Sleep Apnea

Document Sample
Sleep Apnea Powered By Docstoc
					                                 SLEEP APNEA

Pat J. Strollo, Jr., M.D.


   1. To be able to explain the pathophysiologic abnormalities that lead to
   2. To be able to list the cardiovascular, metabolic, and neurocognitive
      complications of OSAH
   3. To be able to describe the major symptoms and signs of OSAH


The focus of this review will be on the diagnosis and management of obstructive
sleep apnea / hypopnea syndrome (OSAH) in adults. This is a common clinical
problem that is associated with significant morbidity and mortality. It is relatively
easily diagnosed and treated. The spectrum of obstructive sleep disordered
breathing will be discussed.


The clinical condition of Obstructive Sleep Disordered Breathing includes
obstructive apnea (OSA) and obstructive hypopnea. An obstructive apnea is
defined as the lack of airflow measured at the nose and mouth for 10 seconds or
longer during sleep despite ongoing effort to breathe. This is usually associated
with a decrease in the oxyhemoglobin saturation and a change in the
electroencephalogram (EEG) indicating arousal from sleep. An obstructive
hypopnea is defined as a decrease in airflow (generally > 30%) at the nose and
mouth despite ongoing effort to breathe. These events are also associated with
a decrease in the oxyhemoglobin saturation and a change in the EEG indicating
arousal from sleep [1] (figure 1).

A variety of methods are available to measure airflow cessation (apnea) and
limitation (hypopnea) during sleep. In 1999, the American Academy of Sleep
Medicine examined the evidence available for the precision of measuring sleep
disordered breathing events and attempted to establish a consensus for the
definitions of obstructive sleep apnea and obstructive sleep hypopnea [2].
Apneas in adults are easily identified even with simple monitoring devices such
as thermal sensors (thermisters or thermocouples). This is not the case for
airflow limitation (i.e. hypopnea). The accuracy of measuring airflow limitation
can be substantially influenced by the method of measurement.

On polysomnography (PSG), both apneas and hypopneas are commonly
associated with changes on the EEG as a marker of sleep disruption. However,
the intra- and inter-rater reliability of visually scoring arousals is variable.
Including arousal criteria for scoring hypopneas has not led to an increase in
precision [3]. This has led to a refined operational definition of Sleep Hypopnea.
In current clinical practice, hypopneas that are associated with > 4 %
desaturations, without arousal criteria, are accepted as physiologically significant
events. Neurocognitive and cardiovascular outcomes identified primarily in the
Sleep Heart Health Study have provided the rationale for combining apneas and
hyponeas together as an apnea / hypopnea index (AHI) in order to rate
syndrome severity [2, 4, 5].

Mild OSA is defined as an AHI between 5 and 15 events per hour of sleep.
Moderate OSA is defined as an AHI of 15 to 30 events per hour of sleep. Severe
OSA is defined as an AHI of greater than 30 events per hour of sleep. In order to
satisfy the criteria for syndrome definition, the clinical complaint of disturbed
sleep and / or daytime sleepiness should be present (Table 1).


The epidemiology of the OSA/H has been well described in North America and
Europe [6]. In predominately Caucasian middle-aged cohorts, the prevalence of
the OSAH defined as AHI > 10 plus symptoms of daytime sleepiness and / or
hypertension is approximately 5%.

Clinical studies indicate an increased risk in men, with a prevalence of 3.3:1
compared to women [7]. The prevalence of OSAH in middle aged individuals
has been reported to be 4% for men and 2% for women [8].

Menopause appears to with increase the risk of OSAH, as does obesity. In a
central Pennsylvania population, Bixler et al. reported a prevalence of 2.7% in
postmenopausal women without hormonal replacement therapy as opposed to
0.6% in the premenopausal population [7]. Preliminary data suggest that the
prevalence of OSAH may be higher in African Americans as opposed to the
Caucasians [9].

In a longitudinal family study, Redline has reported the five year incidence for
mild OSAH (AHI > 10 < 15) to be 7.5 % and moderate to severe OSAH (AHI >
15) to be 16% [10]. Advancing age and increasing weight independently
increase the risk of OSAH [6]. The age effect appears to plateau after age 65
(figure2) implying that there may be an increase in mortality in middle age or
possibly remission of OSAH in the elderly population [11].


