This article originally published on eMedicine. Click here for a link to the original article.

Obstructive Sleep Apnea

Author: Ralph Downey III, PhD, DABSM, FAASM, CEO and President, Sleep Consultants
Coauthor(s): Philip M Gold, MD, Professor of Medicine, Chief of Pulmonary and Critical Care Medicine, Medical Director of Respiratory Care, Loma Linda University Medical Center; Himanshu Wickramasinghe, MD, MBBS, Attending Physician; Pulmonary, Critical Care, and Sleep Medicine; Henry Mayo Newhall Memorial Hospital, Valencia, California
 
Obstructive sleep apnea (OSA) is a sleep disorder that involves cessation or significant decrease in airflow in the presence of breathing effort. Obstructive sleep apnea is a sleep disorder characterized by recurrent episodes of upper airway (UA) collapse during sleep.1 By definition, apnea episodes last 10 seconds or longer and commonly last 30 seconds or longer. Apnea may occur hundreds of times nightly, 1-2 times per minute, in severe obstructive sleep apnea patients, and it is often accompanied by wide swings in heart rate, a precipitous decrease in oxygen saturation, and brief electroencephalogram (EEG) arousals concomitant with stertorous breathing sounds as a bolus of air is exhaled when the airway reopens. This may occur hundreds of times nightly. Obstructive apnea events are most often associated with recurrent sleep arousals and recurrent oxygen desaturation.
 
Three cardinal symptoms of sleep apnea include snoring, sleepiness, and significant-other report of sleep apnea episodes. This 3 S alliteration is a helpful mnemonic to busy clinicians in assessing patients for obstructive sleep apnea. It has proven to be valuable in teaching residents to be sensitive in the identification and appropriate referral of these patients for further study Also helpful is if the patient’s spouse or someone close to him or her can attend the visit because often the sleeper is unaware he or she has obstructive sleep apnea, and, in fact, he or she may regard themselves as "a good sleeper" because they "can sleep anytime, anywhere" (eg, waiting in the physician’s, in traffic, in class, at his or her office). Sleepiness is one of the potentially most morbid symptoms of sleep apnea, owing to the accidents that can occur as a result of it.
 
Obstructive sleep apnea is a very important diagnosis for physicians to consider because of its strong association with and potential cause of the most debilitating medical conditions, including hypertension, cardiovascular disease, coronary artery disease, insulin-resistance diabetes, depression, and, as mentioned, sleepiness-related accidents, which are discussed in greater detail in Mortality/Morbidity and Medical/Legal Pitfalls.
 
Obstructive sleep apnea is an increasingly prevalent condition, in both adults and children, in modern society. Approximately 24% of men and 9% of women have obstructive sleep apnea, with and without excessive daytime sleepiness (EDS).2 The prevalence in children is less certain, but an increasingly large segment of the adolescent population is seen in the author’s sleep center who are often obese and present similar to many of their adult counterparts, with one important exception: they may be sleepy and/or hyperactive. A 2007 study has suggested that approximately 6% of adolescents have weekly sleep-related disordered breathing.3 Also see the eMedicine Pediatrics article, Obstructive Sleep Apnea Syndrome.
 
Obstructive sleep apnea should be diagnosed and treated promptly. Obstructive sleep apnea can be reversed quickly with the appropriate titration of continuous positive airway pressure (CPAP) devices. CPAP is the standard treatment option for obstructive sleep apnea.
 
A sleep-related breathing disorder (SRBD) continuum has been described and is supported by research.4 The idea of the SRBD continuum was first described by Elio Lugaresi: "There is a continuum of intermediate clinical conditions between trivial snoring and the most severe forms of OSAS (which we prefer to call heavy snorers disease). This fact should be taken into consideration for any meaningful approach to the clinical problems posed by snoring. Many issues, however, remain unsettled."5 
 
The SRBD continuum suggests that snoring is the initial presenting symptom, and it increases in severity over time and it increases in association with medical disorders that may serve to exacerbate the disorder, such as obesity. Snoring has a constellation of pathophysiological effects.6 As the disease progresses, SRBD patients begin to develop increased UA resistance that results in a new hallmark symptom: sleepiness. Sleepiness is caused by increased arousals from sleep.7 This syndrome has been described as the UA resistance syndrome (UARS). Note the image below.
 
Sleep-related disordered breathing continuum ranging from simple snoring to obstructive sleep apnea (OSA). Upper airway resistance syndrome (UARS) occupies an intermediate position between these extremes. Note areas of overlap among the conditions.
 
 
UARS patients are not hypoxic, and hypoxia does not explain why they are sleepy, nor can sleep stage percentages or other polysomnography (PSG) variables. The SRBD continuum predicts that over time, a UARS patient develops obstructive sleep apnea, if untreated.
 
Obstructive sleep apnea has as its hallmark symptoms snoring, sleepiness, spouse apnea report, and hypoxia. The SRBD continuum suggests that over time, untreated obstructive sleep apnea may hasten death through heart disease, hypertension, stroke, myocardial infarction, heart failure, cardiac arrhythmia, diabetes, metabolic syndrome, or vehicular or other accident due to sleepiness or other behavioral affects noted.
 
The SRBD continuum suggests that optimal obstructive sleep apnea treatment must correct obstructive sleep apnea, UARS, and snoring. If it does not eliminate all 3 problems, the symptoms and the pathophysiological process that was evident at the start of disease recurs. Therefore, in the treatment of SRBD, CPAP corrects obstructive sleep apnea first, UARS next, and snoring last.
 
An unlikely occurrence is snoring being corrected before obstructive sleep apnea and/or UARS; if this is thought to have occurred, then consideration should be given to the integrity of the snoring microphone.
 
Consider whether snoring has been correctly interpreted on PSG during a CPAP titration. When a mask leak occurs, the noise may be transferred by the microphone to the PSG snore channel and may sound like snoring. One can determine the difference between snoring and a CPAP mask leak because snoring occurs at the point of peak inspiration and the beginning of expiration; mask leak occurs during expiration.
 
Consider whether the patient has had UA corrective surgery. If pharyngeal tissue has been eliminated, snoring may not occur, but obstructive sleep apnea can occur (so-called silent apnea).
 
