AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Obstructive sleep apnea-hypopnea is characterized by recurrent episodes of upper airway collapse and obstruction during sleep. These episodes of obstruction are associated with recurrent oxyhemoglobin desaturation and arousals from sleep. The term obstructive sleep apnea-hypopnea syndrome (OSAHS) is frequently used when the episodes are associated with excessive daytime sleepiness (EDS). Despite being a common disease, OSAHS is unrecognized by most primary care physicians in the United States; an estimated 80% of OSAHS cases in the United States are not diagnosed.

Pathophysiology

The upper airway is a compliant tube and is therefore subject to collapse. Most patients with OSAHS demonstrate upper airway obstruction, either at the level of the soft palate (nasopharynx) or at the level of the tongue (oropharynx). Research indicates that both anatomic and neuromuscular factors are important. Anatomic factors, such as enlarged tonsils, macroglossia, or abnormal positioning of the maxilla and mandible, decrease the cross-sectional area of the upper airway and/or increase the pressure surrounding the airway, both of which predispose the airway to collapse.

Upper airway neuromuscular activity, including reflex activity, decreases with sleep, and this decrease may be more pronounced in patients with OSAHS. Reduced ventilatory motor output to upper airway muscles is believed to be the critical initiating event leading to upper airway obstruction; this effect is most pronounced in patients with an upper airway predisposed to collapse for anatomic reasons.

Central breathing instability has been well established as a contributor to the development of central sleep apnea, particularly in patients with severe congestive heart failure.^{1, 2, 3} Some evidence indicates that central breathing instability also contributes to the development of OSAHS. First, evidence of upper airway obstruction in the absence of ventilatory motor output (central sleep apnea) has been observed.⁴ Second, reduction in pharyngeal dilator activity has been associated with periodic breathing^{5, 6, 7} and hypocapnia in subjects with evidence of inspiratory flow limitation.⁸ Third, men have been shown to be more susceptible to the development of central sleep apnea and have a more decreased responsiveness to carbon dioxide than woman⁹; these findings are consistent with the increased prevalence of OSAHS in men.

Frequency

United States

OSAHS is a common disease in the United States. The prevalence of OSAHS, as indicated by data from the Wisconsin Cohort Study (adults aged 30-60 y), is 9-24% for men and 4-9% for women. The estimated prevalence of OSAHS is 2% in women and 4% in men. Similar data have been reported from an epidemiologic study from Pennsylvania.¹⁰

International

The prevalence of OSAHS in non-US populations has only been studied in men and has been found to be as low as 0.3% in England. It is as high as 20-25% in Israel and Australia; the prevalence of OSAHS in Australian men was estimated to be 3%.

Mortality/Morbidity

The effect of OSAHS on mortality has recently been investigated using observational cohort studies. Marin et al found that severe untreated OSAHS (apnea-hypopnea index [AHI] >30) was associated with an increased risk of cardiovascular mortality, defined by fatal myocardial infarction or stroke (odds ratio, 2.87). Patients with mild OSAHS or those undergoing treatment with continuous positive airway pressure (CPAP) did not have a significantly increased odds ratio compared with a group of subjects without OSAHS.¹¹ In this study, the authors also found that untreated severe OSAHS was a significant risk factor for the development of cardiovascular morbidity, which included nonfatal myocardial infarction and stroke (odds ratio, 3.17).

A 2005 article suggests that mortality is associated with compliance with CPAP therapy. In a historical cohort of 871 patients, patients who used CPAP for more than 6 hours per night had an increased survival rate (96.4%) at 5 years compared with those who used it 1-6 hours per night (91.3%) and less than 1 hour per night (85.5%). Use for more than 6 hours per night was associated with a significantly decreased odds ratio of 0.1.¹²

