Continuing Education Activity

Sleep apnea syndrome (SAS) is defined by frequent episodes of apnea and hypopnea associated with symptoms such as excessive daytime and cardiovascular morbidity and mortality. Obstructive sleep apnea syndrome is a condition in which there is a dynamic collapse of upper airway tissues during sleep. This may result in recurrent respiratory-related events and both short-term symptomatic consequences and long-term physiologic consequences. This activity reviews the evaluation, workup, and management of adult patients with obstructive sleep apnea and highlights the role of the healthcare team in evaluating and treating these patients.

Objectives:

• Summarize the etiology of obstructive sleep apnea.
• Outline appropriate evaluation of obstructive sleep apnea.
• Review the management options for obstructive sleep apnea.
• Describe how the interprofessional healthcare team can implement strategies to improve patient outcomes in sleep apnea syndrome.

Introduction

Sleep apnea syndrome (SAS) is defined by frequent episodes of apnea and hypopnea associated with symptoms such as excessive daytime and cardiovascular morbidity and mortality.[1] SAS encompasses a broad spectrum of sleep-disordered breathing from central to mixed, obstructive apnea, and hypopnea. In obstructive SAS (i.e., obstructive sleep apnea-OSA), there is upper airway collapse and obstruction during sleep, which results in snoring, obstructive apneas (cessations of breathing), hypopneas (abnormally slow or shallow breathing), or respiratory-related arousals.[2][3] The etiology, epidemiology, history and physical manifestation, diagnostic approach, and complications of SAS are reviewed here. More specifics of central and obstructive sleep apnea are also described separately in more detail.[4][5][6]

Etiology

Factors that contribute to the development of upper airway collapse are those that affect upper airway patency. Because the upper airway is enclosed by the craniofacial skeleton, which serves as the scaffold of the upper airway, the craniofacial skeleton is one of the key determinants of upper airway patency or collapse.[7][8] Thus, in situations such as retrognathia or maxillomandibular deficiency, the soft tissues of the upper airway exist within a more compact space, resulting in decreased upper airway patency.

Conversely, the size and compressibility of the soft tissues within the craniofacial skeleton also determine upper airway patency. Upper airway patency decreases with increased soft tissue mass within a given confined space within the craniofacial skeleton. This may be influenced by factors such as the amount of submucosal or lingual adipose tissue, as well as cervical lymphovascular tone, as well as neuromuscular influences on upper airway muscular tone.[9][10][11][12][13] 

Increased age, obesity, male gender, and craniofacial abnormalities are considered to be the primary risk factors for developing OSA. Other risk factors include smoking and a family history of OSA.[14][15][16][17][18]

Epidemiology

The overall prevalence of SAS ranges from 21-59% in the general population and patients with cardiac disease, respectively. [19][20] Obstructive sleep apnea is the most common sleep-related breathing disorder. It is most common in adult males but may also be present in women and children, though rates of OSA in post-menopausal women approach those of men.[1][17][2] 

In North America, the prevalence of OSA is between 15 and 30 percent in males and 10 to 15 percent in females.[14][21][14] The prevalence of OSA varies by race, and in the United States is more prevalent in African Americans than in other groups, independent of body weight.[22][23] 

The prevalence of OSA also appears to be increasing, which is thought to be related to a combination of increasing rates of obesity as well as increased diagnosis and detection. In a study by Peppard et al., it was estimated that the prevalence of OSA increased from 11 to 14 percent from 1990 to 2010 among adult American males.[21]

Pathophysiology

Though many factors contribute to obstructive sleep apnea, changes in respiratory dynamics during sleep are the principal essence of the disorder which are influenced by multiple factors. During sleep, there is decreased tonic activity of the laryngeal, supraglottic, oropharyngeal, nasopharyngeal, and lingual musculature, which results in dynamic collapse with respiration.[9][24] This decreased upper airway tonic activity results in a dynamic decrease in the caliber of the upper airway and therefore increased resistance to airflow. The effects of this dynamic collapse can range from mild collapse without significant changes to respiration and no effect on oxygenation or arousal to complete airway obstruction, decreased oxygenation, and frequent arousals throughout sleep. Over time, this can have significant effects on cardiopulmonary and neurologic function. 

Obstruction during sleep can occur at various sites within the upper airway. These include the nasal cavity, the nasopharynx, the oropharynx, the base of the tongue, and the laryngeal complex. A patient may have one primary site of obstruction; however, many patients have an obstruction at multiple levels. A thorough evaluation and examination are essential to properly identify the most likely sites of obstruction so that treatment may be tailored appropriately. 