Obstructive sleep apnea patients with sleepiness despite apparent effective treatment of obstructive sleep apnea with CPAP 
 
Some patients with optimal correction of SRBD remain excessively sleepy during waking hours. This group is sometimes not be “optimally” treated; rather, they are put on a positive pressure setting which, during the sleep disorders center positive airway pressure study, is sufficient to correct obstructive sleep apnea. They may not be optimally treated for a number of reasons that need to be considered first, before placing patients in this subgroup of patients.
 
A few reasons for suboptimal OSA treatment may include the following:
 
Positive airway pressure titration is insufficient to fully treat obstructive sleep apnea and snoring: Research suggests that pressures used to correct obstructive sleep apnea and snoring are typically lower than those needed to abolish obstructive sleep apnea and snoring.1 Consider empirically increasing the expiratory pressure by 2 cm water.
Once obstructive sleep apnea and snoring are treated, patients may be noted to have complex sleep apnea (ie, residual central sleep apneas that do not resolve spontaneously). Complex sleep apnea is beyond the scope of this article.
Patients may not be using the positive pressure machine at home sufficiently to obtain adequate benefit to abolish sleepiness during waking hours.
A change in medication may have occurred that may decrease arousal from sleep (eg, benzodiazepines), use of alcohol may have changed, or a medication that suppressed rapid eye movement sleep percentage was discontinued on the titration night, but once stopped, an increase in REM sleep percentage may be correlated with obstructive sleep apnea exacerbation (obstructive sleep apnea is typically worse in rapid eye movement sleep). It is also known that sildenafil (Viagra) may increase the severity of OSA. Sildenafil prolongs the action of cyclic guanosine monophosphate (GMP) and nitric oxide by inhibiting cyclic GMP-specific phosphodiesterase 5. Nitric oxide promotes upper airway congestion, muscle relaxation, and pulmonary vasodilation and may be the mechanism by which sildenafil exacerbates OSA.8
Exclude medical disorders that may cause excessive sleepiness (eg, hypothyroidism, even if subclinical).
Weight gain may have occurred.
The patient may not be complying or may only be partially complying with their positive airway pressure device usage. Only rarely do new positive airway pressure devices not have cards that stores data regarding daily positive airway pressure use. All patients in the author’s sleep clinic are encouraged to bring their positive airway pressure device with them so the clinicians can download data from their positive airway pressure machine’s data card. Using the device properly and routinely (eg, >5 h per night, >90% of the time) seems necessary to reduce or correct sleepiness.
Exclude sleepiness due to other sleep disorders known to have hypersomnia as a major presenting symptom (eg, insufficient sleep syndrome, narcolepsy), because insufficient sleep syndrome is the most common cause of hypersomnia and obstructive sleep apnea is more common among patients who have narcolepsy (a 30% incidence rate vs 1-4% in the population). Consider a diagnosis of sleepiness in addition to obstructive sleep apnea (eg, narcolepsy).
If excessive sleepiness is idiopathic, consider adding a stimulant medication to the patient’s treatment regimen.
 
If the above-mentioned potential causes of excessive sleepiness have been excluded, among others that the author may not have considered herein, use of stimulants to treat excessive sleepiness is indicated. One concern clinicians share with this approach is whether improvement in alertness with the use of stimulant medications may lead to noncompliance with their positive airway pressure device.
 
Fortunately, this does not appear to be a problem. One study has shown that stimulant-treated patients are as likely to continue to use CPAP device compared with patients who are not prescribed stimulants.9 More data are needed to increase assurance that use of stimulants does not lead to noncompliance. In the authors’ experience, it is unlikely that stimulant use is sufficient to correct the severe sleepiness obstructive sleep apnea patients experience; hence, both positive airway pressure treatment and stimulant use are preferred by patients.
 
To treat residual sleepiness with medication, after the above-mentioned evaluation has been completed thoroughly, 2 medications should be considered: modafinil and armodafinil. The 2 medications are approved by the US Food and Drug Administration for treating residual sleepiness despite optimal treatment of obstructive sleep apnea using positive airway pressure therapy.
 
Modafinil seems most effective when used at the higher dose of 400 mg/d, whereas fatigue seems to be better treated with lower doses of the medication (100-200 mg/d).
 
If modafinil does not help at higher doses, the authors then consider armodafinil. Armodafinil reaches a peak plasma level nearly as quickly as modafinil and has a larger area under the curve for a given dose; additionally, the duration of action of armodafinil continues at the higher dosage throughout the day. Because of this action, armodafinil has more potency and most often requires only once-a-day dosing (taken in the morning for daytime workers and in the evening for nighttime workers).
 
Historical perspectives
 
The history of the discovery of sleep apnea is interesting and is the topic of a paper published in 2008.10 
 
The most popular reference to the person who first described obstructive sleep apnea is Charles Dickens. Dickens wrote in "The Posthumous Papers of the Pickwick Club" of a man named "Sleepy Joe." Sleepy Joe was an obese man who sat in the corner of an English pub and was most often asleep and snoring. The archetype of a rotund, snoring, and sleepy man became eponymous with "pickwickian syndrome" (ie, sleep-related obesity-hypoventilation syndrome (hypercapnia and/or hypoxemia without evidence of obstructive sleep apnea in an obese patient typically caused by restrictive lung disease due to limited chest wall excursion) that was popularized in the medical literature by Burwell in 1956.11
 
The prevailing belief at the time was that "pickwickians" had breathing disorders and drowsiness due to "carbon dioxide poisoning." However, this is not true. Although far from exact, this author believes the identification of pickwickian syndrome important to draw attention to patients who had obstructive sleep apnea. Obstructive sleep apnea patients are not sleepy because of carbon dioxide narcosis, but because of fragmented sleep due to the necessity to awaken to breathe; they do not all have lung disease or cor pulmonale, although research has clearly shown adverse consequences of obstructive sleep apnea on the heart and other organs, as well as derangements in metabolic processes.
 
If Sleepy Joe were a real person, he would probably have obstructive sleep apnea, and he may also have obesity hypoventilation syndrome due to obesity or chest wall restriction, described by Burwell as pickwickian syndrome. Sleepy Joe may have had "ticks and fleas"; that is, he may have violated Occams’ Razor in that he required 2 diagnoses to explain his symptoms.
 
