Obstructive sleep apnea: diagnosis, risk factors, and pathophysiology

Handbook of Clinical Neurology, Vol. 98 (3rd series) Sleep Disorders, Part 1 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 25

Obstructive sleep apnea: diagnosis, risk factors, and pathophysiology GIORA PILLAR AND PERETZ LAVIE * Sleep Medicine Center, Rambam Hospital and Lloyd Rigler Sleep Apnea Research Laboratory, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

OBSTRUCTIVE SLEEPAPNEA: A BRIEF HISTORY The last two decades have seen an increase in public awareness of the importance of sleep and its disorders. This has led to an unprecedented growth in sleep medicine. It has been estimated that some 2 million diagnostic sleep recordings are done annually in the USA alone. Most of this growth is attributed to the emergence of obstructive sleep apnea (OSA) as a major public health problem with a profound impact on quality of life, on safety on the roads and at work, and on the cardiovascular system. Given the vast number of patients diagnosed nightly with breathing disorders in sleep it is difficult to understand why it has taken the medical community so long to awaken to the importance of sleep apnea. Sleepy and obese patients have been recognized in the medical literature since the turn of the 20th century (for detailed history, see Lavie, 2003). The resemblance of these patients to Joe, the picturesque character from Dicken’s 1836 book The Posthumous Papers of the Pickwick Club, was recognized by several physicians, who independently coined the term “pickwickians” to describe these patients. None of these early descriptions, however, linked the symptoms of the pickwickian patients with disturbances in nocturnal sleep. The first laboratory study that documented cases of breathing disorders in sleep was conducted in Ludolf Krehl Clinic in Heidelberg, Germany, by Gerardy et al. in 1960 and by Drachman and Gumnit at the National Institutes of Health, USA, in 1962. In both studies the physiological recordings of pickwickian patients made during sleep demonstrated repeatedly occurring breathing cessations, each terminated by a brief

physiologic arousal. In both reports slowing of the heart rate during the apneas alternating with quickening of the heart rate during the resumption of breathing was noted by the authors. Anticipating modern observations, in both reports, massive weight reduction resulted in great improvement and even disappearance of disordered breathing in sleep and amelioration of daytime sleepiness. These two pioneering publications remained hidden from the general medical community for many years and have been rarely cited in the literature. Jung and Kuhlo (1965) should be credited for bringing the nocturnal events in pickwickian patients to the attention of the medical community. They also conducted sleep laboratory recordings in pickwickian patients and confirmed that these patients suffer from breathing cessations during sleep. Presenting their findings at the Annual Meeting of the European Neurological Society in Oberstdorf in 1964, Kuhl made the original proposal that the frequent interruptions of sleep in pickwickian patients because of the breathing cessations could be responsible for their excessive daytime sleepiness, and not carbon dioxide retention, as had been proposed in all previous publications (Kuhl, 1997). The importance of this presentation was immediately recognized by Henri Gastaut from Marseilles and Elio Lugaresi from Bologna, who shortly after that confirmed Kuhl and Jung’s observations and conclusions and further extended them (Gastaut et al, 1966; Lugaresi et al., 1968). Later, Guilleminault et al. (1973) showed that obesity is not an obligatory condition for the occurrence of apnea during sleep and that apnea also occurred in patients of normal weight, and thus paved the way for a wide recognition of sleep apnea syndrome by the medical community.

*Correspondence to: Peretz Lavie, Ph.D., Lloyd Rigler Sleep Apnea Research Laboratory, Rappaport Building, Efron St 1, Bat Galim, Haifa, 30961, Israel. Tel: 972-544706020, Fax: 972-8343934, E-mail: [email protected]

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EPIDEMIOLOGY OSA syndrome is very prevalent in the general population. As early as 1983 we estimated that at least 1% of the presumably healthy adult male population have OSA (Lavie, 1983). At that time the syndrome was defined as a sleep laboratory finding of 10 apneas per hour of sleep combined with subjective complaints of excessive daytime sleepiness or disturbed nocturnal sleep. Of note, the importance of hypopneas, that is, partial obstructions of the airways, was not recognized at that time, which probably resulted in an underestimation of the true prevalence of the syndrome. The occurrence of apneas was significantly associated with excessive daytime sleepiness, habitual snoring, frequent headaches, excessive motility in sleep, and hypertension. Others, using similar definitions of the syndrome, reported on similar findings. Based on a study of all patients admitted during 1 year to a hospital in Italy, Franceschi et al. (1982) reported on a prevalence of 1.0% of sleep apnea. Investigating the prevalence of sleep apnea in the general population in the Netherlands, Neven et al. (1998) reported on a prevalence of 0.9%. Higher estimates ranging from 1.3 to 4.7% were reported in studies counting both apneas and hypopneas rather than apneas alone (Bixler et al., 1982; Gislason and Taube, 1987; Cirignotta et al., 1989; Young et al., 1993). The most influential epidemiological study that had a major impact on subsequent recognition of the syndrome and its importance was that of Young et al. (1993). Defining the syndrome as the occurrence of at least 5 apneas or hypopneas per hour of sleep in combination with a complaint of daytime somnolence, they reported that 2% and 4% of middle-aged women and men in the USA, respectively, suffer from OSA. Furthermore, if symptoms were disregarded, 24% of men and 9% of women had at least 5 respiratory events per hour of sleep. Approximately the same rate (Kim et al., 2004), or even slightly higher rates (Schmidt-Nowara et al., 1990; Ong and Clerk, 1998; Udwadia et al., 2004; Villaneuva et al., 2005), were reported for a variety of ethnic groups. It is unclear at this time, however, whether the increased prevalence in specific ethnic groups results from direct genetic causes or from ethnic-related characteristics of body phenotype, such as upper-airway structure or obesity (Villaneuva et al., 2005). Recently, several community-based studies have been performed to learn more about the prevalence and impact of sleep-disordered breathing on general health. In these studies the prevalence of breathing disorders in sleep was investigated irrespective of subjective complaints. In the Sleep Heart Health Study, a very largescale study that longitudinally follows up on the sleep

