Middle-Aged Population

It is estimated that 24% of men and 9% of women have OSA, as defined by an AHI of 5 or greater, and that 15% of men and 5% of women between 30 and 60 years have an AHI of 10 or higher. With use of daytime sleepiness as a clinical syndrome, the prevalence ranges between 3% and 7% in men and 2% and 5% in women in the general population (Box 60-1). Until recently, population-based epidemiologic studies of OSA were available only for North America, Europe, and Australia. However, more recent studies undertaken in other countries, including China, India, and Korea, report similar prevalence rates. The overall incidence of moderate to severe OSA (defined by an AHI of 15 or higher) occurring over a 5-year period is 11% and 5% in men and in women, respectively, which persists even after adjustment for confounding variables. This means that, even in the absence of any weight change, approximately 20% of men and 10% of women will develop moderate to severe OSA in that period of time.

Most population-based studies have found a two- to three-fold higher prevalence of OSA in males than in females. The ratio is even higher for men treated in sleep centers, with reported ratios between 4 : 1 and 8 : 1 or higher. This higher ratio may be the result of multiple factors: Women do not show the “classic” OSA symptomatology—they typically have more comorbid illnesses, use more psychoactive drugs in the absence of a correct diagnosis, and often present with vague, nonspecific symptoms, which widens the differential diagnosis and leads to a higher level of underdiagnosis or misdiagnosis of OSA. An important finding from epidemiologic studies is that gender disparities in prevalence seem to decrease with age, and when women reach postmenopausal status (and are not receiving hormonal replacement treatment), incidence rates for men and women become similar. Table 60-1 summarizes the most important sleep apnea prevalence studies in middle-aged populations.

Elderly Population

The prevalence of OSA in adults increases with age as a result of greater collapsibility of the upper airway and probably reaches a plateau after the age of 65. It is estimated that 65% of older men and 56% of older women between 65 and 95 have OSA as defined by AHI of 10 or greater, and 26% of men and 21% of women between 71 and 100 years have an AHI of 30 or greater. Finally, 20% of older men and 15% of older women have the OSA syndrome (AHI of 10 or higher plus daytime hypersomnia). With age comes an increase in the frequency of both obstructive and central respiratory events. The main problem is to identify the AHI cutoff point that marks the limit of a physiologic and abnormal increase, in order to determine the real prevalence of clinically relevant OSA in the elderly population. In this sense, some investigators state that OSA represents different and distinct clinical entities in middle-aged adults and in older adults, based on morbidity and mortality data, although this position is controversial. Perhaps there is a more complex model of OSA that varies with the patient’s age.

In any case, the two proposed types of OSA consist of (1) a pathologic form of OSA that appears in middle age in those patients who usually are diagnosed in sleep laboratories and (2) OSA that appears after the age of 60 years, with some overlap between the two, mainly caused by physiologic changes (increase in pharyngeal collapsibility) associated with aging, and of less clinical importance. Data also suggest that the interaction between body weight and OSA in elderly persons may be different from that in younger adults. Because of the population-wide increase in longevity, the proportion of elderly persons being treated at sleep units also is increasing; currently one in four sleep studies are performed in patients older than 65 years of age. This scenario will present a scientific challenge in the future, in view of the lack of scientific evidence available on OSA in the elderly. Table 60-2 summarizes the most important epidemiologic studies describing the prevalence of OSA in older people.

Obesity

According to recent estimates, 60% of adults in industrialized nations are overweight (body mass index [BMI] of 25 kg/m² or higher) and at least 15% are obese (BMI of 30 kg/m² or higher). Obesity is a common clinical finding and is present in more than 60% of patients referred for diagnostic sleep evaluations. Twin studies have shown that up to 70% of the variance in obesity within a population may be attributable to genetic factors. Although candidate genes for obesity are numerous, only a few single-gene mutations causally related to obesity have been convincingly detected, including the leptin receptor gene, the leptin gene, the pro-opiomelanocortin gene, the prohormone convertase 1 gene, and the melanocortin MC4 receptor gene, but very few studies on candidate genes associated with weight loss or weight gain have been performed, and no work in this area has been carried out specifically in the OSA population.

