review of sleep medicine || sleep breathing disorders

TEOFILO L. LEE-CHIONG n CHARLES A. POLNITSKY

C H A P T E R

4Sleep Breathing Disorders

43

The snoring person has been historically portrayed inliterature as one peacefully at rest in deepest sleep,perhaps disturbing his companions, but usuallyregarded with humor. There was no concern for thehealth of the individual. The past several decadeshave produced an entirely new picture, in whichsleep-disordered breathing, ranging from snoringand mild increases in upper airway resistance toapnea with profound hypoxemia, actually causes pro-found physiologic reactions. Furthermore, the condi-tions are now recognized in both genders and at allages. The incidence appears to be increasing beyondwhat would be expected from newfound awarenessalone. Obesity, allergic upper airway conditions, andother influences, including survival advantages con-ferred by better health care, have combined to makesleep-disordered breathing one of the new epidemicsof this millennium.

OBSTRUCTIVE SLEEP APNEA

Terminology centered around obstructive sleep apneacontinues to evolve. In general, an obstructiveapnea (OA) occurs when there is complete, or nearlycomplete, cessation of airflow, accompanied by preserva-tion of respiratory drive manifested by persistent respiratorymuscle activity (Figure 4-1). If there is partial reductionin airflow, of >30% of baseline, with preservation ofrespiratory effort, the event is defined as an obstructivehypopnea (OH) (Figure 4-2). Although OA and OHhave different specific definitions, their pathophysiol-ogy and physiologic consequences are essentially simi-lar, and in clinical polysomnographic reporting theyare combined as a single result, the apnea-hypopneaindex (AHI). The American Academy of Sleep Medi-cine standard, in fact, does not call for distinctionbetween OA and OH under routine circumstances.1

The magnitude of the AHI generally reflects theseverity of excessive daytime sleepiness (EDS), cardio-vascular risk, and general metabolic consequen-ces of sleep-disordered breathing. It also providescut points for treatment reimbursement. When

respiratory effort-related arousals (RERAs, see later)are included in the total number of events, the conven-tion is to report the sum as the respiratory disturbanceindex (RDI).

The term obstructive sleep apnea (OSA) is properlyreserved to describe the objective documentation ofOA and OH events. When an individual is diagnosedas having psychological or physiologic manifestationsof OSA(s), that is person is considered to have theobstructive sleep apnea syndrome (OSAS), sometimesalso termed the obstructive sleep apnea/hypopneasyndrome.1

Epidemiology

OSA is thought to affect approximately 5% of the adultUS population.2 Depending on how OSA and OSASare defined, estimates of prevalence are as high as 20%of adults for OSA.3 A general population study ofrandomly chosen, middle-age, State of Wisconsinemployees found mild apnea (AHI � 5) in 17% andmoderate-severe apnea (AHI � 20) in 7%.4 Age, gen-der, and body mass index (BMI) have an importantimpact on prevalence in various cohorts. Apnea ispresent in 60% or more of individuals who have hada stroke (CVA)5 and is increased in context of otherchronic conditions such as congestive heart failure,polycystic ovary syndrome, and asthma. Althoughobesity-related, OSA is also found in context of normalweight, and its prevalence may be markedly under-estimated because of failure of caregivers to considerthe diagnosis in thin individuals.6 A similar concernhas been raised for the female gender.7 OSA is notuncommon in children, although specific diagnosticcriteria are not as clearly defined as in adults.8,9

Definitions

AnOA/OH event is scored if there is a>50% reductionin flow, lasting �10 seconds. If the reduction is clearlyvisible but <50%, it must be accompanied by eitheror both of the following: a drop in oxygen saturation

FIGURE 4-1 n Obstructive apnea. 2-minute screen. Complete cessation of airflow�10 seconds in duration, accompanied by persisting respiratory effort (Thor effort, Abdoeffort). The associated desaturation is not essential for the events to be scored as OAs.

44

REVIEWOFSLEEP

MED

ICINE

FIGURE 4-2 n Obstructive hypopnea. 2-minute screen. Airflow is reduced by � 50% from baseline, accompanied by persisting respiratory effort and >3% drop in oxygensaturation.

SleepBreathing

Disorders

45

46 REVIEW OF SLEEP MEDICINE

>3% or an electroencephalogram (EEG) arousal �3seconds.1 (Qualification is made for some instances inwhich a lesser reduction in airflow occurs.) It shouldbe noted that there is considerable variation in theinterpretation of data in both research and clinicallaboratories, based on an evolving understandingof sleep-disordered breathing.10 For Medicare treat-ment reimbursement, however, scoring of an OH isallowed only when there is a desaturation �4%.

Physiologic Consequences

With each OA or OH, as upper airway resistanceincreases, tidal volume falls, oxygen saturation drops,and CO2 rises. Increased sympathetic activity causesvasoconstriction and frequently tachycardia, yieldingan increase in blood pressure. As respiratory effortsagainst a narrowed or occluded airway increase, theremay be reflex bradycardia and atrioventricular block.Once the apnea has terminated, there may be recoverytachycardia. Supraventricular and ventricular ectopycan occur in susceptible individuals.

A combination of increased preload, leftward shiftof the intraventricular septum, reduction of left ven-tricular compliance, and increased afterload occurs. Asa result, there may be an exacerbation of preexistingcongestive heart failure (CHF).11,12

The physiologic stress imposed by each eventcauses a number of pathological responses. Theseinclude release of inflammatory mediators,13–17eleva-tion of leptin,18 increases in platelet adhesiveness19 andfibrinogen levels, and reduced fibrinolytic activity.20

Insulin resistance is also increased. In females, hyper-insulinemia shifts the androgen-estrogen balance ofovarian hormone synthesis more toward the androgenside.21 Atrial naturetic peptide secretion is augmentedby a false volume-overload signal, causing nocturia.22

There also is cyclic elevation of microvascular resis-tance23 and generalized persistent endothelial dys-function.24,25 Sympathetic responses to the stressof apnea can lead to diurnal persistence of hyperten-sion 26–30 and worsening of CHF.31,32 There appearsto be an increased propensity toward development ofatrial fibrillation and a 50% reduction in maintenanceof normal sinus rhythm if the OSA is not corrected.33

Pulmonary artery pressure may become transientlyelevated, and in a small percentage of individuals,fixed pulmonary hypertension occurs.34 During peri-ods of intense apnea and hypoxia, elevated right-sidedcardiac pressures can lead to opening of a patentforamen ovale, exacerbating systemic hypoxia andincreasing the risk of embolic stroke.35

Long-term intermittent hypoxia results in oxidativestress15,36 and may further worsen pharyngeal muscledilator function37 (see Pathophysiology). Repetitive

mechanical trauma to the muscles can lead to inflam-mation and denervation, yielding a similar effect.38

The final common physiologic pathway is increasedatherogenesis.39 There is evidence for accelerationof coronary artery disease,40 the appearance of newclinical cardiovascular morbidity (recurrent atrialfibrillation, fatal and nonfatal myocardial infarction,and pulmonary hypertension), and an association withstroke.41,42 Furthermore, studies have also shown thatthe progression of cardiovascular disease is retardedwhen OSA is corrected.43–45

Repetitive EEG arousals result in sleep fragmenta-tion and in some cases suppression of normal sleepstaging, especially stage rapid eye movement (REM).The failure to achieve restorative sleep and effects ofoxidative stress are thought to be responsible for ex-cessive daytime somnolence and affective complaintssuch as increased irritability, depression, and cognitivedysfunction, including deterioration of memory andability to concentrate.

Pathophysiology

OSA can develop in any given individual as a result ofthe summation of a variety of predisposing anatomicaland physiologic aberrations in the maintenance ofupper airway patency during sleep. Determinantsrange from central nervous system drive to pharyn-geal size and muscle control. Maintenance of upperairway patency reflects the balance of those forces thatfoster collapse (extraluminal tissue pressure and neg-ative intraluminal pressure generated by inspiratoryairflow) or maintenance of patency (action of pharyn-geal dilator muscles, primarily the genioglossus, andtraction from inspiratory lengthening).46

Although central apnea (CA) (see later) is categor-ized as a distinct and separate condition, there is evi-dence for abnormal central respiratory drive that ispresent in OSA as well.47,48 Inspiration is marked byphasic increases in pharyngeal muscle tone, as well asin the diaphragm and accessory muscles of respiration.When there is instability in ventilatory control (highloop gain, a term that describes increased sensitivityand response to change in physiologic state in systemsgoverned by feedback control), the ability of the con-troller to offset the mechanical forces leading to airwaycollapse may be overcome, resulting in OA.46,49 Con-versely, pharyngeal instability may contribute to thedevelopment of CA.50

Phasic increases in pharyngeal dilator tone are nec-essary to offset the tendency toward collapse. There isevidence of sleep stage-dependent compromisedmaintenance of pharyngeal tone during stage 2 andREM in children with OSA, pointing to an underly-ing alteration in mechanoreceptor/chemoreceptor

TABLE 4-1 n Factors Associated with Development of OSA

Ear, nose, and throat Seasonal allergic rhinitis

Perennial rhinitis/sinusitis

Nasal septal deviation

Hyperplasia of tonsils/adenoids

Retrognathia

Micrognathia

Incisor overjet

Dental mandibular crowding

Macroglossia

High arched hard palate

Extended soft palate

Enlarged/elongated uvula

Vocal cord paralysis

Anatomically reduced pharyngeal area

Increased pharyngeal length

Heredofamilial craniofacial syndromes

Treacher-Collins

Pierre Robin

Metabolic/endocrine Obesity

Testosterone predominance

Iatrogenic androgen supplementation

Male gender

Female postmenopausal state

Pregnancy

Hypothyroidism

Medical/constitutional conditions Stroke

Congestive heart failure

Autonomic dysfunction

Familial predisposition—multiple

Charcot-Marie-Tooth syndrome

Myotonic dystrophy

Cervical spine injury

Sedative use

Alcohol consumption

Tobacco smoking

Sleep Breathing Disorders 47

control.47 To overcome airway floppiness, pharyngealdilator tone is increased even during wakefulness inchildren and adults51,52 to counteract the diurnalincrease in collapsibility.53