An understanding of definitions of respiratory events is imperative in understanding this disorder. An apnea is defined as the cessation of airflow for 10 seconds or more. A hypopnea is defined as either a reduction in airflow for at least ten seconds of 30 percent or more with an associated oxygen desaturation of at least four percent OR a reduction in airflow for at least ten seconds of 50 percent or more with an associated oxygen desaturation of three percent or associated arousal. Respiratory effort-related arousal (RERA) is a sequence of breaths that do not meet the criteria for apnea or hypopnea with increasing effort or with flattening of the nasal pressure waveform that increases for at least ten seconds, which results in arousal.[25]

There is an array of common findings that are characteristic of patients presenting with obstructive sleep apnea. Daytime sleepiness is the most common complaint for patients seeking evaluation and treatment for OSA. Sleepiness is defined as difficulty remaining alert while awake. Patients or their partners will often complain of loud snoring, coughing, or choking during sleep. Though snoring is sensitive for OSA, it has a low specificity and is not useful in diagnosing OSA alone.[26] Patients with OSA often complain of morning headaches. Less common complaints include difficulty remaining asleep, chest pain or palpitations, neuropsychiatric changes, or nocturia.[27][28]

History and Physical

A complete history for a patient presenting with signs or symptoms of OSA must be obtained, including symptoms of daytime sleepiness, associated sleep symptoms, snoring, coughing, or choking during sleep, morning headaches, chest pain, dyspnea, or neuropsychiatric changes. Inquiring regarding sleep hygiene and screening for other sleep-related diagnoses is also important. One of the key points is to determine whether the patient is experiencing sleepiness associated with OSA from fatigue, which indicates alternative medical diagnoses. 

A comprehensive history and physical examination are crucial in the workup for suspected OSA, with special attention to all possible sites of the upper airway obstruction. The nasal cavity is carefully evaluated for conditions that decrease the patency of the nasal airway, including septal deviation, inferior turbinate hypertrophy, masses or lesions, nasal valve collapse, or adenoid hypertrophy. The oropharynx is also carefully examined with attention to factors that may decrease patency, including an enlarged or elongated soft palate or uvula, which is often seen in patients with chronic obstructive respiratory disorders. The physician also evaluates palatine tonsil hypertrophy and macroglossia and their effect on oropharyngeal airway patency. The Updated Friedmann Staging System for Obstructive Sleep Apnea is a widely used screening tool for evaluating oropharyngeal patency, including tongue position, palatine tonsil size, and body mass index into stage I-IV.[29] This is a validated scale that is helpful not only in screening patients but also may be useful in determining optimal treatment modalities and tracking outcomes. 

The hypopharyngeal and laryngeal evaluation includes assessing lateral pharyngeal wall anatomy and collapse, epiglottis size and shape, lingual tonsillar hypertrophy, and assessment for any obstructive lesions or masses. The evaluation of the hypopharynx and laryngeal airway remains controversial. Some advocate an awake assessment of these structures using mirror laryngoscopy or flexible fiberoptic laryngoscopy. Scoring systems such as the Modified Cormack-Lehane scoring systems have been developed, which are useful for efficiently and effectively communicating laryngeal anatomy findings to evaluate obstructive sleep apnea.[30] However, such evaluation is limited as it does not assess the dynamic changes of the airway during sleep. As a result, efforts have been made to evaluate the dynamic collapse of the upper airway. Maneuvers have been previously described to simulate airway collapse in an awake patient; however, these have been shown to have limited utility as simulating the dynamic collapse that occurs during sleep with awake maneuvers is problematic.[31] 

Drug-induced sleep endoscopy (DISE) has emerged as an alternative evaluation of the upper airway during which the patient is evaluated by flexible fiberoptic laryngoscopy while lying supine under sedation, thus providing a more physiologic representation of sleep-related dynamics of the upper airway. DISE is believed to be useful in improving treatment outcomes for patients with OSA; however, controversy exists regarding its use due to lack of standardization as well as the most appropriate use in the workup and treatment for obstructive sleep apnea.[32]

The physical examination also includes evaluating the craniofacial skeleton with an assessment of mandibular anatomy, such as retrognathia, narrow mandibular or maxillary arches, maxillomandibular insufficiency, or any bony lesions that may affect obstruction, such as large mandibular tori. Neck anatomy should also be examined. A neck circumference greater than 17 inches for men and 15.5 inches for women is associated with an increased risk of OSA. Evaluation of general body habitus includes evaluation for obesity and adipose distribution, achondroplasia, or chest wall deformities. The physical examination should also include evaluation for possible cardiovascular sequelae, including arterial hypertension and peripheral edema.

Evaluation

Current recommendations are to obtain diagnostic testing for the workup of OSA in patients with excessive daytime sleepiness on most days as well as two or more of the following symptoms: diagnosed hypertension, loud snoring, witnessed apneas or gasping/choking episodes during sleep. In the absence of these symptoms, some recommend pursuing diagnostic testing for excessive daytime sleepiness alone if there is a concern for obstructive sleep apnea given the overall clinical presentation or if an evaluation for OSA must be ruled out during the workup for another disorder.[33]

A widely used, validated tool that helps differentiate sleepiness from fatigue used in diagnosing OSA, which evaluates daytime sleepiness, is the Epworth Sleepiness Scale. This survey asks the patient to rate the likelihood of falling asleep from 0-3 (0 would never fall asleep to 3-a high chance of dozing off) in various situations. A total score of greater than 10 is suspicious for OSA.[34]