The prevalence of OSA in obese subjects is as high as 45%. Obesity explains 30% to 50% of the variance in AHI and is the only variable that can be modified. Several researchers have speculated that obesity and OSA may share a common genotype, and linkage analysis identified candidate regions at least on chromosomal arms 2p and 19p, but further studies are needed to confirm these results. Some major epidemiologic studies from around the world have consistently identified body weight as the strongest risk factor for OSA and have demonstrated a positive correlation between changes in OSA incidence and changes in weight over time. The Wisconsin Sleep Cohort showed that an increase of one standard deviation in BMI was associated with a four-fold increase in the prevalence of OSA. The longitudinal analysis component of the same study demonstrated that OSA severity changed approximately 3% for every 1% change in weight over a 4-year period. The Sleep Heart Health Study found that the change in AHI with weight changes over a 5-year period was more pronounced in men, and that the change was greater when associated with a weight increase than with a weight decrease. Corroborating this strong association, some studies have shown that dietary or surgical weight loss leads to reduced OSA severity in many patients and that OSA can even be completely cured in some cases. In other words, patients with mild OSA who gain 10% of their baseline weight are at a six-fold increased risk for progression of OSA, and an equivalent weight loss can result in a more than 20% improvement with respect to OSA severity.

Whether OSA predisposes affected persons to the preferential accumulation of visceral fat remains to be determined. More evidence is necessary to determine which specific measure of peripheral or central fat distribution is less compromising for OSA. Some investigators have shown that neck circumference, waist circumference, and BMI are independently associated with OSA severity at all ages, although it seems that neck size is the strongest predictor of sleep-disordered breathing, indicating that upper body obesity (fat deposition around the upper airway or fat deposited in the parapharyngeal fat pads), rather than a more generalized distribution of body fat, is important for the development of OSA. In any case, it is advisable to obtain information from all three measures in clinical practice.

The fundamental mechanisms by which obesity leads to an increase in the number of respiratory events during sleep, and weight loss decreases them, are unknown. It has been postulated that fat deposits surrounding the airway play a role in increasing the critical closing pressure. Other potential contributing factors include the reduction of functional residual capacity, ventilatory control system instability, alterations in neural compensatory mechanisms that maintain airway patency, and functional impairment of the upper airway muscles. Obesity also reduces chest wall compliance and increases whole-body oxygen demand, again predisposing affected persons to development of OSA. The degree to which common conditions associated with obesity, such as diabetes, may cause vascular or neuropathic damage to the dilator pharyngeal muscles and reduced upper airway sensation remains to be fully elucidated.

Aging

Aging in itself is associated with numerous physiologic changes, one of them being an increase in upper airway collapsibility, leading to a higher prevalence of OSA. The critical closing pressure of the upper airway in older people is −8.3 ± 2.3 cm H₂O, whereas in middle-aged people it is −16 ± 6.9 cm H₂O, independent of BMI. This difference may be due to various factors: an age-related decrease in the genioglossus response, an increase in airflow resistance, a decrease in upper airway dilation reflex mechanisms, reduced response to the stimulus of hypoxia, changes in the bony structure surrounding the pharynx, descent of the hyoid bone, increase in soft palate length, or an increase in pharyngeal fat pads. All of these changes lead to a generalized age-related decrease in the size of the upper airway lumen, specifically in men, and a consequent increase in airflow resistance. Age also is associated with an increased incidence of comorbid conditions, postmenopausal hormone status in women, dental disorders, decreased quality of sleep, and intake of psychoactive drugs. All of these factors may increase upper airway collapsibility. Finally, an additional factor that may predispose older persons to development of OSA is the aging-related increase in arousal frequency. Arousals from sleep lead to hyperventilation and relative hypocapnia, which in turn can promote respiratory instability and periodic breathing during subsequent periods of sleep onset.