of community-dwelling adults, it was reported that over 10% of the general population has some degree of sleepdisordered breathing, with daytime somnolence correlated to breathing disorder severity (Gottlieb et al., 1999), most of them undiagnosed (Kapur et al., 2002). The prevalence of breathing disorders in sleep is much higher in specific high-risk populations. Thus, the prevalence of breathing disorders in sleep in the elderly is estimated at around 30% (Ancoli-Israel et al., 1987, 1991), and similar rates were reported for obese patients (Gami et al., 2003; Formiguera and Canton, 2004). Much higher prevalence of 50–98% was reported among the morbidly obese (Valencia-Flores et al., 2000; Resta et al., 2001). Similarly, the prevalence is high in patients with hypothyroidism (Kapur et al., 1998), diabetes (Punjabi et al., 2002; Resnick et al., 2003), gastroesophageal reflux (Gislason et al., 2002), renal failure (Hui et al., 2000, 2002b), acromegaly (Grunstein et al., 1991; Fatti et al., 2001), and women with polycystic ovary syndrome (Fogel et al., 2001b). In populations with cardiovascular disease, the prevalence has been found to be substantially increased, especially in patients with hypertension (Kales et al., 1984; Lavie et al., 1984; Fletcher et al., 1985; Worsnop et al., 1998; Logan et al., 2001), coronary artery disease (Andreas et al., 1996; Schafer et al., 1999), stroke (Hui et al., 2002a; Bassetti, 2005), and heart failure (Javaheri et al., 1998). Thus, OSA is a common disorder in the general population and even more so in specific at-risk populations. Special emphasis should therefore be placed on the recognition of the risk factors of this disorder and understanding its pathophysiology.

DIAGNOSIS The diagnosis of OSA begins with an understanding of the risk factors for this disorder (see below) and the clinical presentation of afflicted patients. The history as related by both the patient and the bed partner is an important source of information. Snoring, witnessed apneas, choking, or gasping during sleep are the most common complaints (Lavie, 1983; Fisher et al., 2002; Caples et al., 2005). Additional symptoms include excessive daytime sleepiness, impaired concentration/cognitive abilities (e.g., memory impairment) (El-Ad and Lavie, 2005), morning headaches, nocturia, sexual impotence (Margel et al., 2004), and possibly depression (Derderian et al., 1988; Pillar and Lavie, 1998). There may be gender-related differences in the presenting symptoms in OSA, with women complaining more of insomnia and men complaining more of excessive daytime sleepiness (Ambrogetti et al., 1991; Lavie and Pillar, 2001), although not all agree on that (Young et al., 1996).

OBSTRUCTIVE SLEEP APNEA: DIAGNOSIS, RISK FACTORS, AND PATHOPHYSIOLOGY The physical exam unfortunately does not add much to the diagnosis, but it can raise suspicion. It may show obesity, an increased neck circumference, a small crowded posterior pharyngeal space (with or without enlarged tonsils), nasal obstruction, lowerextremity edema, and/or systemic hypertension. Using all the information gathered from questionnaires and physical examinations we previously constructed a model to predict sleep apnea severity. We found that the most significant variables were self/spouse report of cessations of breathings and neck circumference, that jointly explained 41% of the variability. The sensitivity of that model in identifying patients with at least 10 respiratory events per hour of sleep was 90%, but its specificity was no more than 20% (Pillar et al., 1994). A later review concluded that using a combination of high-risk symptoms can identify only 30% of patients with at least 10 respiratory events per hour of sleep, and primarily identify patients with very severe disease having more than 40 events per hour (Chesson et al., 1997). Therefore, recording techniques are required to establish the diagnosis of OSA reliably.

Polysomnography (PSG) As stated above, once there is a clinical suspicion of sleep apnea, PSG is recommended, and is the gold standard for the diagnosis of the syndrome. This typically involves monitoring sleep state through the use of the electroencephalogram (EEG), bilateral electrooculogram (EOG), and submental electromyography (EMG). Airflow is monitored via either temperaturesensitive thermistors or a nasal pressure transducer. Respiratory effort is measured using chest and abdominal inductance plethysmography, piezo electrodes, or strain gauges. Other measures often include snoring (microphone or vibration), electrocadiogram, pulse oximetry, body position and anterior tibialis EMG. Whole-night PSG allows for a comprehensive assessment of sleep and respiration with an immediately available technician for detection and correction of technical problems. PSG outcomes provide an index of apnea severity in addition to the sleep quality measures. Apnea severity is provided by two measures: the apnea–hypopnea index (AHI), whch is defined as the total number of respiratory events divided by the hours of sleep, and oxygen desaturations. Generally, in adults AHI < 5, or in some laboratories AHI < 10, are considered normal. The mild apnea range includes 5, 10 < AHI < 20 and minimal oxygen saturation not lower than 85%, while the severe range includes AHI > 40 and/or minimal oxygen saturation lower than 65%. The range in between is considered of moderate severity. Although considered

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the gold standard, the high cost of in-laboratory wholenight PSG, together with long waiting lists for sleep studies because of the relative scarcity of beds, has led to the commonly used procedure of “split night,” in which diagnosis and treatment trial are performed during the same night (Yamashiro and Kryger, 1995). During the first half of the night the patient sleeps for diagnostic purposes, and if the number of respiratory events reaches a certain threshold (usually 20/hour), the patient is awakened after 2 hours and is instrumented with a nasal continuous positive airway pressure (nCPAP) device for the rest of the night to determine the optimal treatment pressure. While theoretically this approach potentially saves time, there are several inherent limitations that should be recognized. First, frequently the diagnosis based on the first 2 hours of sleep is not accurate enough, particularly in patients having apneas exclusively during REM sleep (Rodway and Sanders, 2003). Second, the time remaining for the treatment trial is too short to allow proper CPAP pressure titration (Rodway and Sanders, 2003). This, in turn, can result in decreased patient satisfaction, decreased confidence in the treatment, and subsequently decreased compliance with treatment (Drake et al., 2003). Thus, this approach should be limited to certain types of patients, keeping in mind that it can potentially increase the portion of patients who remain untreated.

