An enhanced understanding of the pathophysiology of OSAS may lead to new and improved therapeutic modalities including pharmacologic therapies, mechanical devices, and surgical interventions

Obstructive sleep apnea syndrome (OSAS) is a common yet underrecognized disorder that affects approximately 4% of middle-aged adults and 20% to 50% of elderly persons.1,2 Of the approximately 75,000 patients seen annually in sleep disorder centers, roughly 75% are diagnosed with OSAS.3 Projections of the prevalence of OSAS in the United States range from 7 to 18 million people.3

OSAS is a potentially life-threatening condition characterized by repeated collapse of the upper airway during sleep, cessation of breathing, and clinical associations with a variety of disease states. The spectrum and severity of clinical presentations of OSAS are extremely variable.

The English novelist Charles Dickens is often given credit for the first description of OSAS in 1836.4 His character, Joe the Fat Boy, had a voracious appetite and exhibited a complex of symptoms and findings suggestive of OSAS: loud snoring, hypersomnolence, bizarre personality, obesity, polycythemia, and congestive heart failure. In 1956, more than a century after Dickens published The Posthumous Papers of the Pickwick Club, the term “Pickwickian,” alluding to Dickens’ character, was used for the first time in the medical literature to describe an obese patient with periodic respiration, hypersomnolence, hypoxemia, polycythemia, and congestive heart failure.5 It was assumed that the mechanical load on the respiratory system led to a blunted respiratory drive and hypoventilation during both sleep and wake states. The observed periodic respiration, polycythemia, and heart failure were attributed to blood gas aberrations resulting from hypoventilation during both sleep and wakefulness, whereas the hypersomnia was attributed to hypoxia and hypercapnia.5

During later decades, improved technology revealed that only a small minority of obese and hypersomnolent patients were hypoxic or hypercapnic while they were awake. This group represents the true Pickwickian patient. Most obese and sleepy patients were found to have normal blood gases while they were awake. Their hypersomnolence was primarily the result of sleep fragmentation caused by sleep disordered breathing (SDB).6

Despite the prevalence of sleep apnea, the pathogenetic mechanisms of this disorder remain incompletely understood. The occurrence of upper airway obstruction during sleep and not wakefulness implicates the removal of the wakefulness stimulus to breathe as a key factor underlying upper airway obstruction during sleep. Most of the data on sleep effect are derived from studies during non–rapid eye movement (NREM) sleep, given the difficulty in achieving REM during invasive studies in the laboratory environment.

Upper Airway Caliber and Compliance
The reduction of tonic upper airway dilating muscle activity caused by sleep is associated with reduced upper airway caliber and increased pharyngeal wall compliance.7 The mechanical corollary of decreased caliber is an increase in upper airway resistance.8 In addition to increased resistance, increased pharyngeal wall compliance during sleep in snorers is manifested by the occurrence of inspiratory flow limitation as flow plateaus during inspiration.

The combination of increased resistance and inspiratory flow limitation leads to increased work of breathing, hypoventilation, and frequent arousals from sleep, and ensuing excessive daytime sleepiness. This has been described as a distinct clinical entity called the upper airway resistance syndrome.9

Load Compensation
The ability of the ventilatory control system to compensate for added loads is essential for the preservation of chemoreceptor homeostasis. However, immediate compensation to added loads is compromised during NREM sleep. Therefore, resistive loading results in decreased tidal volume and minute ventilation and, consequently, alveolar hypoventilation with subsequent elevation of arterial Paco2.10 Furthermore, NREM sleep abolishes the ability of upper airway dilating muscles to respond to negative pressure.

In awake humans and animals, application of negative pressure to the upper airway elicits a reflex activation of the genioglossus muscle, presumably dilating the upper airway. The fact that this reflex is absent during NREM sleep suggests that sleep eliminates a protective reflex that maintains upper airway patency in the face of narrowing or deformation.11 The mechanical consequences of such reflex activation have not yet been determined.

In summary, the failure of immediate load compensation results in hypoventilation and a subsequent increase in respiratory muscle activity. This may explain the noted paradox in heavy snorers who have nocturnal CO2 retention and increased inspiratory and expiratory muscle activity.12

Determinants of Upper Airway Patency During Sleep Upper Airway Size and Shape
Some studies have suggested that the pharyngeal airway is smaller during wakefulness in patients with OSAS relative to that of normal people.13 In addition, the airway in patients with OSAS has an anterior-posterior configuration unlike the horizontal configuration in normal persons.13 The implications of the observed lateral narrowing in the pathogenesis of upper airway obstruction during sleep are yet to be determined.

Transmural Pressure
Pharyngeal patency is a function of the transmural pressure across the pharyngeal wall as well as the compliance of the pharyngeal wall.14 The inspiratory reduction in intraluminal pressure during inspiration is associated with decreased pharyngeal cross-sectional area.13,15 The magnitude of inspiratory narrowing is more pronounced during NREM sleep relative to wakefulness, in patients with OSAS relative to normal persons, and in obese patients relative to thin patients.14

Negative intraluminal pressure is thought to induce upper airway obstruction in patients with OSAS.15 The collapsing subatmospheric intraluminal pressure during inspiration is generated by thoracic pump muscle activity. In addition, when inspiratory narrowing during sleep occurs, the ensuing increase in air velocity results in decreased intraluminal pressure.14 Subsequently, intraluminal pressure becomes more negative and, hence, more collapsing to the upper airway.