Male Gender

It is not known which mechanisms explain the finding that OSA risk is twice as high in men as in women. Some studies have implicated several factors. First, men have increased fat deposition around the upper airways walls. Although data suggest that, in percentage terms, more women (33.4%) than men (27.5%) have a BMI ≥30 kg/m², magnetic resonance imaging (MRI) studies have shown a decreased proportion of pharyngeal fat and soft tissue volume in the neck of obese women in comparison with obese men. Women in general have lower Mallampati scores, suggesting that the fat does not play as large a role in the female tongue as it does in the male tongue. Second, the upper airway in men is more prone to collapse as a result of its greater overall length with a longer vulnerable segment. Third, PSG characteristics of sleep and breathing patterns differ between women and men. Women tend to have a lower AHI in non–rapid eye movement (REM) sleep but have a similar AHI in REM sleep. Moreover, disordered-breathing events in women are of shorter duration and are associated with less oxyhemoglobin desaturation than in men. Finally, several mechanisms have been proposed to explain how male- or female-specific hormones would affect the propensity to develop OSA. One hypothesis is that the different hormones affect the distribution of body fat. Android body fat distribution (in the upper body and trunk) increases with both age and years after onset of menopause, which is a risk factor for the development of OSA. Hormone levels also have been hypothesized to affect central and neural respiratory control mechanisms. In this sense, progesterone has been shown to be a respiratory stimulant, which might protect premenopausal women from OSA; moreover, combined estrogen-progesterone treatment leads to a decrease in the number of apneic and hypopneic episodes during sleep. On the other hand, lower levels of testosterone may be protective against the development of OSA in women. Some researchers have shown that exogenous androgen therapy in men and women can aggravate OSA severity. It is possible that differing levels of hormones, starting from puberty and further modified by later maturational changes, can affect the development of OSA.

Genetic Predisposition

Several studies have confirmed the role of inheritance and familial factors in the genesis of OSA. First-degree relatives of persons with the disorder are more likely to be at risk than first-degree relatives of unaffected persons. Genetic factors explain more than 30% to 40% of the variance in disease severity, although confounding factors must be taken into account. Some OSA risk factors have a demonstrated genetic basis, such as craniofacial morphology, the volume of the lateral parapharyngeal walls, tongue form, total volume of soft tissue structures, abnormalities in breathing control, and finally, genetic determinants of obesity.

Recently, Larkin and associates conducted the first candidate gene study of OSA. More than 1500 single-nucleotide polymorphisms (SNPs) were genotyped, covering 53 genes representing intermediate disease pathways implicated in the disorder. These workers identified significant associations between sleep-disordered breathing and genetic variants of C-reactive protein, glial cell–derived growth factor, and serotonin 2A receptor genes independently of BMI. These results highlight the potential role of genetic analysis to better describe the different phenotypes of OSA, the risk of inheritance of each type, and its relationship with other diseases.

Other Predisposing Factors

Box 60-2 shows other predisposing factors that have been associated with increased risk for OSA. Their mechanisms of action are multiple: anatomic variability (e.g., craniofacial malformations), increased airway inflammation (smoking or infections), physiologic factors (sleep position, REM sleep, pregnancy, or ethnicity-related predilection), and depression of dilator pharyngeal muscle function (alcohol consumption, benzodiazepine or sedative use, stroke, and other comorbid conditions).

Although Asians are less obese than whites, disease prevalence in the East is not less than in the West. For a given age, sex, and BMI, however, Asians demonstrate greater disease severity than whites, which can be explained by differences in craniofacial features (persons of Asian ethnicity have a shorter cranial base and a more acute cranial base flexure). On the other hand, also in comparison with whites, African Americans show a greater role for soft tissue factors in susceptibility to OSA. The epidemiologic studies related to racial predisposition to OSA have to be interpreted carefully. Confounding variables, such as comorbid conditions, differing socioeconomic status, and health care disadvantages, could explain the differences in OSA prevalence between races, indicating that race may be a surrogate variable for other predisposing factors.