Sex hormone levels also play a role. There is anoverall male predominance of OSA, but the associationgoes beyond simple gender influence. Testosteronereplacement therapy in men has been reported toinduce or worsen OSA.54 Variation in OSA severity inwomen has been demonstrated through the menstrualcycle and during pregnancy.55 It is also seen in womenwith polycystic ovary syndrome in excess of the preva-lence that would be expected if caused by obesityalone.21 Furthermore, the prevalence of OSA infemales is approximately tripled after menopause,56,57

thought to result from a drop in female hormonelevels and a relative increase in androgen. This obser-vation holds even with correction for age and BMI.57

Reduction of luminal diameter by hyperplastic ton-sils and other tissues also increases collapsability. Also,increased pharyngeal length58 and diameter appear tobe factors in the development of OSA.59 Obesity is amajor factor, and historically, the phenotypic obesity-hypoventilator (pickwickian) was thought to representmost cases of OSA. There are various mechanisms bywhich an increased BMI predisposes to OSA. Thesimple reduction in upper airway diameter by retro-pharyngeal fat deposition has been seen in imagingstudies.60 Inspiratory resistive loading associated withincreased thoracic and abdominal mass plays a role ineffort-related airway collapse. There is evidence thatautonomic dysfunction such as seen in diabetes mayhave an etiological role.61 Whatever the mechanism,weight reduction can eliminate or reduce OSA severityin some individuals.62,63

In children, hyperplasia of tonsils and adenoids isresponsible for most cases of OSA, although craniofa-cial abnormalities of various types may be etiological.Tonsillectomy is frequently curative, although excep-tions commonly occur.64 Furthermore, it is interestingto note that in a small but significant number of chil-dren successfully treated by surgery, OSA returns inpuberty or adulthood, once again calling attention tothe multifactorial etiology.65

Nasal obstruction in young children with allergy orcongenital nasopharyngeal abnormalities can play arole.66 Mouth breathing predisposes to snoring andincreases the risk of apnea. In the long run, it alsoresults in mandibular developmental insufficiency.Whether acquired, hereditary, or congenital, micro-gnathia and retrognathia cause pharyngeal narrowing.The same is true for macroglossia. With increasingage and BMI, even relatively subtle upper airwaystructural abnormalities predispose to OSA develop-ment. Table 4-1 contains a more comprehensive list ofpredisposing conditions.

Clinical Evaluation

The often cited medical maxim—unless a specific con-dition is considered as a possibility, its timely identifi-cation is unlikely—is especially true for OSA. Theobese middle-age male who snores profoundly atnight and falls asleep readily during the day does notpose a diagnostic challenge. In this circumstance, ex-cessive daytime sleepiness (EDS) should always raisethe possibility of OSA. An Epworth Sleepiness Score(ESS) > 10 is considered abnormal, but the ESS lackssufficient specificity and sensitivity to be relied on ex-clusively. An elevated BMI in either gender and at anyage increases the likelihood of a positive diagnosis;however, an increasing number of people with BMIsin the normal or minimally elevated range are beingdiagnosed with OSA now that the possibility is beingconsidered.6 A wide array of presenting complaints

TABLE 4-2 n Presenting Complaints and Physical Findings

Suggesting OSA Diagnosis

Sleep-related Excessive sleep need

Snoring

Restless sleep

Insomnia

Bruxism

Nonrestorative sleep

Gasping arousals

Nocturnal gastroesophageal reflux disease

Nocturnal panic attacks

Nocturia

Parasomnias

Dreams of exertion or suffocation

Daytime complaints

Morning somnolence

Morning headache

Morning dry mouth

Excessive daytime somnolence

Reduced quality of life

Impaired job performance

Generalized fatigue

Drowsy driving

Cognitive impairment

Mood disorders

Intense menopausal complaints

Reduced libido/erectile dysfunction

Somatic syndrome symptoms

Fibromyalgia

Chronic fatigue syndrome

Irritable bowel syndrome

Headache

Refractory asthma

Miscellaneous conditions Attention deficit disorder

Dysglycemia

Metabolic syndrome

Polycystic ovary syndrome

Refractory systemic hypertension

Angiotensin converting enzyme

Polymorphism

Chronic renal failure

Stroke

Recurrent or unexpected atrial fibrillation

Unexplained pulmonary hypertension

Congestive heart failure

Acromegaly

Myotonic dystrophy

Parkinson’s disease

Multiple system atrophy

Down syndrome

Postpolio syndrome

Difficult intubation or anesthesia recovery


and comorbidities should prompt the clinician to per-form an extended sleep-oriented history, physicalexamination, and laboratory evaluation. In additionto some highlights in the following paragraphs,Table 4-2 summarizes the clinical presentations thatmay suggest consideration of an OSA diagnosis.

Sleep-wake patterns and complaints may vary. Thetypical male with OSA will report feeling groggy in themorning (despite the perception of having had a goodnight’s sleep) and may indicate nodding off while sit-ting quietly or driving; women are more likely to com-plain of insomnia, generalized daytime fatigue, and avariety of psychological and somatic complaints suchas depression and headache.7,67 Sleep fragmentationis sometimes accompanied by paroxysmal nocturnaldyspnea, palpitations, anxiety attacks, or dreams ofphysical exertion. Children may respond to sleepfragmentation from sleep-disordered breathing withhyperactivity, a report of behavioral difficulties, ordiagnosis of attention deficit–hyperactivity disorderthat should prompt a consideration of OSA.68

Hypertension, especially when relatively refractoryto conventional treatment,69 has been linked toOSA via cyclic episodes of apnea-associated hypoxiaand augmented sympathetic discharge. Unexpectednocturia in both genders occurs when apnea resultsin alterations in circulatory dynamics causing inappro-priate nocturnal secretion of atrial naturetic peptide.Gastroesophageal reflux symptoms, especially withnocturnal regurgitation, may be caused or exacerbatedby OSA. The recurrent microaspiration of nasopharyn-geal secretions and/or gastric contents associated withthe inspiratory gasps following airway closure can leadto persistent hoarseness, tickle in the throat, and chron-ic cough. Male erectile dysfunction can be caused byOSA as well as by the many comorbidities that apneasufferers may also have, such as hypertension anddiabetes.

The presence of several specific endocrine abnorm-alities should raise a suspicion of OSA. There is anassociation with hypothyroidism,70 probably multifac-torial and based on reduction in metabolic rate;macroglossia; mucosal abnormalities; obesity; andother influences. Women with polycystic ovary syn-drome have an increased prevalence of OSA in excessof that expected in context of obesity alone.21 Thereis also an increased incidence of OSA in pregnancy.Unexpected difficulty with glycemic control may be anOSA marker. Most individuals with the metabolic syn-drome should at least be queried about symptoms andsigns that might raise suspicion for OSA, especiallybecause of the cardiovascular risks.

Physical examination can also provide clues. A neckcircumference greater than 17 inches has been identi-fied as an OSA predictor. The examiner should alsolook for the craniofacial features discussed previously

as well as the presence of significant nasal obstruction,a high arched palate, tonsillar hyperplasia, engorge-ment of pharyngeal tissues, and uvular prominence.Approximately 70% of individuals with Downsyndrome will have OSA either by history or on


polysomnography. There is also a significantlyincreased incidence in persons with neuromusculardiseases and parkinsonism.

A history of difficult endotracheal intubation, slowpostoperative recovery from anesthesia, unexplainedpostoperative hypoxemia, or need for reintubationafter anesthesia should raise the suspicion of underly-ing OSA.71

Reports from family members or bed partnershould also be elicited. Witnesses often report persis-tent nodding off, especially under inappropriate socialcircumstances. Bed partners may have taken to sleep-ing in another room or have banished the patient fromthe bedroom because of disruptive snoring.

Diagnosis

Attended in-laboratory polysomnography remainsthe reference standard for diagnosis.10 OA and OHare detected by various sensors of oronasal airflowand thoracic and abdominal excursion. Integrated air-flow signals are supplementing or replacing thermis-tor-generated data because their sensitivity andresponse times are better.1 In addition, they provideinformation about more subtle events such as RERAs(see later).72

Transcutaneous oximetry provides data on depthand duration of apnea-associated hypoxia and re-sponse to treatment. An oximeter with appropriatesensitivity and response time is necessary to avoidoverdiagnosis or underdiagnosis of desaturations.73

Pediatric sleep laboratories also frequently monitortranscutaneous CO2 because the identification ofOSA is significantly more challenging and less welldefined in children than in adults.9

Three or four EEG channels are commonly used toidentify sleep stage and document arousals. Extraocu-lar motion and peripheral leg electromyogram chan-nels assist in the definition of stage REM.

An AHI < 5 is considered normal, although there isstrong evidence that persistent snoring and the upperairway resistance syndrome (UARS) confer similar ad-verse health consequences, modifying a negative poly-somnogram (PSG) interpretation in this context (seeUARS, later). An AHI of 5–14 is arbitrarily ranked asmild, 15–30 as moderate, and �30 as severe disease,but the designations vary among laboratories. A casecan be made for designating an AHI > 15–20 as hav-ing increased physiologic significance because it is atthis approximate level that some of the adverse con-sequences (such as increased blood coagulability andplatelet adhesion) appear.

