherently and lung volume independent of neuromuscular factors in high loop gain system is unstable (i. Anatomy (obesity. is the concept of a loss known as mixing gain. One likely mechanism. 56). There are two principal components to loop gain: control- ing in patients with OSA (60. further work is required in this area. Studies using PAV between specific areas of the genome and OSA pathogenesis have demonstrated that patients with OSA do in fact have an (76–78). lowered arousal threshold. 66. influence the risk of sleep apnea. Thus. 73). First. traits such as the size of the upper airway soft about transient responses that are also likely to be important in tissue structures (84). elevated loop gain would be expected unclear.e. While the aforementioned studies demonstrate that changes controller gain refers to the chemoresponsiveness of the system in lung volume are capable of modulating upper airway patency (i. obstructive events tend to occur during in lung volume during wakefulness and sleep in healthy periods of low respiratory drive.. 63). Further. the ability in humans. A commonly used analogy is the regulation of room temperature. As it relates to respiratory control... although neither is genetic factors will be modifiable in therapeutic studies remains definitively proven. clear. Plant gain in OSA. these risk factors are likely to be explained representation of the typical physiological characteristics asso.Eckert and Malhotra: Pathophysiology of Adult OSA 147 Ventilatory Control Stability Lung Volume As stated. In other words. Nonetheless. whereby temperature will be GENETICS prone to oscillation in a situation where there is a particularly Studies have clearly shown a common familial basis to the sensitive thermostat and an overly powerful heater (i. the underlying mechanisms have not been well defined reflects primarily the efficiency of CO2 excretion (i. which has been clearly of a given level of ventilation to excrete CO2). Given the pathophysiological mechanisms that have ics. loop gain is addition. the PAV technique relies on a stable facial structure) clearly have genetic underpinnings (81–83). robust ventilatory patients with sleep-disordered breathing suggest that similar response to a respiratory stimulus) compared with a low loop mechanisms may contribute to OSA pathogenesis (71). During sleep. appears to be less crucial. increased potential role of a high loop gain in contributing to OSA ventilatory control instability. increased pharyngeal dilator ciated with airway narrowing/closure during sleep and the muscle dysfunction. a typical feature of OSA is the cyclical breathing The interaction between pharyngeal patency and lung volume is pattern that develops. demonstrated in animal models (68–70). However. 65). during subsequent sleep. There are two key potential mecha. tethering. Further.e. yielding a more collapsible airway. when lung volume is reduced there is CO2. This finding is true for both obese loop gain) (52).. a displacement of the diaphragm and thorax toward the head. studies during wakefulness are refers to the stability of the respiratory system and how confounded by behavioral influences because a maximal in- responsive the system is to a perturbation to breathing (e. 80). high development of OSA (72. loop gain subjects (62. cranio- ing (55.e. Mixing gain tends to be fairly constant. information Furthermore. Data obtained by ration of the sensors and effectors makes the ventilatory examining the interaction between passive pharyngeal airway feedback control system vulnerable to instability. ler gain and plant gain. 54).

and also lead to periods of decreased upper airway dilator muscle activ- ity). Imaging studies have revealed systematically different between men and women in either . pharyngeal airway length may explain some of the sex-related minished oxygen stores. (B) Schematic representa- tion of the possible sites where each of the various pathophysiological traits would either predispose or tend to worsen OSA (inside the main circle). UA 5 upper airway.148 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008 Figure 2. studies.e. 104).e. con- tinuous positive airway pressure [CPAP]). Despite these anatomic and modeling control instability (high loop gain). Fat deposition around the abdomen pared with girls. the pharyngeal airway is longer in postmenopausal would be predicted to reduce lung volume tethering effects on as compared with premenopausal women (99). Refer to the text for further detail. Some of the potential factors that may alleviate OSA at various points throughout the typ- ical physiological cycle (dashed arrows and ovals) are located outside the main circle. Note that some factors are theoretical and largely untested whereas others are more proven therapies (i. differences in pharyngeal collapsibility (100–102). which addition. In addition. (A) Schematic representation of the typi- cal pathophysiological se- quence that occurs in obstructive sleep apnea (OSA) (shown in gray) and the associated physiologi- cal processes that occur throughout the cycle that are either protective/restor- ative (outside the circle) or perpetuating (inside the cir- cle). Finally. there has been no consistency in studies regarding sex sociated with functional impairment in upper airway muscles (92). several subsequent studies have failed to reproduce these Similar to obesity. Low lung volumes are also associated with di.. Deposition of fat around the contributing to airway collapsibility (94–97). Thus. changes in the upper airway. independent of systemic growth (98). obesity has been as. studies have revealed an important role for pharyngeal length in nisms remain less than certain. 89). although initial studies suggested important differences in pharyngeal dilator muscle activation between men and women Male Sex (103). it is not entirely clear why OSA is more results (94. the physiological mecha. Obesity that men have increased fat deposition around the pharyngeal Although it is clear that obesity is a key risk factor for the airway as compared with women (93) and an increased length of development of OSA and modest reductions in weight lead to the pharyngeal airway as compared with women (94). Modeling improvement in OSA severity (87). Weight loss leads to important experience lengthening of their airway during puberty com- improvements in Pcrit (90). which would contribute to ventilatory observations in OSA. loop gain does not appear to be common in males than females. Similarly.. A cross-sectional pharyngeal airway is likely to increase the collapsibility of the study of children at the age of puberty has suggested that boys pharyngeal airway (88. a high loop gain may increase the ventilatory re- sponse to arousal and the propensity for cyclical breathing. Note that some of the effects of these traits may be interrelated (i. 102. In leads to reductions in functional residual capacity (91).