• Systemic hypertension is observed in 50-70% of patients with OSAHS. Several large cross-sectional studies have demonstrated that OSAHS is a risk factor for developing hypertension independent of obesity, age, alcohol intake, and smoking.^{13, 14} More recently, people in the Wisconsin Cohort Study were prospectively monitored for the development of hypertension. The investigators found a dose-response relationship between the degree of OSAHS and the presence of hypertension 4 years later (odds ratio 2.03 for AHI of 5-15 and 2.89 for AHI of >15) independent of confounding variables. Several small studies have shown small reductions in blood pressure when nasal CPAP therapy is used in the treatment of OSAHS, although whether it was systolic, diastolic, or mean pressure that was lowered varied by study. No definitive study has demonstrated that treating OSAHS with nasal CPAP lowers the blood pressure on a long-term basis.
• Metabolic syndrome is now recognized as an important contributor to the development of atherosclerosis and cardiovascular disease. As defined, a patient with the metabolic syndrome has increased fasting glucose levels, increased blood pressure, lipid abnormalities, and obesity. These patients also have evidence of proinflammatory and oxidative stress. Growing evidence suggests that OSAHS may contribute to the metabolic derangements that characterize the metabolic syndrome (see Media file 1). Note that for most of the abnormalities discussed below, evidence from studies with small numbers of subjects suggests that CPAP therapy partially reverses the metabolic abnormality that is the focus of the study (ie, CPAP decreased insulin resistance, decreased lipid peroxidation, and increased vasodilator responses).
• • Hypertension: The relationship between OSAHS and hypertension is outlined above.
  • Insulin resistance: Multiple studies have shown that patients with OSAHS have increased glucose levels and increased insulin resistance.^{15, 16, 17} The most recent study was from the Sleep Heart Health Study.¹⁶ In this study of 2000 research subjects, the prevalence of diabetic 2-hour glucose tolerance values rose from 9.3% in the group with an AHI less than 5 to 15% in the group with an AHI greater than 15. The odds ratio for having an abnormal glucose tolerance test result was 1.44 (P <.0001) for the group with an AHI greater than 15; insulin resistance was also highest in this group. Correlations were also noted with the degree of oxygen desaturation at night, indicating that the OSAHS may contribute to insulin resistance as a result of the hypoxemia that occurs with the syndrome.
  • Oxidative stress: OSAHS has been associated with increased production of reactive oxygen species¹⁸ and other oxidative stress biomarkers¹⁹.
  • Proinflammatory stress: OSAHS has been associated with increased levels of several proinflammatory cytokines and markers associated with atherosclerosis. These include C-reactive protein in both adults and adolescents^{20, 21}, interleukin 6²⁰, interleukin 18²², and matrix metalloproteinase 9²³.
  • Vasodilator responses: OSAHS has been associated with decreased production of nitric oxide.²⁴ Several studies have shown impaired vasodilator responses, as measured by either flow-mediated dilatation²⁵ or reactive hyperemic blood flow²⁶ techniques. Impaired flow-mediated dilatation was found to be best correlated with the degree of oxygen desaturation in an epidemiologic cohort study.²⁷
• A large epidemiologic study (the Sleep Heart Health Study) is currently being conducted to provide more definitive data regarding the relationship between sleep apnea and cardiovascular morbidity. Initial findings from the Sleep Heart Health Study indicate that a relationship exists between severe OSAHS and an increased risk of coronary artery disease, congestive heart failure, and stroke.²⁸ This study is ongoing to determine if the presence of OSAHS is associated with the development of cardiovascular morbidity.
• Other prospective observational cohort studies have investigated the relationship between OSAHS and stroke. In the Wisconsin Cohort Study, an AHI of greater than 20 was associated with an increased risk of stroke over 4-year follow-up (odds ratio, 4.31), although the odds ratio lost significance when corrected for age, body mass index, and sex.²⁹ In a study from Yale, after a mean follow-up of 3.4 years, an AHI of greater than 5 was associated with increased risk of stroke after adjustment for multiple confounders (hazard ratio, 1.97).³⁰ Both of these studies provide evidence that OSAHS is a risk factor for the development of stroke.
• A 2005 study found that OSAHS was associated with an increased risk of sudden death between the hours of midnight and 6 am, as compared with the general population (sudden death more common between 6 am and noon).³¹
• Recent evidence indicates that OSAHS is not an independent risk factor for the development of pulmonary hypertension in the absence of other lung disease, as evidenced by the presence of daytime hypoxemia, hypercapnia, or obstructive airways disease.

Race

The prevalence of sleep apnea in young black people (<25 y) appears to be greater than in white people. Recent evidence indicates that the prevalence in older age groups is similar between black people and white people, but the severity of OSAHS is worse in black people (ie, African Americans have higher AHIs).

Sex

The male-to-female ratio in community-based studies is 2-3:1.

• Three large epidemiologic studies have demonstrated that the prevalence of OSAHS in women appears to increase after menopause.^{10, 32, 33} In these studies, women taking hormone replacement therapy had a prevalence similar to that of premenopausal women.
• Premenopausal women with OSAHS tend to be more obese than men for the same severity of disease. Thin women with symptoms of OSAHS appear to have an increased frequency of craniofacial abnormalities.
• Evidence exists that women underreport the symptoms of loud snoring and witnessed apneas, leading to underreferral to sleep centers. This may explain the marked male predominance (approximately 8:1) in sleep-center–based studies.
• The AHI of women is less than that of men, even after correction for other demographic factors such as body mass index and neck circumference.^{34, 35, 36}

Age

The prevalence of OSAHS increases with age, with an estimated prevalence as high as 65% in a community sample of people older than 65 years. However, the significance of the incidental finding of OSAHS in elderly persons has been debated (see Elderly populations).