Ambulatory monitoring A different approach, developed in an attempt to beat the cost and long waiting lists for in-lab PSG, is to shift sleep studies from the sleep laboratory to patients’ homes using a variety of ambulatory sleep-monitoring systems. There is a variety of ambulatory devices ranging from a single-channel pulse oximetry monitor, to multichannel recorders that allow a full PSG in the patient’s home (e.g., Watch-PAT, Night-Watch, MESAM 4, Edentrace, and others). The American Academy of Sleep Medicine has classified sleep study systems into four categories: level 1 consists of inlaboratory attended standard PSG. Level 2 consists of unattended home sleep study with comprehensive portable devices incorporating the same channels as the inlab standard PSG. Level 3 comprises unattended devices, which measure at least four cardiorespiratory parameters, and level 4 embraces unattended devices recording one or two parameters (Chesson et al., 2003). While level 2 devices are relatively very accurate, they are complex and cumbersome. Level 4 devices, on the other hand, are frequently not accurate enough. Not included in this classification, however, are novel emerging technologies such as the handmounted Watch-PAT100/200 ambulatory system which

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monitors actigraphy, pulse rate, peripheral arterial tonometry, and oximetry (Bar et al., 2003). This device has been extensively validated for the diagnosis of sleep apnea (Bar et al., 2003; Hedner et al., 2004; Pittman et al., 2004) and detection of arousals from sleep (Pillar et al., 2003), and at the same time it has been shown to be a simple, easy-to-use device with a relatively low failure rate (Margel et al., 2004). It has been shown that the outcome of treatment following diagnosis with this device is very similar to that of full

PSG (Berry et al., 2003). The growing awareness of the clinical importance of sleep apnea and the increased demand for its diagnosis may change the common diagnostic practices in the future.

RISK FACTORS Specific risk factors Table 25.1 summarizes the most important recognized clinical risk factors for OSA.

Table 25.1 Risk factors for sleep apnea syndrome Risk factor

Comments

References

Decreased UAW size

Macroglossia, tonsils/adenoid hypertrophy, increased size of choana/uvula/soft/hard palate/lateral wall tissue, posterior position of the maxilla, inferior displacement of the hyoid bone

Obesity

Predominantly central obesity and increased neck circumference Increased airway length? Hormonal mechanism?

Brown et al., 1987; deBerry-Borowiecki et al., 1988; Hoffstein et al., 1991; Shepard et al., 1991; Morrison et al., 1993; Schwab et al., 1993, 2003; Shelton et al., 1993; Isono et al., 1997a; Jager et al., 1998; Schwab, 1998; Huang et al., 2000; Hsu, 2002; Faber and Grymer, 2003; Kamal, 2004 Wilcox et al., 1994; Brown, 2002; Schafer et al., 2002; Gami et al., 2003 White et al., 1985; Wilhoit and Suratt, 1987; Cistulli et al., 1994; Pillar et al., 1994, 1995, 2000; Millman et al., 1995; Popovic and White, 1995; Lee et al., 1997; Whittle et al., 1999; O’Donnell et al., 2000; Fogel et al., 2001b; Mohsenin, 2001, 2003; Kapsimalis and Kryger, 2002; Malhotra et al., 2002a; Jordan and McEvoy, 2003; Resta et al., 2003; Jordan et al., 2004 White et al., 1985; Ancoli-Israel et al., 1991; Krieger et al., 1997; Ware et al., 2000; Klawe and TafilKlawe, 2003; Malhotra et al., 2006 Redline et al., 1992, 1995; Guilleminault et al., 1995; Mathur and Douglas, 1995; Pillar and Lavie, 1995; Pillar et al., 1997; Desai et al., 2004 Cadieux et al., 1982; Hart et al., 1985; Kittle and Chaudhary, 1988; Main et al., 1988; Grunstein et al., 1991; Lin et al., 1992; Rosenow et al., 1994; Buyse et al., 1997; Kapur et al., 1998; Hira and Sibal, 1999; Hochban et al., 1999; Isono et al., 1999; Fatti et al., 2001; Resnick et al., 2003; Babu et al., 2005 Mendelson et al., 1981; Issa and Sullivan, 1982; Guilleminault et al., 1984; Remmers, 1984; Audenaert et al., 1995 Aldrich, 1990; Guilleminault et al., 1992; Resta et al., 2000; Ayas et al., 2001; Weinberg et al., 2003 Mendelson et al., 1990; Wadhwa et al., 1992; Weitzenblum et al., 1992; Langevin et al., 1993; Hallett et al., 1995; Radwan et al., 1995; Douglas, 1998; Hui et al., 2000; Larsson et al., 2001; Sharma et al., 2002

Male gender

Increased age

Unclear clinical significance in the elderly

Genetic

Multifactorial, two- to fourfold higher risk in first-degree relatives

Endocrine

Hypothyroidism, acromegaly, diabetes

Extrinsic

Alcohol, CNS depressants (hypnotics, narcotics)

Neuromuscular

Myopathies, muscular dystropies, neuromuscular disorders COPD, asthma, renal failure

Other illnesses

UAW, upper airway; CNS, central nervous system; COPD, chronic obstructive pulmonary disease.