The gold standard for the diagnosis of obstructive sleep apnea is an in-laboratory polysomnogram. This is preferred for all patients, but in certain populations/situations, an at-home polysomnogram is an acceptable alternative to an in-laboratory study. Patients in whom an at-home sleep study may be an appropriate alternative include those with no suspicion of another sleep-related diagnosis, an adequate device is available for at-home testing, and a sleep expert is available to interpret the data. If the study is inconclusive or suspicion of OSA remains despite a negative at-home polysomnogram result, an in-laboratory polysomnogram should be completed.[33][35]

An understanding of key indexes of sleep-disordered breathing is required to understand the data of a polysomnogram and diagnose obstructive sleep apnea. The Apnea Index (AI) refers to the total number of apneas per hour of sleep. The Hypopnea Index (HI) is the total number of apneas per hour of sleep. The AI and HI are used to calculate the Apnea-Hypopnea Index (AHI), which is the total apneas or hypopneas per hour of sleep. This calculation serves as one of the important determinants in the diagnosis of OSA. The RERA Index refers to the total number of RERAs that occur per hour of sleep. The Respiratory Disturbance Index (RDI) is an index that is calculated as the total number of apneas, hypopneas, and RERAs per hour of sleep. The Central Apnea Intex is another useful index calculated by the total number of central apneas per hour of sleep. Similarly, the Mixed Apnea Index may be calculated to find the total number of mixed apneas per hour of sleep. 

The diagnosis of OSA is confirmed on polysomnogram if there are five or more predominantly obstructive respiratory events per hour (which refers to an AHI or RDI 5 or greater) in a patient who has one or more sleep-associated symptoms or conditions (which include sleepiness, fatigue, sleep that is unrestful, insomnia, apneas, gasping or choking, consistent snoring breathing interruptions witnessed by a bed partner, mood disorder, diagnosed hypertension, cognitive dysfunction, cerebrovascular accident, coronary artery disease, atrial fibrillation, congestive heart disease, or diabetes mellitus type II). Alternatively, the diagnosis of OSA is also confirmed if there are fifteen or more predominantly obstructive respiratory events per hour (referring to an AHI or RDI of 15 or greater), regardless of associated symptoms or conditions. OSA is generally classified as mild, moderate, or severe. Mild OSA refers to an AHI or RDI between 5 and 14 on a polysomnogram. Moderate OSA refers to an AHI or RDI between 15 and 30. Patients with an AHI or RDI greater than 30 on a polysomnogram are categorized as having severe OSA.[36] 

Treatment / Management

Education and Behavior

Once a patient is diagnosed with OSA, counseling regarding risk factors, natural history, and complications of untreated OSA should be discussed. All patients should also be alerted of the increased risk of motor vehicle collisions (MVC) in patients with OSA. The patients should also be instructed to consult with their primary physician regarding their OSA prior to undergoing anesthesia or starting sedating medications. 

Appropriate behavioral modifications should be identified and discussed with all patients as these are modifiable and low-risk. For obese patients, regular exercise and a healthy diet should be encouraged. Weight loss has been shown to improve AHI/RDI, decrease daytime sleepiness, improve metabolic parameters, and improve blood pressure control.[37][38] Counseling regarding proper sleep hygiene should also be provided, as many patients with OSA also suffer from the simultaneous effects of poor sleep hygiene. Counseling may also be provided regarding recommending a change in sleep position if applicable.[39][40][41][42][43] All patients with OSA should be advised that alcohol and sedating medications may worsen their OSA. 

Positive Airway Pressure Therapy

In positive pressure therapy, the positive transmural pharyngeal pressure so that the upper airway remains patent as the intraluminal pressure exceeds the surrounding pressure.[44] In most patients with OSA, this is delivered via continuous positive airway pressure (CPAP), though in some patients, bilevel positive airway pressure (BI-PAP) or auto-titrating positive airway pressure (APAP) may be appropriate.

Positive airway pressure is the initial treatment for nearly all patients with OSA and remains the mainstay of treatment. Numerous randomized control trials and meta-analyses have concluded that positive airway pressure reduces respiratory event frequency, daytime sleepiness, and frequency of MVCs improves blood pressure control, and improves the overall quality of life.[45][46][47][48][49][50][51][52] The American Academy of Sleep Medicine recommends offering positive pressure therapy to all patients diagnosed with OSA.[53] Adherence to positive pressure therapy is one of the most important factors to assess once therapy is initiated. Twenty to forty percent of patients do not use their devices, and others often do not wear their devices for a sufficient amount of time.[54][55]

Alternative and Adjunctive Therapies 

Oral Appliances are an option for patients with mild to moderate OSA who fail to tolerate positive pressure therapy. In the appropriate patients, these devices decrease respiratory-related arousals, sleepiness, snoring, and oxygen desaturation.[56][57][58][59] Potential adverse effects secondary to oral appliances include dental pain, occlusal changes, temporomandibular joint disease, dry mouth, bruxism, and gingival irritation.[58] Younger patients with lower body-mass indexes with mild to moderate OSA have the greatest benefit from oral appliances.[60]

Surgery Intervention is generally not considered first-line therapy for OSA and instead is considered when therapy from positive pressure therapy and/or oral appliance therapy is either ineffective or declines over time. In these patients, identification of the most likely contributing site or sites of obstruction is assessed in a comprehensive exam as above. In addition, some surgeons advocate performing Drug-Induced Sleep Endoscopy (DISE) to further evaluate the airway under anesthetic conditions - however, there is no current consensus on the role of DISE in assessing patients with OSA.

