Diagnosis and Management of Obstructive Sleep Apnea

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Diagnosis and Management of Obstructive Sleep Apnea A Review (2020)
Daniel J. Gottlieb, MD, MPH; Naresh M. Punjabi, MD, PhD

IMPORTANCE Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA.

OBSERVATIONS The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index of less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefits on rates of cardiovascular or cerebrovascular events.


CONCLUSIONS AND RELEVANCE OSA is common and its prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of a partial or complete collapse of the upper airway during sleep, resulting in reduced (hypopnea) or absent (apnea) airflow lasting for at least 10 seconds and associated with either cortical arousal or a fall in blood oxygen saturation. OSA is present in approximately 25% of adults in the US and is a major cause of excessive sleepiness, contributing to reduced quality of life, impaired work performance, and increased motor vehicle crash risk.1,2 OSA is associated with an increased incidence of hypertension, type 2 diabetes mellitus, atrial fibrillation, heart failure, coronary heart disease, stroke, and death.3-6OSA can be diagnosed with either home- or laboratory-based sleep testing, and effective treatments are available. This review provides an update on the epidemiology, pathophysiology, diagnosis, and management of OSA.


OSA is characterized by the repetitive partial or complete collapse of the upper airway during sleep, resulting in episodic reduction (hypopnea) or cessation (apnea) of airflow despite the respiratory effort. Contraction of upper airway dilator muscles is necessary to maintain airway patency during inspiration. The most important upper airway dilator muscle is the genioglossus muscle, which contracts with each inspiration to prevent the posterior collapse of the tongue, assisted by the levator and tensor palatini muscles (advancing and elevating the soft palate) and the geniohyoid and stylopharyngeus muscles (opposing medial collapse of the lateral pharyngeal walls).3 Most people with OSA have a narrow upper airway, typically caused by fat deposition in the parapharyngeal fat pads and pharyngeal muscles15,16 or abnormalities in craniofacial structure (Figure 1). These abnormalities include both clinically evident anatomic abnormalities, such as micrognathia and retrognathia, or subtle radiographic findings, such as inferior positioning of the hyoid bone and shorter mandibular and maxillary length, which result in a small maxillomandibular volume.2,17 The relative contribution of soft tissue and bony abnormalities to OSA differs among individuals and between populations; for example, for the same severity of OSA, Caucasian individuals tend to be more overweight, while Chinese individuals have more craniofacial bony restrictions.18 In the presence of a small pharyngeal airway, upper airway collapse is prevented when an individual is awakened by the activity of pharyngeal dilator muscles. A decrease in both basal and compensatory dilator muscle tone during sleep permits airway collapse.3,19

Obstructive apneas and hypopneas result in large changes in intrathoracic pressure, intermittent hypoxemia, and arousal from sleep (Figure 2). Although these arousals generally do not wake the patient, this sleep fragmentation is the primary cause of excessive sleepiness in individuals with OSA. Intermittent hypoxemia, particularly with concomitant hypercapnia, activates the sympathetic nervous system and is the major contributor to both acute and chronic elevation of blood pressure (Figure 3).3,4 Increased catecholamine levels decrease insulin sensitivity and, in animal models, promote pancreatic beta-cell apoptosis, suggesting a possible mechanism underlying the association of OSA with type 2 diabetes mellitus,20 which persists after adjustment for demographic factors and BMI.21 Repetitive episodes of hypoxemia increase reactive oxygen species, which may further contribute to vascular disease, metabolic abnormalities, and inflammation.3