CLINICAL

Section 3 of 11  

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History

Symptoms generally begin insidiously and are often present for years before the patient is referred for evaluation.

• Nocturnal symptoms
• • Snoring, usually loud, habitual, and bothersome to others
  • Witnessed apneas that often interrupt the snoring and end with a snort
  • Gasping and choking sensations that arouse the patient from sleep
  • Restless sleep, with patients often reporting frequent arousals and tossing/turning during the night


• Daytime symptoms
• • Waking up without feeling refreshed
  • Morning headache, dry or sore throat
  • EDS that usually begins during quiet activities (eg, reading, watching television): As the severity worsens, patients begin to feel sleepy during activities that generally require alertness (eg, school, work, driving).
    
    
    • EDS is most frequently assessed by a sleep physician using the Epworth Sleepiness Scale (ESS). This is a questionnaire that asks how frequently the patient is likely to doze off in 8 frequently encountered situations.
    • An ESS score greater than 10 is generally considered sleepy. However, a recent study showed that an ESS score of 12 is associated with a greater propensity to fall asleep on the multiple sleep latency test (MSLT), suggesting that 12 would be a better cutoff (Punjabi, 2003).
    • The ESS does not correlate well with the primary objective measurement of sleepiness, the MSLT (see Other Tests)^{37, 38}, in that a higher ESS score does not mean shorter latencies on the MSLT. However, a higher ESS score does mean a greater likelihood of falling asleep on the MSLT (Punjabi, 2003).
    • The ESS is useful in evaluating the response to treatment. The ESS score should decrease with effective treatment.
  • Daytime fatigue/tiredness: Most patients who do not report EDS report being fatigued, having a lack of energy, or being tired during the day. In one study of 190 patients with OSAHS, patients were more likely to report lack of energy (62%), fatigue (57%), and tiredness (61%) than sleepiness (47%). When asked to choose their most significant symptom, 40% of patients chose lack of energy, compared with 22% for sleepiness.³⁹
  • Personality changes and problems with memory or concentration

Physical

The general physical examination is frequently normal for patients with OSAHS, other than the presence of obesity (defined as a body mass index greater than 30 kg/m²), an enlarged neck circumference, and hypertension. The upper airway should be evaluated in all patients, particularly in nonobese adults with symptoms consistent with OSAHS. Features associated with the presence of OSAHS are as follows:

• Neck circumference: A neck circumference greater than 43 cm (17 in) in men and 37 cm (15 in) in women has been associated with an increased risk of OSAHS.
• Mallampati score: This score has been used for many years to identify patients at risk for difficult tracheal intubation. The classification (see Media file 2) provides a score of 1-4 based on the anatomic features of the airway seen when the patient opens his or her mouth and protrudes the tongue. A 2006 study showed that for each 1-unit increase in the Mallampati score, the odds ratio of having OSAHS (defined by an AHI >5) increased by 2.5. In addition, the AHI increased by 5 events per hour.⁴⁰
• Narrowing of the lateral airway walls, which is an independent predictor of the presence of OSAHS in men but not women
• Enlarged (ie, "kissing") tonsils (3+ to 4+) (see Media file 3)
• Retrognathia or micrognathia
• Large degree of overjet
• High, arched hard palate

Causes

• Risk factors include the following:
• • Obesity
  • Age
  • Male sex
  • Craniofacial skeletal abnormalities, particularly in nonobese adults and children (see Physical)
  • Adenotonsillar hypertrophy, particularly in children and young adults
  • Alcohol use

DIFFERENTIALS

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Other Problems to be Considered

Chronic insufficient sleep
Obesity-hypoventilation (pickwickian) syndrome
Simple snoring

WORKUP

Section 5 of 11  

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Lab Studies

• Thyrotropin levels should be obtained in any patient with suspected OSAHS who has other signs or symptoms of hypothyroidism.
• Arterial blood gases should be measured in patients presenting with cor pulmonale to rule out daytime hypoxemia or hypercapnia.

Other Tests

• Polysomnography (overnight sleep study) is required to diagnose OSAHS. It is preferably performed in a sleep center, where specially trained technicians perform the tests. During polysomnography, multiple body functions are monitored.
• • Sleep stages are monitored with EEG, electrooculography, and chin electromyography.
  • Heart rhythm is monitored with single-lead ECG.
  • Leg movements are monitored with anterior tibialis electromyography.
  • Breathing is monitored by assessing airflow at the nose and mouth, effort, and oxygen saturation.