Depending on the sites of obstruction, numerous surgical alternatives exist, including tonsillectomy, uvulopalatopharyngoplasty (for which complications include oropharyngeal bleeding and velopharyngeal insufficiency as well as velopharyngeal stenosis), adenoidectomy, surgical correction for nasal obstruction including septoplasty and inferior turbinate reduction. Craniofacial surgery, including maxillomandibular advancement, may also be performed for maxillomandibular insufficiency with improvement in obstructive sleep apnea for moderate to severe disease but carry the risk of damage to nearby structures, including the inferior alveolar/mental nerve, provides sensation to the chin and lower lip, and marginal mandibular nerve provides motor innervation to the lateral oral aperture. This also requires inpatient hospital stay and recovery and is not a good option for older patients with multiple comorbidities.[61]

An alternative to standard anatomic correction surgery is hypoglossal nerve stimulation, which protrudes the tongue forward via an implantable neurostimulation device that senses respiration to deliver stimulation at the appropriate time. This is indicated in patients with moderate to severe obstructive sleep apnea who have failed positive pressure ventilation or do not obtain enough benefit from positive pressure ventilation with a BMI of less than 32. In selected patients, these devices have shown reductions in AHI and oxygen saturation indexes and decreased subjective sleepiness.[62][63][64][65] 

It should also be noted that tracheostomy is another surgical treatment for obstructive sleep apnea as this bypasses the upper airway; however, this is rarely chosen for treatment of OSA alone but remains an option for patients with severe refractory disease or those with a concomitant disease for which tracheostomy may be appropriate.[66]

Differential Diagnosis

The consideration of alternative diagnoses to OSA is imperative not only for the correct diagnosis of OSA but because patients with OSA may have concomitant alternative sleep-related diagnoses that also must be considered.[67] It is important to differentiate obstructive apnea from central apnea. It is also important to differentiate OSA from primary snoring or laryngospasm. Other causes of excessive daytime sleepiness must be carefully considered, including narcolepsy, periodic limb movement disorder, restless leg syndrome, circadian rhythm disorders, and sleep hygiene-related effects. If one of these diagnoses is suspected, an appropriate workup, such as a multiple sleep latency test, may be considered if there is a concern for narcolepsy.

Prognosis

The short-term prognosis for patients with OSA is generally good. Treatments for patients with mild obstructive sleep apnea have shown improvement in symptoms but do not show differences in long-term cardiovascular outcomes. However, untreated OSA can be life-threatening. Excessive daytime sleepiness results in patients with OSA having increased death rates from MVCs and other sleepiness-related incidents; patients with moderate to severe OSA have an increased risk of developing cardiopulmonary disease, cerebrovascular incidents, and neuropsychiatric dysfunction if untreated. However, treatments have not been shown to decrease mortality, cardiovascular events, and neurocognitive function in the long term.[68][69]

Complications

Patients with OSA are at risk of multiple adverse clinical outcomes. One of the most common adverse outcomes in patients with obstructive sleep apnea is an increased rate of motor vehicle collisions. Patients with OSA are involved in motor vehicle collisions at a rate of 2 to 3 times that of the general population. Thus it is important to counsel patients diagnosed with OSA regarding this risk. In patients who spend a significant amount of time in motor vehicles, such as those in commercial transportation, appropriate treatment for obstructive sleep apnea is particularly important to avoid adverse outcomes.[68] 

Obstructive sleep apnea may also result in neuropsychiatric dysfunction, including difficulties with attention, memory, cognitive deficit, and impaired executive function. Patients with obstructive sleep apnea are also more likely to experience mood disorders, psychosis, and sexual dysfunction than the general population.[70][71][72] 

Cardiopulmonary mortality is another important factor to consider for patients with OSA. Multiple large studies have demonstrated that patients with moderate to severe OSA are at increased risk for coronary artery disease, systemic hypertension, cardiac arrhythmias, congestive heart failure, pulmonary hypertension, right heart failure, and cerebrovascular accident.[73] Patients with OSA also have an increased incidence of metabolic derangements incidence of insulin resistance as well as an increased incidence of the complications of type II diabetes mellitus.[74] There is also a two to threefold increase in non-alcoholic fatty liver disease incidence in patients with OSA independent of obesity.[75][76][77][78] 

Deterrence and Patient Education

Because OSA is so prevalent and has numerous negative health-related outcomes, physicians must appropriately evaluate and screen patients for symptoms and signs of OSA. When diagnosed, patients should be educated regarding the pathophysiology, expected course, and treatment options, including lifestyle modifications, positive pressure therapy, and alternative/additional therapies as indicated. They should also be counseled regarding the need for long-term follow-up and monitoring for potential complications of OSA.

