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Clinical Reviews in Allergy and Immunology © Copyright 2003 by Humana Press Inc. 1080-0549/03/191–210/$25.00
Severe Upper Airway Obstruction During Sleep H. William Bonekat and Kimberly A. Hardin* Division of Pulmonary and Critical Care, Department of Internal Medicine, University of California, Davis, Davis, CA
Abstract
Few disorders may manifest with predominantly sleep-related obstructive breathing. Obstructive sleep apnea (OSA) is a common disorder, varies in severity and is associated with significant cardiovascular and neurocognitive morbidity. It is estimated that between 8 and 18 million people in the United States have at least mild OSA. Although the exact mechanism of OSA is not well-delineated, multiple factors contribute to the development of upper airway obstruction and include anatomic, mechanical, neurologic, and inflammatory changes in the pharynx. OSA may occur concomitantly with asthma. Approximately 74% of asthmatics experience nocturnal symptoms of airflow obstruction secondary to reactive airways disease. Similar cytokine, chemokine, and histologic changes are seen in both disorders. Sleep deprivation, chronic upper airway edema, and inflammation associated with OSA may further exacerbate nocturnal asthma symptoms. Allergic rhinitis may contribute to both OSA and asthma. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. Treatment with CPAP therapy has also been shown to improve both daytime and nighttime peak expiratory flow rates in patients with concomitant OSA and asthma. It is important for allergists to be aware of how OSA may complicate diagnosis and treatment of asthma and allergic rhinitis. A thorough sleep history and high clinical suspicion for OSA is indicated, particularly in asthma patients who are refractory to standard medication treatments.
Index Entries: Obstructive sleep apnea; asthma; allergic rhinitis; airway obstruction.
Background and Definitions Few medical disorders cause clinical manifestations primarily during nocturnal hours. Obstructive sleep apnea (OSA) is one. It is char*Author to whom all correspondence and reprint requests should be addressed. E-mail: kahardin@ ucdavis.edu Clinical Reviews in Allergy & Immunology
acterized by snoring associated with obstructive breathing during sleep. It is frequently associated with gasping/choking sensations leading to fragmented sleep and ultimately daytime symptoms of fatigue, tiredness, lack of energy, and, in some individuals, excessive daytime sleepiness. Sleep-related obstructive breathing is common, varies in severity, and may accompany a 191
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variety of allergic disorders, including asthma and allergic rhinitis, which can confound proper management. A high index of suspicion is needed to diagnose OSA, as 80% of men and women in the United States with moderate- to severe-OSA remain undiagnosed (1,2). OSA is typically thought to occur primarily in obese, middle-aged men who habitually snore. However, many individuals are asymptomatic and only the bedpartner’s testimony will reveal the presence of nocturnal obstructive breathing. In this review, we will describe the most important aspects of diagnosis, treatment, and prevention as we put into perspective the importance of recognizing OSA in relation to various allergic disorders. We will dispel the notion that OSA is found only in obese men and illustrate the broad spectrum of this disorder (3,4). OSA is characterized by complete (apnea) or partial (hypopnea) upper airway obstruction during sleep usually resulting in variable degrees of arousal and oxygen desaturation (5). The obstructive sleep apnea hypopnea syndrome (OSAHS) indicates that OSA is accompanied by the presence of daytime sleepiness. The apnea/hypopnea index (AHI) is used to quantify OSA from normal breathing and represents the number of obstructive events/hour. Until recently, there was no consensus on what AHI is considered indicative of mild, moderate, or severe disease. In 1999 the American Academy of Sleep Medicine initiated a task force and recommended the following AHI parameters to delineate the severity of OSA: 5–14, 15–29, and >30 as mild, moderate, and severe, respectively (6). However, the degree of oxygen desaturation or length of apnea or hypopnea has not been included in defining the severity of the event. In 1993, Guilleminault (7) further delineated another sleep-related breathing disorder, the upper airway resistance syndrome (UARS), in which there is snoring accompanied by increasing respiratory effort terminating with cortical arousals. Although there are no apneas or hypopneas, sleep fragmentation occurs and Clinical Reviews in Allergy & Immunology
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daytime sleepiness results. Controversy exists whether this is indeed a separate clinical entity or represents a point in the continuum of sleeprelated obstructive breathing with primary snoring at one end of the spectrum and OSAHS at the other.
Epidemiology and Demographic Patterns It is estimated that one of every five adult, non-obese Caucasian men and women have at least mild OSA and one of every 15 have at least moderate OSA (8). The National Commission on Sleep Disorders Research extrapolated from all the studies to estimate that between 8 and 18 million people in the United States have mild OSA and between 1.8 and 4 million people have at least moderate OSA (9). Young and coworkers (10) from the Wisconsin Sleep Cohort Study were the first group to report the prevalence of community-based OSAHS in middleaged men and women (ages 30–60 yr) as well as the prevalence based on stratification by age and AHI severity measured by in-laboratory polysomnography. Overall, 2% of women and 4% of men met the minimal criteria (AHI > 5 plus symptoms) for OSAHS. The prevalence of mild OSA (AHI > 5) was 9% in women and 24% in men. The prevalence of OSA with AHI > 15 was 4% in women and 9% in men. In both men and women with habitual snoring, the prevalence of OSA was higher. Other large population-based studies reported similar results (11,12). Studies in the United States have shown that African-Americans are 2.5 times more likely to have OSA than Caucasians (13). However, in the SHHS this was not supported (14). Ip and coworkers (15,16) investigated the prevalence of OSA (AHI > 15) in men and women in China and reported estimates of 5% and 2%, respectively. Further studies are needed outside the United States to evaluate prevalence and associated characteristics in other ethnic populations. Volume 25, 2003
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Fig. 1. Anatomy of the upper airway. Adapted from (23).
To investigate the affects of age on OSA, Ancoli-Israel and coworkers (17) randomly sampled 427 men and women age 65–95 yr and reported OSA (AHI > 10) as present in 70% of men and 56% of women, illustrating that OSA seems much more predominant in the elderly. However, other studies have not supported such a high prevalence (14). Furthermore, the AHI has been reported to be more severe in men than women until the age of 60 yr, when no significant difference was found between the sexes (18). Others (19,20) have shown that the prevalence of and severity in women is underestimated owing to reporting “non-classical” symptoms of fatigue and symptoms of depression.