The upper airway in humans is able to perform a variety of complex functions,
including breathing, swallowing, and speaking. This is possible in part, because
of the lack of rigid support from bone or cartilaginous tissue in the retro-palatal

and retro-lingual airway (figure 3). When increased negative intrathoracic
pressure results in a suction force applied to a small, compliant, upper airway,
narrowing (hypopnea) or closure (apnea) may occur. This is frequently
accompanied by vibration of these structures that produces snoring sounds.
The primary cause for airway closure during sleep is a small airway. Craniofacial
structure and function, in addition to obesity, are the major determinants of a
small airway in adults. Individuals with OSAH are able to maintain airway
patency during wakefulness. When transition occurs from wake to the sleeping
state, muscle tone decreases and snoring, airway narrowing and /or closure may
occur in individuals with a “vulnerable airway” (figure 4).

The uniform stimulus for resumption of normal breathing is a ventilatory related
arousal from sleep [12]. The arousal can usually be identified on the EEG
channel when sleep and breathing are measured in the laboratory. The
ventilatory related arousal may be precipitated by increased airway resistance
(usually associated with snoring), hypopnea, or apnea.

Other important physiologic perturbations occur in conjunction with the sleep
disordered breathing events. Struggling against a partially or completely closed
airway is associated with increased intrathoracic pressure, hypoventilation, and
increased vagal tone. The ensuing arousal is accompanied by augmentation of
sympathetic tone. These phenomena have acute and chronic effects on
cardiovascular function. Acute changes are manifest as bradycardia followed by
tachycardia (i.e. heart rate variability). Over time, sympathetic tone is up-
regulated not only nocturnally but also diurnally. [13].

Intermittent hypoxemia is also a hallmark of OSAH. Recent data suggest that the
ischemia-reperfusion associated with intermittent hypoxemia results in
transcription and translation of bio-markers of oxidative stress and subsequent
endothelial dysfunction [14]. A number of these bio-markers, such as C-reactive
protein and Interleukin 6, have been linked to risk and progression of
cardiovascular disease in addition to altered metabolic function.


OSAH is associated with significant co-morbidities that are the result of the
altered nocturnal physiology. These co-morbidities can be broadly grouped into
three categories that include cardiovascular, metabolic, and neurocognitive
complications (table 1). Recent observational studies have established that
these co-morbidities appear to have a dose response effect with regard to the
severity of OSAH. Data now demonstrate that adequate treatment of OSAH,
primarily with positive pressure, favorably impacts these co-morbidities (see
therapy section below). While one or all of the co-morbidities may affect an
individual patient, each category will be discussed separately for clarity.

Cardiovascular Complications

The normal cardiovascular response to sleep, including a physiologic decrease in
blood pressure and heart rate, is negatively impacted in OSAH. Acute and
chronic physiological effects related to sleep disordered breathing occur.
The repetitive bursts of sympathetic activity triggered by the sleep disordered
breathing events adversely affect nocturnal blood pressure and heart rate. Over
time, a profound toll is taken on the cardiovascular system. Risk is increased for
diurnal systemic hypertension, diurnal pulmonary hypertension, atrial
dysrhythmias, heart failure (systolic and diastolic), myocardial infarction, and

Cross sectional observational studies suggest a link between the AHI and
cardiovascular complications [5, 15]. The best evidence linking OSAH to
cardiovascular complications exists for diurnal systemic hypertension. After
controlling for known confounding risk factors for the development of
hypertension (smoking, alcohol weight, age, and sex), a dose response
relationship exists between apnea and hypopnea and incident hypertension over
a four-year period [15] (figure 5).

Metabolic Complications

A number of investigators have identified the presence of metabolic
dysregulation in patients with OSAH. There is a dose response relationship
between the AHI and bio-markers of the metabolic syndrome (serum glucose and
insulin sensitivity). This relationship persists after controlling for concomitant
obesity [16]. Leptin, an adipokine that appears to play an important role in
metabolic and ventilatory control, is elevated in OSAH [17]. Leptin inhibits the
synthesis of neuropeptide Y, a potent stimulator of food intake. Obese
individuals typically have elevated circulating leptin levels suggesting leptin
resistance. The elevated leptin levels are not explained by obesity alone. Leptin
levels in patients with OSAH are elevated compared to matched obese controls,
suggesting a direct effect of sleep disordered breathing [17].