Pearls and Other Issues

OSA is a condition caused by obstruction of the upper airway during sleep that can lead to symptoms including daytime sleepiness, snoring, gasping for air while sleeping, and morning headaches that are associated with adverse outcomes, including increased rates of MVCs and sleepiness-related accidents as well as increased rates of cardiopulmonary complications, cerebrovascular events, and neurocognitive effects in the long term. 

In addition to a comprehensive history and physical exam, in-lab polysomnography is the gold standard for treating obstructive sleep apnea. 

For patients with OSA, positive pressure therapy is the mainstay of treatment. However, additional treatments are available for those who fail positive pressure therapy or have an inadequate response to positive pressure therapy alone.

Enhancing Healthcare Team Outcomes

Enhancing healthcare outcomes for OSA is multifaceted and involves all interprofessional healthcare team members. Knowledge regarding OSA in the general population is currently poor, and initiatives are underway to address this but must be furthered to improve.[79] Clinicians (MDs, DOs, NPOs, and PAs), nurses, sleep specialists, and other health professionals must consider the implications on healthcare outcomes that may come into effect when treating patients with OSA in any healthcare setting because the complications of OSA are many and may affect patient outcomes if not addressed appropriately.[52] [Level 1]

The clinician will direct the overall direction of case management, but nurses, pharmacists, and other ancillary staff can provide valuable patient counsel, make recommendations from their areas of expertise, and alter other team members if they not any changes in the patient's condition. All interprofessional team members must maintain accurate, updated records, so everyone involved in care has the most accurate and current data to make decisions. This interprofessional paradigm will help drive improved patient outcomes. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993 Apr 29;328(17):1230-5. [PubMed: 8464434]

2.

Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998 Jan;157(1):144-8. [PubMed: 9445292]

3.

Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Leiby BE, Vela-Bueno A, Kales A. Association of hypertension and sleep-disordered breathing. Arch Intern Med. 2000 Aug 14-28;160(15):2289-95. [PubMed: 10927725]

4.

Rana AM, Sankari A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 11, 2023. Central Sleep Apnea. [PubMed: 35201727]

5.

Maggard MD, Sankari A, Cascella M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 11, 2023. Upper Airway Resistance Syndrome. [PubMed: 33232072]

6.

Slowik JM, Sankari A, Collen JF. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar 21, 2024. Obstructive Sleep Apnea. [PubMed: 29083619]

7.

Sforza E, Bacon W, Weiss T, Thibault A, Petiau C, Krieger J. Upper airway collapsibility and cephalometric variables in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):347-52. [PubMed: 10673170]

8.

Dempsey JA, Skatrud JB, Jacques AJ, Ewanowski SJ, Woodson BT, Hanson PR, Goodman B. Anatomic determinants of sleep-disordered breathing across the spectrum of clinical and nonclinical male subjects. Chest. 2002 Sep;122(3):840-51. [PubMed: 12226022]

9.

Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol (1985). 1991 Jun;70(6):2574-81. [PubMed: 1885452]

10.

Worsnop C, Kay A, Pierce R, Kim Y, Trinder J. Activity of respiratory pump and upper airway muscles during sleep onset. J Appl Physiol (1985). 1998 Sep;85(3):908-20. [PubMed: 9729564]

11.

van Lunteren E, Strohl KP. The muscles of the upper airways. Clin Chest Med. 1986 Jun;7(2):171-88. [PubMed: 3522067]

12.

Wasicko MJ, Leiter JC, Erlichman JS, Strobel RJ, Bartlett D. Nasal and pharyngeal resistance after topical mucosal vasoconstriction in normal humans. Am Rev Respir Dis. 1991 Nov;144(5):1048-52. [PubMed: 1952430]

13.

Wasicko MJ, Hutt DA, Parisi RA, Neubauer JA, Mezrich R, Edelman NH. The role of vascular tone in the control of upper airway collapsibility. Am Rev Respir Dis. 1990 Jun;141(6):1569-77. [PubMed: 2350100]

14.

Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009 Aug;108(5):246-9. [PMC free article: PMC2858234] [PubMed: 19743755]

15.

Jennum P, Riha RL. Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing. Eur Respir J. 2009 Apr;33(4):907-14. [PubMed: 19336593]

16.

Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR. Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study. Sleep Med. 2010 May;11(5):441-6. [PubMed: 20362502]

17.

Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001 Mar;163(3 Pt 1):608-13. [PubMed: 11254512]

18.

Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA. 2004 Apr 28;291(16):2013-6. [PubMed: 15113821]

19.

Durán J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med. 2001 Mar;163(3 Pt 1):685-9. [PubMed: 11254524]

20.

Garrigue S, Pépin JL, Defaye P, Murgatroyd F, Poezevara Y, Clémenty J, Lévy P. High prevalence of sleep apnea syndrome in patients with long-term pacing: the European Multicenter Polysomnographic Study. Circulation. 2007 Apr 03;115(13):1703-9. [PubMed: 17353437]

21.

Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013 May 01;177(9):1006-14. [PMC free article: PMC3639722] [PubMed: 23589584]

22.

Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial differences in sleep-disordered breathing in African-Americans and Caucasians. Am J Respir Crit Care Med. 1997 Jan;155(1):186-92. [PubMed: 9001310]

23.

Ancoli-Israel S, Klauber MR, Stepnowsky C, Estline E, Chinn A, Fell R. Sleep-disordered breathing in African-American elderly. Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):1946-9. [PubMed: 8520760]

24.

Tangel DJ, Mezzanotte WS, Sandberg EJ, White DP. Influences of NREM sleep on the activity of tonic vs. inspiratory phasic muscles in normal men. J Appl Physiol (1985). 1992 Sep;73(3):1058-66. [PubMed: 1400018]

25.

Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Loube DL, Owens J, Pancer JP, Wise M. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep. 2005 Apr;28(4):499-521. [PubMed: 16171294]

26.

Myers KA, Mrkobrada M, Simel DL. Does this patient have obstructive sleep apnea?: The Rational Clinical Examination systematic review. JAMA. 2013 Aug 21;310(7):731-41. [PubMed: 23989984]

27.

Cho YW, Kim KT, Moon HJ, Korostyshevskiy VR, Motamedi GK, Yang KI. Comorbid Insomnia With Obstructive Sleep Apnea: Clinical Characteristics and Risk Factors. J Clin Sleep Med. 2018 Mar 15;14(3):409-417. [PMC free article: PMC5837842] [PubMed: 29458695]

28.

Raheem OA, Orosco RK, Davidson TM, Lakin C. Clinical predictors of nocturia in the sleep apnea population. Urol Ann. 2014 Jan;6(1):31-5. [PMC free article: PMC3963340] [PubMed: 24669119]

29.

Friedman M, Salapatas AM, Bonzelaar LB. Updated Friedman Staging System for Obstructive Sleep Apnea. Adv Otorhinolaryngol. 2017;80:41-48. [PubMed: 28738388]

30.

Torre C, Zaghi S, Camacho M, Capasso R, Liu SY. Hypopharyngeal evaluation in obstructive sleep apnea with awake flexible laryngoscopy: Validation and updates to Cormack-Lehane and Modified Cormack-Lehane scoring systems. Clin Otolaryngol. 2018 Jun;43(3):823-827. [PubMed: 29280292]

31.

Huo H, Li W, Tian X, Xu C, Wang J, Yang D. Endoscopic upper airway evaluation in obstructive sleep apnea: Mueller's maneuver versus simulation of snoring. Sleep Breath. 2015 May;19(2):661-7. [PubMed: 25369788]

32.

Chong KB, De Vito A, Vicini C. Drug-Induced Sleep Endoscopy in Treatment Options Selection. Sleep Med Clin. 2019 Mar;14(1):33-40. [PubMed: 30709531]

33.

Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017 Mar 15;13(3):479-504. [PMC free article: PMC5337595] [PubMed: 28162150]

34.

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. [PubMed: 1798888]

35.

Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P., Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from theAmerican College of Physicians. Ann Intern Med. 2014 Aug 05;161(3):210-20. [PubMed: 25089864]

36.

Won CHJ, Qin L, Selim B, Yaggi HK. Varying Hypopnea Definitions Affect Obstructive Sleep Apnea Severity Classification and Association With Cardiovascular Disease. J Clin Sleep Med. 2018 Dec 15;14(12):1987-1994. [PMC free article: PMC6287733] [PubMed: 30518445]

37.

Smith PL, Gold AR, Meyers DA, Haponik EF, Bleecker ER. Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann Intern Med. 1985 Dec;103(6 ( Pt 1)):850-5. [PubMed: 3933396]

38.

Tuomilehto HP, Seppä JM, Partinen MM, Peltonen M, Gylling H, Tuomilehto JO, Vanninen EJ, Kokkarinen J, Sahlman JK, Martikainen T, Soini EJ, Randell J, Tukiainen H, Uusitupa M., Kuopio Sleep Apnea Group. Lifestyle intervention with weight reduction: first-line treatment in mild obstructive sleep apnea. Am J Respir Crit Care Med. 2009 Feb 15;179(4):320-7. [PubMed: 19011153]

39.

Jokic R, Klimaszewski A, Crossley M, Sridhar G, Fitzpatrick MF. Positional treatment vs continuous positive airway pressure in patients with positional obstructive sleep apnea syndrome. Chest. 1999 Mar;115(3):771-81. [PubMed: 10084491]

40.

Cartwright R, Ristanovic R, Diaz F, Caldarelli D, Alder G. A comparative study of treatments for positional sleep apnea. Sleep. 1991 Dec;14(6):546-52. [PubMed: 1798889]

41.

de Vries GE, Hoekema A, Doff MH, Kerstjens HA, Meijer PM, van der Hoeven JH, Wijkstra PJ. Usage of positional therapy in adults with obstructive sleep apnea. J Clin Sleep Med. 2015 Jan 15;11(2):131-7. [PMC free article: PMC4298770] [PubMed: 25406271]

42.