OBSTRUCTIVE SLEEP APNEA: DIAGNOSIS, RISK FACTORS, AND PATHOPHYSIOLOGY 387 The most recognized risk factor for OSA is anato1996; Whittle et al., 1999; Schwab et al., 2003), mical narrowing of the upper airways. This has been decreased upper-airway muscle protective force due demonstrated over recent years by a variety of imaging to fatty deposits in the muscle (Ryan and Love, 1996; techniques (Shepard et al., 1991; Schwab, 1998; Faber Whittle et al., 1999; Carrera et al., 2004), and reduced and Grymer, 2003), such as computed tomography upper-airway size secondary to mass effect of the (CT) (Schwab et al., 1993), magnetic resonance imaging large abdomen on the chest wall and trachel traction (MRI) (Shelton et al., 1993; Schwab et al., 2003), acous(Hoffstein et al., 1984; Wheatley and Amis, 1998). This tic reflection technique (Brown et al., 1987; Huang latter mechanism emphasizes the great importance of et al., 2000; Kamal, 2004), endoscopy (Morrison central obesity as compared with peripheral obesity, et al., 1993; Isono et al., 1997a; Hsu, 2002), fluoroscopy since it is the abdomen much more than the thighs that (fluoroscopic MR; Jager et al., 1998), and cephalometaffects upper-airway size (Brown, 2002; Schafer et al., ric X-ray measurements (deBerry-Borowiecki et al., 2002). For these reasons, it has been clearly shown that 1988; Hoffstein et al., 1991). Most of these studies obesity is associated with increased upper-airway colagreed that patients with OSA have an anatomically lapsibility, which sometimes dramatically improves folnarrower airway, manifested in many potential ways, lowing massive weight reduction (Charuzi et al., 1985; such as enlarged tongue and/or soft palate, increased Schwartz et al., 1991; Fogel et al., 2003a). However, lateral-wall fatty tissue, inferior displacement of the obesity definitely cannot solely explain sleephyoid bone, shorter mandible bone, elongated face, disordered breathing since OSA is seen in nonobese inferior displacement of the mandibular body, postepatients and not every obese patient suffers from rior position of the maxilla, increased choanal size or OSA. Thus, obesity should be considered as a very nasal polyps, enlarged or elongated hard and/or soft important risk factor, but not as the single pathological palate, increased uvular size, reduced and/or change factor that causes OSA. in shape of the nasopharyngeal and/or oropharyngeal OSA occurs significantly more in men than women. and/or hypopharyngeal airway area. These narrower The ratio of men to women among OSA patients is as airways can result from congenital facial structure or high as 8:1 in sleep clinic populations (Guilleminault from acquired factors such as obesity and increased et al., 1988), and about 2–3:1 in community-based samfatty tissue around the upper airway. ples (Young et al., 1993; Redline et al., 1994). The reaAn anatomically compromised airway which is notasons for this gender effect in OSA remain poorly ble during wakefulness may worsen during sleep and understood but could result from a combination of reach a point of zero sectional area at the time of various pathophysiological factors, such as differences obstruction. However, since OSA is an exclusively in body fat distribution (or other gender-related uppersleep disorder, the airway does not obstruct during airway anatomy differences), control of ventilation, wakefulness, probably due to a successful compensaphysiology of the pharyngeal airway dilator muscles tory neuromuscular protective mechanism, which may activation, and hormonal differences (White et al., fail during sleep. Thus, sleep apnea results from a 1985; Wilhoit and Suratt, 1987; Cistulli et al., 1994; combination of both anatomical narrowing of the airPillar et al., 1994, 1995, 2000; Millman et al., 1995; ways and dysfunction of protective mechanisms. Popovic and White, 1995; Lee et al., 1997; Whittle Obesity is probably the most important acquired et al., 1999; O’Donnell et al., 2000; Fogel et al., clinical risk factor for the development of OSA in 2001b; Mohsenin, 2001, 2003; Kapsimalis and Kryger, adults. Some 60–90% of adults with OSA are over2002; Malhotra et al., 2002a; Jordan and McEvoy, weight, and the relative risk of sleep apnea from obe2003; Resta et al., 2003; Jordan et al., 2004). sity (body mass index > 29 kg/m2) may be as great The “male” type of obesity is commonly central, as as 10 or more (Wilcox et al., 1994; Brown, 2002; opposed to female peripheral obesity. This implies that, Schafer et al., 2002; Welch et al., 2002; Gami et al., even when controlled for potential confounders such 2003). Numerous studies have shown the development as age and body mass index, men experience an of OSA, or its worsening, with increasing weight, as increase in abdominal size as well as neck circumferopposed to substantial improvement with weight reducence and neck fat, which likely contributes to the male tion (Schwartz et al., 1991; Loube et al., 1994; Wilcox predisposition to OSA (Whittle et al., 1999). Indeed, et al., 1994; Monteforte and Turkelson, 2000; Brown, when upper-airway lumen size was assessed it was 2002; Fisher et al., 2002; Schafer et al., 2002; Gami reported to be somewhat smaller in women (Lee et al., 2003). There are probably several mechanisms et al., 1997; Mohsenin, 2001), although not in all studies responsible for the increased risk of OSA with obesity. (Mohsenin, 2003; Schwab et al., 2003). More imporThese include reduced lumen size due to fatty tissue tantly, men have a longer airway when compared to within the airway or in its lateral walls (Ryan and Love, women, even after correction for body height

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(Malhotra et al., 2002a). Since the collapsibility of a collapsible tube is strongly inversely related to its length, this can be a very dominant mechanistic explanation for the male predominance in OSA. Regardless of the exact anatomical explanation, the compromised anatomy of the male upper airway may result in increased resistance and subsequently OSA (White et al., 1985; Trinder et al., 1997; Mohsenin, 2003). The possible role of central gender-related differences in control of ventilation as contributors to the differences in the prevalence of OSA is unclear (Pillar et al., 2000; Behan et al., 2002; Jordan et al., 2002, 2004). The observation that in women OSA becomes particularly prevalent after menopause (Wilhoit and Suratt, 1987; Resta et al., 2003), and that medroxyprogesterone administration to patients with OSA resulted in substantial improvement (Cistulli et al., 1994; Collop, 1994; Smith and Quinnell, 2004), has suggested the possible role of sex hormones in the control of breathing. Evidence that blood levels of testosterone were correlated with apnea severity in women with polycystic ovary syndrome (Fogel et al., 2001b) supported this notion. Thus, while progesterone has the potential to activate upper-airway-protecting dilator muscle activation, testosterone probably inhibits their activation and may contribute to the gender-related difference in the prevalence of sleep apnea. OSA is probably most intimidating during middle age. The natural history of OSA is not fully known, but it probably begins as several years of just loud snoring, then gradually over a period of several years cessations of breathing and symptoms of excessive sleepiness develop, and thereafter may remain stable or worsen with weight gain (Sforza et al., 1994; Fisher et al., 2002). Others, however, have reported that mild to moderate OSA has a tendency to worsen in the absence of significant weight gain and that upperairway anatomy and clinical variables did not appear to be useful in predicting the progression of the syndrome (Pendlebury et al., 1997). The explanation for this aging increase in the prevalence of OSA remains unknown, although several potential mechanisms have been proposed. Age was reported to correlate with pharyngeal resistance in men but not in women (White et al., 1985). Age was also reported to be associated with a decrement in respiratory effort during an obstruction (Krieger et al., 1997), and in protecting genioglossus muscle activation (Klawe and Tafil-Klawe, 2003). Extensive studies of the underlying anatomical and pathophysiological mechanisms which may lead to increased OSA with age revealed that older people had a poorer responsiveness of pharyngeal dilator muscles to negative pressure stimuli than did younger subjects (Malhotra et al., 2006). In