Neurocogniitve Complications

One of the defining features of the OSAH syndrome is daytime sleepiness.
There is a dose response relationship between the severity of sleep disordered
breathing and the complaint of daytime sleepiness [4] (figure 6). There is now
strong evidence that the severity of OSAH also correlates with the risk of motor
vehicle and occupational accidents. Terán-Santos et al. examined the risk of
motor vehicle accidents using a case control design [18]. After adjusting for a
number of confounding variables to include body-mass index, alcohol
consumption, eyesight, medications, driving experience, and sleep schedule,
subjects with a AHI of > 10 had a 7.2 odds ratio for having a traffic accident.
Linberg et al. prospectively evaluated the risk of occupational accidents in sleepy

snorers over a ten-year period [19]. In this community sample of over 2000 men,
the risk for occupational accidents in sleepy snorers was 2.2 times that of the
control population.

Neuropsychological performance in OSAH has been examined by a number of
investigators. Beebe et al. recently performed a meta-analysis of the studies
dealing with neuropsychological functioning in adults with untreated OSAH [20].
The analysis involved 25 studies that met inclusion criteria with a total of 1092
patients and 899 controls. Untreated OSAH was associated with significant
impact on vigilance, executive functioning, and coordination. There was
negligible impact on intellectual and verbal functioning.

The association between depression and OSAH has also been studied by a
number of investigators, but the data linking OSAH to depression is conflicting
[21]. A recent analysis of a large managed care database examined the
relationship between prescriptions for antidepressant and antihypertensive
medications and a diagnosis of OSAH [22]. The investigators identified a
significant increase in the prevalence odds ratio (POR) for OSAH in patients
prescribed either an antidepressant or an antihypertensive medication. The
highest prevalence of OSAH was identified in young men and women (age 20 –
39 years) receiving both medications.

Sleepiness and impaired cognitive function undoubtedly impact on quality of life.
Large effect sizes have been reported for the impact of OSAH on both generic
(Nottingham Health Profile and SF-36) and disease specific quality of life
measures [23]. In the generic measures, multiple domains are impacted.

Controlled trials involving treatment of OSAH have demonstrated reversibility in
measures of sleepiness, cognitive function, and quality of life [23]. These
treatment data provide additional evidence for the biologic plausibility of the
relationship of OSAH to neurocognitive impairment.


A number of clinical clues increase the probability of diagnosing OSAH. Findings
in the history and the physical exam can help the clinician select patients for
physiologic testing to confirm the diagnosis and assess its severity.

Clinical Presentation

A number of findings on the history and physical are associated with the
presence of OSA (Table 2). The signs and symptoms of nightly loud snoring,
breathing pauses during sleep, snorting, choking, or subjective daytime
sleepiness all suggest the diagnosis of OSAH. Obesity (particularly upper body
obesity) and systemic hypertension may be present. In selected individuals,
craniofacial abnormalities (retro or micrognathia) and/or soft tissue abnormalities,

such as enlarged tonsils, lateral narrowing of the airway, or an elongated soft
palate, may place the patient at risk for airway closure during sleep [24, 25].
Signs of right sided heart failure in the absence of established heart disease may
be associated with occult OSAH [26]. Unfortunately, these findings alone or in
combination do not provide sufficient precision to confirm a diagnosis of OSAH
[24, 27].

Laboratory Testing

Objective measurement and quantification of sleep and breathing in a sleep
laboratory is currently the standard for confirming a diagnosis of OSAH in the
United States. Sleep stages are identified in addition to the degree of sleep
disruption that is due to sleep disordered breathing events.

Sleep is analyzed by measuring electoroencephalographic (via a central lead),
bilateral electrooculographic, and submental electromyographic (chin) activity.
Cardiopulmonary parameters are measured, including airflow, breathing effort,
oximetry, and electrocardiogram. Sensors are applied to the legs in order to
identify periodic leg movements that may be responsible for disrupting sleep
(Figure 7).