Current Medicare guidelines for treatment are gen-erally accepted by most commercial insurance provi-ders. These are an AHI � 5, determined over a

minimum of 2 hours of actual sleep time, in contextof at least one of the following: hypertension, cardiacdisease, history of stroke, insomnia, excessive daytimesomnolence, depression, or cognitive dysfunction.Medicare also calls for treatment of individuals withan AHI � 15 even in the absence of the additionalmodifiers. As emphasized previously, the guidelinesspecifically require that an OH be defined by an oxy-gen desaturation � 4% and exclude the diagnosisbased on an arousal without desaturation.74

The definition of pediatric OSA is not as precise.9,68

The current accepted PSG criterion is an AHI � 1 forchildren and adolescents up to the age of 16.8

Numerous lower-level diagnostic approaches areavailable. They range from snoring recorders75 andrecording oximetry to multichannel home PSG sys-tems. As a screening technique, overnight oximetryhas adequate sensitivity but may lack specificity and isnot recommended.10,76 Various multichannel data col-lectors, used in both attended and unattended set-tings, have been used in an attempt to substitute forformal PSG, but data are difficult to compare, and theaccuracy of the testing continues to be evaluated.77

American Academy of Sleep Medicine (AASM) guide-lines continue to call for attended, in-lab PSG undermost circumstances.78,79 Simple problems such as lossof electrode contact can be easily repaired. Sleep stagingis provided. Diagnosis of other significant conditionssuch as limbmovement disorders, parasomnias, seizureactivity, and cardiac dysrhythmias is facilitated. In-labPSG also affords an opportunity for continuous positiveairway pressure (CPAP) titration in the second half ofthe night. Studies have demonstrated the equivalence ofthe split-night study to a full-night PSG followed by asecond night devoted to CPAP titration.80

Therapy

CPAP remains the definitive treatment for essentiallyall individuals.81,82 Current AASM practice standardscall for the initial titration to be performed in-labora-tory to facilitate mask fitting, patient training, anddesensitization where needed, as well as to documentthe achievement of well-consolidated sleep under pos-itive airway pressure circumstances. Ideally, a CPAPpressure is determined that achieves essentially totalelimination of apneas, with the patient in supine stageREM sleep (Figure 4-3).

The mechanism by which CPAP reverses airwaycollapse is generally considered to be via the genera-tion of a ‘‘pneumatic splint’’ to the upper airway.83

Since inspiration generates a pressure drop that causesthe airway to collapse, and persons with OSA have anabnormally elevated critical closing pressure, pressur-ization of the airway is thought to counteract

FIGURE 4-3 n Split-night polysomnography. This individual has a combination of respiratory effort–related arousals (Uns),obstructive hypopneas (Hyp), a mixed apnea (Mx.A), obstructive apneas (ObA.), and central apneas (Cn.A), with associateddesaturation. Nearly all events are eliminated by CPAP titration done in the second half of the night.


inspiratory collapse. An alternative recent suggestioninvokes the increased lung volume effect of CPAP as areason for CPAP effectiveness.84 The usual therapeuticrange for CPAP is 4–20 cm H2O. Use of CPAP appearsto reduce the development of cardiovascular diseasepossibly in proportion to nightly duration of use.43,44

When a patient experiences high CPAP pressureintolerance, alternative modes such as bilevel positiveairway pressure (BiPAP) may be used.85 In this in-stance, the inspiratory pressure (iPAP) is usually main-tained at �3–5 CWP above the expiratory (ePAP)setting and pressures are sequentially elevated to pro-vide control of apnea at the lowest possible setting. Al-though there are proponents of BiPAP as an importanttechnique to improve overall CPAP compliance, studieshave failed to demonstrate consistent benefit.81,86

BiPAP, however, may be of use in massively obeseindividuals with marked reduction in chest wall compli-ance who require a degree of noninvasive mechanicalrespiratory assist that the modality provides.81

Similarly, there is scant evidence that autotitratingpositive airway pressure (APAP) devices87 providemajor benefit to most CPAP-intolerant persons.88

In controlled studies, the mean APAP pressure neededto control apnea has not been shown to be consistentlymuch lower than the fixed setting that was determinedduring lab titration, and nightly duration of use hasonly slightly increased in most studies.89 In general,there is no indication for APAP devices to be pre-scribed as first-line therapy.90 APAP devices differ inthe sensor array and algorithms for apnea detection,and units from different manufacturers are not neces-sarily comparable.91 They are not indicated foruse in persons with CHF, chronic obstructive pulmo-nary disease, or hypoxemic respiratory failure or innonsnorers. APAP devices may be used duringattended in-lab titration but should not be used forinitial titration at home.82,91 A small number of per-sons, however, show a strong preference for APAP astheir standard mode of airway pressurization and can


be thus maintained. CPAP generators that featureexpiratory pressure relief are also being offered asalternatives to standard CPAP. They have not beensubjected to sufficient objective study to demonstratetheir therapeutic equivalence or superiority to theconventional CPAP.92,93

At the other end of the therapeutic spectrum, tra-cheostomy is also universally effective. Because of thesurgical risk and potential for long-term complica-tions, tracheostomy is usually reserved for certainspecific cases: (1) when death from hypoxia or corpulmonale is considered imminent and CPAP is noteffective; (2) morbid obesity with hypoventilation thatrequires nocturnal mechanical ventilation; and (3) incases of fixed upper airway obstruction where CPAP isineffective. Individuals who do not require a cuffed tubeto permit mechanical ventilation can be fitted with alow-profile flanged device that can be plugged duringthe daytime to allow normal respiration and speech.

For individuals with genuine CPAP intolerancewhose apnea is based on pharyngeal narrowing atthe level of the base of the tongue, mandibular ad-vancement devices (MAD; also referred to as anteriormandibular positioners) provide an alternative, butoften less effective, option.94 When given the opportu-nity to try both CPAP and MAD, more people havepreferred theMAD and have used it more consistently,but the therapeutic response has not been equiva-lent.95 Whereas CPAP is nearly always close to 100%effective, mandibular advancement has a wide rangeof response. Some individuals experience little or noreduction in AHI. An adjustable device, rather thanone made from a fixed mold, should be used, and thedegree of advancement may need to be titrated overtime. PSG confirmation of effectiveness is essential toavoid a situation inwhich snoring has been silenced butapnea remains.96 Adaptation to MAD use is difficultfor some people who experience excessive salivationor temporomandibular joint discomfort. In contrast toCPAP, which has been extensively studied since itsinception in 1981, MAD experience is limited both incase size and length of follow-up. Application con-tinues to be evaluated.97

There is a wide range of variously invasive surgicalprocedures for the control of OSA,98 but their indica-tions and effectiveness continue to be debated.99,100

The current consensus is as follows. Minor proceduressuch as laser-assisted uvuloplasty (LAUP) have no rolein the treatment of OSA, although they may silencesimple snoring at least temporarily.101 Procedureswith increasing complexity such as uvulopalatophar-yngoplasty (UPPP), genioglossus advancement/hyoidfixation, and mandibulo-maxillary advancement yieldincreasingly better results but have unpredictableeffectiveness on an individual basis, involve someamount of risk and discomfort, and may have

permanent untoward sequelae. The most consistentpositive results are found in cases of pharyngeal nar-rowing with an anatomical etiology that can be specifi-cally corrected. More detailed description is beyondthe scope of this chapter but may be found in recentsummary statements and reviews.98,102

Weight loss can lessen OSA. The most quoted pro-jection is that a 10% reduction in weight results in a26% drop in the AHI, based on a cohort of mildlyoverweight individuals.103 A somewhat less favorableresult was recently reported.104 Results in morbid obe-sity may be more dramatic.105 Except in context ofbariatric surgery, however, maintenance of the loss isdifficult.106 Open and laparoscopic gastric bypass, gas-tric banding, and intragastric balloon techniques arethe most common procedures.107,108 Because OSA ismultifactorial in etiology, several series of patients haveshown that OSA can recur in some individuals, even ifthe weight loss has been maintained.105,108

There is no evidence that noninvasive treatmentsand devices have a therapeutic role.109 Nasopharyn-geal lubricants and sprays, nasal dilators, oral dietarysupplements, and magnetic therapy have failed toshow a beneficial effect on OSA. Plastic soft palatestents, radiofrequency tongue volume reduction, andsoft palate chemical and radiofrequency ablation havealso been used, but datasets are small and results notencouraging. Research is underway on medicationsthat modify neurotransmitter activity110,111 and onhypoglossal nerve stimulation.112

Some individuals who have had OSA eliminated byeffective treatment fail to experience the expectedrelief from excessive daytime somnolence. For them,the judicious use of modafanil as a maintenance ofwakefulness agent has been approved by the Foodand Drug Administration.113 It should be stressedthat recourse to stimulants is only indicated and justi-fied if OSA control has been verified. Because mostpersons are being treated with CPAP, there must bedocumentation via surveillance download data fromthe CPAP generator that compliance is consistentand the CPAP setting is appropriate. Pharmacologicaltreatment of daytime somnolence in lieu of prescribedCPAP use is not medically defensible.114

CENTRAL SLEEP APNEA

CA results from an instability of central nervoussystem controller mechanisms. In contrast to OSA,central apneas occur when there is a temporary ces-sation of signaling to inspiratory muscles. Airwaycollapse may also occur,115 but it is not the pivotalevent or necessary for diagnosis. Rather, gradual orabrupt cessation of airflow results from a lapse incontroller signaling. Thus no inspiratory efforts


accompany central apneas (Figure 4-4). CA frequentlycauses oxygen desaturation but is usually terminatedby the increased PCO2 that results from the apnea.As with OSA, sleep fragmentation is common. BecauseCA may occur under a diverse set of pathologicalconditions, a unifying underlying mechanism isunlikely to be found.