addition, anatomical changes associated with aging included increased parapharyngeal fat pad size and an increase in pharyngeal airway length in women but not in men. Genetic factors are clearly important as well. We (Pillar and Lavie, 1995), and others (Redline et al., 1992; Guilleminault et al., 1995; Desai et al., 2004), have shown that sleep-disordered breathing clusters in families. The relative risk of OSA may be two- to fourfold greater in first-degree relatives of OSA patients. As much as 40% of the variance in AHI may be accounted for by genetic factors, and these familial factors remain significant after adjustment for body mass index and cephalometric measurements (Redline et al., 1995). Furthermore, we have shown that healthy offspring of OSA patients responded to inspiratory resistive loadings with greater decrease in ventilation than controls (Pillar et al., 1997). Whether this was due to inherited compromised upperairway anatomy or another mechanism (i.e., inherited control of breathing characteristics, or local reflex ones) was unclear. However, we speculated that the decreased tolerance to inspiratory resistive loading might predispose those OSA offspring to develop OSA later on in life.

Other risk factors Several endocrinological pathologies (in addition to the sex hormones discussed above) may also predispose to OSA. These include predominantly hypothyroidism, acromegaly, and diabetes. Hypothyroidism can result in increased body weight, central obesity, and reduced upper-airway muscle strength, which may explain the high prevalence of OSA among hypothyroid patients (Kittle and Chaudhary, 1988; Lin et al., 1992; Kapur et al., 1998; Hira and Sibal, 1999). Furthermore, treating patients with hypothyroidism and OSA with thyroxine may alleviate or even cure their sleep-disordered breathing (Rajagopal et al., 1984; Lin et al., 1992; Hira and Sibal, 1999). Excess of growth hormone which leads to acromegaly is also known to be associated with sleep apnea syndrome (Cadieux et al., 1982; Hart et al., 1985; Main et al., 1988; Grunstein et al., 1991; Rosenow et al., 1994; Buyse et al., 1997; Hochban et al., 1999; Isono et al., 1999; Fatti et al., 2001). The exact mechanism, however, is not fully understood. Studying the collapsibility of passive pharynx in patients with acromegaly, Isono et al. (1999) concluded that anatomic abnormality, especially at the base of the tongue, appears to play a significant role in the development of sleep-disordered breathing in acromegaly. This is partially supported by craniofacial studies (Hochban et al., 1999). On the other hand, sleep apnea commonly normalizes with treatment of acromegaly, even before local anatomical changes at

OBSTRUCTIVE SLEEP APNEA: DIAGNOSIS, RISK FACTORS, AND PATHOPHYSIOLOGY the upper-airway level are noticeable (Cadieux et al., 1982; Hart et al., 1985; Leibowitz et al., 1994; Buyse et al., 1997). Furthermore, it appears that central sleep apnea is also very common in acromegaly, which raises the possibility that altered respiratory control is involved in producing sleep apnea in acromegaly (Grunstein et al., 1991). Another important pathology which closely relates to OSA is diabetes, although the exact relationships between the conditions are rather complicated. On the one hand, OSA can result in diabetes by increasing insulin resistance, which improves with nCPAP therapy (Babu et al., 2005). On the other hand, diabetes can result in changes in the central ventilatory control system that can lead to periodic breathing (Resnick et al., 2003). Furthermore, the association between sleep apnea and diabetes is strongly affected by many confounders, most importantly, obesity, and therefore the clear net effect of sleep apnea and diabetes on each other is not that obvious (Sanders and Givelber, 2003). Nevertheless, diabetes is common in OSA and OSA is common in diabetes, regardless of the exact mechanism linking them together. The risk of sleep apnea also increases with the use of substances and medications which weaken upperairway dilator muscle activation. These include alcohol (Issa and Sullivan, 1982; Remmers, 1984), central nervous system depressants such as benzodiazepines (Mendelson et al., 1981; Guilleminault et al., 1984), and barbiturates (Audenaert et al., 1995). Similarly, neuromuscular diseases such as myopathies, muscular dystrophies, spinal cord injuries, and other neuromuscular disorders (Aldrich, 1990; Guilleminault et al., 1992; Short et al., 1992; Resta et al., 2000; Ayas et al., 2001; Weinberg et al., 2003), can change the balance between collapsing and stabilizing forces of the airways and can result in increased upper-airway collapsibility and consequently OSA. Finally, there are some specific diseases that, when they coexist with sleep apnea, exacerbate its severity. The most important of these are chronic obstructive pulmonary disease (COPD), asthma, and renal failure. Sleep has effects on breathing, including changes in respiratory control, airway resistance, and muscular contractility. These sleep-related modifications in the respiratory system do not induce adverse effects in healthy subjects, but may cause problems in patients with COPD. Hypoventilation causes the most important gas exchange alteration during sleep in COPD patients, leading to hypercapnia and hypoxemia, especially during rapid eye movement (REM) sleep. Blood gas alterations lead to increased arousals, sleep disruption, and pulmonary hypertension (Fanfulla et al., 2004). Similarly, nocturnal worsening of asthma, which