Relevant lifestyle interventions should be pursued in all patients. Positive
pressure administered via a mask remains the initial treatment of choice. Second
line therapy can involve oral appliance therapy and, in selected patients, upper
airway surgery.

Lifestyle Interventions

As noted above, obesity is a major risk factor for OSAH. Weight loss has been
demonstrated to improve both sleep and breathing [28]. Avoiding sleep
deprivation will not only decrease daytime sleepiness related to sleep debt but
also increase upper airway muscle tone. Alcohol and sedatives also negatively
affect upper airway muscle tone. The magnitude of the impact of sedatives on
the unstable upper airway is not well defined. If the patient has clearly has
positional OSAH, lateral positioning or head of bed elevation may be helpful.

Positive Pressure Therapy

Positive pressure reliably treats airway closure during sleep. It works primarily by
“pneumatically splinting” the airway open during sleep (figure 8). When a proper
positive pressure prescription is performed, the treatment effect is virtually

Positive pressure can be applied as continuous positive airway pressure (CPAP)
or as bi-level positive airway pressure (BPAP). With BPAP, the pressure setting
during inspiration is higher than expiration, taking advantage of the fact that
during inspiration the airway pressure is more negative than during expiration.
This is accomplished by the machine sensing changes in airflow associated with
breathing. Both CPAP and BPAP machines are electrically operated and are
highly portable, usually weighing less than 10 pounds.

Of all the treatment options for OSAH, positive pressure therapy (primarily
CPAP) has been the most rigorously studied. Placebo controlled, randomized
clinical trials have documented a favorable effect on quality of life, objective
daytime function, and blood pressure. Emerging data indicates that CPAP
improves insulin sensitivity, left ventricular function, pulmonary hypertension,
endothelial function, and cardiovascular and overall mortality.

Despite its effectiveness, objective adherence to therapy is similar to most
medical regimens at approximately 50% without structured educational
interventions. Acceptance and adherence to positive pressure can be improved
with patient education and appropriate attention to patient – machine related
problems. In general, CPAP or BPAP is delivered via a nasal interface. Proper
fit is essential. Nasal congestion and / or dryness need to be treated. Patients
with OSAH frequently report symptoms of nasal congestion prior to treatment.
This problem can be exacerbated by positive pressure therapy. The airflow
through the nose at flow rates of 30 to 60 liters per minute (depending on the
seal) can be drying to nasal mucosa. This frequently triggers rebound nasal
congestion that precipitates mouth breathing. When the mouth opens, the
machine increases the flow to maintain the set pressure exacerbating the
congestion. Heated humidifiers in-line with the CPAP/BPAP unit can frequently
improve the nasal dryness and subsequent congestion. Occasionally, a mask
that covers both the nose and mouth can be helpful. In patients who are
claustrophobic, desensitization may be helpful.

Oral Appliance Therapy

The goal of oral appliance therapy (OAP) is to modify the position of the
mandible and the tongue in order to increase the upper airway size and favorably
affect collapsibility. OAP should be regarded as second line therapy for OSAH.
The primary reasons are as follows: 1) Effective treatment requires multiple
adjustments that require weeks to months to accomplish, 2) Treatment is not
100% effective, 3) Objective adherence cannot be measured.

High quality studies on the effectiveness of OAP are limited [29]. Subjective
sleepiness and sleep disordered breathing are favorably impacted when
compared to control. A recent randomized controlled trial has demonstrated a
favorable effect on blood pressure [30]. When compared to positive pressure,
patients frequently prefer OAP to CPAP/BPAP.

Oral appliances for adults can be divided into two basic types – tongue retaining
devices (TRD) and mandibular advancement devices (MAD). TRDs apply
suction to the anterior portion of the tongue to maintain tongue protrusion and
increase in the retrolingual airway. In addition, a degree of downward rotation of
the mandible is achieved. They can be used in edentulous patients. Many
patients are bothered by the bulk of the TRDs, which negatively impacts
adherance. Adjustable MADs are more comfortable and generally yield better
results than nonadjustable “boil and bite” appliances. Sequential adjustment
requires weeks to accomplish and as a result, limits the utility of MADs in severe
OSAH that requires expeditious treatment. Randomized controlled trials have
demonstrated that optimal therapy is achieved in approximately one third of the
subjects studied [31]. Case series data suggest that patients who respond best
are those with mild OSAH, supine-dependent OSAH, and snoring [32].

