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Obstructive sleep apnea
Classification and external resources
ICD-10 G473
ICD-9 327.23
eMedicine ped/2114
MeSH D012891

Obstructive sleep apnea (OSA) is a common sleep apnea caused by obstruction of the airway. It is characterized by pauses in breathing during sleep. These episodes, called apneas (literally, "without breath"), each last long enough that one or more breaths are missed, and occur repeatedly throughout sleep. In obstructive sleep apnea, breathing is interrupted by a physical block to airflow, despite the effort to breathe.

The individual with sleep apnea is rarely aware of having difficulty breathing, even upon awakening. Sleep apnea is recognized as a problem by others witnessing the individual during episodes or is suspected because of its effects on the body (sequelae).

Symptoms may be present for years, even decades without identification, during which time the sufferer may become conditioned to the daytime sleepiness and fatigue associated with significant levels of sleep disturbance. Persons who sleep alone without a long-term human partner may not be told about their sleep disorder symptoms.


Since the muscle tone of the body ordinarily relaxes during sleep, and since, at the level of the throat, the human airway is composed of walls of soft tissue, which can collapse, it is easy to understand how breathing can be obstructed during sleep. Although a very low level of obstructive sleep apnea is considered to be within the bounds of normal sleep, and many individuals experience episodes of obstructive sleep apnea at some point in life, a much smaller percentage of people are afflicted with chronic, severe obstructive sleep apnea.

Many people experience episodes of obstructive sleep apnea for only a short period of time. This can be the result of an upper respiratory infection that causes nasal congestion, along with swelling of the throat, or tonsillitis that temporarily produces very enlarged tonsils. The Epstein-Barr virus, for example, is known to be able to dramatically increase the size of lymphoid tissue during acute infection, and obstructive sleep apnea is fairly common in acute cases of severe infectious mononucleosis. Temporary spells of obstructive sleep apnea syndrome may also occur in individuals who are under the influence of a drug (such as alcohol) that may relax their body tone excessively and interfere with normal arousal from sleep mechanisms.

Signs and symptomsEdit

Common signs of obstructive sleep apnea include unexplained daytime sleepiness, restless sleep, and loud snoring (with periods of silence followed by gasps). Less common symptoms are morning headaches; insomnia; trouble concentrating; mood changes such as irritability, anxiety and depression; forgetfulness; increased heart rate and/or blood pressure; decreased sex drive; unexplained weight gain; increased urination and/or nocturia; frequent heartburn or Gastroesophageal reflux disease; and heavy night sweats.

AdultsEdit

In adults, the most typical individual with obstructive sleep apnea syndrome suffers from obesity, with particular heaviness at the face and neck. Obesity is not always present with OSA, in fact a significant number of adults with normal body mass indices (BMI) have decrease in muscle tone causing airway collapse and sleep apnea. The cause of the decreased tone is not presently understood. The hallmark symptom of obstructive sleep apnea syndrome in adults is excessive daytime sleepiness. Typically, an adult or adolescent with severe long-standing obstructive sleep apnea will fall asleep for very brief periods in the course of usual daytime activities if given any opportunity to sit or rest. This behavior may be quite dramatic, sometimes occurring during conversations with others at social gatherings.

The hypoxia (absence of oxygen supply) through OSA may cause changes in the neurons of the hippocampus and the right frontal cortex in the brain. Research through the use of neuro-imaging revealed evidence of hippocampal atrophy in people suffering from OSA. They found some OSA sufferers to have problems in mentally manipulating nonverbal information and executive function.[1]

ChildrenEdit

Although this so called "hypersomnolence" (excessive sleepiness) may also occur in children, it is not at all typical of young children with sleep apnea. Toddlers and young children with severe obstructive sleep apnea instead ordinarily behave as if "over-tired" or "hyperactive." Adults and children with very severe obstructive sleep apnea also differ in typical body habitus. Adults are generally heavy, with particularly short and heavy necks. Young children, on the other hand, are generally not only thin, but may have "failure to thrive," where growth is reduced. Poor growth occurs for two reasons: the work of breathing is high enough that calories are burned at high rates even at rest, and the nose and throat are so obstructed that eating is both tasteless and physically uncomfortable. Obstructive sleep apnea in children, unlike adults, is often caused by obstructive tonsils and adenoids and may sometimes be cured with tonsillectomy and adenoidectomy.