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can result from sleep or circadian effects, is a common manifestation of this disease that indicates increased disease severity. Potential mechanisms which associate COPD/asthma and sleep apnea include decreased ventilatory responsiveness to hypercapnia, reduced respiratory muscle output, and marked increases in upper-airway resistance (potentially secondary to allergy, inflammation, and congestion). Thus, in some cases of COPD/asthma, OSA coexists (overlap syndrome), and is usually of greater severity (Weitzenblum et al., 1992; Radwan et al., 1995; Douglas, 1998; Larsson et al., 2001; Sharma et al., 2002). It is well established that sleep apnea is more common in patients with renal failure (Mendelson et al., 1990; Wadhwa et al., 1992; Langevin et al., 1993; Hallett et al., 1995; Hui et al., 2000). The exact mechanism is still not fully understood, but can potentially be affected by edema, which may be seen in patients with renal failure. In addition, abnormalities in respiratory control mechanisms from chronic hypocarbia, metabolic acidosis, and uremic toxins have been blamed for this association in patients with chronic renal failure. Hypertension may play a role as well. Interestingly, although apnea severity did not change much following dialysis (Mendelson et al., 1990), OSA was almost completely resolved after kidney transplantation (Langevin et al., 1993). The association between OSA and renal failure is further complicated by reports of improved renal function following treatment with CPAP to the respiratory disorder (Krieger et al., 1988; Zhang et al., 1997). In this context, several factors associated with OSA can contribute to progressive renal dysfunction in these patients. These include predominantly hypertension, hypoxemia, and increased sympathetic nerve activity. Thus, although the exact relationships between these two diseases need to be better understood, renal failure is considered a potential risk factor for sleep apnea and some researchers and clinicians even proposed that patients with chronic renal failure should be screened for sleep apnea.

PATHOPHYSIOLOGY The pathogenesis of OSA has been the subject of intense research activity in recent years. Research has focused on the neurochemical and physiological changes that occur at sleep onset leading to the loss of muscle activity and diminished reflex pharyngeal control and a loss of the neuromuscular compensation present during wakefulness, resulting in pharyngeal collapse. Characteristics of the central respiratory centers (ventilatory control instability) and arousal threshold may play a role as well.

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Pharyngeal anatomy As discussed above, the majority of the evidence supporting an anatomic abnormality in adult OSA patients is derived from imaging and endoscopic studies. Haponik et al. (1983) originally reported a substantially smaller minimal pharyngeal cross-sectional airway area in sleep apnea patients compared to controls when imaged during wakefulness, although the groups were not controlled for weight. Since this original report, several authors, using a variety of imaging techniques (CT, MRI, acoustic reflection, cephalometrics), have demonstrated a small pharyngeal airway in sleep apnea patients, with the smallest airway luminal size generally occurring at the level of the velopharynx (behind the soft palate) in both patients and controls (Abbey et al., 1989; Hoffstein et al., 1991; Schwab et al., 1993, 2003; Jager et al., 1998; Morrell et al., 1998; Schwab, 1998; Whittle et al., 1999; Ciscar et al., 2001; Ikeda et al., 2001; Sanner et al., 2002; Macey et al., 2003). However, these studies suffer from two important limitations. First, they have focused, for the most part, on airway luminal size with little attention to airway soft-tissue structures and characteristics. Second, during wakefulness, airway luminal size does not reflect pure anatomy, but rather the interaction between anatomy and muscle activation, as stated above. Therefore, the information available on the determinants of upper-airway anatomy is somewhat limited. The most convincing evidence supporting functional abnormality in OSA patients comes from Isono et al. (1997a, b). These authors measured the critical pressure (Pcrit) required to close (completely collapse) the upper airway of humans undergoing general anesthesia with complete neuromuscular paralysis. Under the condition of absent neuromuscular activity, the authors observed a positive Pcrit in OSA patients, meaning that the airway was collapsed at atmospheric pressure and required positive pressure to reopen (Isono et al., 1997b). Normal controls, on the other hand, had patent airways at atmospheric pressure and required suction (negative pressure) to collapse the pharynx. This observation strongly supports the existence of a biomechanical abnormality of the upper airway in sleep apnea patients. In addition, the authors showed a strong correlation between Pcrit and the oxygen desaturation index, indicating a clear relationship between airway anatomy and apnea severity. Endoscopic evaluation also demonstrated a larger cross-sectional area of the velopharynx in controls compared to apneics, again suggesting deficient anatomy in the apnea patients (Isono et al., 1997b). One possible limitation of this otherwise unique and persuasive study is the potential development of atelectasis and reduced lung volume

under conditions of anesthesia and hyperoxia. Lung volume can have a substantial influence on upper-airway size, especially in apneics (Hoffstein et al., 1984). In addition to airway size, airway shape may also be an important determinant of upper-airway collapsibility. Several studies have reported an oval shape of the pharyngeal airway in individuals with OSA when compared to controls (i.e., a relatively high anteroposterior/lateral luminal airway dimension) (Horner et al., 1989; Rodenstein et al., 1990). Leiter (1996) has also suggested a reduced ability of muscles to dilate the pharynx when it is oval in shape. Whether it represents an important component of apnea pathogenesis, or is simply a marker of fat deposition in the fat pads lateral to the airway, remains to be elucidated. Finally, the soft tissues surrounding the upper airway may have an independent role. Using sophisticated analyses of soft-tissue variables, sleep apnea patients were shown to have increased thickness of the lateral pharyngeal walls, independent of fat pad thickness (at the level of the minimum axial airway lumen) (Schwab et al., 1993; Schwab, 1998, 2005; Whittle et al., 1999; Ciscar et al., 2001). This finding is helpful in explaining the reduced lateral diameter of the airway lumen in apneics as compared to weight-matched controls. No important skeletal differences were observed, implicating soft tissues as the major anatomic difference between apneics and nonapneic controls. Schwab et al. (1993) and Schwab (1998) have argued therefore that lateral wall thickening and ultimately collapse are important components in the pathogenesis of OSA in adults. The measurement of an upper airway Pcrit during sleep (not anesthesia) is increasingly appreciated as a useful measure of an individual’s propensity or vulnerability to pharyngeal collapse (Issa and Sullivan, 1984a, b; Smith et al., 1988; Schwartz et al., 1989; Jordan et al., 2005). Indeed, OSA patients often require positive pressure to maintain airway patency during sleep (i.e., positive Pcrit, needed for nCPAP therapy during sleep). Patients with mild disease or simple snoring tend to have a slightly negative Pcrit whereas normal controls have a substantially negative Pcrit (–10 to – 15 cmH2O) (Schwartz et al., 1988, 1989; Sforza et al., 1999). These Pcrit measurements, which reflect both anatomy and neuromuscular activity, also support an upper-airway anatomic abnormality among patients with OSA (Schwartz et al., 1988, 1989; Smith et al., 1988; Gleadhill et al., 1991; Sforza et al., 1999).