• The breathing pattern is analyzed for the presence of apneas and hypopneas. Standard definitions have been proposed but are still not consistently used by sleep centers (American Academy of Sleep Medicine Task Force, 1999).
• • Obstructive apnea is the cessation of airflow with persistent respiratory effort (see Media file 4).
  • Central apnea is the cessation of airflow with no respiratory effort (see Media file 5).
  • Mixed apnea is an apnea that begins as a central apnea and ends as an obstructive apnea (see Media file 6).
  • Hypopnea is defined very differently at different sleep centers; however, according to a recent consensus statement, hypopnea is a 30% or greater reduction in flow associated with a 4% drop in oxygen saturation. Many centers also score a hypopnea if a decrease in flow is associated with an arousal (see Media files 7-8).
  • Respiratory event–related arousal is a recently defined event. It recognizes cases in which a series of breaths with increasingly negative pleural pressure terminates with an arousal. These cases have no clear decrease in flow that would cause the event to be labeled an apnea or hypopnea; because this event cannot be scored if the esophageal pressure is not monitored, it is not used by many sleep centers.


• The AHI is derived from the total number of apneas and hypopneas divided by the total sleep time.
• • A normal cutoff for AHI has never been defined in an epidemiological study of healthy subjects. Most sleep centers use a cutoff between 5 and 10 events per hour.
  • The severity of OSAHS is defined arbitrarily and differs widely between centers. Recent recommendations for cutoffs are as follows:
    
    
    • Mild - AHI of 5-15 events per hour
    • Moderate - AHI of 15-30 events per hour
    • Severe - AHI of greater than 30 events per hour


• The polysomnography is often followed by an MSLT. The MSLT is considered an objective measure of EDS.
• • The MSLT consists of 4-5 naps of 20 minutes duration every 2 hours during the day. The latency to sleep onset for each nap is averaged to determine the daytime sleep latency.
  • Normal daytime sleep latency is greater than 10-15 minutes. OSAHS is generally associated with latencies less than 10 minutes.
  • The routine use of the MSLT in the evaluation of OSAHS is decreasing because sleep physicians generally treat OSAHS on the basis of the subjective symptoms reported by the patient.
  • The MSLT is helpful to rule out narcolepsy in patients in whom narcolepsy is a consideration. As opposed to people without narcolepsy, patients with narcolepsy have rapid eye movement sleep on at least 2 of the 4-5 naps during the day.


• Pulmonary function testing should be performed if any evidence of cor pulmonale is noted or if the nocturnal symptoms are suggestive of nocturnal asthma (patients wake up short of breath, which does not resolve immediately or is associated with wheezing).

TREATMENT

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Medical Care

The treatment of OSAHS partly depends on the severity of the sleep-disordered breathing. Patients with mild apnea have a wider variety of options, while those with moderate-to-severe apnea should be treated with a nasal CPAP device.

Conservative measures include weight loss, avoidance of alcohol for 4-6 hours prior to bedtime, and sleeping on the sides. These measures should be included in the treatment of all patients with OSAHS, but they should be used exclusively only in patients with very mild apnea whose main symptom is snoring. In a recent practice parameter, both weight loss and positional therapy were rated as "guidelines," indicating a patient care strategy with a moderate degree of evidence.⁴¹

• Nasal CPAP
• • CPAP is the most effective treatment for OSAHS, and it has become the standard of care. CPAP works by splinting the upper airway, preventing the soft tissues from collapsing. By this mechanism, it effectively eliminates the apneas and hypopneas, decreases the arousals, and normalizes the oxygen saturation (see Media file 9).
  • Most sleep center physicians still titrate the CPAP level during a sleep study. This can be conducted as a second night of study or during the second half of the diagnostic study (this type of study is called split-night polysomnography). Currently, CPAP devices are available that automatically change pressures based on the presence or absence of OSAHS. The exact indications for these devices are still being determined.
  • Recent Medicare guidelines specify criteria for ordering CPAP therapy for patients with OSAHS. All patients with an AHI greater than 15 are considered eligible for CPAP therapy, regardless of symptomatology. For patients with an AHI of 5-14.9, CPAP therapy is indicated only if the patient has one of the following: EDS, hypertension, or cardiovascular disease.
  • CPAP has been shown to improve daytime sleepiness, mood, and cognitive function in people with both mild and moderate apnea. CPAP has also been shown to increase quality of life and decrease health care costs. Some data indicate that CPAP decreases blood pressure, primarily in patients with severe OSAHS.^{42, 43, 44} Evidence also suggests that CPAP may improve left ventricular ejection fraction in patients with congestive heart failure and OSAHS.⁴⁵
  • The most common adverse effects of CPAP are dry mouth, rhinitis, and sinus congestion. These can be treated effectively with humidification and antihistamines and/or nasal steroids.
  • Unfortunately, compliance is a major problem, with only approximately 50% of patients using the CPAP device on a regular basis. However, some evidence indicates that these patients will continue to use CPAP on an indefinite basis.
• Oral appliances
• • These dental devices act by moving the tongue or mandible forward, enlarging the posterior airspace. Multiple different devices are available on the market. The American Academy of Sleep Medicine has recently published practice parameters and a review of the use of oral appliances in persons with OSAHS.^{46, 47}
  • Multiple small cohort studies have shown that these devices effectively lower the AHI and improve overnight sleep architecture. The recent American Academy of Sleep Medicine review identified 4 factors that influenced the efficacy of oral appliances: (1) mild-to-moderate disease (AHI <30), (2) lower body mass index, (3) increased mandibular protrusion with the device, and (4) the presence of positional OSAHS.
  • Several studies have directly compared treatment with CPAP to treatment with oral appliances. In general, these studies show that CPAP is more effective than oral appliances for lowering the AHI to less than 5-10 events per hour. However, many other outcomes, such as sleepiness and cognitive functioning, are not different between the 2 devices. When asked which device the participant would use at home, the responses varied; in some studies, the participants favored CPAP and in others they favored the oral appliance.
  • Recent guidelines recommend that oral appliances are indicated for (1) patients with mild or moderate OSAHS who prefer oral appliances to CPAP devices, (2) patients with mild or moderate OSAHS who do not respond to CPAP therapy, and (3) patients with mild or moderate OSAHS in whom treatment attempts with CPAP devices fail.
  • Oral appliances should not be considered effective therapy for patients with severe OSAHS.