Pathophysiology of Upper Airway Obstruction There are anatomic, mechanical, and neurologic components that individually or in combination result in recurrent closure or collapse of the pharyngeal airway during sleep.
Upper Airway Anatomy and Determinants of Upper Airway Patency The upper airway is divided into four areas (Fig. 1): the nasopharynx (between the nasal Clinical Reviews in Allergy & Immunology
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turbinates and hard palate), the velopharynx or the retropalatal area (between the hard palate and the caudal soft palate), the oropharynx or the retroglossal area (between the caudal soft palate and the epiglottis), and the hypopharynx (between the base of the tongue and the larynx). The normal airway is elliptical in shape with the largest circumference oriented horizontally. The velopharynx is the narrowest portion of the pharynx. The retropalatal and superior retroglossal areas are surrounded by parapharyngeal fat pads (21,22). Pharyngeal dilator and constrictor muscles compose the walls of the pharynx. Their complicated interactions permit swallowing and phonation. The palatal dilator muscles, tensor palatini (TP), maintain patency of the velopharynx. The oropharynx is particularly prone to collapse due to lack of bony structural support. During wakefulness the pharyngeal dilator muscles, particularly the genioglossus (GG) maintain tonic activation and stiffening of the airway, thus maintaining airway patency. The geniohyoid (GH) is the main dilator muscle, which stabilizes the anterior wall of the hypopharynx. Under phasic activation during inspiration, they contract and promote ventral movement of the tongue, soft palate, hyoid bone, and mandible. The pharyngeal constrictor muscles surround the posterior and lateral walls of the oral and hypopharynx and constrict during exhalation. A balance exists between the dilator muscle contractility (keeping the airway open), the normal negative inspiratory pressures (sucking the airway closed) generated by the diaphragm during inspiration, and the normal pressure of the surrounding tissue during wakefulness. Women have a smaller airway caliber than men. However, they also have higher resting activity of the pharyngeal muscles (23–25). Airway resistance is normally highest through the nasal passages. The determinants of airway caliber in the posterior nasopharynx are the skeletal structure, the mucosal thickness, and vascular tone. Vascular tone is under Volume 25, 2003
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automonic nervous system (ANS) control and varies throughout the day in response to environmental stimuli (e.g., pollen). If nasopharyngeal resistance is too high, a decrease in pressure (more negative) is generated caudally to maintain airflow velocity (Bernoulli effect) and collapse can occur distally. Mouth breathing markedly decreases resistance. Of particular interest is nasal obstruction beginning in childhood. As nasal resistance increases, there is increased negative pharyngeal pressure as described previously. To overcome the resistance, the child becomes a “mouth breather” which displaces the mandible and tongue dorsally into the airway. As the child grows, his craniofacial structure changes to allow his tongue and tonsils more space and results in an elongated face with a high, arched palate. Any cause of nasal obstruction, such as adenoids, polyps, or edema from allergies, can cause increased nasal resistance and convert the individual to a mouth breather, thus putting him at risk for retroglossal obstruction. Snoring results from turbulent flow from partial obstruction and may be the first noticeable sign of obstructive breathing (26,27). Pharyngeal resistance is influenced by the craniofacial structures, particularly the size and position of the mandible and maxilla, parapharyngeal fat and lymphoid tissue during wakefulness, thickness of the pharyngeal walls, and the neuromuscular function of airway muscles. Obesity can also increase pharyngeal resistance through increased parapharyngeal fat, lateral pharyngeal wall thickness, and tongue and uvula size (28–31). The upper airway muscles are innervated by the cranial nerves (V, VII, IX, X, XII). Any neurologic injury to the brainstem nuclei or nerve itself can alter activation of the pharyngeal muscles. Sensory innervation of the pharynx also influences tone and activity of the airway. The entire pharynx has pressure receptors that sense subatmospheric airway pressure generated at inspiration (32). These receptors send afferent signals to the medulla, where Clinical Reviews in Allergy & Immunology
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efferent signals are sent back to the pharyngeal dilator muscles. This precedes phrenic nerve innervation, and therefore precedes diaphragm contraction. This allows the pharynx to stiffen and remain patent as the intraluminal pressure becomes more negative and prevents the pharynx from being sucked closed (33). This reflex can be abolished by local anesthesia to the airway, inducing obstruction in normal individuals (34). Therefore an intact afferent reflex seems necessary to prevent airway collapse. Peripheral chemoreceptors, as well as central chemoreceptors, send afferent inputs to the medulla where information is integrated with higher brain structures and efferent ANS output is generated. Hypercapnia and hypoxia stimulate these receptors and increase pharyngeal muscle activity. Furthermore, the upper airway motor neurons are less responsive to hypercapnia than the diaphragm motor neurons. Therefore when carbon dioxide (CO2) rises, the diaphragm will contract before the pharyngeal muscles creating increased negative interpharyngeal pressure and collapse (23,35). Mucosal surface tension may also play a role in maintaining airway patency. Reduced surface tension has been shown to decrease closing pressure of the airway and enhance upper airway reflexes (36). Therefore, any repetitive inflammation (e.g., tobacco smoking) of the pharynx may alter mucosal surfaces and result in thickening, decrease in fluid content of the mucus layer, and predispose to narrowing. Body position and lung volumes also influence airway diameter. The upright position allows greater lung expansion and contraction of the diaphragm than the supine position. Larger lung volumes during inspiration create caudal traction on the pharynx (23).