This problem can also be caused by excessive weight in children. In this case, the symptoms are more like the symptoms adults feel: restlessness, exhaustion, and more.

Children with OSA may experience learning and memory deficits. OSA has also been linked to lowered childhood IQ scores (Halbower, et al. 2006).[1]

Risk factorsEdit

Old age is often accompanied by muscular & neurological loss of ability of the airways. Premature aging is temporarily caused by chemical depressants; alcoholic drinks being the most common. Permanent premature airway aging may be caused by traumatic brain injury, or poor adherence to chemical and or speech-therapy treatments.

Individuals with decreased muscle tone, increased soft tissue around the airway, and structural features that give rise to a narrowed airway are at high risk for obstructive sleep apnea. Men, whose anatomy is typified by increased body mass in the torso and neck, are more typical sleep apnea sufferers, especially through middle age and older. Adult women suffer typically less frequently and to a lesser degree than men do, owing partially to physiology, but possibly to emerging links to levels of progesterone. Prevalence in post-menopausal women approaches that of men in the same age range.

CausesEdit

Most cases of OSA are believed to be caused by:

  • old age (natural or premature),
  • brain injury (temporary or permanent),
  • decreased muscle tone,
  • increased soft tissue around the airway (sometimes due to obesity), and
  • structural features that give rise to a narrowed airway.

Decreased muscle tone can be caused by drugs or alcohol, or it can be caused by neurological problems or other disorders. Some people have more than one of these issues. There is also a theory that long-term snoring might induce local nerve lesions in the pharynx in the same way as long-term exposure to vibration might cause nerve lesions in other parts of the body. Snoring is a vibration of the soft tissues of the upper airways, and studies have shown electrophysiological findings in the nerves and muscles of the pharynx indicating local nerve lesions.

Craniofacial syndromesEdit

There are patterns of unusual facial features that occur in recognizable syndromes. Some of these craniofacial syndromes are genetic, others are from unknown causes. In many craniofacial syndromes, the features that are unusual involve the nose, mouth and jaw, or resting muscle tone, and put the individual at risk for obstructive sleep apnea syndrome.

Down Syndrome is one such syndrome. In this chromosomal abnormality, several features combine to make the presence of obstructive sleep apnea more likely. The specific features in Down Syndrome that predispose to obstructive sleep apnea include: relatively low muscle tone, narrow nasopharynx, and large tongue. Obesity and enlarged tonsils and adenoids, conditions that occur commonly in the western population, are much more likely to be obstructive in a person with these features than without them. Obstructive sleep apnea does occur even more frequently in people with Down Syndrome than in the general population. A little over 50% of all people with Down Syndrome suffer from obstructive sleep apnea (de Miguel-Díez, et al. 2003), and some physicians advocate routine testing of this group (Shott, et al. 2006).

In other craniofacial syndromes, the abnormal feature may actually improve the airway, but its correction may put the person at risk for obstructive sleep apnea after surgery, when it is modified. Cleft palate syndromes are such an example. During the newborn period, all humans are obligate nasal breathers. The palate is both the roof of the mouth and the floor of the nose. Having an open palate may make feeding difficult, but generally does not interfere with breathing, in fact - if the nose is very obstructed an open palate may relieve breathing. There are a number of clefting syndromes in which the open palate is not the only abnormal feature, additionally there is a narrow nasal passage - which may not be obvious. In such individuals, closure of the cleft palate- whether by surgery or by a temporary oral appliance, can cause the onset of obstruction.