On the other hand, some epidemiologic studies show that both active smoking and second-hand smoke exposure have been independently associated with habitual snoring and even with an increase in OSA prevalence in some subjects, especially in active smokers. It seems that the inflammation and alteration of some mechanical and neural protective properties of the airway due to cigarette smoke increase the collapsibility of the upper airway. Alcohol intake also can promote pharyngeal collapse, even in normal persons, inducing apneic activity and prolonging apnea duration, probably by reducing respiratory motor output to the upper airway, resulting in hypotonia of the pharyngeal muscles.

The frequency and duration of OSA events and the extent of associated desaturation may increase in the supine compared with the side-lying sleep position. Positional OSA is defined as a supine-measured AHI at least double that measured in the lateral position. The prevalence of positional OSA varies in relation to OSA severity. It was recently identified in 50% of mild, 19% of moderate, and 6.5% of severe OSA cases. The main mechanism has been suggested to involve the effects of gravity on the upper airway size through displacement of the soft tissues, by mandibular retropulsion, and indirectly, by upward displacement of abdominal contents, thereby reducing lung volume and compromising airway cross-sectional area or length. Other studies have shown that one of the main mechanisms is change in the shape of the airway from a transversely oriented ellipse when the subject is supine to a more circular shape with assumption of the side-lying position.

Pregnancy also is associated with a higher prevalence of OSA, particularly in the third trimester. Many changes occur in the respiratory system during pregnancy. Factors recognized to contribute to this phenomenon include elevation of the diaphragm secondary to an enlarged uterus, leading to alterations in pulmonary mechanics including reduced functional residual capacity; an increase in Mallampati score secondary to fluid retention and edema; enlargement of neck circumference; reduced nasal patency; changes in hormonal concentrations (estrogen and progesterone); and weight gain. OSA is an important diagnosis to consider in symptomatic pregnant women, especially in view of possible adverse side effects including pregnancy-induced hypertension and intrauterine growth retardation.

Upper Airway in Normal Subjects

It has long been recognized that, for what on casual consideration may appear to be a simple tube, the human upper airway is deceptively and enigmatically complex, performing functional tasks such as swallowing and the passage of air for breathing and speech, governed by anatomy and neural controls. Under normal physiologic conditions, the pharynx remains open at all times, except during short closures associated with swallowing, regurgitation, and speech. It is separated into three regions: the nasopharynx, extending from the nasal turbinates to the hard palate; the oropharynx, composed of the retropalatal region (from the hard palate to the caudal margin of the soft palate) and the retroglossal region (from the caudal margin of the soft palate to the base of the epiglottis); and the hypopharynx, extending from the base of the tongue to the larynx. It is composed of more than 20 muscles and soft tissues without rigid or bony support. Pharyngeal muscles can be divided into three groups: muscles controlling the position of the hyoid bone (geniohyoid and sternohyoid), muscles of the tongue (genioglossus), and palatal muscles (palatopharyngeus, tensor palatini, and levator palatini). The largest of the dilator pharyngeal muscles is the genioglossus, the muscle that forms the major portion of the body of the tongue (Figure 60-2).

Figure 60-2 Action of upper airway muscles. Ant., anterior, HP, hypopharynx; NP, nasopharynx; OP, oropharynx.

Human speech requires pharyngeal mobility, such that the hyoid bone, which is a key anchoring site for pharyngeal muscles, is not firmly attached to the skeleton. Thus, the upper airway has rigid support in its proximal and distal segments but has a collapsible portion extending from the hard palate to the larynx, with the size of its lumen being subject to the influence of surrounding pressures and the activity of dilator muscles. Other well-known biologic examples of mobility in respiratory physiology include intrathoracic airway collapse on forced exhalation, collapse of pulmonary capillaries in the lung apex, and collapse of the alae nasi under high inspiratory flow rates.