Surgical Care

Surgical correction of the upper airway is still performed but is not considered primary therapy for OSAHS. The theoretic advantage of surgery is that if the patient is cured; compliance with CPAP or an oral appliance is no longer an issue. However, a primary reason that surgery has not become a standard therapy is the lack of long-term outcome studies that show that the surgical correction continues to be effective 5 or more years after it is performed.

Factors that increase the likelihood of successful surgery include (1) lower AHI, (2) lower body mass index, (3) the location of collapse (Surgeries targeted specifically to collapse at either the nasopharynx or oropharynx improve outcome.), (4) the degree of mandibular protrusion (Better outcomes are achieved in patients with clear deficiencies.), and (5) the presence of fewer comorbidities.

• The reader is referred to a review of surgical procedures for a full listing of possible surgeries.⁴⁸ Surgeries include the following:
• • Uvulopalatopharyngoplasty (UPPP) is resection of the uvula and soft palate. It is effective in approximately 40% of patients, but predicting which patients will benefit from the procedure is problematic. Long-term, patients with treatment success often present with a recurrence of symptoms, especially if they continue to gain weight.
  • Craniofacial reconstruction involves advancement of the tongue (ie, geniohyoid advancement with hyoid myotomy [GAHM]) or maxillomandibular bones (ie, maxillomandibular osteotomy [MMO]). These surgeries should be performed only at centers with expert personnel. Short-term success rates are approximately 70% for GAHM and 95% for MMO. No good long-term studies have been performed to evaluate the success for either GAHM or MMO.
  • Tracheostomy provides definitive correction because it bypasses the obstruction. It is recommended for patients with very severe OSAHS, especially if he or she cannot tolerate CPAP or has cor pulmonale.
• Several studies have compared surgery with both CPAP and oral appliances.
• • In one randomized study comparing temperature-controlled radiofrequency tissue ablation of the tongue with CPAP, CPAP was more effective at lowering the AHI but no differences were noted in functional outcome measures, such as sleepiness, at approximately 1 month of treatment.⁴⁹ In a retrospective cohort study, UPPP was found to be associated with decreased mortality compared with CPAP⁵⁰ over a 3-5 year period of follow-up.
  • One long-term outcome study has compared UPPP with oral appliance therapy. In this study, 63% of the oral appliance subjects had a normal AHI at 4-year follow-up, compared with only 33% for the UPPP subjects.⁵¹
• Patients should be considered for surgery primarily if multiple attempts at therapy with CPAP have failed and if an oral appliance is not an option. If the patient opts for surgery, ensure the following:
• • Surgery should be performed by a qualified ear, nose, and throat surgeon.
  • Surgery should be based on the location of collapse.
  • Patient should be willing to undergo combination or multiple surgeries.
• For additional reading on surgery in OSAHS, the reader is referred to a 2005 pro-con debate in the Journal of Clinical Sleep Medicine by Powell (Upper Airway Surgery Does Have a Major Role in the Treatment of Obstructive Sleep Apnea: "The Tail End of the Dog") and Phillips (Upper Airway Surgery Does Not Have a Major Role in the Treatment of Sleep Apnea).
• Bariatric surgery as therapy for OSAHS has been investigated in several nonrandomized, uncontrolled studies, with most showing a decrease in the AHI with weight loss. The recent practice parameter on medical therapies for OSAHS lists bariatric surgery as an option for OSAHS, although with limited evidence.⁴¹

Consultations

• All patients with signs or symptoms of OSAHS should be referred to a sleep-disorder center for an evaluation by a sleep physician and for polysomnography. A comprehensive sleep evaluation is recommended because as many as 25% of sleep-disordered patients have more than one sleep disorder, many of which are identified only because of the sleep consultation.
• Any patient with loud, habitual snoring and any other feature of OSAHS who is being considered for surgery should be referred for a sleep study prior to surgery. This is important to rule out OSAHS because the surgery will probably correct the snoring but may not correct the apnea/hypopneas, which are associated with other morbid conditions.