Skeletal advancement in an effort to physically increase the pharyngeal airspace is often an option for craniofacial patients with upper airway obstruction and small lower jaws (mandibles). These syndromes include Treacher Collins Syndrome and Pierre Robin Sequence. Mandibular advancement surgery is often just one of the modifications needed to improve the airway, others may include reduction of the tongue, tonsillectomy or modified uvulopalatoplasty.

Complication of pharyngeal flap surgeryEdit

Obstructive sleep apnea is a serious complication that seems to be most frequently associated with pharyngeal flap surgery, compared to other procedures for treatment of velopharyngeal inadequacy (VPI).[2] In OSA, recurrent interruptions of respiration during sleep are associated with temporary airway obstruction. Following pharyngeal flap surgery, depending on size and position, the flap itself may have an “obturator” or obstructive effect within the pharynx during sleep, blocking ports of airflow and hindering effective respiration.[3][4] There have been documented instances of severe airway obstruction, and reports of post-operative OSA continue to increase as healthcare professionals (i.e. physicians, speech language pathologists) become more educated about this possible dangerous condition.[5] Subsequently, in clinical practice, concerns of OSA have matched or exceeded interest in speech outcomes following pharyngeal flap surgery.

The surgical treatment for velopalatal insufficiency may cause obstructive sleep apnea syndrome. When velopalatal insufficiency is present, air leaks into the nasopharynx even when the soft palate should close off the nose. A simple test for this condition can be made by placing a tiny mirror at the nose, and asking the subject to say "P". This p sound, a plosive, is normally produced with the nasal airway closed off - all air comes out of the pursed lips, none from the nose. If it is impossible to say the sound without fogging a nasal mirror, there is an air leak - reasonable evidence of poor palatal closure. Speech is often unclear due to inability to pronounce certain sounds. One of the surgical treatments for velopalatal insufficiency involves tailoring the tissue from the back of the throat and using it to purposefully cause partial obstruction of the opening of the nasopharynx. This may actually cause obstructive sleep apnea syndrome in susceptible individuals, particularly in the days following surgery, when swelling occurs (see below: Special Situation: Anesthesia and Surgery).

AHIRating
<5Normal
5-15Mild
15-30Moderate
>30Severe

PathophysiologyEdit

Normal sleep/wakefulness in adults has distinct stages numbered 1 to 4, REM sleep, non-REM sleep (NREM) and consciousness. The deeper stages (3 to 4) of REM sleep are required for the physically restorative effects of sleep, and in pre-adolescents are the focus of release for human growth hormone. Stages 2 and REM, which combined are 70% of an average person's total sleep time, are more associated with mental recovery and maintenance. During REM sleep in particular, muscle tone of the throat and neck, as well as the vast majority of all skeletal muscles, is almost completely attenuated, allowing the tongue and soft palate/oropharynx to relax, and in the case of sleep apnea, to impede the flow of air to a degree ranging from light snoring to complete collapse. In the cases where airflow is reduced to a degree where blood oxygen levels fall, or the physical exertion to breathe is too great, neurological mechanisms trigger a sudden interruption of sleep, called a neurological arousal. These arousals rarely result in complete awakening, but can have a significant negative effect on the restorative quality of sleep. In significant cases of obstructive sleep apnea, one consequence is sleep deprivation due to the repetitive disruption and recovery of sleep activity. This sleep interruption in stages 3 and 4 (also collectively called slow-wave sleep), can interfere with normal growth patterns, healing, and immune response, especially in children and young adults.

DiagnosisEdit

Diagnosis is often based on a combination of lab tests and patient history.