Clinical Presentation

The most common symptom of OSA is unrefreshing sleep, with excessive sleepiness reported by up to 90% of patients with OSA referred to sleep clinics22,23 (Table 1). Patients may also report fatigue, tiredness, or lack of energy.24 In some studies, these symptoms are more common than sleepiness.24 Excessive sleepiness is reported by 15% to 50% of people with OSA identified through general population screening.7,12,13,25 While some patients experience awakenings accompanied by gasping or choking, awakenings without accompanying symptoms are more typical. A systematic review concluded that on history and physical examination, nocturnal gasping or choking is the most reliable indicator of OSA, while snoring is not specific.26 A population study reported nocturia at least 2 times per night in 37.4% of individuals with an AHI of at least 20 per hour compared with 25.6% of those with an AHI of less than 20 per hour (adjusted odds ratio, 1.64 [95% CI, 1.03-2.55]).27 Chronic morning headache (occurring at least half of the day) is twice as common in individuals with OSA as in the general population.28 These headaches, characterized by a bilateral pressure sensation, resolve within hours of awakening and are of unknown etiology. Nocturnal gastroesophageal reflux is approximately twice as common in patients with OSA in the general population.29 Difficulty falling asleep is unlikely to be caused by OSA.30 Typical signs of OSA include habitual snoring, present in 50% to 60% of those with OSA, and witnessed apneas during sleep, present in 10% to 15% of those with OSA. The latter is twice as common as in those without OSA.11,14,31 Recent studies estimate the prevalence of OSA at 73% to 82% in individuals with resistant hypertension,32,33 76% to 85% in individuals with atrial fibrillation,34,35 65% to 85% in individuals with type 2 diabetes,36 71% in individuals with stroke,37 and 71% to 77% in patients undergoing bariatric surgery.38,39

*Assessment and Diagnosis


*Asymptomatic OSA



This review has some limitations. First, it was restricted to English-language publications and was developed primarily from published systematic reviews, meta-analyses, and clinical practice guidelines. Second, the literature search may have missed some relevant publications. Third, not all aspects of OSA were discussed. Fourth, high-quality data are lacking for some covered topics.


OSA is common and the prevalence is increasing. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as PAP are recommended for those with excessive sleepiness and resistant hypertension. Treating individuals with asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.
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Figure 1. Anatomic Features Contributing to Obstructive Sleep Apnea (OSA)
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Screenshot (17981).png

Narrowing of the upper airway is common in patients with OSA. This can result from a long soft palate, enlargement of the tongue and pharyngeal wall, and a more inferior and posterior position of the hyoid bone, commonly due to fat deposition, or from skeletal features including mandibular retrognathia and a shorter mandibular or maxillary length.


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Figure 3. Putative Causal Mechanisms of Obstructive Sleep Apnea–Related Cardiovascular and Metabolic Disease
Screenshot (17983).png
Obstructive sleep apnea results in 3 proximate pathophysiological events: intermittent hypoxemia, sleep fragmentation, and large swings in intrathoracic pressure. These events initiate a cascade of interacting processes that contribute to adverse health outcomes. Intermittent hypoxemia, particularly in the presence of hypercapnia, causes elevation of sympathetic nervous system activity that persists during wakefulness. Arousal from sleep, due to the increased respiratory effort against an obstructed airway and to hypoxemia and hypercapnia, also contributes to sympathetic activity and activation of the hypothalamic-pituitary-adrenal axis. Intermittent hypoxemia and reoxygenation result in the production of reactive oxygen species. Both sympathetic activity and oxidative stress contribute to blood pressure elevation, metabolic dysregulation, systemic inflammation, and endothelial dysfunction. These abnormalities are likely precursors of clinical hypertension, type 2 diabetes, and coronary and cerebrovascular disease. Large intrathoracic pressure swings, which result from respiratory efforts against an obstructed upper airway, increase cardiac preload and afterload that, together with the effects of sympathetic activity, oxidative stress, inflammation, and gas exchange abnormalities, may contribute to heart failure and cardiac rhythm disturbances.


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Table 1. Risk Factors and Clinical Features of Obstructive Sleep Apnea
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Screenshot (17986).png

a Odds ratios reflect the range of values reported from population-based cohort studies, excluding extreme values. Prevalence estimates are from population- or clinic-based patient samples referenced in the text.


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Table 2. Methods to Identify Obstructive Sleep Apnea (OSA)
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Screenshot (17988).png

a Sensitivity and specificity for the diagnosis of moderate to severe OSA (apneahypoxia index [AHI] 15) using the laboratory-based polysomnography as the criterion standard. Data for questionnaires43 and HSAT44 are presented as mean (95% CI), where a positive result is a score of 2 or 3 on the Berlin Questionnaire, a score of at least 3 on the STOP-Bang questionnaire, a score of at least 11 on the Epworth Sleepiness Scale, and an AHI of at least 15 on the HSAT. Data for oximetry are presented as the range of reported values.45


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Box. Commonly Asked Questions About Obstructive Sleep Apnea (OSA)

What is the most sensitive and specific question for identifying OSA?