It now clear that there are contraindications and complications associated with
MAD treatment. Contraindications include insufficient tooth number, substantial
tooth mobility, untreated periodontal disease, and active temporomandibular joint
syndrome [33]. Side effects are usually mild and infrequently require
intervention. Common side effects are mucosal dryness, tooth discomfort, and
hypersalivation [34]. MADs are known to change occlusion over time. Regular
dental follow-up is mandatory in patients using these devices long term.

Surgical Therapy

Surgical therapy has a small but definite role in the management of OSAH in
adults. While palatal surgery alone is useful in treating primary snoring, it is
rarely effective in treating OSAH. There is a lack of well designed studies in the
literature to definitively evaluate the effect of upper airway surgery on OSAH [35].
A number of case series provide some support for surgery as a treatment option.
Surgery therapy can be broadly divided into two categories: 1) tracheostomy
(bypass of the upper airway) and 2) reconstruction of the upper airway.

Tracheostomy was the original treatment for OSAH. CPAP/BPAP have largely
replaced tracheostomy as the treatment of choice for severe OSAH. There
remains a small group of patients with severe and potentially life-threatening
OSAH who are intolerant of CPAP/BPAP who require trachesotomy.
Although the appearance of the tracheostomy can result in psychological and
social morbidity, the treatment is well tolerated and results in cure of OSAH.
Local complications involving the tracheal stoma can occur within the first year
post-tracheostomy [36]. It is important to reassess the patient’s nocturnal oxygen
saturation post-tracheostomy because the morbidly obese patient can still exhibit
significant non-obstructive oxyhemoglobin desaturation in rapid eye movement

Reconstruction of the upper airway is a better option from a cosmetic perspective
but unfortunately is associated with less certain results. It is now clear that in
OSAH airway closure occurs at more than one site during sleep [37]. In order to
effectively treat OSAH, airway closure involving the palate and the base of the
tongue must be considered. A phased approach to upper airway reconstruction
has been popularized by the Stanford group [38]. Phase I surgery generally
involves a palatoplasty and a genioglossal advancement procedure. Phase II
surgery involves maxillomandibular advancement. Phase I surgery is associated
with low morbidity but less than optimal results ranging from a success of 22% to
60% in the literature [38, 39]. Phase II surgery is more effective with reported
success rates ranging from 75% to 100%. Phase II procedures produce changes
in occlusion that invariably require postoperative orthodontics.

Upper airway reconstruction for OSAH is an elective surgery that should be
contemplated only after CPAP/BPAP have been tried. If there are cosmetic
considerations such as retrognathia or micrognathia, particularly in a young adult,
this treatment may make good sense.


Obstructive sleep apnea is a common clinical condition that is associated with
significant metabolic, cardiovascular, and neurocognitive morbidity and mortality.
Clinical clues such as heavy snoring, observed apnea, and daytime sleepiness
suggest the diagnosis. The diagnosis needs to be confirmed by an overnight
sleep study. The initial medical therapy of choice is nasal CPAP. Treatment with
nasal CPAP is highly effective in patients with moderate to severe OSA and
daytime sleepiness. In addition to eliminating snoring, the evidence clearly
demonstrates that nocturnal cardiovascular function, daytime sleepiness, and
quality of life are substantially improved. Selected patients who do not accept or
adhere to nasal CPAP may benefit from OAP therapy or surgery. The current
literature supports the notion that long-term treatment can favorably impact
cardiovascular outcomes.