Effects of Sleep on Upper Airway Function and Respiration During wakefulness, breathing is controlled by the ANS and voluntary behavior to mainVolume 25, 2003
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tain oxygenation and acid–base homeostasis. Wakefulness creates a tonic stimulus to the brainstem to promote ventilation. During sleep, voluntary control is lost and the ANS predominates. There is an increase in parasympathetic tone and decreased sympathetic tone in nonrapid eye movement (NREM) sleep and tonic rapid eye movement (REM) sleep. In phasic REM there is an increase in sympathetic activity. Muscle activity is sleep state- and sitedependent. In NREM sleep there is both decreased medullary output and excitability of motor neurons in the upper airway muscles leading to a decrease in electromyographic (EMG) activity (37–39). This is accompanied by an increase in EMG activity of the intercostal muscles but essentially no change in the diaphragm. In REM sleep, data is conflicting in regard to upper airway resistance. Generally, there is a more pronounced decrease in the EMG of the upper airway muscles and the intercostal muscles during phasic REM. Diaphragmatic muscle activity is maintained. This results in what is commonly observed as mild periodic breathing and central apneas seen in REM sleep. However, anyone with underlying cardiac, pulmonary, or upper airway disease may have more pronounced effects during REM sleep, resulting in profound oxygen desaturations, i.e., Sa02 <85%. Reduction in muscle activity and the recumbent position creates an increased inspiratory load and results in a decrease in the functional residual capacity and lower lung volumes. Tidal volume and respiratory rate are also decreased in NREM sleep. Therefore minute ventilation decreases resulting in alveolar hypoventilation with a slight increase in arterial CO2 (2–8 mm Hg), and a decrease in arterial oxygen (3–10 mm Hg), but minimal decrease in oxygen saturation (2%). Hypoxic and hypercapnic ventilatory responses are blunted in both NREM and REM sleep because of decreased medullary chemosensitivity and increased upper airway resistance. Hypercapnia is a much stronger arousal stimulus than hypoxemia. Oxygen saturations have to decrease to 75% in a norClinical Reviews in Allergy & Immunology
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mal individual in order to arouse someone from sleep (40–43). It is postulated that the major cause of hypoventilation and blunted hypercapnic ventilatory response is owing to the increased upper airway resistance. Studies have shown that the pressure at which upper airway collapse occurs (Pcrit) in normal subjects changes from approx –40 cm H2O during wakefulness to –13 cm H2O during sleep (33,44). To overcome this resistance and increased mechanical load, an increased work of breathing is required. Indeed, sleep seems to actively suppress the usual ventilatory response to elevated CO2 levels. This creates a new sleep-induced cerebral CO2 set point. If an individual awakens, hyperventilation occurs and CO2 returns to wake levels. When sleep resumes, hypoventilation reoccurs. If hyperventilation resulted in an overshoot in lowering the CO2, central apneic episodes may occur until the CO2 levels increase to the sleep-induced set point.
Proposed Mechanism for Obstruction in Patients With OSA Although a precise mechanism for pharyngeal collapse during sleep in OSA patients is unclear, one hypothesis may be that OSA is due to a chronic exaggerated expression of the normal sleep-induced physiologic responses in individuals with an underlying structural abnormality. The structural abnormality may be genetic or familial as seen in OSA patients with body mass indices less than 28 m2 or may be obesity-related. When adaptive mechanisms can no longer compensate, a pathologic state with snoring, hypopneas, and apneas results that will further impair ventilation and oxygenation. Patients with OSA are adversely affected by normal sleep-induced upper airway changes. They have a smaller airway diameter, even during wakefulness, than normal subjects. Furthermore, the airway is more round, not elliptical and is more susceptible to lateral wall collapse (45). The most common site for airway Volume 25, 2003
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Fig. 2. Pcrit and Ptherapeutic values for patients. Pcrit: the mean pharyngeal pressure where collapse occurs; Ptherapeutic: the mean CPAP pressure required to overcome collapse; UARS: upper airway resistance syndrome; OSA, obstructive sleep apnea. Adapted from (49).
obstruction is the soft palate. Morrison and colleagues (46) evaluated 64 patients with OSA and found 75% had more than one site of narrowing. Eighty-one percent of subjects had primary narrowing (>75% reduction) in the velopharynx, 38% in the oropharynx, and 22% in the hypopharynx. Furthermore, 33% of subjects had secondary narrowing (<75% reduction) in the hypopharynx. This markedly influences treatment strategies for these patients. Sleep deprivation and fragmentation have been shown to increase upper airway resistance in normal subjects (47). Repetitive arousals owing to increased airway resistance, hypercapnia, and hypoxemia create sleep fragmentation. In patients with OSA, sleep fragmentation may further exacerbate upper airway collapse, thus creating a vicious cycle. It has been shown in normal subjects that pharyngeal pressure (Pcrit) increases (becomes less negative) during sleep, making it more susceptible to collapse under negative inspiratory pressure. Patients with OSA have Pcrit levels between –17 cm H2O and –40 cm H2O during wakefulness (48). During sleep, Pcrit pressures have been shown to increase to –6.5 cm H2O in asymptomatic snorers and to + 2.5 cm H2O in patients with moderate-to-severe Clinical Reviews in Allergy & Immunology
apnea (49). In patients with UARS, Pcrit was in between normal subjects and patients who had mild OSA illustrating the continuum of sleepdisordered breathing (Fig. 2). This further illustrates that patients with severe OSA are prone to upper airway collapse even at normal atmospheric pressure and therefore, obstruction may occur during both inspiration and expiration. The level of Pcrit is important for determining treatment strategies. Studies investigating muscle activity in OSA patients support the hypothesis that loss of muscular compensation occurs. Patients with OSA demonstrated a threefold increase in EMG activity of the TP and GG muscles during wakefulness than control subjects, whereas during sleep OSA, patients had a greater decrease in EMG activity than controls (50). EMG has also been shown during wakefulness to be greater in women than men (51). However, EMG activity was not different, nor was minute ventilation. This may indicate an intrinsic muscle tissue characteristic may be different between genders (52). OSA patients are able to compensate for increased airway resistance during wakefulness. Muscular activity therefore seems to be intact and the loss of activity may be related to Volume 25, 2003
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a lack of neuromodulation. In animals, CO2 levels have been inversely related to Pcrit levels and decreased GG muscle activity. Serotonin (5-HT) has been shown to be an excitatory neurotransmitter on hypoglossal nerve activity. Several subtypes of 5-HT receptors exist and it has recently been determined that the subtype receptor 5-HT2A is the receptor that contributes to respiratory activity (53). In an animal model, Jelev and colleagues (54) demonstrated that 5-HT increased GG activation 91 to 251% in all sleep states and was able to maintain GG activity to the waking state. It has also been shown that 5-HT receptors are required for hypoxic-induced long-term facilitation of both phrenic motor output and hypoglossal motor output (55). An alternative hypothesis for generation of sleep-induced obstruction may be related to the 5-HT receptors. Upregulation of the receptor sites may occur in response to increased upper airway resistance. During wakefulness these receptors may be adequately stimulated and compensation can occur. During sleep there is loss of the tonic stimulus and these receptors may not be adequately occupied to continue an excitatory motor stimulus. This could result in decreased motor output of the pharyngeal muscles, particularly the GG. It is likely that the OSA occurs in a predisposed individual and that neuromuscular decompensation occurs with sleep. Loss of the wakeful stimulus may result in insufficient 5-HT and decreased motor output, resulting in upper airway collapse. Once upper airway collapse occurs, changes in mucosal surface, lung volumes, and oxygenation begin to take place, further compounding the problem. In the era of serotonin uptake inhibitors, one could speculate that this class of drugs may improve muscle function but clinical efficacy awaits clinical trials.