“Do you snore” is the most sensitive and “Do you stop breathing during sleep” is the most specific question to identify a patient at risk for OSA.

Does every patient with overweight or obesity need to be referred for a sleep study?
Although overweight and obesity are strong risk factors for OSA, not every patient overweight or obese needs to undergo a sleep study. However, they should be questioned for OSA-related signs and symptoms. Most asymptomatic patients do not need to be referred for a sleep study.

Do patients need to spend a night in the sleep laboratory for diagnosis and management of OSA?
For most patients in whom OSA is suspected, the diagnosis can be made with a home sleep apnea test, in which a sleep apnea monitor is worn overnight in the patient’s home. If OSA is confirmed by the home test, positive airway pressure (PAP) therapy can usually be initiated at home using an automatic titrating PAP device. If there is a high suspicion of OSA and the home test findings are negative for OSA, laboratory-based polysomnography should be recommended.

What are the benefits of managing OSA?
Daytime sleepiness, fatigue, quality of life, and blood pressure have all been documented to improve the management of OSA. Current evidence suggests that treatment does not reduce the risk of cardiovascular disease, stroke, or metabolic abnormalities in asymptomatic patients.

What should a patient with OSA do if they need to have surgery?

Patients with known OSA should inform all clinicians involved in their perioperative care, including their surgeon and anesthesiologist, of their OSA diagnosis. Patients using PAP should continue this therapy in the perioperative period. Patients with known or suspected OSA should be monitored closely during the perioperative period, and the use of opiate analgesics should be minimized or avoided if possible.

Are there nonsurgical alternatives for patients who are unable to tolerate PAP therapy?
Mandibular advancement devices, weight loss, exercise, avoiding sleep in the supine position, and abstaining from alcohol can be beneficial for patients who are unable to tolerate PAP therapy. There are no medications currently approved for the management of OSA.


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Missed this little gem!

post #5 (PDF)


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*TRT aggravates OSA through several physiologic mechanisms including neuromuscular changes to the airways, changes in metabolic requirements, and changes in the physiologic response to hypoxia and hypercapnia


As TTh is increasingly used, it is important to understand its potential adverse effects. The idea that TTh may exacerbate OSA dates back more than 40 years. For several decades, the association was explored using only case studies or small uncontrolled case series, which suggested that TTh worsened OSA. As larger cohort studies and RCTs became available, this relationship has been questioned. The best current evidence suggests that short-term, high-dose testosterone administration mildly worsens OSA. Longer-term TTh in subjects undergoing concomitant weight loss was shown to mildly worsen OSA but only initially. By 18 weeks, patients demonstrated a return to baseline levels of OSA risk.
These results suggest that TTh's role in exacerbating OSA is small and may be time-limited. However, it is also possible that weight loss acted as a confounding factor. Additional studies are needed to determine if men who are more obese at baseline have a higher risk of developing OSA with TTh than nonobese men. Why testosterone would have a time-dependent effect, however, remains unanswered. Regarding the mechanisms by which TTh may worsen OSA, anatomic TTh-induced airway changes and altered sleep stage architecture have been largely refuted. The mechanism of action is more likely related to altered hypoxic and hypercapnic ventilatory response with testosterone administration, though work is still needed to resolve inconsistencies in currently available studies. Until these questions are more fully understood, clinicians may choose to exercise caution in prescribing TTh to individuals with severe, untreated OSA.


In summary, this review summarizes the evidence on the mechanisms involved in the pathogenesis of hypogonadism in patients with OSAS, such as the abnormal circadian rhythm of gonadotrophin secretory patterns associated with obesity. TRT may represent a risk factor for OSA development and therefore, respiratory function monitoring is recommended especially in obese patients during TRT. Scanty evidence has been released on the effect of TRT in patients with OSA. Data from recent randomized placebo-controlled studies address TRT as a time-dependent influence on nocturnal hypoxia, showing a positive impact after a long time of exposure. Also, CPAP and PDE5i can be considered safe procedures to ameliorate sexuality in hypogonadal patients with OSA. We suggest using TRT cautiously in obese hypogonadal patients with hypoventilatory syndrome especially if they are not on CPAP. The latter aspect needs to be further confirmed by larger controlled studies.