1.    Strollo, P.J., Jr. and R.M. Rogers, Obstructive sleep apnea. New England
      Journal of Medicine., 1996. 334(2): p. 99-104.
2.    Anonymous, Sleep-related breathing disorders in adults:
      recommendations for syndrome definition and measurement techniques in
      clinical research. The Report of an American Academy of Sleep Medicine
      Task Force.[comment]. Sleep., 1999. 22(5): p. 667-89.
3.    Tsai, W.H., et al., A comparison of apnea-hypopnea indices derived from
      different definitions of hypopnea. American Journal of Respiratory &
      Critical Care Medicine., 1999. 159(1): p. 43-8.

4.    Gottlieb, D.J., et al., Relation of sleepiness to respiratory disturbance
      index: the Sleep Heart Health Study. American Journal of Respiratory &
      Critical Care Medicine., 1999. 159(2): p. 502-7.
5.    Shahar, E., et al., Sleep-disordered breathing and cardiovascular disease:
      cross-sectional results of the Sleep Heart Health Study.[comment].
      American Journal of Respiratory & Critical Care Medicine., 2001. 163(1):
      p. 19-25.
6.    Young, T., P.E. Peppard, and D.J. Gottlieb, Epidemiology of obstructive
      sleep apnea: a population health perspective. American Journal of
      Respiratory & Critical Care Medicine., 2002. 165(9): p. 1217-39.
7.    Bixler, E.O., et al., Prevalence of sleep-disordered breathing in women:
      effects of gender.[see comment]. American Journal of Respiratory &
      Critical Care Medicine., 2001. 163(3 Pt 1): p. 608-13.
8.    Young, T., et al., The occurrence of sleep-disordered breathing among
      middle-aged adults.[comment]. New England Journal of Medicine., 1993.
      328(17): p. 1230-5.
9.    Ancoli-Israel, S., et al., Sleep-disordered breathing in African-American
      elderly. American Journal of Respiratory & Critical Care Medicine., 1995.
      152(6 Pt 1): p. 1946-9.
10.   Tishler, P.V., et al., Incidence of sleep-disordered breathing in an urban
      adult population: the relative importance of risk factors in the development
      of sleep-disordered breathing. Jama., 2003. 289(17): p. 2230-7.
11.   Young, T., et al., Predictors of sleep-disordered breathing in community-
      dwelling adults: the Sleep Heart Health Study. Archives of Internal
      Medicine., 2002. 162(8): p. 893-900.
12.   Gleeson, K., C.W. Zwillich, and D.P. White, The influence of increasing
      ventilatory effort on arousal from sleep. American Review of Respiratory
      Disease., 1990. 142(2): p. 295-300.
13.   Somers, V.K., et al., Sympathetic neural mechanisms in obstructive sleep
      apnea. Journal of Clinical Investigation., 1995. 96(4): p. 1897-904.
14.   Lavie, L., Obstructive sleep apnoea syndrome - an oxidative stress
      disorder. Sleep Medicine Reviews, 2003. 7(1): p. 35-51.
15.   Peppard, P.E., et al., Prospective study of the association between sleep-
      disordered breathing and hypertension.[comment]. New England Journal
      of Medicine., 2000. 342(19): p. 1378-84.
16.   Punjabi, N.M., et al., Sleep-disordered breathing, glucose intolerance, and
      insulin resistance. Review Respiratory Physiology & Neurobiology., 2003.
      136((2-3)): p. 167-78.
17.   Ip, M.S., et al., Serum leptin and vascular risk factors in obstructive sleep
      apnea.[comment]. Chest., 2000. 118(3): p. 580-6.
18.   Teran-Santos, J., A. Jimenez-Gomez, and J. Cordero-Guevara, The
      association between sleep apnea and the risk of traffic accidents.
      Cooperative Group Burgos-Santander.[see comment]. New England
      Journal of Medicine., 1999. 340(11): p. 847-51.