One mechanistic physiologic representation of this collapsible model is the Starling resistor (Figure 60-3). According to this model, when air pressure is applied to the upper airway, the collapsible portion of the upper airway is bound by an upstream segment (nasal segment) and a downstream segment (tracheal segment). Nasal and tracheal segments have their corresponding intraluminal pressures and resistances. The nasal segment has atmospheric pressure at the airway opening. In the surrounding collapsible segment, pressure is generated by soft tissues and structures surrounding the pharynx. Occlusion of the collapsible portions occurs when the surrounding pressure (Pout) becomes greater than the intraluminal pressure (Pin) (transmural pressure [Pout − Pin] above 0).

Figure 60-3 Starling resistor model of obstructive sleep apnea. Pus, upstream (nasal) segment intraluminal pressure; Pds, downstream (tracheal) segment intraluminal pressure; Pin, intraluminal pressure in the collapsible segment (pharynx); Pout, pressure surrounding collapsible segment; Rus, upstream (nasal) airflow resistance.

(From Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP: Pathophysiology of sleep apnea, Physiol Rev 90:47–112, 2010.)

The oropharynx represents the collapsible segment, the critical closing pressure (Pcrit) of which is defined as the pressure inside the airway at which airway collapse occurs. Flow is partially limited when nasal pressure is higher than Pcrit, Pcrit being higher than tracheal pressure, and total occlusion occurs when Pcrit is greater even than nasal pressure. Pcrit in the human upper airway is determined by lowering the nasal pressure until inspiratory airflow ceases. Its measurements have been shown to define a spectrum of upper airway obstruction ranging from normal breathing to total collapse (apnea), depending on the equilibrium between mechanical upper airway loads that provoke collapse and neuromuscular dilator functions that maintain upper airway patency. In general, these measures when applied in sleeping or paralyzed humans have shown that passive Pcrit is below −10 cm H₂O in normal subjects with lower airway resistance and minimal CO₂ retention during non-REM sleep. In sleep-disordered breathing, however, it varies, with reported values of −10 to −5 cm H₂O in snorers, −5 to 0 cm H₂O in those with sufficiently high airway resistance to induce airflow limitation and transient hypopneas, and above 0 cm H₂O in patients with apneas associated with complete airway obstruction (Figure 60-4). Increases in airway resistance or hypercapnia provoke the activation of the muscle through neural control pathways composed of pressure receptors, sleep-wake brain centers, chemoreceptors, and respiratory centers.

Figure 60-4 Patency equilibrium between upper airway mechanical load and neuromuscular response. Pcrit, critical closing pressure of collapsible segment of upper airways.

(Modified from Patil SP, Schneider H, Schwartz AR, Smith PL: Adult obstructive sleep apnea: pathophysiology and diagnosis, Chest 132:325–337, 2007.)

Upper Airway in Patients With Obstructive Sleep Apnea

During sleep, the ventilatory system is under automatic control. Even in normal subjects, airway resistance increases during sleep as a consequence of body position, decreased pharyngeal tone, depression of the respiratory drive, and depression of protective reflexes, leading to an increased probability of upper airway collapse. A number of factors contribute to the pathogenesis of OSA, including the activity of the dilated pharyngeal muscles during sleep, upper airway anatomy, lung volume, ventilatory control stability, sleep state stability, rostral fluid shifts, and others; all of these factors probably are mediated, at least in part, by genetic factors.

The primary site of collapse is in the retropalatal and oropharyngeal area in a majority of patients (up to 75%), with frequent caudal extension to the base of the tongue (25% to 44%) and, less often, to the hypopharynx (0 to 33%). The site of collapse depends on the equilibrium of functions exercised by the skeletal structure, soft tissue, and pharyngeal muscles. In obese patients, the most frequent area of collapse evidently is the velopharynx, whereas in nonobese patients, both the velopharynx and the oropharynx constitute the primary site of collapse. The extent of collapse varies by sleep stage, with caudal collapse being more extensive in REM sleep owing to changes in neuromuscular activation (Box 60-3).