Previously, a number of researchers paid attention to studying the relationship between OSA and ED while a small number of participants from each study were not able to draw a conclusive conclusion. Utilizing the IIEF-5 scoring system in this meta-analysis found that CPAP therapy is effective in relieving the ED symptoms for male OSA patients with ED in a 3-month length setting. Long-term CPAP therapy may be needed for further evaluation.


The results of the current study indicate that CPAP therapy provides benefits to patients with severe OSAS in terms of improvement of LUTS, nocturia, and ED. Therefore, patients presenting to the urology clinic with complaints of LUTS and ED should be questioned about OSAS. Moreover, those presenting to a neurology clinic with complaints of OSAS should be asked about LUTS and ED. Better-designed studies with a larger sample size are needed to verify and support our findings.

Obstructive Sleep Apnea

Liu et al26 analyzed the effect of TTh on sleep and breathing in a small double-blind, placebo-controlled, RCT, in which 17 men older than 60 years received either 3 intramuscular (IM) T injections (500 mg, 250 mg, and 250 mg) or placebo followed by the T regimen after 8 weeks of washout. The authors reported that T treatment reduced total time slept by ~1 h/night, increased the duration of hypoxemia by ~5 min/night, and disrupted breathing during sleep (total and nonrapid eye movement respiratory disturbance indices both increased by ~7 events per hour) (all P < .05). The authors concluded that short-term administration of high-dose T shortens sleep and worsens OSA in older men, but does not alter physical, mental, or metabolic function. These changes did not appear to be due to upper airway narrowing

Killick et al27 also analyzed the association between T and breathing quality during sleep in a randomized, double-blind, placebo-controlled, parallel-group trial in which 21 obese men received either 3 IM 1000-mg T undecanoate injections or a placebo. Awake chemoreflex testing was performed at baseline, during week 6, and after the completion of week 18. The authors reported that TTh worsened sleep-disordered breathing at 6- 7 weeks, but not at 18 weeks, citing changes in ventilatory chemoreflex as a potential cause. The data from these studies26,27 provide supporting evidence that there is a positive association between TTh and the development of OSA.

Cignarelli et al28 conducted a meta-analysis of 12 studies which included 388 men who were either eugonadal or hypogonadal and had OSA to assess the effect of continuous positive airway pressure (CPAP) utilization on T levels in this cohort. The authors reported that CPAP use was not associated with a change in serum total T levels (mean difference ¼ 1.08 nmol/L; 95% CI, -0.48 to 2.64; P ¼ .18). Despite the observation that serum T levels appeared to increase more in hypogonadal than in eugonadal men, these increases also failed to reach statistical significance. Thus, while TTh may be associated with an increased risk of OSA, treatment of OSA via CPAP does not appear to be associated with subsequent increases in serum T levels

In conclusion, we found that all domains of sexual function as assessed by IIEF-5 have been affected in patients with OSA more than normal controls and IIEF-5 score is inversely related to the severity of OSA; as measured by AHI, which in turn has a complex interaction with other factors like hormones, obesity, age, and psychological status. So in OSA patients, sexual dysfunction should be considered and assessed by IIEF-5 along with these factors.

*Some authors recommend that TTh be discontinued if hematocrit is >54%, which may be reasonable while baseline hematocrit level >50% is a relative contraindication for starting testosterone therapy. However, these recommendations are based on assumptions – the clinical significance of a hematocrit >54% is unknown

*The lack of increase in cardiovascular events with elevated hematocrit may be due to the fact that T acts as a vasodilator and has anti-atherosclerotic effects [223]. In addition, testosterone is able to decrease plasma concentrations of procoagulatory substances such as fibrinogen and PAI-1 as well as Factor XII [224] Isolated hematocrit elevations can be the result of insufficient fluid intake on a hot day. Only repeated measures of hematocrit >54% should be followed by concomitant administration of aspirin, bleeding, therapeutic phlebotomy, and/or discontinuation of TTh until hematocrit declines below 54%. After normalization of hematocrit levels, TTh can be continued with a reduced dosage