Pharyngeal Compliance
The compliance of the pharyngeal wall is an important determinant of the effect of transmural pressure.14 A stiff pharyngeal wall (as during wakefulness) remains patent even with a significant collapsing transmural pressure. In contrast, a compliant upper airway (as in patients with OSAS during sleep) is closed even at atmospheric pressure.

The intrinsic stiffness of the pharyngeal wall is attributed to neuromuscular and nonneuromuscular factors. Upper airway dilating muscles such as the genioglossus muscle are presumed to be critical to the preservation of upper airway patency. However, there is conflicting evidence regarding the effect of upper airway muscles on pharyngeal compliance.

Thoracic Caudal Traction
The upper airway is connected to the thoracic cage and the mediastinum by several structures. Increased lung volume during inspiration is associated with upper airway caliber in awake persons, probably because of thoracic inspiratory activity providing caudal traction on the upper airway, independent of upper airway dilating muscle activity.16 Caudal traction may transmit subatmospheric pressure through the trachea and ventrolateral cervical structures to the soft tissues surrounding the upper airway, increasing transmural pressure, and thereby dilating the pharyngeal airway. This mechanism has been shown in sleeping subjects by reduced upper airway resistance and increased retropalatal airway size when end-expiratory lung volume was increased by passive inflation.17 Caudal traction may either dilate or stiffen the pharyngeal airway.16

Patients with OSAS may be more dependent on the effects of increased lung volume because dilatation and/or stiffening may be more prominent in a highly compliant upper airway.

Pathogenesis of OSAS Anatomic Abnormalities
Increased upper airway resistance and collapsibility in patients with OSAS can be the result of an anatomic compromise. Pharyngeal resistance during wakefulness is increased in patients with OSAS compared with normal individuals, and pharyngeal resistance correlates with the severity of OSAS.18 The pharynx of adults with OSAS collapses when experimentally exposed to subatmospheric pressure during wakefulness, whereas that of normal controls does not.19 The upper airway is anatomically smaller in patients with OSAS than in normal individuals, particularly at the retropalatal and retroglossal levels. Pharyngeal cross-sectional area correlates inversely with OSAS severity.20

OSAS has been associated with anatomic compromise resulting from neoplasia (benign or malignant), metabolic abnormalities, and traumatic compromise. Inflammatory disorders may cause diffuse enlargement of structures such as the tongue and pharyngeal lymphoid tissues (as in tonsillitis), resulting in a compromise of the airway. However, in the majority of patients with OSAS, no specific focus of upper airway pathology can be identified.

The association between obesity and OSAS is well recognized. Weight gain in patients with OSAS usually results in an increase in the severity of apnea. It has long been hypothesized, and later documented by magnetic resonance imaging, that the region surrounding the collapsible segment of the pharynx in patients with OSAS has a greater fat load than does the same region in equally obese patients who do not have OSAS. This finding—in conjunction with the finding of an increase in airway resistance and a decrease in airway stability documented when applying lard-filled bags to the neck to simulate cervical fat accumulation—suggests that the effect of obesity on OSAS might be related to local parapharyngeal fat deposits.21 Histopathologic studies of uvulas excised during uvulopalatopharyngoplasty for OSAS have demonstrated higher amounts of both fat and muscle mass compared with those seen during normal postmortem studies.20,22

Many people who snore or have OSAS mouth-breathe during sleep. Although this has not been systematically investigated, increased nasal or nasopharyngeal resistance might explain it. The open-mouth posture unfavorably alters the pharyngeal airway by creating a relatively unstable passage. With the mouth open, the tongue and soft palate are exposed to atmospheric pressure. This releases the anterior part of the tongue, producing a dorsal motion of the belly of the genioglossus, and decreases the dimensions of the oropharyngeal lumen. The entire transmural pressure of the pharynx is exerted across the soft palate, moving it dorsally and narrowing further the oropharyngeal lumen.

Open-mouth posture further compromises the pharyngeal airway by diminishing the length of the axis of action of the genioglossus and, therefore, its efficacy in pulling the tongue forward out of the airway. Furthermore, the nasal mucosa, which is bypassed in mouth breathing, might have receptors that respond to airflow and serve as afferent stimuli for the neural regulatory mechanisms of respiration. Eliminating this afferent input to reflex arcs involving upper airway muscles could predispose to OSAS.

Clinical studies have confirmed that nasal obstruction exacerbates a tendency toward OSAS.20 The larynx—the other high-resistance structure in the upper airway—can be the site of OSAS when compromised by space-occupying lesions or abductor paralysis.

Many advances in the sleep field will be seen during the next decade as a result of the growing recognition of the pathogenetic mechanisms responsible for OSAS and other causes of SDB. An enhanced understanding of the pathophysiology of OSAS is expected to lead to new and improved therapeutic modalities, including pharmacologic therapies, mechanical devices, and surgical interventions.

a01b.jpg (7491 bytes) a01a.jpg (7448 bytes) John D. Zoidis, MD, is a contributing writer for RT Magazine, and Phyllis C. Braun, PhD, is a professor in the Department of Biology, Fairfield University, Fairfield, Conn.

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