Risk Factors Several factors during sleep increase susceptibility to upper airway obstruction. Some Clinical Reviews in Allergy & Immunology
197 Table 1 Difference in Risk Factors Associated with Age
Male Gender Obesity/large neck Soft tissue/ enlarged tonsils Comorbidity Cardiopulmonary Metabolic Neurologic Familial Factors Environmental Tobacco Alcohol Sedatives
Pediatric
Adult
Elderly
+/– +++
+++ ++++
++ +++
++++
++
+
+/– +/– + +++
++ ++ + ++
+++ ++ +++ +
— — —
+ +/– +
+ +/– ++
+/– Questionable risk. ++ Odds of SDB approx 1.5–3.5. +++ Odds of SDB approx 3.5–8.0. ++++ Odds of SDB > 8.0. SDB: sleep disordered breathing (sleep-related respiratory disturbances). Adapted from (57).
of the stronger risk factors include obesity, gender, and age (56). Obese, middle-aged men seem to be prime targets for developing severe obstruction during sleep. Additional conditions may include craniofacial features, familial and genetic factors, certain environmental elements (use of alcohol, smoking, sedatives) and comorbid conditions. Redline et al. (57) looked at strength of several risk factors in the pediatric, adult, and elderly populations (Table 1). It appears that in adults, the strongest risk factors appear to be male gender and obesity. In the elderly, gender plays a lesser role, however, underlying comorbid conditions such as neurological and cardiopulmonary disorders increase the risk for obstructive breathing. The use of sedatives also plays a more significant role. In the pediatric population, tonsillar and adenoid hypertrophy and familial disorders such as Down syndrome (58) and Pierre Robin sequence (59) pose the greatest risks for snoring and OSA. Volume 25, 2003
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Fig. 3. Spectrum of breathing during sleep. UARS: upper airway resistance syndrome; OSA: obstructive sleep apnea. Adapted from (66).
Clinical Features The cardinal manifestations of OSA include snoring and excessive daytime sleepiness. Studies confirm these symptoms are common among the general population. Habitual snoring occurs in 35% of the population and daytime hypersomnolence in 18% (60). Other symptoms including morning headaches, choking sensations during sleep, fitful sleep, nocturnal enuresis, intellectual and personality changes, as well as hallucinations may be present.
Snoring Snoring is much like a whistle. One cannot whistle with your mouth open, but with pursed lips a resulting sound will occur. Snoring is a “whistle” which results from turbulent airflow through the narrowed posterior oropharynx. It is typically an inspiratory sound, but an expiratory component may be present (61). It can be intermittent, continuous or more disruptive associated with snorting or gasping frequently elicited in patients with more significant OSA. It is this loud snoring and snorting that is such an acoustic annoyance that may drive the bed partner to sleep in a separate bedroom. Studies have reported noise levels up to 70–85 dB recorded at a distance of 25 cm from the snorer’s mouth (62). These decibel levels can be compared to working in a noisy factory and are often above the safe noise level acceptable by the Occupational Safety and Health Administration (OSHA) (63). A recent study (64) however, failed to reveal a relationship between snoring and hearing loss and chronic exposure to snoring noise was not felt to be a contributing factor to development of presbycusis. The bed partner is frequently helpful in assessing snoring. Primary snoring, as defined previously by the American Academy of Sleep Clinical Reviews in Allergy & Immunology
Medicine (65), is snoring without sleep disruption in the absence of complaints of insomnia or excessive daytime sleepiness. However, the bed partner may recognize more arousal breathing with frequent snorts or gasps, which can be interrupted by periods of silence (apnea). This type of disruptive snoring leads to fragmented sleep and the presence of daytime symptoms. Snoring is probably part of the general aging process and may constitute a spectrum of breathing during sleep, ranging from mildly abnormal to severely elevated upper airway resistance and obstruction. It is suggested that patients can move from being a quiet sleeper and progress to loud snoring with increasing UARS to significant obstructive sleep apnea (66). Various risk factors, including obesity, can move patients along the spectrum (Fig. 3).
Daytime Hypersomnolence Excessive daytime sleepiness is a common complaint but can be a challenge for proper interpretation, as it may arise from a variety of disorders. A history of tiredness, fatigue, and lack of energy may be elicited from the patient, which can lead to potential semantic confusion (67,68). Importantly, patients with OSA are not refreshed when awakening from sleep in the morning and this frequently leads to nonintentional naps throughout the day. Patients can fall asleep while watching television, while reading, and at public gatherings. Sleepiness is especially dangerous while driving. Certain subjective and objective tests are available to quantitate historical sleepiness (6). Perhaps the most widely utilized non-instrumental procedure is the Epworth Sleepiness Scale (ESS) (69; Fig. 4). The questionnaire consists of 8 situations related to daily life and the subject is asked to score (on a 0 to 3 scale) how likely he/she is likely to doze off in these situaVolume 25, 2003
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199 Questionnaire: Epworth Sleepiness Scale (ESS)
Fig. 4. Questionnaire: Epworth Sleepiness Scale (ESS). Adapted from (69).
tions. There is a maximal score of 24 and normal subjects score between 0 and 10. Scores greater than 12 suggest excessive sleepiness and further evaluation of OSA should be considered. The test is inexpensive and does provide evaluation of chronic sleepiness (70). It is limited by the subjective feelings of the individual patients, and some may poorly perceive their own sleepiness. The Multiple Sleep Latency Test (MSLT) is an objective test usually performed in conjunction with a formal sleep study (nocturnal polysomnography) (71). The MSLT consists of four to five nap opportunities spread over the day, usually at 2 hr intervals. Sleep latency (the amount of time between the beginning of the nap and the onset of sleep) and the onset of REM sleep is determined. Normal subjects have a sleep latency longer than 10 min. Severe sleepiness is usually associated with an MSLT mean sleep latency of less than 5 min. These patients need prompt evaluation, as the potential for motor vehicle accidents is high. From a practical standpoint, most clinicians should be able to include a simple subjective Clinical Reviews in Allergy & Immunology
measure such as the ESS to evaluate sleepiness. More expensive and sophisticated objective measures are best left to certain sleep referral centers (67).