PolysomnographyEdit

Results of polysomnography in obstructive sleep apnea show pauses in breathing. As in central apnea, pauses are followed by a relative decrease in blood oxygen and an increase in the blood carbon dioxide. Whereas in central sleep apnea the body's motions of breathing stop, in obstructive sleep apnea the chest not only continues to make the movements of inhalation, the movements typically become even more pronounced. Monitors for airflow at the nose and mouth show efforts to breathe are not only present, but that they are often exaggerated. The chest muscles and diaphragm contract and the entire body may thrash and struggle.

Obstructive sleep apnea is the most common category of sleep-disordered breathing. The prevalence of OSA among the adult population in western Europe and North America has not been confidently established, but in the mid-1990s was estimated to be 3-4% of women and 6-7% of men.

An "event" can be either an apnea, characterised by complete cessation of airflow for at least 10 seconds, or a hypopnea in which airflow decreases by 50 percent for 10 seconds or decreases by 30 percent if there is an associated decrease in the oxygen saturation or an arousal from sleep (American Academy of Sleep Medicine Task Force, 1999). To grade the severity of sleep apnea, the number of events per hour is reported as the apnea-hypopnea index (AHI). An AHI of less than 5 is considered normal. An AHI of 5-15 is mild; 15-30 is moderate and more than 30 events per hour characterizes severe sleep apnea.

Home oximetryEdit

In patients who are at high likelihood of having OSA, a randomized controlled trial found that home oximetry may be adequate and easier to obtain than formal polysomnography.[6] High probability patients were indentified by an Epworth Sleepiness Scale (ESS) score of 10 or greater and a Sleep Apnea Clinical Score (SACS) of 15 or greater.[7]

Treatment Edit

There are a variety of treatments for obstructive sleep apnea, depending on an individual’s medical history, the severity of the disorder and, most importantly, the specific cause of the obstruction.

In acute infectious mononucleosis, for example, although the airway may be severely obstructed in the first 2 weeks of the illness, the presence of lymphoid tissue (suddenly enlarged tonsils and adenoids) blocking the throat is usually only temporary. A course of anti-inflammatory steroids such as prednisone (or another kind of glucocorticoid drug) is often given to reduce this lymphoid tissue. Although the effects of the steroids are short term, in most affected individuals, the tonsillar and adenoidal enlargement are also short term, and will be reduced on its own by the time a brief course of steroids is completed. In unusual cases where the enlarged lymphoid tissue persists after resolution of the acute stage of the Epstein-Barr infection, or in which medical treatment with anti-inflammatory steroids does not adequately relieve breathing, tonsillectomy and adenoidectomy may be urgently required.

Obstructive sleep apnea in children is sometimes due to chronically enlarged tonsils and adenoids. Tonsillectomy and adenoidectomy is curative. The operation may be far from trivial, especially in the worst apnea cases, in which growth is retarded and abnormalities of the right heart may have developed. Even in these extreme cases, the surgery tends to cure not only the apnea and upper airway obstruction, but allows normal subsequent growth and development. Once the high end-expiratory pressures are relieved, the cardiovascular complications reverse themselves. The postoperative period in these children requires special precautions (see surgery and obstructive sleep apnea syndrome below).

The treatment for obstructive sleep apnea in adults with poor oropharyngeal airways secondary to heavy upper body type is varied. Unfortunately, in this most common type of obstructive sleep apnea, unlike some of the cases discussed above, reliable cures are not the rule.

Some treatments involve lifestyle changes, such as avoiding alcohol and medications that relax the central nervous system (for example, sedatives and muscle relaxants), losing weight, and quitting smoking. Some people are helped by special pillows or devices that keep them from sleeping on their backs, or oral appliances to keep the airway open during sleep. For those cases where these conservative methods are inadequate, doctors can recommend continuous positive airway pressure (CPAP), in which a face mask is attached to a tube and a machine that blows pressurized air into the mask and through the airway to keep it open. There are also surgical procedures intended to remove and tighten tissue and widen the airway, but none are reproducibly successful.[citation needed] Some individuals may need a combination of therapies to successfully treat their sleep apnea.