Detailing the history of obstructive sleep apnea is beyond the scope of this article; however, a few highlights are mentioned.
 
Gestaut, Tassinari, and Duron12 in France and Jung and Kuhlo13 in Germany provided perhaps the most accurate descriptions of obstructive sleep apnea at about the same time, in 1965.
 
The first known successful treatment for obstructive sleep apnea was tracheostomy in 1970 by Elio Lugaresi and colleagues at the University of Bologna in Italy. A primary reason a tracheostomy was important to the understanding of obstructive sleep apnea is that performing the tracheostomy left little doubt that obstructive sleep apnea was due to an obstructed UA and not due to a dysfunction of the brain’s respiratory centers. The elevated blood pressure in these patients was of grave concern to Dr Lugaresi, and, post tracheostomy, the blood pressure dropped substantially. For the next 11-16 years, tracheostomy and weight loss were the only established beneficial remedies for obstructive sleep apnea.
 
In 1981, Sullivan et al introduced CPAP as a treatment for obstructive sleep apnea.14 It quickly gained worldwide acceptance by 1986, and it replaced tracheostomy as the most useful and desirable treatment. As is often the case in history, it is perplexing how such a simple device introduced so long ago can transform modern medicine in ways not sooner foreseen. CPAP was a tremendous advance for thousands of obstructive sleep apnea patients who needed care and for clinicians who would soon solely specialize in sleep medicine.
 
Around the time when CPAP was introduced, corrective surgery was introduced and would become the forerunner of further developments in the field of sleep medicine. In 1981, Fugita and colleagues introduced uvulopalatopharyngoplasty (UPPP).15
 
Other treatments, including oral appliance (OA) therapy, are also now treatment alternatives for obstructive sleep apnea. Future advances in these and other therapies (eg, stimulation of the genioglossus muscle) are exciting. As was the case with CPAP, the simplest procedure, mechanical device, or drug may astound the medical community by providing the next revolution in the treatment of obstructive sleep apnea. For a complete and elegant description of the history of sleep medicine, see Principles and Practice of Sleep Medicine.16
 
Definition
 
According to the American Academy of Sleep Medicine (AASM) International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition,17 obstructive sleep apnea is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) UA obstruction occurring during sleep. By definition, apneic and hypopneic events last a minimum of 10 seconds. At least 5 apnea events must occur per hour of sleep time in association with clinical symptoms, or at least 15 apnea events must occur per hour of sleep time with or without clinical symptoms.
 
Centers for Medicare & Medicaid Services criteria for the positive diagnosis and treatment of obstructive sleep apnea18
 
A positive test for obstructive sleep apnea is established if either of the following criteria using the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI) is met:
 
AHI or RDI greater than or equal to 15 events per hour, or
AHI or RDI greater than or equal to 5 and less than or equal to 14 events per hour with documented symptoms of EDS; impaired cognition; mood disorders; insomnia; or documented hypertension, ischemic heart disease, or history of stroke
The AHI is equal to the average number of episodes of apnea and hypopnea per hour. The RDI is equal to the average number of respiratory disturbances per hour.
 
If the AHI or RDI is calculated based on less than 2 hours of continuous recorded sleep, the total number of recorded events to calculate the AHI or RDI during sleep testing is at least the number of events that would have been required in a 2-hour period.
 
One study has demonstrated that use of the AHI alone leads to the underdiagnosis of obstructive sleep apnea in 30% as compared to the use of the RDI.19
 
Pathophysiology
 
Obstructive sleep apnea (OSA) is caused by soft tissue collapse in the pharynx. The mechanism and factors that contribute to the pathophysiology of OSA are discussed.
 
Transmural pressure and its relationship to the critical closing pressure of pharynx
 
Transmural pressure is the difference between intraluminal pressure and the surrounding tissue pressure. If transmural pressure decreases, the cross-sectional area of the pharynx decreases. If this pressure passes a critical point, pharyngeal closing pressure is reached. Exceeding pharyngeal critical pressure (Pcrit) causes a juggernaut of tissues collapsing inward. The airway is obstructed. Until forces change transmural pressure to a net tissue force that is less than Pcrit, the airway remains obstructed. OSA duration is equal to the time that Pcrit is exceeded.
 
Static and dynamic factors associated with obstructive sleep apnea
 
Static factors and dynamic factors increase the risk of obstructive sleep apnea. Static factors include surface adhesive forces, neck and jaw posture, tracheal tug, and gravity. Gravitational forces are felt simply by tilting one's head back to where the retroposition of the tongue and soft palate reduce the pharyngeal space. For most patients, obstructive sleep apnea worsens in the supine sleeping position.
 
An important static factor that has been found is the reduced diameter of the pharyngeal airway in wakefulness in OSA patients compared with non-OSA patients. In the absence of craniofacial abnormalities, the soft palate, tongue, parapharyngeal fat pads, and lateral pharyngeal walls are enlarged in OSA patients versus non-OSA patients.
 
Dynamic factors include nasal and pharyngeal airway resistance, the Bernoulli effect, and dynamic adherence.
 
Any anatomic feature that decreases the size of the pharynx increases the likelihood of obstructive sleep apnea. One example of this effect is retrognathia. Dr Robin was the first to work on a mandibular-advancement device to help patients with what became known as Pierre Robin syndrome or Robin syndrome. His patients benefitted because protrusion of the mandible increased the cross-sectional area of the pharynx, among other effects.
 
The Bernoulli effect plays an important dynamic role in obstructive sleep apnea pathophysiology. In accordance with this effect, airflow velocity increases at the site of stricture in the airway. As airway velocity increases, pressure on the lateral wall decreases. If the transmural closing pressure is reached, the airway collapses. The Bernoulli effect is exaggerated in areas where the airway is most compliant. Loads on the pharyngeal walls increase adherence and, hence, increase the likelihood of collapse.
 