Role of pharyngeal muscles Three groups of muscles have been investigated in the context of pathogenesis of sleep apnea: (1) the muscles influencing hyoid bone position (geniohyoid,

OBSTRUCTIVE SLEEP APNEA: DIAGNOSIS, RISK FACTORS, AND PATHOPHYSIOLOGY sternohyoid); (2) the muscle of the tongue (genioglossus); and (3) the muscles of the palate (tensor palatini, levator palatini). The activity of many of these muscles is increased during inspiration, thus stiffening and dilating the upper airway and by that counteracting the collapsing influence of negative airway pressure (van Lunteren and Strohl, 1986). These are referred to as inspiratory dilator phasic upper-airway muscles. The genioglossus is the best-studied such muscle. The activity of the genioglossus is substantially reduced (although not eliminated) during expiration when pressure inside the airway becomes positive and there is less tendency for collapse. Other muscles, such as the tensor palatini, do not consistently demonstrate inspiratory phasic activity but instead maintain a relatively constant level of activity throughout the respiratory cycle (Tangel et al., 1991). These are called tonic or postural muscles, and are also thought to play a role in the maintenance of airway patency. These two types of pharyngeal muscles are likely controlled by groups of neurons within the brainstem that have different firing patterns relative to the respiratory cycle. The activity of the pharyngeal dilator muscles can be influenced during wakefulness by a number of physiological stimuli. Chemical stimulation (rising PaCO2 or falling PaO2) can substantially augment the activity of these muscles (Onal et al., 1981a, b). Perhaps more importantly, negative pressure in the pharynx (which would tend to collapse the airway) markedly activates these muscles which in turn counteract this collapsing influence (Fogel et al., 2000; Malhotra et al., 2000, 2001a, 2002b; Pillar et al., 2001a; Berry et al., 2003). This response to negative pressure is likely driven by topical, pressure, or stretch-sensitive receptors, as it can be substantially attenuated by the application of topical anesthesia (Fogel et al., 2000). It is this receptor mechanism that is likely activated in an individual with an anatomically small airway in response to greater negative pressure, airway stretch, or collapse itself. In patients with sleep apnea who have an anatomically small airway, this negative-pressure reflex is substantially activated during wakefulness, leading to augmented dilator muscle activity as a neuromuscular compensatory mechanism to protect the airways. The genioglossus muscle in sleep apnea patients functions at nearly 40% of its maximum capacity during wakefulness, while in control subjects the muscle functions at only about 12% of maximum (Mezzanotte et al., 1992). That negative pressure drives this augmented muscle activity is suggested by the observation that nCPAP can reduce the level of activity in the genioglossus muscle of sleep apnea patients to near-normal levels (Mezzanotte et al., 1992). Thus, were it not for this increased activity of the pharyngeal dilator

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muscles, the airway of the sleep apnea patient would substantially narrow or collapse, even during wakefulness. Therefore, the individual’s propensity for upperairway collapse during sleep depends on two variables: (1) predisposing anatomy; and (2) the level of pharyngeal dilator muscle activity. The effect of sleep on upper-airway muscle activity probably plays an important role in the pathophysiology of OSA. The activity of tonic pharyngeal muscles such as the tensor palatini is markedly reduced during NREM sleep (to 20–30% of awake values) while phasic muscles generally maintain waking levels of activity (Tangel et al., 1992). This fall in tonic muscle activity conceivably contributes to the observed increments in airflow resistance commonly seen in normal individuals with the transition from wakefulness to sleep. Phasic muscle activity, on the other hand, remains stable or even slightly increases in normal subjects in sleep in comparison with wakefulness (Tangel et al., 1992; Wheatley et al., 1993a, b). However, the protective reflex activation of these muscles which can be observed during wakefulness is markedly diminished during sleep. This reflex-driven augmentation of dilator muscle activity compensates for deficient anatomy in apnea patients during wakefulness. During sleep, there is a marked attenuation or loss of this reflex mechanism, even in normal subjects. Using a model of passive negative pressure ventilation, a tight relationship between varying intrapharyngeal negative pressures and genioglossal muscle activation during wakefulness has been shown both in controls and in sleep apnea patients (Fogel et al., 2001a). Using the same model, it has been found that the stable relationship between negative epiglottic pressure and genioglossal EMG was markedly reduced during sleep while ventilated with negative pressure (Fogel et al., 2003b), or with inspiratory resistive loading (Malhotra et al., 2001b). This was associated with a markedly higher pharyngeal airflow resistance during sleep. At the transition from wakefulness to sleep there was also a greater reduction in peak genioglossal EMG. Thus, while the negative pressure reflex is able to maintain genioglossal EMG during wakefulness, this reflex is unable to do so during sleep. Furthermore, it has been shown that the strong dependency of the dilator muscle activation on CO2 that is seen during wakefulness is substantially diminished during either stage 2 or slowwave sleep (Pillar et al., 2001b). Thus, the loss of the negative pressure reflex protecting mechanism with the reduced dependency of dilator muscle activation on negative pressure and rising CO2 leads to falling dilator muscle activity and airway collapse (Wheatley et al., 1993a, b; Malhotra et al., 2001a, 2002b; Pillar et al., 2001b; Fogel et al., 2003c).

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The finding that the protective genioglossal activation is almost completely lost during REM sleep may help understand why apnea worsens during REM in most OSA patients (Shea et al., 1999). Interestingly, it has been shown that a fall in genioglossal EMG was seen during sleep onset followed by subsequent muscle recruitment in the third to fifth breaths following the transition from alpha to theta EEG activities. It has been suggested that the initial sleep-onset reduction in upper-airway muscle activity is due to loss of a wakefulness stimulus, rather than to loss of responsiveness to negative pressure, and that this wakefulness stimulus may be greater in the OSA patient than in healthy controls (Fogel et al., 2005). This finding emphasizes the potential role of the arousal/awakening stimuli and the potential importance of other central nervous mechanisms in the patophysiology of sleep apnea.