Benoist L, de Ruiter M, de Lange J, de Vries N. A randomized, controlled trial of positional therapy versus oral appliance therapy for position-dependent sleep apnea. Sleep Med. 2017 Jun;34:109-117. [PubMed: 28522078]

43.

Beyers J, Dieltjens M, Kastoer C, Opdebeeck L, Boudewyns AN, De Volder I, Van Gastel A, Verbraecken JA, De Backer WA, Braem MJ, Van de Heyning PH, Vanderveken OM. Evaluation of a Trial Period With a Sleep Position Trainer in Patients With Positional Sleep Apnea. J Clin Sleep Med. 2018 Apr 15;14(4):575-583. [PMC free article: PMC5886435] [PubMed: 29609712]

44.

Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014 Feb 22;383(9918):736-47. [PMC free article: PMC3909558] [PubMed: 23910433]

45.

Jonas DE, Amick HR, Feltner C, Weber RP, Arvanitis M, Stine A, Lux L, Harris RP. Screening for Obstructive Sleep Apnea in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2017 Jan 24;317(4):415-433. [PubMed: 28118460]

46.

Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981 Apr 18;1(8225):862-5. [PubMed: 6112294]

47.

Giles TL, Lasserson TJ, Smith BJ, White J, Wright J, Cates CJ. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001106. [PubMed: 16437429]

48.

Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med. 2003 Mar 10;163(5):565-71. [PubMed: 12622603]

49.

McDaid C, Durée KH, Griffin SC, Weatherly HL, Stradling JR, Davies RJ, Sculpher MJ, Westwood ME. A systematic review of continuous positive airway pressure for obstructive sleep apnoea-hypopnoea syndrome. Sleep Med Rev. 2009 Dec;13(6):427-36. [PubMed: 19362029]

50.

Martínez-García MÁ, Chiner E, Hernández L, Cortes JP, Catalán P, Ponce S, Diaz JR, Pastor E, Vigil L, Carmona C, Montserrat JM, Aizpuru F, Lloberes P, Mayos M, Selma MJ, Cifuentes JF, Muñoz A., Spanish Sleep Network. Obstructive sleep apnoea in the elderly: role of continuous positive airway pressure treatment. Eur Respir J. 2015 Jul;46(1):142-51. [PubMed: 26022945]

51.

Salord N, Fortuna AM, Monasterio C, Gasa M, Pérez A, Bonsignore MR, Vilarrasa N, Montserrat JM, Mayos M. A Randomized Controlled Trial of Continuous Positive Airway Pressure on Glucose Tolerance in Obese Patients with Obstructive Sleep Apnea. Sleep. 2016 Jan 01;39(1):35-41. [PMC free article: PMC4678362] [PubMed: 26350474]

52.

McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS., SAVE Investigators and Coordinators. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016 Sep 08;375(10):919-31. [PubMed: 27571048]

53.

Epstein LJ, Kristo D, Strollo PJ, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD., Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009 Jun 15;5(3):263-76. [PMC free article: PMC2699173] [PubMed: 19960649]

54.

Waldhorn RE, Herrick TW, Nguyen MC, O'Donnell AE, Sodero J, Potolicchio SJ. Long-term compliance with nasal continuous positive airway pressure therapy of obstructive sleep apnea. Chest. 1990 Jan;97(1):33-8. [PubMed: 2403899]

55.

Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, Redline S, Henry JN, Getsy JE, Dinges DF. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis. 1993 Apr;147(4):887-95. [PubMed: 8466125]

56.

Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli PA. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med. 2001 May;163(6):1457-61. [PubMed: 11371418]

57.

Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral appliance therapy improves symptoms in obstructive sleep apnea: a randomized, controlled trial. Am J Respir Crit Care Med. 2002 Sep 01;166(5):743-8. [PubMed: 12204875]

58.

Cistulli PA, Gotsopoulos H, Marklund M, Lowe AA. Treatment of snoring and obstructive sleep apnea with mandibular repositioning appliances. Sleep Med Rev. 2004 Dec;8(6):443-57. [PubMed: 15556377]

59.

Marklund M, Carlberg B, Forsgren L, Olsson T, Stenlund H, Franklin KA. Oral Appliance Therapy in Patients With Daytime Sleepiness and Snoring or Mild to Moderate Sleep Apnea: A Randomized Clinical Trial. JAMA Intern Med. 2015 Aug;175(8):1278-85. [PubMed: 26030264]

60.

Chen H, Eckert DJ, van der Stelt PF, Guo J, Ge S, Emami E, Almeida FR, Huynh NT. Phenotypes of responders to mandibular advancement device therapy in obstructive sleep apnea patients: A systematic review and meta-analysis. Sleep Med Rev. 2020 Feb;49:101229. [PubMed: 31785583]

61.