Diagnosis History and Physical OSA is frequently diagnosed with a proper history and a high index of suspicion. Having the bed partner present during the historytaking is extremely helpful, as the patient is frequently unaware of certain events taking place during slumber. Unfortunately, there has been a trend to devote less emphasis on the physician’s clinical skills and to rely on more expensive and time-consuming laboratory patient evaluations. For this reason, it is important for the physician to collect accurate and appropriate information to properly evaluate and diagnose sleep-related disorders. With a proper database, the physician is then best able to decide whether an adjunctive sleep laboratory for definitive diagnosis is necessary. Studies have shown that experienced physicians uncommonly obtain sleep histories (72). Volume 25, 2003
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Likewise, sleep histories are seldom documented by medical house officers either in an ambulatory setting or on a general medical service (73,74). A proper sleep history should include defining the specific sleep problem (75). Since this exercise will also expose other medical problems germane to allergists (i.e., asthma, gastroesophageal reflux, rhino-sinusitis), both nighttime and daytime behavior should be questioned. General nighttime questions concerning when the patient goes to bed and how long the patient sleeps should be supplemented by specific queries regarding sleep latency, presence of insomnia, nightmares, snoring, shortness of breath, wheezing, coughing, gasping sensations, and fitful sleep. Obviously, much information can be obtained from the patient’s bed partner, because such features as disruptive snoring, snorting, and obstructive breathing may not be apparent to the patient while asleep (63). Daytime symptoms should also be elicited. Does the patient have daytime tiredness or fatigue? Does the individual fall asleep watching television or while reading? Perhaps the patient develops excessive sleepiness while driving or on the job. Does the patient fall asleep when inactive; does a short nap refresh the patient (63)? Daytime sleepiness, tiredness, and physical inactivity is common and the physician must be able to differentiate between other medical disorders such as narcolepsy and underlying mood disorders. A history of morning headaches, sexual dysfunction, ability to concentrate on the job, and personality changes should also be sought. As with any history, prescribed and recreational drug use should be obtained. Quality of sleep is affected by the use of nicotine, alcohol, and caffeine. Hypnotics also may have an adverse effect by promoting respiratory depression. Comorbid conditions can also contribute to disordered breathing during sleep. Finally, a sleep diary may be helpful to further document the patient’s sleep Clinical Reviews in Allergy & Immunology
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patterns, which may not be evident during the initial patient interview (63). The physical examination is frequently unremarkable, except perhaps for obesity. A short, thick neck with a measured collar size of 17 in in men and 16 in in females may suggest obstructive breathing. Routine examination of the upper airway for a small oropharyngeal space, redundant soft tissue, tonsillar hypertrophy, small chin, and malocclusion with overbite should be looked for (76). The nose should be examined for obstruction and deviated nasal septum. Persistent elevated blood pressure may be present and subtle evidence of cor pulmonale may be seen in severe cases.
Nocturnal Polysomnography Once obstructive sleep apnea has been suspected the patient should then be referred for nocturnal polysomnography for definitive diagnosis. Polysomnography (PSG) is the only objective way to document evidence of disordered breathing during sleep. The testing includes electroencephalography, electrooculography, electromyography, electrocardiography, oronasal airflow, respiratory effort, oxyhemoglobin saturation, snoring microphone, and position of body and leg movements. Infrared cameras should be available for surveillance as well as video recording. The patient is monitored during a full night at times the patient usually sleeps at home. A sleep technician is available to monitor sleep stages and sleep positions for thorough analysis. Traditionally, the patient undergoes a diagnostic sleep study over a full night. If results are consistent with obstructive sleep disordered breathing, the patient will then be asked to return for a second night of CPAP titration. However, since PSG is time-consuming and expensive, split-night studies combining diagnosis and treatment have become popular. If the patient has significant obstructive breathing during the first 2–3 hr of monitoring, the sleep technician then offers a trial of nasal continuous positive airway pressure (CPAP) titraVolume 25, 2003
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tion. Advantages include less cost for one study, and more efficient use of sleep laboratory resources so more patients can be diagnosed and treated. If a therapeutic level of CPAP cannot be reached during the allotted sleep time then the individual may be brought back for a second night of CPAP titration alone. Portable studies, including home testing devices, are now available and have the added advantages of being less costly, and may be more representative of how patients would sleep in a home environment. However, some studies still suggest that multi-channel portable devices may not be reliable in the home setting (77). Data from the Sleep Heart Health Study (SHHS), however, reveal that reliable and quality information could be attained in 7000 in-home studies regarding sleep staging and detection of arousals (78). Because of the present back log in patients awaiting diagnosis at our present sleep laboratories, there is continued interest in finding ways to better screen patients with simpler devices or perform more home studies (79). Examples where an unattended portable device may be appropriate include when urgent treatment is deemed necessary and standard PSG is not available, or when a patient is unable to be transferred to a sleep lab in a safe situation (79,80). Controversy still exists, but current studies suggest that at least in patients with severe OSA, that in-home studies are reliable in diagnosis (79).
Treatment The treatment of obstructive sleep apnea is dependent on severity of symptoms, results of the AHI and any associated comorbid conditions. Various conservative measures and medical and surgical interventions are available. Conservative measures should be advocated in all patients and consist of weight loss, avoidance of the supine position during sleep, as well as avoidance of sedatives and alcohol prior to sleep. The patient should also get adequate hours of sleep every night. Clinical Reviews in Allergy & Immunology
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CPAP Therapy The treatment choice for moderate to severe OSA is the use of CPAP therapy. CPAP works as a pneumatic splint to effectively eliminate upper airway obstruction including the resulting apnea sequelae of daytime sleepiness (81,82), cognitive dysfunction, mood impairment, reduced quality of life (83), and elevated blood pressure (84,85). Simulated driving performance may also show improvement with CPAP therapy (86,87) and studies reveal traffic car accidents are reduced after 1 yr of treatment (88–91). Unfortunately, the effectiveness of CPAP therapy continues only while the treatment is being used and failure to comply with a nightly regimen has been reported to be as high as 25 to 50% of patients (92–96). Many patients abandon CPAP therapy within the first month of treatment secondary to side effects. Janson et al. (97) examined 40 patients who had ceased using CPAP after finding the treatment unacceptable. A control group of 63 patients still compliant with CPAP therapy was utilized for comparison. Patients who had stopped CPAP treatment had a higher mean age, had more frequently undergone uvulopalatopharyngoplasty (UPPP) and had a lower mean oxygen desaturation index compared with the compliant patients. The two most common reasons for non-adherence were nasal and pharyngeal side effects as well as lack of subjective benefit from the therapy. It appears that patients with more severe sleep apnea coupled with substantial sleepiness are more likely to adhere to a CPAP program (98).