19.   Lindberg, E., et al., Role of snoring and daytime sleepiness in
      occupational accidents. American Journal of Respiratory & Critical Care
      Medicine., 2001. 164(11): p. 2031-5.
20.   Beebe, D.W., et al., The neuropsychological effects of obstructive sleep
      apnea: a meta-analysis of norm-referenced and case-controlled data.
      Sleep, 2003. 26(3): p. 298-307.
21.   Sateia, M.J., Neuropsychological impairment and quality of life in
      obstructive sleep apnea. Clinics in Chest Medicine., 2003. 24(2): p. 249-
22.   Farney, R.J., et al., Simultaneous use of antidepressant and
      antihypertensive medications increases likelihood of diagnosis of
      obstructive sleep apnea syndrome. Chest., 2004. 125(4): p. 1279-85.
23.   Engleman, H.M. and N.J. Douglas, Sleep. 4: Sleepiness, cognitive
      function, and quality of life in obstructive sleep apnoea/hypopnoea
      syndrome. Thorax, 2004. 59(7): p. 618-22.
24.   Schellenberg, J.B., G. Maislin, and R.J. Schwab, Physical findings and the
      risk for obstructive sleep apnea. The importance of oropharyngeal
      structures. American Journal of Respiratory & Critical Care Medicine.,
      2000. 162(2 Pt 1): p. 740-8.
25.   Zonato, A.I., et al., Association of systematic head and neck physical
      examination with severity of obstructive sleep apnea-hypopnea syndrome.
      Laryngoscope, 2003. 113(6): p. 973-80.
26.   Guidry, U.C., et al., Echocardiographic features of the right heart in sleep-
      disordered breathing: the Framingham Heart Study.[comment]. American
      Journal of Respiratory & Critical Care Medicine., 2001. 164(6): p. 933-8.
27.   Rowley, J.A., L.S. Aboussouan, and M.S. Badr, The use of clinical
      prediction formulas in the evaluation of obstructive sleep apnea. Sleep.,
      2000. 23(7): p. 929-38.
28.   Peppard, P.E., et al., Longitudinal study of moderate weight change and
      sleep-disordered breathing. Jama., 2000. 284(23): p. 3015-21.
29.   Lim, J., et al., Oral appliances for obstructive sleep apnoea. Cochrane
      Database of Systematic Reviews., 2003. 4: p. CD004435, 2003.
30.   Gotsopoulos, H., J.J. Kelly, and P.A. Cistulli, Oral appliance therapy
      reduses blood pressure in obstructive sleep apnea: a randomized
      controlled trial. Sleep, 2004. 27(5): p. 934-41.
31.   Mehta, A., et al., A randomized, controlled study of a mandibular
      advancement splint for obstructive sleep apnea.[see comment]. American
      Journal of Respiratory & Critical Care Medicine, 2001. 163(6): p. 1457-61.
32.   Marklund, M., H. Stenlund, and K.A. Franklin, Mandibular advancement
      devices in 630 men and women with obstructive sleep apnea and snoring:
      tolerability and predictors of treatment success. Chest, 2004. 125(4): p.
33.   Petit, F.X., et al., Mandibular advancement devices: rate of
      contraindications in 100 consecutive obstructive sleep apnea patients.
      American Journal of Respiratory & Critical Care Medicine., 2002. 166(3):
      p. 274-8.

34.   Fritsch, K.M., et al., Side effects of mandibular advancement devices for
      sleep apnea treatment. American Journal of Respiratory & Critical Care
      Medicine, 2001. 164(5): p. 813-8.
35.   Bridgman, S.A. and K.M. Dunn, Surgery for obstructive sleep apnoea.
      Cochrane Database of Systematic Reviews, 2000(2): p. CD001004.
36.   Thatcher, G.W. and R.H. Maisel, The long-term evaluation of
      tracheostomy in the management of severe obstructive sleep apnea.
      Laryngoscope, 2003. 113(2): p. 201-4.
37.   Morrison, D.L., et al., Pharyngeal narrowing and closing pressures in
      patients with obstructive sleep apnea. American Review of Respiratory
      Disease., 1993. 148(3): p. 606-11.
38.   Riley, R.W., N.B. Powell, and C. Guilleminault, Obstructive sleep apnea
      syndrome: a review of 306 consecutively treated surgical patients.
      Otolaryngology - Head & Neck Surgery., 1993. 108(2): p. 117-25.
39.   Bettega, G., et al., Obstructive sleep apnea syndrome. fifty-one
      consecutive patients treated by maxillofacial surgery. American Journal of
      Respiratory & Critical Care Medicine., 2000. 162(2 Pt 1): p. 641-9.