Pathophysiology

CA occurs in a number of distinct patterns. Randomevents meeting the preceding criteria can be seen inmany individuals undergoing PSG. Because an insta-bility of ventilatory control is thought to underlie allforms of apnea, it has been proposed that there is anoverlap in the mechanisms by which central and ob-structive apneas occur.116 In the awake state, control ofventilation is a function of responses to changes inPaCO2 and PO2, as well as input from behavioral andwakefulness activity.46 In sleep, most of the modulat-ing influence originates from changes in PaCO2 andPaO2. Hypoxic and hypercapnic responses in generalare blunted in sleep, especially in stage REM, althoughsome gender-specific variation has been described.117

Changes in PaO2 within the normal physiologic rangedo not cause a large respiratory variation. Relativelysmall changes in PaCO2, however, result in brisk,inversely proportionate responses in minute ventila-tion. PaCO2 variation is considered to be the domi-nant respiratory controller in sleep.116 Because CO2

responsiveness falls during sleep, sleep-onset centralapneas are commonly seen.

CAs can also occur as CPAP pressures reach thera-peutic levels during titration for OSA. This is thoughtto result from reflex controller inhibition as partialpharyngeal closure occurs.50 CA has been describedfollowing tracheostomy for OSA, illustrating the over-lap between the two forms of apnea. Occasionally,mixed apneas are encountered. There is an apparentinitial CA event in which the terminal portion ismarked by a return of respiratory efforts in whatappears to have become an OA (Figure 4-5). Thespecific underlying mechanism has not been fullyresolved.118,119 Other, more significantly pathologicalforms of CA are outlined next.

Cheyne-Stokes Respiration

When an alternating hyperventilation/hypoventilationcycle is evident, the term periodic breathing (PB) is ap-plied. The most commonly recognized form of PB isCheyne-Stokes respiration (CSR), typically seen in thecontext of CHF. Individuals with CHF-linked CSRgenerally have a reduced baseline PaCO2 secondaryto hyperventilation associated with heightened

sympathetic activity and pulmonary vagal stimula-tion120 in the context of increased controller respon-siveness to CO2, although some disagreement aboutspecifics exists.46 Any source of a further increase inminute ventilation pushes the PaCO2 below the apneicthreshold and a CA occurs. As PaCO2 rises, respira-tions resume. It appears that the prolonged circulationtime in CHF results in an overshoot of the hyperpneaand an extension of the periodic breathing cycle, yield-ing the characteristic cyclic crescendo-decrescendopattern of CSR with a periodicity of about 1 minute121

(Figure 4-6). Thus a rhythmic oscillation betweenhyperpnea and hypopnea/apnea around the apneicthreshold occurs. CSR is usually seen in NREM sleep.A more subtle but similar pattern can be seen duringwakefulness in some CHF-afflicted individuals.

CSR has also been described in stroke, but in mostcases it is now thought to be a manifestation of coexist-ing occult or subclinical left ventricular dysfunction.122

The hyperpneic phase of CSR has also been shownto be the origin of ventricular ectopy that persists evenif associated hypoxia is corrected.123 The presence ofCSR in CHF increases mortality risk, and its correctionreduces this trend.124

High-Altitude Periodic Breathing

Hypoxic drive is augmented by the reduced baromet-ric pressure at high altitude, yielding hyperpnea andconsequent hypocapnia. As in CSR, hyperpnea is onlyretarded when PaCO2 falls sufficiently to triggeralkalosis-induced apnea. Increasing hypoxia andrising PaCO2 will propagate the cycle, which is morepronounced in sleep. Periodic breathing at sea level,having a similar disorder of respiratory control, canalso occur125 (Figure 4-7).

Idiopathic Central Sleep Apnea

Idiopathic central sleep apnea is a relatively uncom-mon condition afflicting individuals who have an in-herent high chemoreceptor responsiveness that drivesventilation and results in hypocapnia even at sea level.46

As with high-altitude PB, the cycling is exaggeratedduring sleep; the smooth crescendo-decrescendo pat-tern of CRS and PB, however, is frequently absent, andapneas may be abruptly terminated. This observationindicates that additional mechanisms may also exist.

Central Apnea Associated withBaseline Hypercapnia

A wide variety of conditions, having different etiolo-gies, comes under this heading. The most common is

FIGURE 4-4 n Central apnea. 2-minute screen during CPAP application. Airflow (CPAP flow channel) and muscular effort simultaneously stop with each event.

SleepBreathing

Disorders

53

FIGURE 4-5 n Mixed apnea. 2-minute screen. Each event begins with simultaneous interruption of both airflow and muscular effort, resembling a CA, but resumption ofeffort precedes reestablishment of respiration, characteristic of OA.

54

REVIEWOFSLEEP

MED

ICINE

FIGURE 4-6 n Central sleep apnea/Cheyne-Stokes respiration. 10-minute screen. Persisting CAs with a waxing and waning pattern and a periodicity of �1 minute.Oxygen desaturations accompany each event.

SleepBreathing

Disorders

55

FIGURE 4-7 n Periodic breathing. 10-minute screen. The characteristic spindle pattern of respirations with a periodicity of �1 minute is interrupted only once by anairflow cessation. Desaturations accompany most events (values are read vertically).

56

REVIEWOFSLEEP

MED

ICINE

TABLE 4-3 n Central Apnea Classification

Nonhypercapnic Central sleep apnea/Cheyne-Stokes respiration

Idiopathic central sleep apnea

High-altitude central apnea

Periodic breathing at sea level

Incidental (e.g., at sleep onset)

Hypercapnic Obesity/hypoventilation syndrome

Congenital central apnea

Neuromuscular diseases


the obesity-hypoventilation syndrome, discussed later.Other neuromuscular diseases compromising mech-anical gas exchange and leading to chronic hypercap-nia can result in CA, but upper airway instability mayalso result in OSA in these instances. Central alveolarhypoventilation secondary to various acquired neu-rological abnormalities or lesions, especially in thebrainstem, may be accompanied by CA. Table 4-3summarizes the classification of CA.

MIXED CENTRAL ANDOBSTRUCTIVE APNEA

Some individuals show combined OSA and CA. Ascontrol of airway stability is established with CPAP,they develop intractable CA, especially during NREMsleep. Once again, this phenomenon reflects commonunderlying pathophysiology.126

Clinical Manifestations

As partially considered previously, the manifestationsof CA vary in the context of the specific form andunderlying etiology.116 In general, a considerablysmaller database on CA has been collected comparedwith the extensive literature on OSA. Obesity-hypo-ventilators are typically plethoric and lethargic, and showsigns of congestive heart disease. Those with idiopathiccentral apnea present with a variety of complaints,including fatigue and other problems found withOSA, but more commonly these patients complain ofinsomnia or sleep fragmentation. They are often notobese. As CA also results in hypoxic periods, as withOSA, it can result in pulmonary and systemic hyper-tension.

Diagnosis

PSG is the primary diagnostic tool for CA of any etiol-ogy. The current standards vary somewhat but gener-ally call for an AI> 5 in pure CA, or for�80% of apneasto be central in cases of mixed disease. Central apneas

are scored when airflow and thoracoabdominal move-ment simultaneously pause for �10 seconds.1 Centralhypopneas are scored if there is a 30–80% drop inairflow and muscle effort channels for the sameduration. Refinements in diagnosis are based on clini-cal context and patterns of frequency, such as are seenin CSR.

Treatment

The underlying etiology of the specific form of CAoften determines specific treatment.127 For CSR, theuse of CPAP has become established. The mechanismappears to be indirect, via augmentation of cardiacoutput. CPAP produces this result via a number ofeffects, including improvement in afterload and shiftingof the interventricular septum. CPAP also effects a slightincrease in PaCO2 (possibly by reducing hyperventila-tion caused during apnea recovery or by increasedlung water), pushing the value beyond the apneicthreshold and triggering the resumption of controllersignaling. CPAP improves left ventricular functionparameters, but it remains unclear whether mortalityis reduced.128 BiPAP has also been used, but recentevidence indicates that it may in fact worsen CSR byinducing further controller instability.129 Noninvasiveadaptive positive pressure ventilation has also beenreported to be effective.130 Oxygen therapy has alsobeen shown to cause a significant reduction in theAHI131 but does not appear to improve left ventricle(LV) function132 or arrhythmia.133 When neuromus-cular disease is the underlying etiology, BiPAP has alsobeen used.134

Idiopathic central sleep apnea is not responsive to aspecific treatment approach. Oxygen administration,respiratory stimulants, and metabolic agents such asacetazolamide have been used with variable success.In some cases in which OSA and CA are combined,CPAP has been shown to control both forms. For re-fractory mixed disease unresponsive to conventionalapproaches, continuously controlled CO2 added topositive airway pressure has shown promise.135

Patients with hypercapnic central sleep apnea mayrequire nocturnal ventilation. Most are currently man-aged with the use of noninvasive positive pressureventilation. Historically, and in selected cases today,there is a role for external ventilatory assist devicesor mechanical ventilation via tracheostomy.

SNORING

Vibration of upper airway structures, including thesoft palate, uvula, and lateral walls of the pharynx,during sleep causes snoring. The character and timbre


of the audible sound produced is influenced by thesite(s) of vibration. Although snoring is often notedduring inspiration, it can also occur during exhalation.There is a male predominance in snoring prevalence.Women may develop snoring during pregnancy.A positive family history can often be elicited.