Compliance Interventions Studies have shown that nasal and pharyngeal side-effects occur in 15–45% of CPAP users and are important reasons for poor compliance (96). Complaints of nasal dryness, congestion, and sinus discomfort are common. Table 2 outlines some of the more common problems related to the use of nasal CPAP. Volume 25, 2003
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Table 2 Common Problems Associated With the Use of Nasal CPAP Therapy Problem
Possible Cause
Mask leaks Skin irritation/ breakdown
Poor strap adjustment Incorrect mask fit
Nasal/throat dryness Nasal congestion Epistaxis
Lack of proper humidification
Dry mouth
Mouth opening during sleep
Eye irritation/ conjunctivitis
Mask leaks/poor mask fit
Rhinorrhea/rhinitis
Lack of proper humidification
Aerophagia Sinus discomfort Difficulty exhaling
May require less pressure/change to bilevel positive airway pressure
CPAP unit too noisy
Blocked air intake/unit too close to sleeper
Adapted from (92).
Mechanisms for these side effects are not clear. Some authors believe that CPAP can provoke pressure-sensitive mucosal receptors causing vasodilatation and mucus production (96). Mouth leaks cause high unidirectional nasal airflow with resulting large increases in nasal resistance and may also be playing a role (99). Older patients appear to be more prone to mucosal drying and this is perhaps related to their higher incidence of mucosal atrophy (97). Warm humidification has been shown to be especially helpful in averting some of the dryness associated with nasal CPAP use (100–102). Other therapeutic strategies including nasal saline and steroid sprays, nasal decongestants, and antihistamines may be utilized. It should be emphasized that the success of CPAP therapy is closely related to patient comfort. Proper patient education is especially important during the first month of therapy and proper attention to patients’ needs during Clinical Reviews in Allergy & Immunology
this time frame promotes better long-term compliance (103,104). It is common for patients to require initial changes regarding mask fit, headgear problems, and nasal symptoms. For this reason, the physician or sleep laboratory technician may need to have frequent contact with the patient for resolution of problems. In many communities, the medical durable equipment company has respiratory therapists available to follow-up and intercede when necessary during the initial set-up process. Close communication with the prescribing physician can frequently eliminate tolerance problems early and lead to better patient compliance. Indeed, the initial perception of improvement with the addition of nasal CPAP therapy made by a patient early in the treatment process can nurture further compliance (105,106). Zozula et al. have recently reviewed treatment outcomes in patients with CPAP therapy (92). Particular attention to tolerance problems as well as certain psychological factors is an important goal in OSA treatment and early patient education and intervention strategies can maximize patient compliance (107). Other alternative methods including bilevel positive airway pressure (BiPAP) and autotitrating CPAP (APAP) may be useful in selective cases. The BiPAP is utilized to permit higher inspiratory and lower expiratory pressures and is frequently utilized in patients with combined hypoventilation and central sleep apnea. This therapy may not necessarily improve patient compliance (108), but in a subgroup of patients who complain of excessive expiratory pressures, or who experience inadequate nocturnal ventilation, better acceptance may be achieved (109,110). APAP devices automatically adjust CPAP pressures through the night and the overall mean pressure during the night is less than the standard CPAP (110). There is conflicting evidence whether or not APAP increases adherence compared to standard CPAP (111). Further studies are needed, as such devices may be difficult to justify because of increased cost (112). Volume 25, 2003
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Oral Appliances Oral mandibular prostheses have been designed to maintain airway patency during sleep. These devices appear to prevent retroglossal collapse, and by gradually moving the mandible and tongue forward in the mouth, the posterior oral cavity and oropharynx is enlarged (110,113). Most devices fit over the upper and lower teeth and referral to a dentist skilled in making these appliances is usually necessary. Several studies have shown good results with less than severe OSA (114,115), although in some individuals even more severe OSA may respond (116). Overall, a mandibular advancement device should be considered in patients with milder OSA, patients intolerant to CPAP therapy, and patients who have not responded to upper airway surgery. Reasons for discontinuation of the device include excessive salivation and discomfort. On the positive side, oral appliances appear to be preferred by patients, and have low morbidity with improved long-term compliance rates (117,118).
Consequences of Obstructive Sleep Apnea OSA has been associated with neurocognitive impairment as well as cardiovascular and cerebrovascular sequelae. Numerous adverse physiologic changes occur during sleep in patients with OSA. Both acute and chronic hemodynamic changes occur in association with obstructive events and may lead to or potentate vascular changes (119). We will briefly review the neurocognitive and cardiovascular consequences associated with OSA.
Neurocognitive Consequences Repetitive hypopneas and apneas associated with cortical arousals can lead to sleep fragmentation. This is thought to cause excessive daytime somnolence, poor concentration, and difficulty maintaining alertness for social interactions and job performance. Sleepiness Clinical Reviews in Allergy & Immunology
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may be underreported in patients with OSA and complaints of fatigue may predominate (120). Furthermore, diminished quality of life has been reported by patients with OSA. Confounding factors may include other disease comorbidities (121). Motor vehicle accidents are a primary concern in OSA patients. Thirtysix percent of fatal motor-vehicle accidents take place between 3 AM and 6 AM, coinciding with peak sleep tendency (122). Several studies have indicated that patients with OSAHS are more likely to have motor vehicle accidents. TeranSantos and coworkers (123) conducted a casecontrol study and found that the odds ratio of having OSA (AHI > 5) in accident subjects compared with controls was 6.3. Self-reported sleepiness was significantly correlated. However, self-reporting is obviously prone to error, given the legal implication on driving. These findings have been confirmed in other studies, indicating that OSA creates a significant public safety risk (2).