This effect helps to partially explain why obese patients, and particularly those with fat deposition in the neck, are most likely to have obstructive sleep apnea. Moreover, the cross-sectional area of the airway in patients with obstructive sleep apnea is smaller than that of people without obstructive sleep apnea; this difference is due to the volume of the soft tissue, including the tongue, lateral pharyngeal walls, soft palate, and parapharyngeal fat pads. In one study, the increased volume of these areas was independent of sex, age, ethnicity, craniofacial size, and fat deposition surrounding the UA.20
 
Given these principles, the reasons why the likelihood of obstructive sleep apnea is increased among obese patients, why weight loss decreases the risk of obstructive sleep apnea, and why physical examination helps in predicting the presence of obstructive sleep apnea are understandable. However, the clinical situation is complex because of the interplay of known static and dynamic factors and because of unknown factors. Data do not explain why sex, age, and ethnicity are not evenly distributed across epidemiologic studies of obstructive sleep apnea patients. Furthermore, data or physical findings are not helpful for determining with precision who will or will not have obstructive sleep apnea and who can or who cannot be cured with UA surgery.
 
Ramachandran et al have developed and validated a clinical score for predicting the diagnosis of obstructive sleep apnea preoperatively in a general surgical population. Their perioperative sleep apnea prediction (P-SAP) score is based on 3 demographic variables (age >43 y, male sex, and obesity), 3 history variables (history of snoring, diabetes mellitus type 2, and hypertension), and 3 airway measures (thick neck, modified Mallampati class 3 or 4, and reduced thyromental distance). A diagnostic threshold P-SAP score of 2 or higher showed excellent sensitivity (0.939) but poor specificity (0.323), whereas P-SAP score of 6 or higher had poor sensitivity (0.239) but excellent specificity (0.911).21 
 
 
Other mechanisms involved in perpetuating obstructive sleep apnea
 
Obstructive sleep apnea often occurs in clusters. An oxygen desaturation occurs with each apnea. The end of the apnea sequence typically ends with a brief (>3 sec) EEG arousal. In patients with severe obstructive sleep apnea, the cluster of apneas occurs throughout sleep. The desaturation from the first apnea event is typically associated with a higher desaturation percentage change than subsequent apneas in the series.
 
An underlying mechanism for how clusters of apneas occur and the rate of oxygen desaturation has been recently studied.20 The researchers paralyzed lambs and withdrew mechanical ventilation to produce apnea and target oxygen saturation. Once the target was reached and the number of recurrent apneas was met, they stimulated respiration through the ventilator so that oxygen saturation was more than 85%. These events were not obstructive events but were apneas associated with hypoxemia. These events were not terminated by EEG arousals in a natural way to end an apnea sequence and were not produced in humans. Therefore, this study’s clinical application is associated with several caveats.
 
The study found that resting oxygen saturation was not significantly correlated with resting oxygen saturation, independent of mixed-venous oxygen saturation, using forward stepwise regression modeling. The study revealed that the most rapid change in oxygen desaturation occurred after the second apnea in a series of 10 apneas produced; apneas that followed the second apnea did not have accelerated changes when compared with the second apnea. Isolated apneas did not show rapid changes in oxygen saturation.
 
Using a mathematical model, in which the destruction rate is directly proportional to pulmonary oxygen uptake during recurrent apnea (using the slope of the oxyhemoglobin dissociation curve) and lung volume is unchanged, a study predicted increased desaturation rates solely based on the size of oxygen reuptake.22 This occurs when mixed-venous blood with depleted oxygen saturation arrives at the lung in time with the apnea phase. The researchers suggested that a decrease in the duration of the ventilatory phase or an increase in circulatory delay increases the phase lag toward 270º and accelerator desertion; whereas if venous saturation peaks while oxygen saturation is falling (arterial-venous phase lag, 90º or 450º), the amplitude is minimized.
 
The clinical implications of these findings suggest that the reason that CPAP and supplemental oxygen may work to ameliorate rapid desaturation is related to the extent that apneas can remain isolated. This results in a longer ventilatory phase to allow venous reoxygenation.
 
 
Genes
 
A study examined 52 candidate genes most likely to influence obstructive sleep apnea.23 The sample size was large and included 792 African Americans and 694 European Americans, all older than 18 years. An apnea hypopnea index equal to or more than 15 was used to define obstructive sleep apnea as a clinical entity; AHI was statistically used as both a continuous trait and as a dichotomous trait. In the African American subjects, 1,080 single nucleotide polymorphisms (SNPs) were genotypes; in the European Americans, 505 SNPs were genotypes. The statistical analysis controlled for adjusted for age, age-squared, and sex, with and without body mass index.
 
The study found the following variants in European Americans: C-reactive protein (CRP) and glial cell line-derived neurotrophic factor (GDNF) that were associated with the AHI both as a longitudinal and dichotomous trait. CRP findings increased the odds ratio for obstructive sleep apnea between 1.45 and 2.87, using the 95% confidence interval; GDNF increased the odds ratio for the risk of obstructive sleep apnea between 1.53 and 3.89-3.92 for the GDNF gene that looked at risk allele G and GDNF risk allele A, respectively.
 
The study found the following variant in African Americans with obstructive sleep apnea: r9s526240 within serotonin receptor 2a. Risk allele A increased the odds ratio for risk of obstructive sleep apnea between 1.45-2.91 using the reported 95% confidence interval.
 
CRP appears to mediate inflammation; it is thought to be a marker of inflammation. Such inflammation may increase obstructive sleep apnea by increasing mucosal edema and reducing airway caliber.
 
GDNF influences ventilatory control. It appears to sense oxygen and carbon dioxide at sleep onset transitions, hence playing a role in central sleep apnea. GDNF influences the growth of sensory afferent neurons of the carotid body, influencing responses to hypoxia. Its role extends to influencing the growth of neural pathways that are important for normal respiration, specifically at the A5 nucleus of the ventrolateral pons, a critical area that regulates respiratory pattern generation.
 
The role of 5HT2A includes effects on sleep-wake cycles, importantly influencing REM sleep stage percentage. Medications such as selective serotonin reuptake inhibitors that occupy 5HT2A receptors reduce or eliminate REM sleep percent time. Other mentioned roles include regulation of upper airway dilator muscle through an excitatory influence on hypoglossal motor output. 5HT2a is involved in appetite regulation, thus playing a role in obesity, a well-known risk factor for obstructive sleep apnea.
 
The study used rather strict criteria to identify other candidate genes, and less stringent criteria identified other possible candidate genes that may influence the risk of obstructive sleep apnea.
 