The upper airway, from the nares to the larynx, is aflexible collapsible tube that performs various func-tions in respiration, swallowing, and phonation.In anatomically susceptible upper airways, snoring isproduced when the inspiratory luminal negative pres-sure exceeds the distending activity of the upper air-way muscles.136 Collapsibility increases during sleep asa result of a reduction in upper airway muscle tone.Differences in collapsibility of the upper airway, de-fined by its critical closing pressure (Pcrit), determinewhether snoring, hypopneas, or apneas result.137

Sleep disordered breathing can also stem from, or bemade worse by, nasal obstruction. Nasal congestionmay give rise to oronasal breathing that furthercompromises the upper airway.138

Data from theWisconsin SleepCohort Study revealedthat habitual snorers tend to have a higher prevalenceof apnea-hypopnea indices of 15 or higher.139 Nonethe-less, snoring by itself lacks specificity for obstructivesleep apnea syndrome.

Snorers may present for evaluation and manage-ment when snoring is causing significant disruptionof the bed partner’s or roommate’s sleep or whenthere is concern that snoring is associated withobstructive sleep apnea syndrome.

The bed partner should be asked about duration,frequency, and intensity of snoring. Risk factors forsnoring include a supine sleep position, nasal conges-tion, and the ingestion of alcohol, muscle relaxants,opioid analgesics, and sedative-hypnotic agents closeto bedtime, as well as smoking. In one study, currentsmokers had a significantly greater risk of snoringcompared with never smokers and former smokers.140

Snoring can also worsen with sleep deprivation.Snoring should be differentiated from stridor

resulting from laryngeal narrowing, incoherent sleeptalking, and expiratory groaning during sleep (cata-threnia) in which groaning usually occurs during thesecond part of the night during REM and non-REM(NREM) stage 2 sleep. Otorhinolaryngological andneurological evaluation is normal in patients withcatathrenia.141

Snorers share many of the upper airway features ofpatients with OSA. Examination may demonstrateswollen nasal mucosa; enlargement of the tonsils,uvula, and tongue; narrowing of the airway by thelateral pharyngeal walls; a low palate; and retrognathia.Referral to an otorhinolaryngologist for fiberopticpharyngoscopy may provide additional informationthat might be useful for patients with incomplete

response to medical therapy or those who are consider-ing surgery for their snoring.However, pharyngoscopicfeatures do not reliably predict responses to surgicalinterventions for snoring.

PSG is not routinely indicated in the evaluation ofsnorers, but it might be helpful in patients undergoingupper airway surgery, especially if other symptomssuggestive of obstructive sleep apnea, such as daytimesleepiness, are present. Snoring is identified duringPSG either by using microphones or sound/vibrationsensors placed either on the neck or near the oronasalopening, or from reports of audible snoring by thesleep technologists.

Patients with problematic snoring should be ad-vised to maintain optimal weight, avoid smoking andalcohol consumption, and restrict the use of musclerelaxants and sedatives. If snoring is present only, or isworse, during a supine sleep position, measures tomaintain a nonsupine posture during sleep maybe beneficial. The bed partner can be offered noise-reducing therapies, such as the use of earplugs. Need-less to say, appropriately titrated CPAP therapy willeliminate snoring, but this therapy is not universallycovered by medical insurers.

Causes of nasal congestion, if present, should beidentified and addressed appropriately. Medical thera-pies for nasal congestion might include avoidance ofallergens, oral antihistamines, nasal decongestants,nasal anticholinergic agents, or nasal corticosteroids. Areport by the Clinical Practice Committee of the AASMindicated that there is limited data available on the ben-eficial effect of external nasal dilator strips, internalnasal dilator devices, and oral-nasal lubricants for snor-ing; therefore there is currently insufficient informationto provide standards of practice recommendations.142

An oral device constructed to advance the mandibleor tongue is an effective treatment option for snor-ing,94 and clinical guidelines for its use in patientswith snoring or obstructive sleep apnea have beenpublished.143

Surgical approaches to snoring include radiofre-quency surgery of the soft palate,144 LAUP,101 UPPP,and palatal implants to reduce palatal flutter.145 Spe-cific nasal surgery (septoplasty for nasal septal devia-tion, polypectomy for nasal polyps, and turbinectomyfor engorged nasal turbinates) can be consideredfor patients with considerable nasal narrowing orobstruction.

UPPER AIRWAY RESISTANCESYNDROME

As its name implies, UARS is characterized by repeti-tive episodes of increase in resistance to airflow inthe upper airways associated with arousals from


sleep. Frequent arousals, in turn, result in sleep frag-mentation and complaints of hypersomnolence.146

Other associated features include fatigue and a higherprevalence of systemic hypertension.147 Snoring may ormay not be present. Patients may also present withless-specific somatic complaints including headaches,irritable bowel syndrome, and sleep-onset insomnia.148

Accurate identification of UARS is hampered by thelack of standardizeddiagnostic criteria.Definitions com-monly include the presence of EEG arousals after one tothree breaths with increased inspiratory effort (morenegative peak end-inspiratory esophageal pressure[Pes] swings) and decrement in airflow. Pes is an indica-tor of respiratory effort. This is then followed by lessnegativePesexcursions asairflow increasesduringarou-sals. The apnea-hypopnea index should be less than fiveevents per hour, and there is no oxygen desaturation.Respiratory events may be accompanied by increases inheart rate and systolic and diastolic pressures andchanges in electrocardiographic R-R intervals.149

Two types of breathing patterns have been de-scribed in patients with UARS. A crescendo pattern,seen commonly during stages 1 and 2 NREM sleep,consists of a more negative peak end-inspiratory Pes.In contrast, regular and continuous high respiratoryefforts are seen during stages 3 and 4 NREM sleep.150

Nasal cannula/pressure transducers may capture apattern of airflow limitation with an inspiratory‘‘plateauing’’ or flattened contour of the tracing corres-ponding with the increasingly negative pleural pressureexcursions, followed by a rounded contour during arou-sals.151 Although more accurate than thermistors, nasalcannula/pressure transducers may, nonetheless, fail todetect all abnormal breathing episodes during sleep.150

Mild upper airway abnormalitiesmay be appreciatedduring physical examination. There is no apparentgender difference.

Polysomnography often demonstrates a longer dura-tion of wake after sleep onset and decreased duration ofslow wave sleep.147

The proper identification of UARS might be partic-ularly important in patients with a presumptivediagnosis of idiopathic hypersomnia.152

Therapies proposed for patients with UARS haveincluded nasal CPAP146 and anterior mandibular posi-tioning devices.153 A variety of surgical interventions,including tonsillectomy and adenoidectomy for pedi-atric cases and palatal surgery, have been described.Novel treatment options such as internal jaw distractionosteogenesis are being investigated.154

OBESITY HYPOVENTILATIONSYNDROME

Obesity hypoventilation syndrome is characterizedby the presence of severe obesity (defined as a BMI3

> 40 kg/m2) and hypercapnia (elevated arterial partialpressure of carbon dioxide [PaCO2]) during wakeful-ness. Hypercapnia develops as a result of increasedproduction of carbon dioxide owing to greater workof breathing and decreased ventilation (e.g., decreasedexpiratory reserve volume, decreased tidal volume,increased resistive load, and increased dead space).In addition, ventilatory response to hypercapnia andhypoxemia is decreased.

Although weight is a significant factor in the patho-genesis of OHS, even among obese persons, OHS isuncommon. In one study of hospitalized patients withsevere obesity, hypoventilation was present in 31%of subjects who did not have other reasons for hyper-capnia. These patients required greater intensive care,long-term care at discharge, and mechanical ventila-tion, and they had higher mortality at 18 months afterhospital discharge compared with patients with simpleobesity without OHS.155

Patients may present with complaints of hypersom-nolence, decreased objective attention or concentra-tion, peripheral edema, or cyanosis. Evaluation maydisclose the presence of periodic respiration, hypox-emia, pulmonary hypertension, and polycythemia.Severe obesity can be associatedwithmild-to-moderatedegrees of restrictive ventilatory impairment.

Although OSA is present in most cases of OHS,patients may present without OSA. Diurnal arterialblood gas measurements are worse and pulmonaryartery hypertension is more frequent in those withOHS compared with patients with OSA.156

Other causes of chronic hypoventilation, such assevere chronic obstructive pulmonary disease, neuro-muscular disorders, or diaphragmatic paralysis, shouldbe excluded.

Nasal CPAP therapy and nasal noninvasive mechani-cal ventilation (NIMV) during sleep are effective thera-pies for patients with OHS.157 The use of NIMV inpatients with OHS has resulted in improvements inhypersomnolence, dyspnea, morning headache, legedema, and arterial blood gas parameters.158 Gastricsurgery for morbid obesity has also been shown toimprove symptoms, increase PaO2, and decreasePaCO2.

159 No pharmacological agent has, thus far,been found to be effective for OHS.

CONGENITAL CENTRALHYPOVENTILATION SYNDROME

Hypoventilation and failure of the autonomic respira-tory control in patients with congenital central hypo-ventilation syndrome (CCHS) is present from birth.Ventilatory responses to hypoxia and hypercarbia areimpaired because of a disorder of central chemoreceptorresponsiveness.


Hypoventilation during sleep can be severe withlack of ventilatory or arousal response. In one study,significant abnormalities of arterial blood gas para-meters were observed with PaCO2 (mean � structuralequation modeling) of 62 � 2.5 mm Hg and a hemo-globin saturation of 65%� 3.3%.160 Hypoventilation ischaracteristically most severe during REM sleep.