Zaghi S, Holty JE, Certal V, Abdullatif J, Guilleminault C, Powell NB, Riley RW, Camacho M. Maxillomandibular Advancement for Treatment of Obstructive Sleep Apnea: A Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2016 Jan;142(1):58-66. [PubMed: 26606321]

62.

Eastwood PR, Barnes M, Walsh JH, Maddison KJ, Hee G, Schwartz AR, Smith PL, Malhotra A, McEvoy RD, Wheatley JR, O'Donoghue FJ, Rochford PD, Churchward T, Campbell MC, Palme CE, Robinson S, Goding GS, Eckert DJ, Jordan AS, Catcheside PG, Tyler L, Antic NA, Worsnop CJ, Kezirian EJ, Hillman DR. Treating obstructive sleep apnea with hypoglossal nerve stimulation. Sleep. 2011 Nov 01;34(11):1479-86. [PMC free article: PMC3198202] [PubMed: 22043118]

63.

Goding GS, Tesfayesus W, Kezirian EJ. Hypoglossal nerve stimulation and airway changes under fluoroscopy. Otolaryngol Head Neck Surg. 2012 Jun;146(6):1017-22. [PubMed: 22307575]

64.

Schwartz AR, Barnes M, Hillman D, Malhotra A, Kezirian E, Smith PL, Hoegh T, Parrish D, Eastwood PR. Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea. Am J Respir Crit Care Med. 2012 Feb 15;185(4):420-6. [PMC free article: PMC3297092] [PubMed: 22135343]

65.

Woodson BT, Strohl KP, Soose RJ, Gillespie MB, Maurer JT, de Vries N, Padhya TA, Badr MS, Lin HS, Vanderveken OM, Mickelson S, Strollo PJ. Upper Airway Stimulation for Obstructive Sleep Apnea: 5-Year Outcomes. Otolaryngol Head Neck Surg. 2018 Jul;159(1):194-202. [PubMed: 29582703]

66.

Camacho M, Certal V, Brietzke SE, Holty JE, Guilleminault C, Capasso R. Tracheostomy as treatment for adult obstructive sleep apnea: a systematic review and meta-analysis. Laryngoscope. 2014 Mar;124(3):803-11. [PubMed: 24549987]

67.

Sansa G, Iranzo A, Santamaria J. Obstructive sleep apnea in narcolepsy. Sleep Med. 2010 Jan;11(1):93-5. [PubMed: 19699146]

68.

George CF. Sleep apnea, alertness, and motor vehicle crashes. Am J Respir Crit Care Med. 2007 Nov 15;176(10):954-6. [PubMed: 17823357]

69.

Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. J Clin Sleep Med. 2019 Feb 15;15(2):301-334. [PMC free article: PMC6374080] [PubMed: 30736888]

70.

Wheaton AG, Perry GS, Chapman DP, Croft JB. Sleep disordered breathing and depression among U.S. adults: National Health and Nutrition Examination Survey, 2005-2008. Sleep. 2012 Apr 01;35(4):461-7. [PMC free article: PMC3296787] [PubMed: 22467983]

71.

Chen YH, Keller JK, Kang JH, Hsieh HJ, Lin HC. Obstructive sleep apnea and the subsequent risk of depressive disorder: a population-based follow-up study. J Clin Sleep Med. 2013 May 15;9(5):417-23. [PMC free article: PMC3629313] [PubMed: 23674930]

72.

Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 2006 Sep 18;166(16):1709-15. [PubMed: 16983048]

73.

Gonzaga C, Bertolami A, Bertolami M, Amodeo C, Calhoun D. Obstructive sleep apnea, hypertension and cardiovascular diseases. J Hum Hypertens. 2015 Dec;29(12):705-12. [PubMed: 25761667]

74.

Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med. 2009 Dec;122(12):1122-7. [PMC free article: PMC2799991] [PubMed: 19958890]

75.

Türkay C, Ozol D, Kasapoğlu B, Kirbas I, Yıldırım Z, Yiğitoğlu R. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir Care. 2012 Feb;57(2):244-9. [PubMed: 21762556]

76.

Minville C, Hilleret MN, Tamisier R, Aron-Wisnewsky J, Clement K, Trocme C, Borel JC, Lévy P, Zarski JP, Pépin JL. Nonalcoholic fatty liver disease, nocturnal hypoxia, and endothelial function in patients with sleep apnea. Chest. 2014 Mar 01;145(3):525-533. [PubMed: 24264333]

77.

Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Semin Liver Dis. 2012 Feb;32(1):49-64. [PubMed: 22418888]

78.

Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes Rev. 2013 May;14(5):417-31. [PubMed: 23387384]

79.

Sia CH, Hong Y, Tan LWL, van Dam RM, Lee CH, Tan A. Awareness and knowledge of obstructive sleep apnea among the general population. Sleep Med. 2017 Aug;36:10-17. [PubMed: 28735905]

Disclosure: Evan Cumpston declares no relevant financial relationships with ineligible companies.

Disclosure: Philip Chen declares no relevant financial relationships with ineligible companies.