Physical intervention Edit

The most widely used current therapeutic intervention is positive airway pressure whereby a breathing machine pumps a controlled stream of air through a mask worn over the nose, mouth, or both. The additional pressure splints or holds open the relaxed muscles, just as air in a balloon inflates it. There are several variants:

  • (CPAP), or continuous positive airway pressure, in which a controlled air compressor generates an airstream at a constant pressure. This pressure is prescribed by the patient's physician, based on an overnight test or titration. Newer CPAP models are available which slightly reduce pressure upon exhalation to increase patient comfort and compliance. CPAP is the most common treatment for obstructive sleep apnea.
  • (VPAP), or variable positive airway pressure, also known as bilevel or BiPAP, uses an electronic circuit to monitor the patient's breathing, and provides two different pressures, a higher one during inhalation and a lower pressure during exhalation. This system is more expensive, and is sometimes used with patients who have other coexisting respiratory problems and/or who find breathing out against an increased pressure to be uncomfortable or disruptive to their sleep.
  • (APAP), or automatic positive airway pressure, is the newest form of such treatment. An APAP machine incorporates pressure sensors and a computer which continuously monitors the patient's breathing performance. It adjusts pressure continuously, increasing it when the user is attempting to breathe but cannot, and decreasing it when the pressure is higher than necessary. Although FDA approved, these devices are still considered experimental by many, and are not covered by most insurance plans.

A second type of physical intervention, a Mandibular advancement splint (MAS), is sometimes prescribed for mild or moderate sleep apnea sufferers. The device is a mouthguard similar to those used in sports to protect the teeth. For apnea patients, it is designed to hold the lower jaw slightly down and forward relative to the natural, relaxed position. This position holds the tongue farther away from the back of the airway, and may be enough to relieve apnea or improve breathing for some patients. The FDA accepts only 16 oral appliances for the treatment of sleep apnea. A listing is available at its website.

Oral appliance therapy is less effective than CPAP, but is more 'user friendly'. Side-effects are common, but rarely is the patient aware of them.

Pharmaceuticals Edit

There are no effective drug-based treatments for obstructive sleep apnea that have FDA approval. However, a clinical trial of mirtazapine,[8] has shown early promise at the University of Illinois at Chicago. This small, early study found a 50% decrease in occurrence of apnea episodes and 28% decrease in sleep disruptions in 100% of patients (twelve patients) taking them.[9][10] Nonetheless, due to the risk of weight gain and sedation (two risk factors and consequences of sleep apnea) it is not recommended.[11] An effort to improve the effects of mirtazapine by combining it with another existing medication was cancelled during Phase IIa trials in 2006.[12] Dr. David Carley and Dr. Miodrag Radulovacki, the sleep researchers who were behind the initial clinical trial of mirtazapine are now working on a new treatment that consists of two other existing medications taken off-label together for treatment of sleep apnea.[13]

Other serotonin effecting agents[14] that have been explored unsuccessfully as a treatment for apnea include prozac,[15] tryptophan[16] and protriptyline.[17]

Oral administration of the methylxanthine theophylline (chemically similar to caffeine) can reduce the number of episodes of apnea, but can also produce side effects such as heart palpitations and insomnia. Theophylline is generally ineffective in adults with OSA, but is sometimes used to treat central sleep apnea (see below), and infants and children with apnea.

When other treatments do not completely treat the OSA, drugs are sometimes prescribed to treat a patient's daytime sleepiness or somnolence. These range from stimulants such as amphetamines to modern anti-narcoleptic medicines. The anti-narcoleptic medicine modafinil is seeing increased use in this role as of 2004Template:Dated maintenance category.

In most cases, weight loss will reduce the number and severity of apnea episodes. In the morbidly obese, a major loss of weight (such as what occurs after bariatric surgery) can sometimes cure the condition.