Activity and exercise can result in worsening gasexchange with greater hypoxemia and hypercarbiaand a lesser increase in heart rate.161 Affected patientshave no subjective sensation of dyspnea.162 Despitethe absence of chemoreceptor function, however,hyperpnea can occur during exercise with increasingrespiratory frequency rather than an augmentation oftidal volume responsible for the increase in minuteventilation.163

Clinical manifestation, including tachycardia, dia-phoresis, and cyanosis, vary depending on disease se-verity.Onset is typically during thenewbornperiodwithepisodic apnea, cyanosis, feeding difficulties, or brady-cardia. Proper diagnosis might be delayed until infancywhen apparent life-threatening events, respiratoryarrest, or pulmonary hypertension may develop.

Children with CCHS can develop arrhythmias (e.g.,heart block and sick sinus syndrome), seizures, syncope,heat intolerance, esophageal dysmotility, and ophthal-mological abnormalities. Hirschsprung disease andtumors of neural-crest derivatives (i.e., ganglioneu-romas and neuroblastomas) have been reported.160

Growth may be impaired with hypotonia or majormotor delay.160 Impaired mental processing may bepresent. CCHS patients may also have dysfunction ofthe autonomic nervous system control of the heartwith decreased heart rate variability.164 This potential-ly life-threatening disorder appears to be rare.

The exact pathophysiological mechanisms remainincompletely defined.165 Heterozygous de novo muta-tions in PHOX2B have been described in patients withCCHS and associated autonomic dysfunction. A ma-jority of mutations consist of 5–9 alanine expansionswithin a 20-residue polyalanine tract (exon 3).166

There was an association between repeat mutationlength and severity of the CCHS phenotype. Diagnosisof CCHS is aided by genetic testing for mutations ofthe polyalanine expansion sequence of the PHOX2bgene. Less commonly, patients may demonstrate anEDN3 frameshift point mutation.167

CCHS should be distinguished from other congeni-tal syndromes that are associated with abnormalities inrespiratory control, such as Prader-Willi syndrome andfamilial dysautonomia. Other causes of chronic hypo-ventilation, such as cardiopulmonary, neuromuscular,and metabolic disorders, should also be excluded.168

Patients require either continuous 24-hour ventila-tory support or, if they are able to maintain adequatespontaneous respiration while awake, ventilatory

support during sleep.160 Ventilatory support can beprovided at home with positive-pressure ventilation(via a tracheostomy or a nasal/oronasal mask), bi-levelpositive airway pressure device, negative-pressureventilation, or diaphragm pacers using phrenic nervestimulation.162

REFERENCES

1. Sleep-related breathing disorders in adults: recommen-dations for syndrome definition and measurement tech-niques in clinical research: The report of an AmericanAcademy of SleepMedicine Task Force. Sleep 22(5):667–689, 1999.

2. Caples SM, Gami AS, Somers VK: Obstructive sleepapnea. Ann Intern Med 142(3):187–197, 2005.

3. Young T, Skatrud J, Peppard PE: Risk factors for ob-structive sleep apnea in adults. JAMA 291(6):2013–2016,2004.

4. Young T, Peppard PE, Gottleib DJ: Epidemiology ofobstructive sleep apnea: a population health perspective.Am J Resp Crit Care Med 165(9):1217–1239, 2002.

5. Bassetti C, Aldrich MS: Sleep apnea in acute cerebro-vascular diseases: final report on 128 patients. Sleep22(2):217–223, 1999.

6. Lettieri CJ, Eliasson AE, Andrada T, et al: Obstructivesleep apnea syndrome: are we missing an at-risk popu-lation? J Clin Sleep Med 1(4):381–385, 2005.

7. Young T, Peppard PE: Clinical presentation of OSAS:gender does matter. Sleep 28(3):293–295, 2005.

8. Uliel S, Tauman R, Greenfield M, Sivan Y: Normal poly-somnographic respiratory values in children and adoles-cents. Chest 125(3):872–878, 2004.

9. Carroll JL: Obstructive sleep-disordered breathing inchildren: new controversies, new directions. Clin ChestMed 24(2):261–282, 2003.

10. Kushida CA, Littner MR, Morgenthaler T, et al: Practiceparameters for the indications for polysomnographyand related procedures: an update for 2005. Sleep28(4):499–521, 2005.

11. Pinsky MR: Sleeping with the enemy: the heart in ob-structive sleep apnea. Chest 121(4):1022–1024, 2002.

12. Bradley TD, Hall MJ, Ando S, Floras JS: Hemodynamiceffects of simulated obstructive apneas in humanswith andwithout heart failure. Chest 119(6):1827–1835, 2001.

13. Hatipoglu U, Rubenstein I: Inflammation and obstruc-tive sleep apnea syndrome. Chest 126(1):1–2, 2004.

14. Terramoto S, YamamotoH, Yamaguchi Y, et al: Obstruc-tive sleep apnea causes systemic inflammation and meta-bolic syndrome. Chest 127(3):1074, 2005.

15. Minoguchi K, Tazaki T, Yokoe T, et al: Elevated pro-duction of tumor necrosis factor-a by monocytes inpatients with obstructive sleep apnea syndrome. Chest126(5):1473–1479, 2004.

16. Parish JM, Somers VK: Obstructive sleep apnea andcardiovascular disease. Mayo Clin Proc 79(8):1036–1046, 2004.

17. Goldbart AD, Goldman JL, Li RC, et al: Differentialexpression of cysteinyl leukotriene receptors 1 and 2 in


tonsils of children with obstructive sleep apnea syn-drome or recurrent infection. Chest 126(1):13–18, 2004.

18. Phillips BG, Kato M, Narkiewicz K, et al: Increases inleptin levels, sympathetic drive, and weight gain in ob-structive sleep apnea. Am J Physiol Heart Circ Physiol279:H234–H237, 2000.

19. Hui DS, Ko FW, Fok JP, et al: The effects of nasal contin-uous positive airway pressure on platelet activation inobstructive sleep apnea syndrome. Chest 125(5):1768–1775, 2004.

20. von Kanel R, Dimsdale JE: Hemostatic alterations inpatients with obstructive sleep apnea and the implicationsfor cardiovascular disease. Chest 124(5):1956–1967,2003.

21. Ehrmann DA: Polycystic ovary syndrome. N Engl J Med352(12):1223–1236, 2005.

22. Umlauf MG, Chasens E, Greevy RA, et al: Obstructivesleep apnea, nocturia, and polyuria in older adults.Sleep 27(1):139–144, 2004.

23. Shamsuzzaman ASM, Gersh BJ, Somers VJ: Obstructivesleep apnea. Implications for cardiac and vascular dis-ease. JAMA 290(14):1906–1914, 2003.

24. Ip MS, Tse HF, Lam B, et al: Endothelial function inobstructive sleep apnea and response to treatment. AmJ Resp Crit Care Med 169(3):348–353, 2004.

25. Nieto FJ, Herrington DM, Redline S, et al: Sleep apneaand markers of vascular endothelial function in a largecommunity sample of older adults. Am J Resp Crit CareMed 169(3):354–360, 2004.

26. Budhiraja R, Sharief I, Quan S: Sleep disordered breath-ing and hypertension. J Clin Sleep Med 1(4):401–404,2005.

27. Phillips C, Hedner J, Berend N, Grunstein R: Diurnaland obstructive sleep apnea influences on arterialstiffness and central blood pressure in men. Sleep28(5):604–609, 2005.

28. Peppard PE, Young T, Palta M, Skatrud J: Prospectivestudyof theassociationbetweensleep-disorderedbreathingand hypertension. N Engl J Med 342(19):1378–1384,2000.

29. Nieto FJ, Young TB, Lind BK, et al: Association of sleep-disordered breathing, sleep apnea, and hypertension in alarge community-based study. Sleep Heart Health Study.JAMA 283(14):1829–1836, 2000.

30. Hla KM, Skatrud JB, Finn L, et al: The effect of correc-tion of sleep-disordered breathing on BP in untreatedhypertension. Chest 122(4):1125–1132, 2002.

31. Kaneko Y, Floras JS, Usui K, et al: Cardiovascular effectsof continuous positive airway pressure in patients withheart failure and obstructive sleep apnea. N Engl J Med348(13):1233–1241, 2003.

32. Laaban J-P, Pascal-Sebaoun S, Block E, et al: Left ven-tricular systolic dysfunction in patients with obstruc-tive sleep apnea syndrome. Chest 122(4):1133–1138,2002.

33. Kanagala R, Murali NS, Friedman PA, et al: Obstructivesleep apnea and the recurrence of atrial fibrillation.Circulation 107(20):2589–2594, 2003.

34. Marrone O, Bonsignore MR: Pulmonary haemody-namics in obstructive sleep apnoea. Sleep Med Rev6(3):175–193, 2002.

35. Beelke M, Angeli S, Del Sette M, et al: Obstructive sleepapnea can be provocative for right-to-left shuntingthrough a patent foramen ovale. Sleep 25(8):856–862,2002.

36. Lavie L, Vishnevsky A, Lavie P: Evidence for lipid per-oxidation in obstructive sleep apnea. Sleep 27(1):123–128, 2003.

37. Veasey SC, Zhan G, Fenik P, Pratico D: Long termintermittent hypoxia. Reduced excitatory hypoglossalnerve output. Am J Resp Crit Care Med 170(6):665–672, 2004.

38. Boyd JH, Petrof BJ, Hamid Q, et al: Upper airwaymuscle inflammation and denervation changes in ob-structive sleep apnea. Am J Resp Crit Care Med170(5):541–546, 2004.