Diet

All patients who are obese should be counseled about the importance of diet and exercise and should be referred to a dietitian and/or weight loss program.

MEDICATION

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The American Academy of Sleep Medicine recently published a practice parameter and review of the medical therapies of OSAHS.^{41, 52} Use of protriptyline for OSAHS was listed as a guideline (patient-care strategy based on level 2 or 3 evidence).

The use of modafinil is recommended for the treatment of residual sleepiness in persons with OSAHS and was considered a standard treatment (generally accepted patient-care strategy with level 1 or excellent level 2 evidence).

The parameters state as standards that selective serotonin reuptake inhibitors, methylxanthines, and estrogen replacement therapy should not be considered for the treatment of OSAHS.

Drug Category: Tricyclic antidepressants

Protriptyline in low doses has been used in people with mild apnea and snoring with mild success. Increases upper airway neuromuscular activity and decreases rapid eye movement sleep. Protriptyline is not considered primary therapy for OSAHS.

Drug Category: Central nervous system stimulants, nonamphetamine

Used for treatment of fatigue without interfering with normal sleep architecture. They promote wakefulness.

The US Food and Drug Administration recently approved the use of modafinil (Provigil) for the management of residual EDS in patients with OSAHS who are on nasal CPAP therapy. The approval was based on several recent studies on the use of modafinil in this patient population.^{53, 54, 55}

The largest of these studies was a double-blinded, randomized, placebo-controlled study.⁵⁴ Subjects received either placebo or modafinil (200 mg/d in week 1, 400 mg/d in weeks 2-4) for 4 weeks. Subjects had an AHI greater than 15, ESS greater than 10, and CPAP use for more than 4 hours per night or for more than 5 of 7 nights during 3 weeks of home monitoring. One hundred fifty-seven patients were randomized (77 modafinil, 80 placebo), with 143 completing the study (66 modafinil, 77 placebo). The primary efficacy measures were ESS, daytime sleep latency based on MSLT results, and CPAP use. Both the ESS and daytime sleep latency improved in the modafinil group. No difference was noted in CPAP use between groups. A more recent randomized, double-blinded study of modafinil versus placebo for 12 weeks showed that the efficacy of modafinil as measured subjectively by the ESS and objectively by the maintenance of wakefulness test did not change over an extended period (12 wk).

Concern exists that the use of modafinil (or other stimulants) in the management of OSAHS may result in decreased CPAP usage. This is important because stimulants do not control the sleep-disordered breathing, resulting in worsening symptom control and potentially increasing the risk of cardiovascular morbidity. The 2 largest trials^{54, 56} did not show a decrease in CPAP usage in patients who used modafinil. However, decreased CPAP usage was noted in the smaller randomized study of modafinil⁵³ and in an open-label extension trial⁵⁵. Therefore, if a patient is prescribed a stimulant, CPAP compliance must be closely monitored.

The effectiveness of modafinil in this clinical situation has been confirmed by a second randomized study.⁵⁶

Drug Name	Armodafinil (Nuvigil)
Description	R-enantiomer of modafinil (mixture of R- and S-enantiomers). Elicits wake-promoting actions similar to sympathomimetic agents, although pharmacologic profile is not identical to sympathomimetic amines. In vitro, binds dopamine transporter and inhibits dopamine reuptake. Not a direct- or indirect-acting dopamine receptor agonist. Indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.
Adult Dose	150 mg PO qam; may increase dose, not to exceed 250 mg/d
Pediatric Dose	<17 years: Not established >17 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Weakly induces CYP1A2 and CYP3A; may decrease levels of drugs metabolized by CYP1A2 (eg, theophylline) and CYP3A (eg, cyclosporine, midazolam, triazolam, steroidal contraceptives); may inhibit CYP2C19 activity, thereby increasing serum levels of CYP2C19 substrates (eg, omeprazole, phenytoin, propranolol)
Pregnancy	C - Safety for use during pregnancy has not been established
Precautions	Caution in hepatic impairment and decrease dose with severe hepatic impairment; serious rash, including Stevens-Johnson syndrome, has been reported; other serious hypersensitivity reactions include angioedema, anaphylactoid reactions, and multiorgan hypersensitivity reactions; psychiatric adverse events (eg, mania, delusions, hallucinations, suicidal ideation) have been reported with modafinil; may increase blood pressure; monitor patients closely for signs of misuse or abuse, especially those with a history of drug or stimulant abuse (eg, methylphenidate, amphetamine, or cocaine)