Frequency
 
United States
 
Although early investigators estimated the prevalence of sleep-disordered breathing (SDB) to be 2% for middle-aged women and 4% for middle-aged men, more recent research indicates a prevalence of 4% for women and 9% for men.2
 
The National Commission on Sleep Disorders Research estimated that minimal SDB (respiratory disturbance index [RDI] >5) affects 7-18 million people in the United States and that relatively severe cases (RDI >15) affect 1.8-4 million people. The prevalence increases with age. SDB remains undiagnosed in approximately 92% of affected women and 80% of affected men.
 
Mortality/Morbidity
 
Related morbidity is detailed below.
 
 
Excessive Daytime Sleepiness
 
Excessive daytime sleepiness (EDS) is one of the most common and difficult symptoms clinicians treat in patients with obstructive sleep apnea. Patients do not always accurately describe their sleepiness on the Epworth Sleepiness Scale (ESS) compared with objective measures. Nonetheless, EDS is one of the most debilitating symptoms because it reduces quality of life, impairs daytime performance, and causes neurocognitive deficits (eg, memory deficits).
 
Although CPAP treatment quickly reverses EDS in most patients, not all patients use the CPAP device. Moreover, some patients remain sleepy despite effective CPAP treatment. In these patients, modafinil at 200-400 mg/d can effectively enhance alertness without changing CPAP use.9 Patients with residual excessive sleepiness despite effective CPAP use are an interesting subgroup of patients. The mechanism of EDS in these patients awaits further study.
 
Performance and Neurocognitive Deficits
 
Partly because of their EDS, patients with obstructive sleep apnea have substantially impaired daytime functioning, intellectual capacity, memory, psychomotor vigilance (decreased attention and concentration), and motor coordination. Causes include both sleep fragmentation and hypoxemia due to obstructive sleep apnea.
 
Can these neurocognitive deficits be reversed with continuous positive airway pressure (CPAP) treatment? Obstructive sleep apnea patients showed an overrecruitment of brain regions compared with controls, in the presence of the same level of performance on a working-memory task.24 
 
Risk for Motor Vehicle Accidents
 
People with obstructive sleep apnea have more automobile accidents than people without obstructive sleep apnea. Determining which obstructive sleep apnea patients are likely to have an accident is unpredictable from the existing data.
 
Patients with obstructive sleep apnea do not perform as well as healthy control subjects during driving-simulation tests, but their performance may return to normal after treatment. Therefore, access to effective treatment is a pivotal concern in sleep medicine.
 
 
Cardiovascular
 
A scientific statement was published by the American Heart Association and the American College of Cardiology Foundation on August 25, 2008. This expert review examined obstructive sleep apnea and cardiovascular disease. The results are paraphrased below.25 
 
The possible mechanisms through which obstructive sleep apnea may lead to cardiovascular disease were examined. Obstructive sleep apnea patients often have hypoxemia, reoxygenation, sleep arousals, less sleep time than healthy individuals, elevated negative intrathoracic pressure, and, in some individuals, hypercapnia. The commonly accepted contributions of these obstructive sleep apnea–related pathophysiological factors may affect sympathetic activation, metabolic dysregulation, left atrial enlargement, endothelial dysfunction, systemic inflammation, and hypercoagulability. These mechanisms can lead to hypertension (both systemic and pulmonary), heart failure, cardiac arrhythmias, renal disease, stroke and myocardial infarction, and sudden death in sleep.
 
Two of the most significant findings from the review by Somers et al25 are (1) that the data suggest that evaluation and treatment for obstructive sleep apnea is not recommended in every patient with cardiac disease, but the threshold for a referral for a polysomnography (PSG)study and for treatment of obstructive sleep apnea should be low and (2) because obstructive sleep apnea affects younger individuals with cardiovascular disease to a greater extent than older individuals with cardiovascular disease, this threshold for obstructive sleep apnea evaluation and treatment should be even lower.
 
Hypertension 
 
All-cause mortality rates are higher individuals with a blunted or absent decrease in nighttime blood pressure. Additionally, CPAP treatment has been shown to have moderate and variable effects on blood pressure in obstructive sleep apnea patients.26 Further, antihypertensive drug treatment does not improve obstructive sleep apnea; however, clonidine, which is a rapid eye movement (REM) sleep suppressant, may improve obstructive sleep apnea by reducing the patient’s percentage of REM sleep because the REM sleep is when obstructive sleep apnea is most severe. Finally, ACE inhibitor use may worsen obstructive sleep apnea because of the adverse effects of cough and rhinopharyngeal inflammation, 2 effects that cease with discontinuation of the drug.
 
Treatment has been shown to decrease both systolic and diastolic hypertension. CPAP has been investigated in nonsleepy hypertensive obstructive sleep apnea patients. CPAP treatment for 1 year was associated with decreases in both systolic and diastolic pressure. This effect was only evident in patients who used their CPAP device for more than 5.6 hours per night.27 
 
 
Patients with hypertension and obstructive sleep apnea may require CPAP and antihypertensive medication. A randomized, controlled study examined the use of valsartan (160 mg/d) and CPAP in patients with newly diagnosed hypertension and newly diagnosed obstructive sleep apnea.28 Each treatment arm was 8 weeks in duration.
 
Because OSA patients use CPAP regardless of whether they are taking medication for hypertension, the success of the combination of CPAP and valsartan was the most important clinically relevant finding. Together, the treatments synergistically reduced blood pressure. Significant reductions in various blood pressure measurements over 24 hours, daytime blood pressure, and nighttime blood pressure were noted.
 
Decreased CPAP use was associated with higher nighttime systolic blood pressure (R=-.043, P <0.04 with 23 subjects who completed the study). Office blood pressure, reported as entry criteria, was not reported after treatments in the results. Systolic and diastolic blood pressures were not within normal limits on every time period measured. Because of the reported negative correlations with CPAP use and nocturnal systolic blood pressure as a function of the duration of CPAP use, an intervention to augment CPAP use would likely have been helpful to adequately assess CPAP’s effect on blood pressure alone; the time spent on CPAP during this study was perhaps too low to demonstrate a larger change in blood pressure parameters.
 