Cardiovascular Consequences Hypertension, myocardial ischemia, congestive heart failure, arrhythmias, and pulmonary hypertension have all been associated with OSA (124–127). The parasympathetic nervous system generally predominates during sleep; however repetitive apneas associated with hypoxia and/or hypercarbia increase sympathetic output causing vasoconstriction and increase arterial pressure in both the systemic and pulmonary circulation. Furthermore, during the apneic episode, negative intrathoracic pressure is increased to overcome upper airway resistance and results in increased intravascular volume to the right heart and pulmonary circulation causing a leftward intracardiac displacement and poor left-sided filling, decreased cardiac output, pulsus paradoxus, and further increases sympathetic stimulation. Consequences of chronically elevated sympathetic tone and vasoconstriction are systemic hypertension and pulmonary hypertension. Previous studies demonstrated that hypertenVolume 25, 2003
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sion was more prevalent in patients with OSA and that patients with OSA more frequently had hypertension. However, confounding variables, such as obesity, were not controlled for. Grote and colleagues (128) demonstrated an independent association with sleep disordered breathing. The relative risk for hypertension after controlling for confounding variables was shown to increase as the AHI increased. This was also supported in other studies where the odds ratio was reported to be 2.89 for hypertension when the AHI was >15 (129). Sustained hypertension can lead to long-term consequences of left ventricular hypertrophy and congestive heart failure. Although data is conflicting, left ventricular mass has been reported to be increased in subjects with OSA (119). Data supports that pulmonary hypertension occurs at night in subjects with OSA owing to hypoxic induced vasoconstriction. However daytime hypoxemia is felt to be necessary for the development of cor pulmonale (130). Endothelin-1 is stimulated by hypoxia with potent cardiovascular consequences, including mitogenic influences on vascular smooth muscle and cardiocytes, and may contribute to hypertension and coronary artery disease. Patients with OSA have been shown to have elevated daytime levels of endothelin-1 compared to normal subjects (131). Furthermore, Phillips and associates (132) demonstrated that 4–5 hr of CPAP pressure in patients with OSA significantly decreased endothelin-1 and blood pressure. Patients with untreated OSA and ischemic heart disease have been shown to have a higher cardiovascular mortality. It is speculated that OSA-induced hypoxia promotes an inflammatory stress response with release of mediators causing accelerated atherogenesis. Inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-1 induce endothelial-leukocyte adhesion molecules in vessels. These molecules, intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM-1) enhance endothelial stickiness, leuClinical Reviews in Allergy & Immunology
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kocyte trapping, and promote vascular inflammation and atherosclerosis (133,134). El-Solh and coworkers (134) reported significantly elevated ICAM-1 and VCAM-1 levels in patients with OSA. The increased adhesion molecule levels were correlated with the AHI and oxygen desaturation index, but not with the severity of oxygen desaturations or frequency of arousals. The episodic nature of hypoxia in OSA is consistent with known hypoxiareoxygenation reaction injury and promotes greater inflammatory reaction and free radical generation (135). During the episodes of profound oxygen desaturation, severe bradycardia, asystoles, and even sudden death, can occur because of carotid body stimulation and increased vagal output. During periods of severe hypoxemia (saturations of ~65%) and bradycardia, poor coronary filling may occur and the myocardium may become irritable, leading to lethal dysrhythmias as premature ventricular contractions and ventricular tachycardia. When the apneic episode has resolved, vagal stimulation ceases and the underlying sympathetic tone is again more prominent and creates tachy-bradycardia rhythm. These changes can be averted with CPAP treatment.
Nocturnal Asthma, Sleep, and OSA Asthma is a common chronic disease of the airways manifested by bronchial inflammation, edema, mucus production, and hypersensitivity resulting in airflow obstruction. In a survey by Turner-Warwick (136) of 7729 asthmatics, 74% reported experiencing nocturnal symptoms at least once per week. Nocturnal death rate is also high in asthmatics with approx 53% of asthma-related deaths occurring between 6 PM and 4 AM (137). Asthmatics have frequent nocturnal symptoms that disrupt sleep and can result in sleep deprivation. Sleep deprivation has been shown to blunt the arousal response to bronchoconstriction as well as to hypoxia and hypercapnia. Ballard and colleagues (138) investigated Volume 25, 2003
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the effect of sleep deprivation of asthmatics and the effect on airway resistance, arousal response, and ventilation. They induced bronchoconstriction with aerosolized methacholine while awake, during normal sleep, and after 36 hr of sleep deprivation, and measured inspiratory pressures with esophageal balloon, supraglottic pressures, tidal volumes, respiratory rate, and minute ventilation. They found that airway resistance and arousal threshold increased, but that ventilation was well-maintained during sleep deprivation. Preservation of ventilatory response was attributed to increased ventilatory drive. Blunted arousal response to bronchoconstriction may significantly contribute to fatal nocturnal asthma caused by delayed awareness of symptoms and seeking treatment. Factors that may contribute to sleep-related asthma include circadian changes in hormone levels, ventilation, bronchial hyperresponsiveness, and inflammation. Cortisol was one of the first hormones found to have a circadian rhythm. The peak plasma cortisol level occurs at approx 6 AM and the nadir at approx 12 AM. Plasma histamine (conversely) is highest at approx 4 AM. Serum epinephrine levels are also lower at 4 AM (139). Peak expiratory flow rates (PEFR) also demonstrate a circadian variation with decreased flow rates in the early morning in normal subjects. Barnes and coworkers found that asthmatic patients had much more pronounced decreases in PEFR (139) at 4 AM and higher plasma histamine levels than normal subjects. Oxygen desaturations were greater in asthmatics and corresponded to PEFR. It was speculated that low catecholamine levels were responsible for the decrease in PEFR. Low doses of epinephrine given intravenously modestly improved PEFR and histamine levels decreased. Other studies (140) have not found this improvement, despite changes in histamine levels. In these patients, beta-adrenergic receptors on monocytes and leukocytes showed a 30% decrease in receptor density and therefore may not respond as well to beta-agonists. Although there is some effect Clinical Reviews in Allergy & Immunology