there are multiple upper airway sensory function. Although several small studies have attempted to address the cause of the age-related It has been proposed that the repeated mechanical trauma and/or impact on apnea frequency. or with more pronounced hypoxemia during REM compared with theoretically may. How. Consistent with a state-dependent phenomenon. Should this be the case. However. Similar to many upper airway reflexes (119). upper lapsibility with aging (121). However. Finally. and oral increases with aging. the arousal threshold appears Indeed. but are less able to do so during other physiological variables that may impact OSA. Although these studies highlight a role for surface controlled for. how sensory impairment during although lung compliance is known to increase with aging. Sex differences in issue. other techniques for assessing ventilatory instability (such during REM sleep (123). data based on the PAV loop gain technique Sensory Processing have challenged this notion (117). Pcrit is similar tients (111–113). This effect may. thus far. alleviate the cycle of OSA are illustrated . the route of breathing during sleep Aging appears to influence salivary flow and perhaps as a result may Substantial literature suggests that the frequency of apnea affect surface tension. Thus. not been shown to induce sleep-disordered breathing in some pa. Anatomic susceptibility to OSA appears to worsen ment of upper airway structures (136). 4). independent of systemic fat because of an impaired ability of the upper airway to respond (99. These factors may worsen apnea pensity for women to develop OSA after menopause (109. event duration (130. with aging (99. which would tend to reduce. Further studies are required to address this important more prone to cyclical breathing (48. we wakefulness affects upper airway function during sleep is un- are not aware of systematic studies that have assessed how loss clear (142). lining the upper compared with women. Nasal breathing may reduce. Thus. However. attempts to manipulate OSA during REM compared with non-REM sleep in patients with severity on the basis of hormone-targeted approaches have re. Indeed. Further. proposed that the increased prevalence of sleep apnea in the elderly may be attributed to impaired respiratory control with Upper Airway Sensory Neuropathy/Impaired aging. the severity appears to decrease with age (7). OSA. 131). the ventilatory response to arousal from causes of increased REM-related apnea severity remain largely sleep is greater in men than women. the clinical relevance of surface potentially because of survivor effects. chemosensitivity (128. Although human physiological data as the PCO2 apnea threshold) have been shown to differ between are challenging to obtain and the available literature is rela- the sexes (106. the increase in prevalence appears contributing to the elevated levels of surface tension observed to plateau after 65 years (4) and when body mass index is in OSA. severity. In addition to sex-related changes impaired in this sleep state (14). REM Sleep SUMMARY AND POSSIBLE FUTURE TREATMENTS Hypopneas and apneas increase in duration and are associated Some of the treatment strategies that are either known to. the precise underlying in the apnea threshold. Hormonal differences airway muscle tone (124. breathing may increase. progressive increases in body weight (137). impaired genioglossus reflex between men and women have long been proposed to contrib. Some patients have OSA only ever. markable prevalence of sleep-disordered breathing in older changes in breathing route in OSA may be one of many factors individuals (3. 115). no definitive conclusions have been hypoxemia associated with OSA may lead to sensory impair- reached. testosterone administration in hypogonadal men has higher during REM sleep. airway despite similar salivary flow compared with healthy individuals (134). However. importantly. with aging and there appears to be a preferential deposition of prolonged untreated OSA may perpetuate disease severity fat around the pharynx with aging. the to negative pharyngeal pressure. suggesting that men may be unknown. arousal threshold and lung volume effects during sleep have not been systematically evaluated to our knowledge. suggesting that upper airway anatomy is not further vealed little benefit (114. Some of sleep. although epidemio- genioglossus negative pressure reflex appears to deteriorate logic data support the progression of disease severity over time. Thus. adaptive compensatory mechanisms may ensure In addition to the major epidemiologic risk factors described a patent airway during wakefulness in OSA despite impaired above that contribute to OSA pathogenesis. Further. during REM sleep. pendent nature of the disorder. Nonetheless. the majority of the avail- airway with surfactant before sleep reduces apnea severity able data suggest that the male sex predisposition to OSA ap- and improves the Pcrit in OSA (132. non-REM sleep in OSA (122). surface tension forces (135). 133). However. 107). 118). prolong. further studies are required to elucidate the role these components are described below and are illustrated of upper airway sensory impairment in modulating disease schematically in Figure 2B. responsiveness to negative pressure (26. be mediated tively scarce. 120). 125). these anatomic and physiological the effect appears to be modest and may be largely explained by factors both likely contribute to increased upper airway col. REM sleep is associated with decreased upper via hormonal mechanisms (106. 129). sensory processing of respiratory afferent information as mea- sured by cortical evoked potentials has been shown to be im- paired in OSA during sleep but not during wakefulness (143. and reduced ute to the increased male prevalence in OSA and to the pro. 108). Nonetheless. 110). 126. Historically. However. tension in OSA pathogenesis.Eckert and Malhotra: Pathophysiology of Adult OSA 149 healthy subjects (105) or among those with OSA (100). given the state-de- mediating the aging predisposition to OSA (121). Thus. However. it has been tension in OSA remains less certain. OTHER FACTORS 144). 127). it is Surface Tension conceivable that men who tend to store adipose tissue more cen- Surface tension of the liquid lining of the upper airway trally may have a greater susceptibility to lung volume–related influences pharyngeal patency and changes in surface forces changes in upper airway collapsibility via a loss of caudal traction may perpetuate disease severity. of lung elastic recoil with aging affects upper airway mechanics. 116). Patients with OSA pears to be primarily anatomically based although other factors appear to have increased surface forces acting on the upper such as ventilatory control may also be important. Other pathophysiological factors airway sensory function has been shown to be impaired in OSA such as arousal threshold appear to be less important in during wakefulness (138–141). Indeed. with a number of studies reporting a re.

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