The ability of CPAP to reduce hypertension has been shown, in others studies, to require 5.6 hours per night for an effect. Subjects in this study used CPAP approximately 5 hours per night; again, this limits the effect of CPAP on hypertension as a treatment alone and in combination with valsartan. On other hand, blood pressure reductions with fewer hours of CPAP use than previous published studies further supports CPAP’s robust effect on blood pressure and that fewer than 5.6 hours of CPAP use can lead to blood pressure reductions.
 
Congestive heart failure 
 
Obstructive sleep apnea has not been established as a cause of heart failure, and whether obstructive sleep apnea hastens death in patients with heart failure is uncertain. However, a 2007 study examined untreated obstructive sleep apnea in patients with heart failure and reported that those with an apnea-hypopnea index (AHI) of greater than 15 had increased mortality compared with those with an AHI of less than 15.29 Also note that CPAP treatment in patients with obstructive sleep apnea and heart failure may reduce mortality,30 but the evidence is less than absolute because no randomized clinical trials have tested the effects.
 
Cardiac arrhythmias 
 
Patients with severe SDB have a 2- to 4-fold increased risk of experiencing nocturnal complex arrhythmia. Bradyarrhythmia is more common in obstructive sleep apnea patients (occurs in approximately 10% of obstructive sleep apnea patients), especially in the REM sleep state and when a greater than 4% drop in oxygen saturation occurs. Additionally, atrioventricular block and asystole may occur in the absence of conduction disease. Premature ventricular contractions also are much more common in patients with obstructive sleep apnea compared with those who do not have obstructive sleep apnea (66% vs 0-12%, respectively), and they are most likely to occur during an apnea; however, CPAP treatment reduces the frequency of the premature ventricular contractions (by up to 58% reported in one study).
 
Myocardial ischemia and infarction
 
Obstructive sleep apnea patients have double the prevalence of coronary artery disease, and an independent association has been shown between obstructive sleep apnea and subclinical coronary artery disease, as demonstrated by coronary artery calcification. Further, obstructive sleep apnea apparently affects the timing of sudden cardiac death because research shows that greater than 50% of sudden cardiac deaths that occur in obstructive sleep apnea patients do so between 10 PM and 6 AM; the more common time for sudden cardiac death is from 6-11 AM. Men with untreated obstructive sleep apnea and an AHI of greater than 30 had an increased number of fatal and nonfatal cardiovascular events, but treated obstructive sleep apnea patients have a number of events similar to snorers who do not have obstructive sleep apnea.
 
Atrial fibrillation or complex ventricular ectopy 
 
In a study of SDB and nocturnal cardiac arrhythmias in older men, Mehra et al found that the likelihood of atrial fibrillation or complex ventricular ectopy increased along with the severity of SDB. In addition, different forms of SDB were associated with the different types of arrhythmias. PSG in 2911 participants showed that the odds of atrial fibrillation (P = .01) and of complex ventricular ectopy (P <.001) increased with increasing quartiles of the RDI (a major index including all apneas and hypopneas).31 
 
Stroke
 
The Sleep Heart Health Study32 showed the strongest relationship was between obstructive sleep apnea and stroke versus any other cardiovascular disease.
 
Patients with obstructive sleep apnea are more likely to have a stroke and die than people without obstructive sleep apnea. This correlation persists even if researchers control for the risk factors of age, sex, race, smoking, alcohol consumption, body mass index (BMI), diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension. Time-to-event analyses have shown that patients with obstructive sleep apnea (who were undergoing weight loss, CPAP treatment, or surgery) have an increased hazard ratio for stroke or death of 1.97 (95% confidence interval, 1.12-3.48; P = .01). The risk of stroke or death was most severe in the quartile of patients with the most severe AHI. The hazard ratio increased to 3.30 (95% confidence interval, 1.74-6.26) when the AHI was greater than 36. This study was not powered sufficiently to determine if obstructive sleep apnea treatment affects survival.
 
Diabetes
 
Obstructive sleep apnea is associated with an increased risk of type 2 diabetes. Whether obstructive sleep apnea causes type 2 diabetes or whether it is associated with insulin resistance and diabetes is unclear. Use of CPAP can reverse insulin resistance. Sleep fragmentation, sleep deprivation, and hypoxemia (which all occur in obstructive sleep apnea) are thought to play independent roles in glucose intolerance. Conflicting results show that reversal of glucose intolerance may occur when obstructive sleep apnea is treated.
 
A 2009 study increases support for the role of obstructive sleep apnea in exacerbating insulin control in patients with type 2 diabetes. This was found as an effect, independent of adiposity and other confounders.33 
 
 
Oxidative Stress and Inflammatory Processes
 
An excellent review article by Gozal and Kheirandish-Gozal provides a model that attempts to integrate how oxidative stress and inflammatory processes link obstructive sleep apnea and cardiovascular disease.34 
 
Genetic studies have revealed that the gene that encodes for oxidative stress uniquely contributes toward obstructive sleep apnea.23 This suggests that the development of obstructive sleep apnea may be related to inflammation and is not necessarily related to a trigger for oxidative stress, as was previously thought. The gene may play a pivotal role by operating in a positive feedback loop, causing the obstructive sleep apnea to begin with and then triggering an inflammatory response that further narrows the UA, exacerbating the obstructive sleep apnea.
 
Oxidant-related microcirculatory endothelial dysfunction, in a group of patients who had no known vascular disease, improved when CPAP effectively treated the patient’s OSA, compared with no improvement in the control group.35
Race
 
African American individuals appear to be more predisposed to SDB than white persons. This increased predisposition varies according to age. The odds ratio is greater than 3 in children younger than 13 years and is 1.88 in persons younger than 25 years. In elderly African Americans, the risk is increased 2-fold.
 
Other populations that may be at increased risk include Mexican Americans and Pacific Islanders.
 