Ventilatory control instability (loop gain) and arousal effects It has been argued that an intrinsic instability of the ventilatory control mechanisms leads to variable activity in the diaphragm and the pharyngeal muscles, resulting in airway collapse (Onal et al., 1986). Others have suggested that a “mismatch” in the timing of activation of the diaphragm and pharyngeal muscles renders the pharyngeal airway susceptible to collapse during sleep. Thus, if the diaphragm is activated before the upper-airway muscles, then negative pressure would develop in the pharynx at a time when the airway was relatively unprotected. Such alterations in the timing of the pharyngeal muscles relative to the diaphragm have been demonstrated in apneics in one study but it is unclear if this is a primary abnormality (Hudgel and Harasick, 1990). Younes et al. (2001) studied 32 patients with OSA (12 severe) during sleep while their upper airway was stabilized with continuous positive airway pressure. Susceptibility to periodic breathing was assessed by gradually increasing controller gain, using proportional assisted ventilation. Nine of 12 patients with severe OSA developed periodic breathing, with recurrent central apneas, compared with only 6 of the 20 patients in the mild/moderate group. The authors concluded that the chemical control system is less stable in patients with severe OSA than in patients with milder OSA, and speculated that this may contribute to the severity of OSA (Younes et al., 2001). In a later study, loop gain magnitudes were found to be similar in 6 OSA and 5 normal subjects, but the chemoreflex loop impulse response in the OSA patients exhibited faster and more oscillatory dynamics, implying unstable upper-airway mechanics and an underdamped chemoreflex control system (Asyali

et al., 2002). This may be another important factor that promotes the occurrence of periodic obstructive apneas during sleep, although studies failed to relate the higher susceptibility to OSA seen in men or with increasing age to this ventilatory control instability mechanism (Browne et al., 2003; Wellman et al., 2003; Jordan et al., 2005). However, in vulnerable patients with collapsible airway (closing pressure near atmospheric pressure), loop gain may have a substantial impact on apnea severity (Wellman et al., 2004). Once the patient with apnea falls asleep and the cycle of repetitive airway obstruction begins, recurrent hypoxemia and hypercapnia develop. The rate at which these chemical disturbances evolve is related to a number of factors, including: (1) the PaO2 and PaCO2 at which the apnea starts; (2) the individual oxygen stores, which relate to lung volume; and (3) whether there is continued effort during the apnea (Bradley et al., 1985). The severity of hypoxemia and hypercapnia is also dependent on apnea length. Termination of the apnea generally requires a transient arousal from sleep, thus activating the upper-airway muscles and reestablishing airway patency. Without such an arousal profound hypoxemia and hypercapnia would likely ensue. The possible mechanisms leading to arousal include direct stimulation of peripheral and central chemoreceptors by rising PaCO2 and falling PaO2, afferent central nervous system input from the lung, chest wall, or upper-airway receptors resulting from the increasing ventilatory effort that develops over the course of an apnea, or direct stimulation of the reticular activating system by respiratory neurons activated during the apnea (Gleeson et al., 1989, 1990). Regardless of the exact route by which apneas are terminated, arousal remains an important mechanism that prevents asphyxia, but at the same time arousals may increase the severity of the sleepdisordered breathing by promoting greater ventilatory instability (Younes, 2004). In summary, the principal abnormality in OSA is an anatomically small pharyngeal airway. During wakefulness the individual is able to compensate for the deficient anatomy, by increasing the activity of upper-airway muscles which maintain airway patency. However, with sleep onset, this compensation is lost and airway collapse occurs. The physiological consequences of apnea are a rise in PaCO2, a fall in PaO2, and increasing ventilatory effort against an occluded airway. Ultimately, transient arousal from sleep occurs, which reestablishes the airway and ventilation. The individual subsequently returns to sleep and the cycle begins again, to be repeated frequently over the course of the night. Figure 25.1 summarizes the balance of forces which result in upper-airway patency or collapse. Inspiratory negative pressure, anatomically

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Promotion of airway patency

Promotion of airway collapse Negative pressure on inspiration

Pharyngeal dilator muscle contraction (genioglossus)

Extraluminal positive pressure Fat deposition Small mandible Lung volume (longitudinal traction)

Fig. 25.1. The balance of forces. Inspiratory negative pressure, anatomically narrow airway, and extraluminal positive pressure tend to promote pharyngeal collapse. Upper-airway dilator muscle and increased lung volume tend to maintain pharyngeal patency. (Reproduced from Malhotra and White (2002), with permission.)

narrow airway, and extraluminal positive pressure tend to promote pharyngeal collapse. Upper-airway dilator muscle and increased lung volume tend to maintain pharyngeal patency (Malhotra and White, 2002).

SUMMARY OSA syndrome is a disorder characterized by repetitive episodes of upper-airway obstruction that occur during sleep, usually associated with a reduction in blood oxygen saturation and characteristic complaints such as excessive daytime sleepiness and chronic fatigue. The diagnosis is typically confirmed by overnight PSG or ambulatory monitoring, during which sleep is recorded while breathing, respiratory effort, oxygen saturation, and the electrocardiogram are simultaneously monitored. Upper-airway obstruction can be complete, in which case there is no airflow (obstructive apnea), or partial, during which there is a substantial reduction in, but not a complete cessation of airflow (obstructive hypopnea). The severity of the syndrome is indexed by the AHI – the average number of apneas plus hypopneas per hour of sleep. OSA is a prevalent syndrome, affecting 4% and 2% of adult men and women, respectively, and its prevalence is considerably higher in specific patient groups. The prevalence of disordered breathing in sleep regardless of symptoms is sixfold higher than that of OSA. The most important risk factors for OSA are decreased upper-airway size, obesity, male gender, age, certain diseases, and substances that affect upper-airway tone. Genetic factors also appear to play a role, as the syndrome was shown to cluster in families. Extensive research has shown that the

principal abnormality in OSA is a biomechanical one. While during wakefulness sleep apnea patients are able to compensate for their deficient airways anatomy by increasing the activity of upper-airway muscles which maintain airway patency, during sleep this compensation is lost and airway collapse occurs. The physiological consequences of apnea are a rise in PaCO2, a fall in PaO2, and increasing ventilatory effort against an occluded airway. Ultimately, transient arousal from sleep occurs, which reestablishes the airway and ventilation.

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