39. Drager LF, Bottolotto LA, Lorenzi MC, et al: Early signsof atherosclerosis in obstructive sleep apnea. Am RespCrit Care Med 172(5):613–618, 2005.

40. Leineweber C, Kecklund G, Janszky I, et al: Snoring andprogression of coronary artery disease: the StockholmFemale Coronary Angiography Study. Sleep 27(7):1344–1349, 2004.

41. Arzt M, Young T, Finn L, et al: Association of sleep-disordered breathing and the occurrence of stroke.Am J Resp Crit Care Med 172(11):1442–1447, 2005.

42. Yaggi HK, Concato J, Kernan WN, et al: Obstructivesleep apnea as a risk factor for stroke and death. NEngl J Med 353(19):2034–2041, 2005.

43. Doherty LS, Kiley JL, Swan V, McNichols WT: Long-term effects of nasal continuous positive airway pressuretherapy on cardiovascular outcomes in sleep apnea syn-drome. Chest 127(6):2076–2084, 2005.

44. Campos-Rodriguez F, Pena-Grinan N, Reyes-NunezN, et al: Mortality in obstructive sleep apnea-hypopneapatients treated with positive airway pressure. Chest128(2):624–633, 2005.

45. Marin JM, Carrizo SJ, Vicente E, Agusti AGN: Long-term cardiovascular outcomes in men with obstructivesleep apnoea-hypopnoea with or without treatment withcontinuous positive airway pressure: an observationalstudy. Lancet 365(9464):1046–1053, 2005.

46. White DP: Pathogenesis of obstructive and central sleepapnea. Am J Resp Crit Care Med 172(11):1363–1370,2005.

47. Katz ES, White DP: Genioglossus activity during sleep innormal control subjects and children with obstructivesleep apnea. Am J Resp Crit Care Med 170(5):553–560, 2004.

48. Onal E, Lopata M, O’Connor T: Pathogenesis of apneasin hypersomnia-sleep apnea syndrome. Am Rev RespDis 125(2):167–174, 1982.

49. Wellman A, Jordan AS, Malhotra A, et al: Ventilatorycontrol and airway anatomy in obstructive sleep apnea.Am J Resp Crit Care Med 170(11):1225–1232, 2004.

50. Issa FG, Sullivan CE: Reversal of central sleep apneausing nasal CPAP. Chest 90(2):165–171, 1986.

51. Katz ES, White DP: Genioglossus activity in childrenwith obstructive sleep apnea during wakefulness andsleep onset. Am Rev Resp Dis 168(6):664–670, 2003.

52. Fogel RB, Malhotra A, Pillar G, et al: Genioglossalactivity in patients with obstructive sleep apnea versus


control subjects. Am Rev Resp Dis 164(11):2025–2030,2001.

53. Gozal D, Burnside MM: Increased upper airway collaps-ibility in children with obstructive sleep apnea dur-ing wakefulness. Am Rev Resp Dis 169(2):163–167,2003.

54. Rhoden EL, Morgentaler A: Medical progress: risks oftestosterone-replacement therapy and recommendationsfor monitoring. N Engl J Med 350(5):482–492, 2004.

55. Polnitsky CA: Sleep in women. In Shigley L, Jones-Parker M, Lee-Chiong T (eds): Textbook of Polysomno-graphy. Philadelphia, Lippincott, Williams & Wilkins,2006.

56. Young T, Finn L, Austin D, Peterson A: Menopausalstatus and sleep-disordered breathing in the Wisconsinsleep cohort study. Am J Resp Crit Care Med167(9):1181–1185, 2003.

57. Bixler EO, Vgontzas AN, Lin H-O, et al: Prevalence ofsleep disordered breathing in women: effects of gender.Am J Resp Crit Care Med 163(3):608–613, 2001.

58. Malhotra A, Huang Y, Fogel RB, et al: The male predis-position to pharyngeal collapse. Importance of airwaylength. Am J Resp Crit Care Med 166:1388–1395, 2003.

59. Jordan A, Malhotra A: The pharyngeal lumen: bothlength and size matter. J Clin Sleep Med 1(3):264–265,2005.

60. Olson EJ, Moore WR, Morgenthalerr TI, et al: Obstruc-tive sleep apnea-hypopnea syndrome. Mayo Clin Proc78:1545–1552, 2003.

61. Sanders MH, Givelber R: Sleep disordered breathingmay not be an independent risk factor for diabetes, butdiabetes may contribute to the occurrence of periodicbreathing in sleep. Sleep Med 4(4):349–350, 2003.

62. Peppard PE, Young T, Palta M, et al: Longitudinal studyof moderate weight change and sleep-disordered breath-ing. JAMA 284:3015–3021, 2000.

63. Newman AB, Foster G, Givelber R, et al: Progressionandregression of sleep-disordered breathing with changes inweight. Arch Intern Med 165(20):2048–13, 2005.

64. Guilleminault C, Biol D, Li K, et al: A prospective studyon the surgical outcomes of children with sleep-disor-dered breathing. Sleep 27(1):95–100, 2004.

65. McNamara F, Sullivan CE: Pediatric origins of adult lungdiseases. 3: The genesis of adult sleep apnea in child-hood. Thorax 55(11):964–969, 2000.

66. Meltzer EO: Introduction: Stuffy is also related to Sleepyand Grumpy: the link between rhinitis and sleep-disor-dered breathing. J Allergy Clin Immunol 114:S133–S134, 2004.

67. Shepertycky MR, Banno K, Kryger MH: Differencesbetween men and women in the clinical presentation ofpatients diagnosed with obstructive sleep apnea syn-drome. Sleep 28(3):309–314, 2005.

68. Gottlieb DJ: The future risks of childhood sleep-disor-dered breathing. Sleep 28(7):796–797, 2005.

69. Logan AG, Perlikowski SM, Mente A, et al: Highprevalence of unrecognized sleep apnoea in drug-resistanthypertension. J Hypertension 19(12):2271–2277, 2001.

70. Kapur VH, Koepsell TD, deMaine J, et al: Association ofhypothyroidism and obstructive sleep apnea. Am J RespCrit Care Med 158(5 Pt 1):1379–1383, 1998.

71. den Herder C, Schmeck J, Appelboom DJK, de Vries N:Risks of general anaesthesia in people with obstructivesleep apnoea. BMJ 329(7472):955–959, 2004.

72. Hosselet JJ, Norman RG, Ayappa I, Rapoport DM:Detection of flow limitation with a nasal cannula/pres-sure transducer system. Am J Resp Crit Care Med 157(5Pt 1):1461–1467, 1998.

73. Zafar S, Ayappa I, Norman RG, et al: Choice of oximeteraffects apnea-hypopnea index. Chest 127(1):80–88, 2005.

74. Department of Health and Human Services Centersfor Medicare and Medicaid Services: Medicare CoverageIssues Manual 12-26-2001: transmittal 150, section 60-17.Washington, DC, Department of Health and HumanServices.

75. Liesching TN, Carlisle C, Marte A, et al: Evaluation ofthe accuracy of SNAP technology sleep sonography indetecting obstructive sleep apnea in adults comparedto standard polysomnography. Chest 125(3):886–891,2004.

76. Magalang UJ, Dmochowski J, Veeramachaneni S, et al:Prediction of the apnea-hypopnea index from overnightpulse oximetry. Chest 124(5):1694–1701, 2003.

77. Flemons WW, Littner MR, Rowley JA, et al: Home diag-nosis of sleep apnea: a systematic review of the literature.Chest 124(4):1543–1579, 2003.

78. Chesson AL Jr, Berry RB, Pack A: Practice parametersfor the use of portable monitoring devices in the investi-gation of suspected obstructive sleep apnea in the adult.Sleep 26(7):907–913, 2003.

79. Iber C: Home portable monitoring and obstructive sleepapnea. J Clin Sleep Med 1(1):11–13, 2005.

80. Sanders MH, Constantino JP, Strollo PJ, et al: The im-pact of split-night polysomnography for diagnosis andpositive pressure therapy titration on treatment accep-tance and adherence in sleep apnea/hyopopnea. Sleep23(1):17–24, 2000.

81. Loube DI, Gay PC, Strohl KP, et al: Indications forpositive airway treatment of adult obstructive sleepapnea patients: a consensus statement. Chest115(3):863–866, 1999.

82. Littner M, Hirshkowitz M, Davila D, et al: Practice para-meters for the use of auto-titrating continuous positiveairway pressure devices for titrating pressures and treat-ing adult patients with obstructive sleep apnea syndrome.An American Academy of Sleep Medicine Report. Sleep25(2):143–147, 2002.

83. Abbey N, Cooper K, Kwentus J: Benefit of nasal CPAP inobstructive sleep apnea is due to positive pharyngealpressure. Sleep 12:420–422, 1989.

84. Heinzer RC, Stanchina ML, Malhotra A, et al: Lungvolume and continuous positive airway pressurerequirements in obstructive sleep apnea. Am J RespCrit Care Med 172(1):114–117, 2005.

85. Sanders MH, Kern N: Obstructive sleep apnea treatedby independently adjusted inspiratory and expirat-ory positive airway pressures via nasal mask. Chest98(2):317–324, 1990.

86. Reeves-Hoche MK, Kudgel DW, Meck R, et al: Continu-ous versus bilevel positive airway pressure for obstruc-tive sleep apnea. Am J Resp Crit Care Med 151(2 Pt1):443–449, 1995.