Neurostimulation Edit

Some researchers believe that OSA is at root a neurological condition, in which nerves that control the tongue and soft palate fail to sufficiently stimulate those muscles, leading to over-relaxation and airway blockage. A few experiments and trial studies have explored the use of pacemakers and similar devices, programmed to detect breathing effort and deliver gentle electrical stimulation to the muscles of the tongue.[citation needed]

This is not a common mode of treatment for OSA patients as of 2004, but it is an active field of research.

Surgical intervention Edit

A number of different surgeries are available to improve the size or tone of a patient's airway. For decades, tracheostomy was the only effective treatment for sleep apnea. It is used today only in rare, intractable cases that have withstood other attempts at treatment. Modern operations employ one or more of several options, tailored to each patient's needs. Long term success rates are low, resulting in most doctors favoring CPAP.

  • Nasal surgery, including turbinectomy (removal or reduction of a nasal turbinate), or straightening of the nasal septum, in patients with nasal obstruction or congestion which reduces airway pressure and complicates OSA.
  • Tonsillectomy and/or adenoidectomy in an attempt to increase the size of the airway.
  • Removal or reduction of parts of the soft palate and some or all of the uvula, such as uvulopalatopharyngoplasty (UPPP) or laser-assisted uvulopalatoplasty (LAUP). Modern variants of this procedure sometimes use radiofrequency waves to heat and remove tissue.
  • Reduction of the tongue base, either with laser excision or radiofrequency ablation.
  • Genioglossus Advancement, in which a small portion of the lower jaw that attaches to the tongue is moved forward, to pull the tongue away from the back of the airway.
  • Hyoid Suspension, in which the hyoid bone in the neck, another attachment point for tongue muscles, is pulled forward in front of the larynx.
  • Maxillomandibular advancement (MMA). MMA is the most effective sleep apnea surgical procedure currently available. The success rate is usually between 75 and 100% with a long-term success approaching 90%. Although MMA is considered a fairly invasive procedure, the associated surgical risks are low, including bleeding, infection, malocclusion, and permanent numbness. In general, patient perceptions of surgical outcome have been very favorable.[18]

The role of surgery in the treatment of sleep apnea has been questioned repeatedly as the long term success rate of the procedures has come into question. Surgery is generally only effective in obstructive sleep apnea where the obstruction can be effectively removed. The patient's age, weight and other factors may make them a bad candidate for surgery. Many sleep specialists still regard positive air pressure treatment as the gold standard.[19]

Special situation: surgery and anesthesia in patients with sleep apneaEdit

Many drugs and agents used during surgery to relieve pain and to depress consciousness remain in the body at low amounts for hours or even days afterwards. In an individual with either central, obstructive or mixed sleep apnea, these low doses may be enough to cause life-threatening irregularities in breathing.[citation needed]

Use of analgesics and sedatives in these patients postoperatively should therefore be minimized or avoided.[citation needed]

Surgery on the mouth and throat, as well as dental surgery and procedures, can result in postoperative swelling of the lining of the mouth and other areas that affect the airway. Even when the surgical procedure is designed to improve the airway, such as tonsillectomy and adenoidectomy or tongue reduction - swelling may negate some of the effects in the immediate postoperative period.[citation needed]

Individuals with sleep apnea generally require more intensive monitoring after surgery for these reasons.[citation needed]

Alternative treatmentsEdit

The most common treatment is offered by speech therapists, strengthening the muscle tone and neural pathways involved in breathing.

Breathing exercises, such as those used in Yoga, the Buteyko method, or didgeridoo playing can be effective.[20] There are muscles which act to tension and open the airway during each inspiration. Exercises can, in some cases, restore sufficient function to these muscles to prevent or reduce apnea.