Examination of craniofacial morphology found that brachycephaly is associated with an increased AHI in whites but not in African Americans.36
 
Chinese patients with obstructive sleep apnea have a more crowded upper airway and relative retrognathia compared with their white counterparts, with statistical controls for BMI and neck circumference.37 Asians are known to have a shorter cranial base and a more acute cranial base flexure, increasing obstructive sleep apnea risk, with BMI and neck circumference being roughly equal. Therefore, interestingly, obesity plays a more prominent role in OSA predisposition in whites than in Chinese persons. This may serve to underscore the role that craniofacial factors have in Chinese patients.
Sex
 
In adults, the male-to-female ratio is approximately 3:1. In population studies that have examined the incidence of obstructive sleep apnea, women were less likely than men to have obstructive sleep apnea and are less likely to be diagnosed early in the disease process. Survival rates are lower for women than for men, after an obstructive sleep apnea diagnosis has been established by PSG, presumably due to the delayed obstructive sleep apnea diagnosis.
 
Postmenopausal women are 3 times more likely to have moderate-to-severe obstructive sleep apnea compared with premenopausal women. Women who are on hormone replacement therapy are half as likely to have obstructive sleep apnea compared with postmenopausal women who are not on hormone replacement therapy.38 
 
Androgenic patterns of body fat distribution (deposition in the trunk, including the neck area) predispose men to obstructive sleep apnea. In general, sex hormones may affect neurologic control of UA-dilating muscles and ventilation. For further information, see History.
 
Age
 
Aging is an important consideration of risk for obstructive sleep apnea. Obstructive sleep apnea prevalence increases 2-3 times in older persons (>65 y) compared with individuals aged 30-64 years. After age 65 years, no further relative disparity is noted in the incidence of obstructive sleep apnea. One explanation for this plateau is the relative increase in mortality in persons older than 65 years; however, data to support this contention, as attractive as it appears, are insufficient. Scant data are available to help clinicians determine if clinical management should differ between the age cohorts.
 
Clinical
 
History
 
Signs of obstructive sleep apnea are as follows:
 
Snoring (loud)
Daytime sleepiness or fatigue
Spouse or significant other witnessed apnea report
Hypertension
Nonrestorative sleep (ie, "waking up as tired as when they went to bed")
A choking sensation or gasping during the night; though in a very low proportion relative to the number of apneas they experience
Morning headaches
Patient report of "trouble sleeping"
Insomnia
Restless sleep
Sore throat or dry mouth in the morning
Nocturia
Symptoms of obstructive sleep apnea are as follows:
 
Cognitive deficits; memory and intellectual impairment (short-term memory, concentration)
Decreased vigilance
Morning confusion
Personality and mood changes, including depression and anxiety
Sexual dysfunction, including impotence and decreased libido
Gastroesophageal reflux
Depression
Risk factors for obstructive sleep apnea are as follows:
 
Male sex
Age 40-65 years
Positive family history
Body habitus, to include the following:
Overweight and obese
Central body fat distribution
Large neck girth (>17 in)
Increased Mallampati score (crowded-appearing pharyngeal airway)
UA abnormalities, including nasal congestion
Craniofacial abnormalities (eg, tonsillar hyperplasia, crowded pharyngeal airspace, retrognathia, reduced cricomental space, macroglossia, lateral peritonsillar narrowing)
Lower extremity edema
Brachycephaly – Associated with an increased apnea-hypopnea index (AHI) in whites but not in African Americans.36
Menopause (in women)
Alcohol use
Sedative use
Smoking
Supine sleep position
Rapid eye movement (REM) sleep state
Consequences of obstructive sleep apnea may include:
 
Hypertension
Stroke
Diabetes mellitus
Pulmonary hypertension
Definitions of respiratory events and indices
 
Breathing events include the following:
 
Apnea – Cessation of airflow for at least 10 seconds
Hypopnea – At least 30% reduction in thoracoabdominal movement or airflow compared with baseline lasting at least 10 seconds, and with at least 4% oxygen desaturation
Respiratory effort–related arousal (RERA) – Sequence of breaths with increasing respiratory effort leading to an arousal from sleep as shown pressure transducer airflow sensor of at least 10 seconds preceding an arousal with resumption of more normal flow
Types of breathing events are as follows:
 
Obstructive – Continued thoracoabdominal effort in the setting of partial or complete airflow cessation
Central – Lack of thoracoabdominal effort in the setting of partial or complete airflow cessation
Mixed – Respiratory event with both obstructive and central features (Mixed events generally begin without thoracoabdominal effort and end with several thoracoabdominal efforts in breathing. Mixed events are tabulated in the obstructive apnea index.)
Indices of sleep-disordered breathing are as follows:
 
AHI – Number of apneas (mixed and complete obstructive) and hypopnea per hour of total sleep time
Apnea index – Number of apneas per hour of total sleep time
Hypopnea index – Number of hypopneas per hour of total sleep time
RERA index – Number of RERAs per hour of total sleep time
Respiratory disturbance index – Number of apneas, hypopneas, and RERAs per hour of total sleep time
Central apnea index – Number of central apneas per hour of total sleep time
Mixed apnea index – Number of mixed apneas per hour of total sleep time
Predictive value of clinical history and examination
 
Predictive value can be based on the following:
 
Disruptive snoring: A history of disruptive snoring has 71% sensitivity in predicting sleep-disordered breathing (SDB).
Disruptive snoring and witnessed apneas: These factors taken together have 94% specificity for SDB.
Questioning patients and others is necessary, as follows:
 
Others: Obtaining a history from someone who has observed the patient's sleep behavior is important. Patients are usually unaware of snoring and/or sleepiness or may minimize these symptoms. Sleepiness may develop insidiously. Patients may be unaware that they are sleepy; that is, they may forget how normal alertness feels.
Patients: Question the patient about drowsiness in boring or monotonous situations and about sleepiness while driving.
Sex-related differences include the following:
 
Reporting of symptoms: Women are twice as likely as men to not report snoring and apneas, even after one corrects for the respiratory disturbance index (RDI).
Presentation: Women commonly present with symptoms atypical of the classic presentation of obstructive sleep apnea. Women are more likely than men to report fatigue and are less likely than men to report sleepiness.
Diagnosis and referrals: Although the male-to-female ratio for the prevalence of SDB in the general population is approximately 2-3:1, the male-to-female ratio for patients referred to sleep clinics for an evaluation of possible obstructive sleep apnea is approximately 10:1. Obstructive sleep apnea appears to be notably underdiagnosed in females. A high index of suspicion must be maintained when screening females for SDB.
Menstruation: In 1 study, 43% of premenopausal women with SDB had menstrual irregularities that disappeared with the treatment of SDB.
The mnemonic STOP is helpful and includes the following:
 
S: “Do you snore loudly, loud enough to be heard through a closed door?”
T: “Do you feel tired or fatigued during the daytime almost every day?”
O: “Has anyone observed that you stop breathing during sleep?”
P: “Do you have a history of high blood pressure with or without treatment?”
If the patient answers yes to more than 2 questions, the sensitivity of him or her having an AHI of greater than 5 is 66% and the sensitivity of him or her having an AHI of greater than 15 is 74%.
 