Anatomic Factors

Anatomic factors include increased airway length, lateral wall thickness, tongue volume (macroglossia), skeletal structure (retrognathia or micrognathia), and nasal or pharyngeal abnormalities (nasal obstruction, polyps, or enlarged tonsils, adenoids, or uvula) and probably constitute the most important heritable determinants of OSA. Studies of cephalometric and computed tomography scans have demonstrated differences in the craniofacial structure of patients with OSA in comparison with that of normal subjects, including lower facial weight, retroposition of both the maxilla and the mandible, and shorter and medially displaced mandibular rami, all of them correlated with decreased pharyngeal size. The role of enlarged soft tissues has been demonstrated using MRI (Figure 60-5). In patients with OSA, pharyngeal lumen is smaller than normal and tissues are narrowed laterally, rather than in the anteroposterior dimension, especially at the retropalatal level, mainly owing to increased thickness of the muscular pharyngeal wall as well as an increase in tongue and total soft tissue volume. The interaction between the bony and soft tissue structures determines upper airway collapsibility. Nevertheless, increased airway length has been observed in subjects with OSA and has been shown to correlate with severity, especially in men. Usually, the longer the upper airway, the greater the risk of collapse.

Figure 60-5 Magnetic resonance imaging study of cross-sectional and longitudinal upper airway lumen in a normal subject (white arrows in A and B) and in a patient with obstructive sleep apnea (white arrows in C and D).

(Courtesy J.L. Fernandez, MD.)

Data from early physiologic studies suggest that upper airway narrowing and consequent snoring and apnea can be induced by subatmospheric nasal pressure. In theory, inspiratory nasal obstruction would not provoke continuing collapse of the pharynx: With cessation of flow, upstream resistance becomes irrelevant, intrapharyngeal pressure returns to atmospheric, and the pharynx reopens—a cycle generating snoring but not apneas. It is unlikely, however, that the pharynx does behave as a perfect Starling resistor, partly because of hysteresis and partly as a result of surface tension forces from mucus, which will tend to hold the pharynx closed once collapsed. Various observational and cross-sectional studies have documented a relationship among chronic nasal obstruction, snoring, and OSA.

Pharyngeal Muscle Activity

Despite compromised anatomic dimensions of the upper airway, subjects with OSA show upper airway collapse only during sleep, because the upper airway musculature can maintain patency during the awake state but has a reduced ability to do so during sleep. This phenomenon is thought to be related to a reduction in upper airway dilator muscle activity, especially in the transition from wakefulness to sleep. Paradoxically, some studies have shown that during the awake state, genioglossus activity is increased in patients with OSA compared with normal subjects, probably because the drive of the upper airway muscles is increased to compensate for anatomic compromise. During sleep, however, the relative decrease in genioglossus activity is greater in patients with OSA than in control subjects. Various mechanisms may explain the reduction in dilator muscle activity seen in patients with OSA: alterations in the mechanoreceptor reflex related to negative intraluminal pressure; changes in the 5-hydroxytryptamine 2A receptor, which has been shown to be the predominant receptor subtype in hypoglossal motor neurons; altered upper airway neuromechanical function; or even an upper airway denervation neuropathy or muscle denervation. In OSA, upper airway neuromuscular compensatory mechanisms during sleep are attenuated compared with those in control subjects in studies using electromyograms and often fail to restore airway patency in the absence of arousals. Furthermore, impaired upper airway afferent neural function has been described, which could attenuate the transmission of information related to intraluminal pressure. This impairment has been observed in the mechanosensitivity receptor of the oropharynx and thermal sensitivity receptors and sensory receptors in the velopharynx and larynx in persons with OSA. Some of these afferent impairments have been associated with OSA severity.

All of these findings point to the presence of an upper airway neuropathy in OSA, probably due to mechanical trauma associated with snoring and apneas, oxidative stress related to hypoxia-reoxygenation, and inflammation resulting from both of these insults. One of these forms of neuropathies appears in the form of muscle denervation, including fiber type grouping, grouped atrophy, and increased fiber size variability. This airway muscle denervation presumably also may result from damage to brain stem motor neurons, as has been reported in a murine model of intermittent hypoxia.