FOLLOW-UP

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Further Outpatient Care

• Once OSAHS is diagnosed and nasal CPAP therapy is started, patients require regular follow-up visits with a sleep specialist. Most patients are seen within 2 months of initiating CPAP therapy to determine if it has been effective in alleviating symptoms, to troubleshoot problems preventing regular use of the CPAP device, and to reinforce the importance of daily use. Further follow-up depends on whether the CPAP has been effective.
• • If CPAP is effective, the patient is generally seen at 6- to 12-month intervals to troubleshoot new problems, to reinforce daily use, and to be certain the CPAP remains effective.
  • If CPAP has not been effective, problems preventing effectiveness are identified and steps are taken to eliminate problems; the patient then is seen at 2- to 3-month intervals until the patient is using CPAP regularly and symptoms are alleviated. Repeat titration may be necessary.
  • Repeat polysomnography generally is not indicated for patients who report improved symptoms. CPAP device titrations are usually repeated (1) in patients without effective relief of their symptoms despite intervention and (2) in patients who had relief of symptoms but present months to years after reporting the return of symptoms, generally in association with weight gain.


• Management of residual EDS is as follows:
• • Residual EDS after treatment with CPAP is a commonly encountered problem for the physician. An exact percentage of patients has not been determined but was estimated at 5% in one study.⁵⁷
  • Residual EDS is generally considered present if the ESS score remains higher than 10 after treatment.
  • If present, a series of questions must be asked to determine the etiology of the sleepiness. The residual sleepiness should never be considered idiopathic until all questions have been answered satisfactorily. The algorithm used by the authors can be found in Media file 10.
    
    
    • Question 1: Is the patient compliant with CPAP? Compliance has been generally defined in the modafinil studies as more than 4 hours of use at least 5 nights per week. Patient self-reporting may not be adequate to determine compliance. Objective monitoring with one of the newer CPAP units that measures compliance may be necessary. If identified, work with the patient to improve compliance.
    • Question 2: Is the titration pressure adequate? This is particularly important in 2 situations. The first is if the patient had a difficult first titration, resulting in a prescription that may not be adequate to relieve symptoms. The second is if symptoms develop months to years after initial relief, generally due to weight gain. In both cases, repeat titration is recommended. Some authorities advocate autotitration CPAP units in these situations.
    • Question 3: Is the patient sleeping sufficiently or performing shift work? Chronic insufficient sleep and shift work are 2 of the more common causes of sleepiness. In both cases, the patient must be counseled to sleep more.
    • Question 4: Is the patient taking any medications that cause sleepiness? The most common medications causing this are over-the-counter antihistamines. Other common agents are tricyclic antidepressants, benzodiazepines, narcotics, and many neurologic and psychiatric medications.
    • Question 5: Does the patient have evidence of another sleep disorder that could cause sleepiness? A full evaluation by a sleep physician can often determine a second sleep disorder, such as narcolepsy or periodic limb movement disorder.


• If a patient opts for upper airway surgery or a dental device, he or she requires repeat polysomnography after surgery or with the device in place to be sure that OSAHS has been effectively treated.

Prognosis

• The short-term prognosis, in relation to symptoms such as daytime sleepiness and snoring, is good to excellent with regular use of CPAP.
• Several studies, including placebo-controlled studies, have shown significant improvement in measures of cognitive function and general health status (as measured by the Short-Form 36) after 4-8 weeks of treatment with CPAP. However, studies have not been performed in a large population or for more than a 4- to 8-week treatment period.
• Because no randomized treatment studies have investigated the effect of CPAP for preventing the development of cardiovascular sequelae, the long-term prognosis is unknown.

Patient Education

• All patients with OSAHS should receive education about sleep and proper sleep hygiene, OSAHS, and the risks of driving while sleepy. They should also receive education regarding the role of nasal CPAP and the importance of daily use.
• For excellent patient education resources, visit eMedicine's Ear, Nose, and Throat Center; Mental Health and Behavior Center; and Sleep Disorders Center. Also, see eMedicine's patient education articles Snoring, Fatigue, Insomnia, Sleep Disorders and Aging, and Sleep Disorders in Women.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Driving and sleep apnea
• • The frequency of motor vehicle accidents is increased in patients with OSAHS, particularly in patients with severe OSAHS. These patients pose a hazard to themselves and to other drivers. Public policy in this area is controversial.
  • One approach to this problem is the concept of shared responsibilities. The physician has the responsibility of educating the patient about the risks of driving while sleepy or inattentive. That the patient acknowledges this education by signing a statement to that effect has been suggested. After being properly educated, the patient assumes the responsibility not to drive while sleepy and preferably not until he or she has started treatment for OSAHS.
  • Physicians are referred to their individual state motor vehicle departments for local guidelines. As of 1995, only Maine, Texas, and California had proposed actual guidelines for driving and OSAHS. Canada and the United Kingdom also have specific guidelines.
  • Theoretically, US federal regulations regarding commercial motor carrier safety include guidelines that, if interpreted broadly, would exclude truck drivers with OSAHS. However, OSAHS is not mentioned specifically, so the individual physician's discretion is required. Canada and the United Kingdom require a period of satisfactory treatment before allowing truck drivers to resume driving.