Positional treatmentsEdit

Many people benefit from sleeping at a 30 degree elevation of the upper body[21] or higher, as if in a recliner. Doing so helps prevent the gravitational collapse of the airway. Lateral positions (sleeping on a side), as opposed to supine positions (sleeping on the back), are also recommended as a treatment for sleep apnea,[22][23][24] largely because the gravitational component is smaller than in the lateral position. A 30 degree elevation of the upper body can be achieved by sleeping in a recliner, an adjustable bed, or a bed wedge placed under the mattress. This approach can easily be used in combination with other treatments and may be particularly effective in very obese people.

PrognosisEdit

Although it takes some trial and error, most patients find a combination of treatments which reduce apnea events and improve their overall health, energy, and well-being. Without treatment, the sleep deprivation and lack of oxygen caused by sleep apnea increases health risks such as cardiovascular disease, high blood pressure, stroke, diabetes, clinical depression,[25] weight gain and obesity.

The most serious consequence of untreated obstructive sleep apnea is to the heart. In severe and prolonged cases, there are increases in pulmonary pressures that are transmitted to the right side of the heart. This can result in a severe form of congestive heart failure (cor pulmonale).

Elevated arterial pressure (commonly called high blood pressure) can be a consequence of obstructive sleep apnea syndrome.[26] When high blood pressure is caused by OSA, it is distinctive in that, unlike most cases of high blood pressure (so-called essential hypertension), the readings do not drop significantly when the individual is sleeping.[27] Stroke is associated with obstructive sleep apnea.[28] Sleep apnea sufferers also have a 30% higher risk of heart attack or death than those unaffected.[29]

Many studies indicate that it is the effect of the "fight or flight" response on the body that happens with each apneic event that increases these risks. The fight or flight response causes many hormonal changes in the body; those changes, coupled with the low oxygen saturation level of the blood, cause damage to the body over time.[30][31][32][33]

EpidemiologyEdit

OSA is a common condition in many parts of the world. If studied carefully in a sleep lab by polysomnography, approximately 1 in 5 American adults has at least mild OSA.[34] OSA is more frequent than central sleep apnea.

See alsoEdit

ReferencesEdit

  1. Gale SD, Hopkins RO (2004). Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc 10 (1): 60–71.
  2. Sloan, G.M. (2000). Posterior pharyngeal flap and sphincter pharyngoplasty: The state of the art. Cleft Palate-Craniofacial Journal, 37(2), 112-122.
  3. Pugh, M.B. et al. (2000). Apnea. Stedman’s Medical Dictionary (27th ed.) Retrieved June 18, 2006 from STAT!Ref Online Medical Library database.
  4. Liao, Y., Noordhoff, M.S., Huang, C., Chen, P.K.T., Chen N., Yun, C. et al. (2004). Comparison of obstructive sleep apnea syndrome in children with cleft palate following Furlow palatoplasty or pharyngeal flap for velopharyngeal insufficiency. Cleft Palate-Craniofacial Journal, 41(2), 152-156.
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  8. First Effective Drug For Sleep Disorder Identified
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  20. Didgeridoo playing as alternative treatment for obstructive sleep apnoea syndrome: randomised controlled trial - Puhan et al. 332 (7536): 266 - BMJ
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  28. H. Klar Yaggi, M.D., M.P.H., John Concato, M.D., M.P.H., Walter N. Kernan, M.D., Judith H. Lichtman, Ph.D., M.P.H., Lawrence M. Brass, M.D., and Vahid Mohsenin, M.D. (November 10, 2005). Obstructive Sleep Apnea as a Risk Factor for Stroke and Death. The New England Journal of Medicine 353 (19): 2034–2041.
  29. N.A. Shah, M.D., N.A. Botros, M.D., H.K. Yaggi, M.D., M., V. Mohsenin, M.D., New Haven, CT Sleep Apnea Increases Risk of Heart Attack or Death by 30%. American Thoracic Society.
  30. www.yale.edu
  31. www.sciencedaily.com
  32. http://www.schlaflabor-breisgau.de/Bild_gif/Peppard.pdf
  33. www.sciencedaily.com
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