On the other hand, another potential mechanism contributing to altered upper airway muscle function in OSA could be impaired contractile function. In patients with OSA , the upper airway muscle works under considerable load in adverse hypoxic conditions, which could generate some injuries and morphologic changes, increasing force but making the muscle more prone to fatigue. Histologic and biochemical studies have shown an increased proportion of fast-twitch type IIa fibers in the uvula and genioglossus and increased levels of enzymes associated with anaerobic metabolism in patients with OSA, leading to the maintenance of increased muscle contractility at the cost of increased fatigability. Moreover, other factors such as increased airway inflammation and secondary tissue changes could compromise contractile function and alter mechanical coupling of upper airway muscles.

Finally, considerable interest has emerged in the role of some neural pathways and neurotransmitters in the modulation of upper airway muscle activity. Animal studies have shown that the withdrawal of serotoninergic excitation reduces hypoglossal motor output (which drives the major upper airway dilator muscle, i.e., the genioglossus), although human studies using selective serotonin reuptake inhibitors showed only modest effects on OSA severity. Noradrenergic inputs to the hypoglossal motor pool contribute to both the tonic and the phasic components of genioglossus muscle activity in the awake state, and withdrawal of noradrenergic input accounts for some of the reduction in hypoglossal motor activity during non-REM sleep. Glutamatergic inputs seem to play a similar role. The two main inhibitory neurotransmitters in the central nervous system are glycine and gamma-aminobutyric acid (GABA). Stimulation of GABA or glycine receptors suppresses respiration-related genioglossus muscle activity, whereas antagonism of those receptors increases it.

Ventilatory Control Stability

Ventilatory control stability is believed to be an important contributor to OSA pathogenesis, because obstructive events tend to occur during periods of low respiratory drive. One of the most important mechanisms that control the ventilatory system is the hypoxic or hypercapnic ventilatory response (PaCO₂ is maintained at a stable level by negative feedback control). This mechanism has a high degree of heritability. During non-REM sleep, reductions in CO₂ below eupneic levels will produce apnea, although this phenomenon does not occur during wakefulness. The CO₂ level at which this occurs (apneic threshold) typically is 1 to 2 mm Hg below waking eupneic levels. Thus, the sudden increase in ventilation occurring in association with arousal, which typically is seen at the termination of apneic and hypopneic episodes, will lead to hypocapnia, so that on returning to sleep, CO₂ is below the apneic threshold, and another apnea ensues. In this manner, postventilatory overshoot and loss of drive to the upper airway may lead to airway collapse with initiation of a subsequent obstructive event.

Other factors may contribute to reduced drive after postapneic hyperpnea, such as vagal stimuli generated during large inspired volumes and baroreceptor-mediated ventilatory inhibition due to postapneic blood pressure surges. Another important concept is loop gain, a term used to describe the stability of the respiratory system as a whole and how responsive the system is to a perturbation in breathing during sleep. The higher the loop gain, the lower the ventilatory stability. Patients with OSA have greater ventilatory control instability and higher loop gain when compared with control subjects. The two principal components of loop gain are controller gain, representing chemoreceptor responsiveness to hypoxia and hypercapnia (high controller gain is due to increased hypercapnic responsiveness), and plant gain, reflecting the effectiveness of a given level of ventilation to eliminate CO₂. In the context of high plant gain, a small change in ventilation would produce a large change in PaCO₂. Because upper airway muscles receive input from respiratory control centers, an unstable ventilatory drive will cause greater fluctuation in the activity of these muscles and promote upper airway collapse when ventilatory drive is at its nadir.

Lung Volume and Pharyngeal Patency

The interaction between pharyngeal patency and lung volume is believed to be an important contributor to the pathogenesis of OSA. Across the range from residual volume to total lung capacity, there is a lung volume dependence on upper airway diameter that appears to be more pronounced in subjects with OSA. During sleep, airway resistance increases as lung volume decreases. This combination leads to upward displacement of the diaphragm and thorax, with loss of caudal traction on the upper airway, yielding a more collapsible airway. Central obesity is believed to result in a reduction in lung volume during sleep, promoting pharyngeal collapse.