*Periodic hematological assessment is, however, indicated, i.e. before TTh, then 3–4 months and 12 months in the first year of treatment, and annually thereafter. Although it is not yet clear what upper limit of hematocrit level is clinically desirable, dose adjustments may be necessary to keep hematocrit below 52–54%

*Men with significant erythrocytosis (hematocrit >52%), severe untreated obstructive sleep apnea, or untreated severe congestive heart failure should not be started on treatment with TTh without prior resolution of the co-morbid condition.


Men on TTH who are eugonadal and experience polycythemia have high rates of OSA. 80% of the patients undergoing the sleep study had OSA. These data suggest that men with polycythemia on TTH should be screened for OSA.

4. Discussion

This is the first randomized trial to conduct a head-to-head comparison of NT gel and intramuscular TC. Among the short-acting testosterone modalities, NT is dosed the most frequently and has the shortest half-life. This theoretically has the ability to more closely mimic the physiological release of testosterone and thus lead to fewer adverse events [2]. It has been shown that NT preserves spermatogenesis and gonadotropins [2], and the evidence now suggests that it also appears to avoid secondary erythrocytosis. This is particularly important for comorbid men on testosterone, as polycythemia while on testosterone can increase the rates of major adverse cardiovascular events [8]. Having options to treat TD is essential for both providers and patients [9– 11].

7 Obstructive sleep apnea

7.1 OSA, obesity, and testosterone in aging men

Testosterone therapy is widely believed to induce or worsen sleep apnea, and recent European and North American societal guidelines recommend vigilance in the detection of new OSA, and/or avoiding testosterone therapy in those with severe OSA [123, 124]. Surprisingly, other national guidelines from the United Kingdom make no mention of OSA at all [125]. The issue of testosterone effects on OSA should not be ignored because two randomized controlled trials show that testosterone therapy can acutely (within 2–3 weeks) induce sleep-disordered breathing [126, 127]. Whether these adverse findings would have occurred with longer-term near-physiological testosterone replacement is uncertain because one of the studies utilized testosterone doses that resulted in sustained supraphysiological testosterone levels [127], and the other likely induced intermittent supraphysiological peaks and assessed for OSA during these peaks [126].

Two other randomized, placebo-controlled, parallel-group studies have partly addressed this uncertainty [128, 129]. The first study administered a testosterone patch or a matching dose-titrated placebo patch for 3 years to 108 healthy men over the age of 65 years [128]. The initial dose was 6 mg/day, which was titrated every 3 months to maintain blood testosterone levels below 34.7 nmol/liter. No significant difference in sleep-disordered breathing was detected between groups after 6, 12, 24, or 36 months of therapy. However, the method of detection was relatively insensitive and may have missed the development of mild or even moderate OSA. The second study remains the only study to purposefully administer testosterone to men with known moderate-severe OSA [129]. Sixty-seven middle-aged obese men with OSA were treated with 3 doses of testosterone undecanoate 1000 mg every 6 weeks, or a matching placebo, and received recommendations for a hypocaloric diet that caused weight loss that was comparable between the two groups. Testosterone treatment significantly increased sleep-disordered breathing by a moderate amount (10 events/hour) at week 7 (one week after the second injection of testosterone undecanoate), but not at week 18. Both studies allow for the possibility that the worsening of OSA could dissipate with longer-term therapy. Another possibility is that OSA has only been induced acutely, potentially due to transient effects on ventilatory drive [130–132].

Despite these adverse effects on breathing during sleep, 18 weeks of testosterone therapy in men with OSA increased muscle mass, reduced liver fat, improved insulin sensitivity, and heightened sexual desire compared with placebo therapy [87, 133]. Studies advancing our knowledge regarding the relative risks and benefits of testosterone therapy in older men have recently become available [134], but further research is needed. More studies examining the risks and benefits of testosterone therapy in men with OSA over the longer term are required. Until such data are available, expert opinion will appropriately continue to caution against the use of testosterone therapy in men with untreated severe OSA [123].
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