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of nocturnal variation in hormone and mediator levels on PEFR, nocturnal bronchoconstriction may be influenced by other mechanisms, particularly cholinergic mediation and inflammation. As previously discussed, parasympathetic tone is increased during sleep. This increase in vagal output is thought to affect the muscarinic receptors located in the central airways and contribute to bronchoconstriction (133). The benefit of anticholinergic drugs in treating asthma is no longer controversial. Earlier studies showed mixed results in improvement in flow rates. Recent studies demonstrate improved flow rates compared with patients receiving beta-agonist alone (141). A meta-analysis of 10 randomized, placebo-controlled studies further supported this, and indicated that airflow improvement was greatest in patients with the most severe asthma (142). Morrison and colleagues (143) investigated the effect of intravenous atropine in seven asthmatic patients at 4 PM and 4 AM and found almost complete reversal of bronchoconstriction. The greatest improvement in PEFR occurred at 4 AM . Increased parasympathetic tone at night may significantly contribute to nocturnal asthma exacerbations. Chronic inflammation of the airways is the major underlying mechanism of airway damage and bronchoconstriction. The reader is referred to other articles in this review for full details of inflammatory mediators. Many chemical mediators and cyokines are released from eosinophils, mast cells, neutrophils, and Thelper lymphocytes, resulting in an early- and late-phase response to antigen challenge. These include histamine, leukotrienes, interleukins (IL)-4, -5, -3, TNF, histamine, and plateletactivating factor. These substances lead to airway hypertrophy, edema, hypersensitivity, and direct tissue injury from free radical generation. Most importantly, bronchoalveolar lavage fluid in patients with nocturnal asthma compared with asthma patients without nighttime symptoms shows marked increase in Volume 25, 2003
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neutrophil and eosinophil counts at nighttime than in the daytime. Furthermore, PEFR decline correlated with increased eosinophil count (144). Patients with nocturnal asthma seem to a have more exaggerated inflammatory response during the nighttime. It has been shown that stable asthmatics have milder reactions to morning antigen challenge as compared to evening antigen challenge (145). This may be related to the circadian variation in cortisol level. What is the relationship between OSA and nocturnal asthma? The overlap is unavoidable both immuno-biologically and clinically. As previously discussed, patients with OSA and patients with asthma express similar cytokine and chemokine patterns. Vgontzas and colleagues (146) demonstrated that patients with OSA also have higher levels of TNF and IL-6 than control subjects. TNF is a potent inflammatory cytokine and has also been shown to be increased in asthmatics. One may hypothesize that increased TNF levels in OSA patients may promote or exacerbate more frequent or severe asthmatic attacks. Furthermore, histologic changes in the pharyngeal epithelium in patients with snoring and OSA are similar to changes in the bronchi of asthmatics. Chronic inflammation with increased interstitial edema, mucous gland hypertrophy, and infiltration of the uvula lamina propria with T-cells has been shown (147,148). A vicious cycle of nocturnal worsening of asthma with OSA and airway narrowing in both upper and lower respiratory tracts is likely to occur. Large, negative intrathoracic pressure changes in sleep-related obstructive breathing worsen asthma. Treating OSA can significantly improve asthma control (149,150) but sleep disorders alone do not appear to cause asthma nor its characteristic hyperresponsiveness. Allergic rhinitis is also associated with asthma. Allergen exposure leads to histamine release, nasal congestion, and/or postnasal drip. In children, chronic allergen exposure Clinical Reviews in Allergy & Immunology
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Fig. 5. Relationship between OSA, asthma, and allergic rhinitis.
causes hypertrophy of adenoid and tonsillar tissue, which can result in upper airway obstruction and possible OSA (Fig. 5). Chronic nasal congestion increases upper airway resistance and downstream pharyngeal collapse. In both children and adults, mouth breathing results and pharyngeal obstruction can result. Furthermore, postnasal drip causes irritation of the oral pharynx and can increase edema and inflammation (151). Stimulation of neural receptors located in the glottic inlet has been shown to produce potent bronchoconstriction. Chronic stimulation may occur with snoring, postnasal drip, and gastroesophageal reflux. Mouth breathing may directly contribute to stimulation of irritant receptors by drying of the throat and inadequate warming of air. Chan and colleagues (150) demonstrated that both daytime and nighttime PEFR improved in patients with concomitant OSA and asthma when nocturnal CPAP was applied, suggesting that removal of the mucosal irritant and/or obstruction may decrease reflex bronchoconstriction. However when CPAP was applied to asthmatic patients without snoring or OSA, sleep efficiency was reduced and no significant change was observed in the PEFR (152). Whether patients with simple snoring or UARS and asthma would also improve with CPAP is unknown. OSA may prove to be a chronic inflammatory state with increased cytokines and inflammatory mediators overlapping and contributing to other comorbid Volume 25, 2003
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ailments. Whether treatment with antiinflammatory agents would alter OSA outcome has not been studied.
Summary Obstructive sleep apnea (OSA) is a common disorder, variable in severity and associated with significant morbidity. It is estimated that between 8 and 18 million people in the United States have at least a mild degree of OSA. Obese, middle-aged men seem to be prime targets for developing more severe obstruction during sleep. Although the pathogenesis of OSA is not clearly understood, various anatomic, mechanical, neurologic, and inflammatory components appear to contribute to relaxation and closure of the pharyngeal airway during sleep. It is imperative for allergists to be aware of how OSA can coexist and complicate asthma and allergic rhinitis. Taking a meticulous history coupled with a high index of suspicion frequently makes the diagnosis of OSA much easier. Snoring and daytime hypersomnolence are common features and the spouse or bedpartner is helpful during the interviewing process. Snoring in patients with asthma, especially with persistent symptoms, should raise clinical suspician of OSA. Polysomnography is the only definitive way to document objective evidence of disordered breathing during sleep and is also helpful in prescribing proper treatment. The treatment of moderate to severe OSA is the use of CPAP therapy, which has been shown to improve daytime sleepiness, cognitive function, mood, quality of life, and elevated blood pressure. Unfortunately, side effects are common and early attention to tolerance problems as well as proper patient education can lead to improved compliance. This is important, since untreated OSA has been linked to hypertension, as well as possible cardiovascular and cerebrovascular consequences. Likewise, although the exact mechanism for nocturnal asthma has not been delineated, similar Clinical Reviews in Allergy & Immunology
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inflammatory mediators have been noted to be present in patients with OSA. Evidence now supports improvement in asthmatic patients with OSA when treated with CPAP therapy (149).
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