Stability of Sleep and upper Airway Patency

Arousal from sleep is believed to be an important if not essential mechanism for reestablishing airway patency in OSA. The preeminence of arousal is based on a temporal association between arousal and upper airway opening. Arousal mechanisms and upper airway motor neuron pools receive excitatory input from mechanoreceptors and probably also from chemoreceptors. The amount of excitation required to cause arousal is, on average, the same as that required to activate the upper airway motor neuron pool enough to open independently. Because the two systems are subject to different influences, however, the opportunity exists for either event to occur before the other. If arousal occurs prematurely in the context of a respiratory event during sleep, it may abort compensatory mechanisms such as increased pharyngeal dilator muscle activity, engendering ventilatory instability by stimulating hyperventilation. This can in turn promote upper airway collapse and worsening of OSA. These early arousals also have been associated with prolongation of respiratory events and worsened hypoxemia.

Edema and Rostral Fluid Shifts

Fluid shifts from the legs to the neck, caused by lower body positive pressure, have been shown to reduce upper airway size and increase collapsibility and appear to play a role in the pathogenesis of OSA. This mechanism is especially important in patients in whom the upper airway lumen is relatively small, because even a small amount of fluid could further compromise its patency. Some studies in patients with heart failure or superior vena cava syndrome corroborate this finding. In these patients, intensive diuresis was associated with an increase in oropharyngeal caliber and a significant reduction in AHI. Finally, vascular tone also may play a role in pharyngeal collapsibility. Animal studies have shown that vasodilatation increases and vasoconstriction decreases upper airway closing and opening pressures.

Surface Tension of upper Airway Fluid

Upper airway collapsibility is affected by the surface tension of the liquid lining the airway, increasing both reopening and closing pressures. Increased surface tension has been reported in patients with OSA over that in normal subjects, as a consequence of mucosal trauma during apneas and use of the oral breathing route. Instillation of a surfactant has been shown to reduce AHI in persons with OSA as a consequence of improvement of airway collapsibility (reduced Pcrit).

Upper Airway Inflammation

Substantial evidence has shown that inflammation is increased in the upper airway in OSA based on nasal lavage, induced sputum, exhaled breath condensate, and airway mucosal tissue biopsy specimens and that the level of inflammation is related to the severity of OSA. Factors associated with increased inflammation include mechanical trauma associated with snoring, suction collapse and traction during apneas, intense activation of dilator muscles at airway opening, increases in oxidative stress related to hypoxia-reoxygenation and other external factors such as gastroesophageal reflux, alcohol intake, smoking, allergic inflammation, the effect of systemic inflammation, and upper airway infections. Negative consequences appear in the context of repeated intense inflammation, because this could contribute to tissue injury and fibrosis, disorganization of the elastic tissue fibrillar network in uvular tissue, and changes in the connective tissue content, altering airway dimensions and compliance.

Rapid Eye Movement Sleep

Hypopneas and apneas increase in duration and are associated with more pronounced hypoxemia during REM sleep in patients with OSA, because REM sleep is associated with decreased upper airway muscle tone, impaired genioglossus reflex responsiveness to negative pressure, and reduced chemosensitivity. Some patients experience OSA only during REM sleep. Certain protective mechanisms, however, tend to reduce event duration: The arousal threshold seems to be higher during REM sleep than during non-REM sleep in patients with OSA, and Pcrit does not change during REM sleep.

Bernoulli Effect

Two physical phenomena cause a reduction in intraluminal pressure as air flows though the upper airway: loss of energy and the Bernoulli effect. The first phenomenon occurs when air flows through a segment (nasal segment) with high resistance, and potential energy is dissipated in overcoming friction, leading to a decrease in intraluminal pharyngeal pressure. The Bernoulli effect is related to the acceleration of the air as it flows through a narrowed segment of the tube, contributing to a decrease in intraluminal pharyngeal pressure.