Special Concerns

• Elderly populations
• • The prevalence of OSAHS increases with age. However, the clinical significance of OSAHS in healthy, community-dwelling people has been questioned because these people do not show significant sequelae (eg, sleepiness).
  • Elderly patients presenting to sleep centers for evaluation present with similar symptomatology (including EDS) and polysomnographic results as nonelderly patients, except that elderly patients underreport snoring as a chief complaint, they tend to have less obesity, and they are less objectively sleepy on the MSLT.
  • Thus, all elderly people, particularly if overweight, should be questioned about snoring, witnessed apneas, and daytime sleepiness and should be referred for evaluation if necessary.


• Pediatric populations
• • OSAHS in children has an estimated prevalence of 2%, affecting boys and girls in equal numbers.
  • Children most often present with loud snoring and symptoms and signs of adenotonsillar hypertrophy.
  • EDS is not a common symptom in children with OSAHS. Instead, school-aged children often report problems with schoolwork. Studies have shown improvement in cognitive function and grades after adenotonsillectomy in children with OSAHS.^{58, 59, 60}
  • Evidence also suggests an association between attention-deficit/hyperactivity disorder and OSAHS in children.^{61, 62}
  • Adenotonsillar hypertrophy is the predisposing factor in most cases, although obesity is becoming a more common factor as the prevalence of obesity in children increases.
  • Craniofacial syndromes (eg, Pierre Robin syndrome) and trisomy-21 (Down syndrome) are also predisposing factors in children.
  • Resection of the enlarged tonsils is the standard therapy for most children presenting with OSAHS; CPAP use is becoming more common as more children with obesity and craniofacial syndromes are recognized to have OSAHS.


• Pregnancy
• • Several case reports have associated intrauterine growth restriction in the fetuses of pregnant women with concomitant, untreated OSAHS. Very recent evidence suggests that the rate of preeclampsia is higher in snoring women. All pregnant women with signs and symptoms of OSAHS should be evaluated and started on CPAP therapy to prevent this complication.
  • Note, however, that while the incidence of self-reported snoring increases in pregnant women, the prevalence of OSAHS was not higher in one study. Thus, pregnant women should be referred for evaluation only if the snoring is loud, habitual, and associated with other symptoms of OSAHS.


• Long-haul truck drivers
• • Commercial truck drivers have an increased prevalence of OSAHS, as well as irregular sleep/wake schedules, both of which may have an impact on alertness.
  • Snoring and sleepy truck drivers should be referred for evaluation.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Potential relationship between obstructive sleep apnea-hypopnea syndrome (OSAHS) and the metabolic syndrome. OSAHS has been associated with 3 of the 5 major clinical abnormalities associated with the metabolic syndrome: hypertension, insulin resistance, and proinflammatory/oxidative stress. OSAHS may be contributing to and/or modulating the severity of these metabolic abnormalities.
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Media file 2:  The Mallampati score has been used for many years to identify patients at risk for difficult tracheal intubation.
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Media file 3:  Tonsil grades.
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Media file 4:  Obstructive apnea: Note the absence of flow despite respiratory effort.
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Media file 5:  Central apnea: Note the absence of both flow and respiratory effort.
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Media file 6:  Mixed apnea: Note that the apnea begins as a central apnea (effort absent) and ends as an obstructive apnea (effort present).
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Media file 7:  Hypopnea: Note that the flow is decreased and that a desaturation follows this decreased flow; the hypopnea is followed by a central apnea.
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Media file 8:  A 2-minute recording of sleep showing 3 hypopneas and associated oxygen desaturations. This recording illustrates the recurrent nature of the sleep-disordered breathing observed in many patients.
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Media file 9:  Effect of nasal continuous positive airway pressure (CPAP) on oxygen saturation in sleep apnea. The upper portion of this figure shows the raw oxygen saturation trace from one night of a sleep study. Below the raw trace are vertical lines that indicate the presence of either an apnea or hypopnea. Before CPAP, frequent respiratory events with significant desaturations occurred. During the night, CPAP was applied, resulting in the elimination of the apnea and hypopneas and normalization of the oxygen trace.
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Media file 10:  Approach to a patient with excessive daytime sleepiness after treatment with nasal continuous positive airway pressure.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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