The mnemonic BANG is also useful, as follows:
 
B: Body mass index greater than 35
A: Age older than 50 years
N: Neck circumference greater than 40 cm
G: Gender, male
If the criteria from both the STOP and BANG mnemonics are met, the sensitivity of the patient having an AHI of greater than 5 is 93% and an AHI of greater than 15 is 83%.39 
 
 
Ramachandran et al have developed and validated a clinical score for predicting the diagnosis of obstructive sleep apnea preoperatively in a general surgical population. Their perioperative sleep apnea prediction (P-SAP) score is based on 3 demographic variables (age >43 y, male sex, and obesity), 3 history variables (history of snoring, diabetes mellitus type 2, and hypertension), and 3 airway measures (thick neck, modified Mallampati class 3 or 4, and reduced thyromental distance). A diagnostic threshold P-SAP score of 2 or higher showed excellent sensitivity (0.939) but poor specificity (0.323), whereas a P-SAP score of 6 or higher had poor sensitivity (0.239) but excellent specificity (0.911).21
 
Pathophysiology and diagnosis 
 
Collectively, such studies confirm that craniofacial abnormalities are important in the pathogenesis of obstructive sleep apnea, particularly in nonobese patients. Moreover, given that different racial groups are inclined to develop obstructive sleep apnea at varying degrees of obesity, clinicians should particularly consider the possibility of this disorder in the presence of clinically detectable craniofacial abnormalities.40,41
 
Previous studies of craniofacial risk factors for obstructive sleep apnea have been based predominantly on cephalometry. However, differences in head form (measured by the cranial index) and facial form (measured by the facial index) are considered by anthropologists to provide a basis for structural variation in craniofacial anatomy.
 
The association of head and facial form with the AHI was assessed in 364 whites and 165 African Americans. Cranial and facial dimensions were measured using anthropometric calipers, and other data collected included BMI, neck circumference, and AHI.
 
Cranial index and facial index was different for whites with obstructive sleep apnea (AHI =15) compared with those who did not have obstructive sleep apnea (AHI <5). The cranial index was increased (P = .005) and the facial index was decreased (P = .006) in subjects with obstructive sleep apnea. Cranial and facial indices did not differ in African American subjects based on obstructive sleep apnea diagnosis. In whites with obstructive sleep apnea, the cranial index was again greater and the facial index was again smaller compared with African Americans (P = .007 for cranial index and P = .004 for facial index). The researchers suggested that the cranial index may be useful in phenotyping and identifying population subsets with obstructive sleep apnea.36
 
Physical
 
Physical examination findings may include the following:
 
 
Obesity: Approximately 30% of patients with a BMI greater than 30 have obstructive sleep apnea, and 50% of patients with a BMI greater than 40 have Obstructive sleep apnea. In the United States, 20% of men and 25% of women have a BMI greater than 30. Unfortunately, obesity has become an epidemic in industrialized nations. One study showed that the number of people with a BMI greater than 40 has tripled since 2000.42 Patients with obesity hypoventilation syndrome and some patients with obstructive sleep apnea may have evidence of pulmonary hypertension and right-sided heart failure.
Large neck circumference: Neck circumference may correlate with obstructive sleep apnea better than BMI. In one study, subjects with obstructive sleep apnea had a neck circumference 4 cm larger than subjects without obstructive sleep apnea. In addition, neck circumference of 40 cm or greater had a sensitivity of 61% and a specificity of 93% for obstructive sleep apnea, regardless of the person's sex.
Abnormal Mallampati score (1-4 scale) (Note the image below.)
 
 
Mallampati Classification System as part of the physical examination in predicting the presence and the severity of obstructive sleep apnea (OSA).
 
Systemic arterial hypertension present in approximately 50% of patients with obstructive sleep apnea
Congestive heart failure
Pulmonary hypertension
Stroke
Metabolic syndrome
Type 2 diabetes mellitus
Causes
 
Structural factors
 
Structural factors related to craniofacial bony anatomy that predispose patients with obstructive sleep apnea to pharyngeal collapse during sleep include the following:
 
Genetic variations (facial elongation, posterior facial compression)
Retrognathia and micrognathia
Mandibular hypoplasia
Brachycephalic head form
Inferior displacement of the hyoid
Pierre Robin syndrome
Down syndrome
Marfan syndrome
Prader-Willi syndrome
High, arched palate (particularly in women)
Structural factors related to nasal obstruction that predispose patients with obstructive sleep apnea to pharyngeal collapse during sleep include polyps, septal deviation, tumors, trauma, and stenosis.
 
Structural factors related to retropalatal obstruction that predispose patients with obstructive sleep apnea to pharyngeal collapse during sleep include (1) an elongated, posteriorly placed palate and uvula and (2) tonsil and adenoid hypertrophy (particularly in children).
 
Structural factors related to retroglossal obstruction that predispose patients with obstructive sleep apnea to pharyngeal collapse during sleep include macroglossia and tumor.
 
Nonstructural risk factors
 
Some nonstructural risk factors include obesity, age, male sex, postmenopausal state, and habitual snoring with daytime somnolence. Familial factors also play a role. Families with a high incidence of obstructive sleep apnea are reported. Relatives of patients with SDB have a 2- to 4-fold increased risk of SDB compared with control subjects. Additionally, environmental exposures include smoke, environmental irritants or allergens, and alcohol and hypnotic-sedative medications.
 
Both hypothyroidism and acromegaly are associated with macroglossia and increased soft tissue mass in the pharyngeal region. They are associated with an increased risk of SDB. Hypothyroidism is also associated with myopathy that may contribute to UA dysfunction.