87. Roux FJ, Hilbert J: Continuous positive airway pres-sure: new generations. In Lee-Chiong TL, Mohsenin V(eds): Clinics in Chest Medicine, Philadelphia, Saunders,pp 315–342, 2003.

88. Berry RB, Parish JM, Hartse KM: The use of autoti-trating continuous positive airway pressure for treat-ment of adult sleep apnea: an American Academy ofSleep Medicine review. Sleep 25(2):148–173, 2002.

89. Noseda A, Kempenaers C, Kerkhofs M, et al: Constantvs auto-continuous airway pressure in patients withsleep apnea hypopnea syndrome and a high variabilityin pressure requirement. Chest 126(1):31–37, 2004.

90. Ayas NT, Patel SR, Malhotra A, et al: Autotitratingversus standard continuous positive airway pressurefor the treatment of obstructive sleep apnea: results ofa meta-analysis. Sleep 27(2):249–253, 2004.

91. Kessler R,Weitzenbaum E, Chaouat A, et al: Evaluationof unattended automated titration to determine thera-peutic continuous positive airway pressure in patientswith obstructive sleep apnea. Chest 123(3):704–710,2003.

92. Gay PC, Herold DL, Olson EJ: A randomized, double-blind clinical trial comparing continuous positive air-way pressure with a novel bilevel pressure system fortreatment of obstructive sleep apnea syndrome. Sleep26(7):864–869, 2003.

93. Aloia MS, Stanchinaa M, Arendt JT, et al: Treatmentadherence and outcomes in flexible vs standardcontinuous positive airway pressure therapy. Chest127(6):2085–2093, 2005.

94. Ferguson KA: The role of oral appliance therapy in thetreatment of obstructive sleep apnea. In Lee-Chiong T,Mohsenin V (eds): Clinics in Chest Medicine. Philadel-phia, Saunders, 2003, pp 355–364.

95. Randerath WJ, Heise M, Hinz R, Ruehle K-H: Anindividually adjustable oral appliance vs continuous pos-itive airway pressure in mild-to-moderate obstructivesleep apnea syndrome. Chest 122(2):569–575, 2002.

96. Marklund M, Franklin KA, Sahlin C, Lundgren Rune:The effect of a mandibular advancement device onapneas and sleep in patients with obstructive sleepapnea. Chest 113(3):707–713, 1998.

97. Marklund M, Stenlund H, Franklin KA: Mandibularadvancement devices in 630 men and women withobstructive sleep apnea and snoring. Chest125(4):1270–1278, 2004.

98. Li KK: Surgical therapy for adult obstructive sleepapnea. Sleep Med Rev 9:201–209, 2005.

99. Powell N: Upper airway surgery does have a major rolein the treatment of obstructive sleep apnea. J Clin SleepMed 1(3):236–240, 2005.

100. Phillips B: Upper airway surgery does not have a majorrole in the treatment of sleep apnea. J Clin Sleep Med1(3):241–245, 2005.

101. Littner M, Kushida CA, Hartse K, et al: Practice para-meters for the use of laser-assisted uvuloplasty: anupdate for 2000. Sleep 24(5):603–619, 2001.

102. Li KK: Surgical therapy for obstructive sleep apneasyndrome. Sem Resp Crit Care Med 26(1):80–88,2005.

103. Peppard PE, Young T, Palta M, et al: Longitudinalstudy of moderate weight change and sleep-disorderedbreathing. JAMA 284(23):3015–3021, 2000.

104. Newman AB, Foster G, Givelber R, et al: Progressionand regression of sleep-disordered breathing withchanges in weight. Arch Intern Med 165(20):2408–2413, 2005.

105. Busetto L, Enzi G, Inelmen EM, et al: Obstructive sleepapnea syndrome in morbid obesity. Chest 128(2):618–623, 2005.

106. Brolin RE: Bariatric surgery and long-term control ofmorbid obesity. JAMA 128(22):2793–2796, 2002.

107. Steinbrook R: Surgery for severe obesity. N Engl J Med350(11):1075–1079, 2004.

108. Verse T: Bariatric surgery for obstructive sleep apnea.Chest 128(2):485–487, 2005.

109. Meoli AL, Rosen CL, Kristo D, et al: Nonprescriptiontreatments of snoring or obstructive sleep apnea: anevaluation of products with limited scientific evidence.Sleep 26(5):619–624, 2003.

110. Fenik VB, Davies RO, Kubin L: REM sleep-like atoniaof hypoglossal (XII) motoneurons is caused by loss ofnoradrengeric and serotonergic inputs. Am J Resp CritCare Med 172(10):1322–1330, 2005.

111. Berry RB, Koch GL, Hayward LF: Low-dose mirtaza-pine increases genioglossus activity in the anesthetizedrat. Sleep 28(1):78–84, 2005.

112. Bellemare F, Pecchiari M, Bandini M, et al: Reversibilityof airflow obstruction by hypoglossus nerve stimulationin anesthetized rabbits. Am J Resp Crit Care Med172(5):606–612, 2005.

113. Schwartz JRL, Hirshkowitz M, Erman MK, Schmidt-Nowara W: Modafanil as adjunct therapy fordaytime sleepiness in obstructive sleep apnea. Chest124(6):2192–2199, 2003.

114. Vastag B: Poised to challenge need for sleep, ‘‘wakeful-ness enhancer’’ rouses concerns. JAMA 291:167–168,2004.

115. BadrMS, Toiber F, Skatrud JB, Dempsey J: Pharyngealnarrowing/occlusion during central sleep apnea. J ApplPhysiol 78(5):1806–1815, 1995.

116. White DP: Central sleep apnea. In Kryger MH, Roth T,Dement WC (eds): Principles and Practice of Sleep Medi-cine, 4th ed. Philadelphia, Elsevier Saunders, 2005,pp 969–982.

117. Douglas NJ: Respiratory physiology: control of ventila-tion. In Kryger MH, Roth T, Dement WC (eds):Principles and Practice of Sleep Medicine, 4th ed.Philadelphia, Elsevier Saunders, 2005, pp 224–231.

118. Sanders MH, Rogers RM, Pennock BE: Prolonged ex-piratory phase in sleep apnea: a unifying hypothesis.Am Rev Resp Dis 131(3):401–408, 1985.

119. Gold AR, Bleeker ER, Smith PL: A shift from centraland mixed sleep apnea to obstructive sleep apnearesulting from low–flow oxygen. Am Rev Resp Dis132(2):220–223, 1985.

120. Mansfield DR, Solin P, Roebuck T, et al: The effect ofsuccessful heart transplant treatment of heartfailure on central sleep apnea. Chest 124(5):1675–1681, 2003.


121. Bradley TD, Floras JS: Sleep apnea and heart failure.Part II: central sleep apnea. Circulation 107:1822–1826, 2003.

122. Nopmaneejumruslers C, Kaneks Y, Hajek V, et al:Cheyne-Stokes respiration in stroke. Relationship tohypocapnia and occult cardiac dysfunction. Am J RespCrit Care Med 171(9):1048–1052, 2005.

123. Leung RS, Diep TM, Bowman ME, et al: Provocationof ventricular ectopy by Cheyne-Stokes respiration inpatients with heart failure. Sleep 27(7):1337–1343,2004.

124. Sin DD, Man GCW: Cheyne-Stokes respiration. A con-sequence of a broken heart? Chest 124(5):1627–1628,2003.

125. Krieger J: Respiratory physiology: breathing in normalsubjects. In Kryger MH, Roth T, Dement WC (eds):Principles and Practice of Sleep Medicine, 4th ed. Philadel-phia, Elsevier Saunders, 2005, pp 232–243.

126. Dempsey J, Skatrud J, Smith C: Powerful stabilizingeffects of CO2 treatment. Sleep 28(1):12–13, 2005.

127. Brown L: ‘‘Dephlogisticated air’’ revisited: oxygentreatment for central sleep apnea syndrome. Chest111(2):269–271, 1997.

128. Bradley TD, Logan AG, Kimoff RJ, et al: Continuouspositive airway pressure for central sleep apnea andheart failure. N Engl J Med 353(19):2025–2033, 2005.

129. Johnson KG, Johnson DC: Bilevel positive airwaypressure worsens central apneas during sleep. Chest128(4):2141–2150, 2005.

130. Pepperel JCT, Maskell NA, Jones DR, et al: A rando-mized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Resp Crit CareMed 168:1109–1114, 2003.

131. Franklin KA, Eriksson P, Sahlin C, Lundgren R:Reversal of central sleep apnea with oxygen. Chest111:163–169, 1997.

132. Krachman SL, Nugent T, Crocetti J, et al: Effects ofoxygen therapy on left ventricular function in patientswith Cheyne-Stokes respiration and congestive heartfailure. J Clin Sleep Med 1(3):271–276, 2005.

133. Javaheri S, Ahmed M, Parker TJ: Effects of nasal O2

on sleep-related disordered breathing in ambulatorypatients with stable heart failure. Sleep 22(8):1101–1106, 1999.

134. Guilleminault C, Philil P, Robinson A: Sleep and neu-romuscular disease: bilevel positive airway pressure bynasal mask as a treatment for sleep disordered breath-ing in patients with neuromuscular disease. J NeurolNeurosurg Psychiatry 65(2):225–232, 1998.

135. Thomas RJ, Daly RW, Weiss JW: Low-concentrationcarbon dioxide is an effective adjunct to positive airwaypressure in the treatment of refractory mixed centraland obstructive sleep-disordered breathing. Sleep28(1):69–77, 2005.

136. Ayappa I, Rapoport DM: The upper airway in sleep:physiology of the pharynx. Sleep Med Rev 7(1):9–33,2003.

137. Gleadhill IC, Schwartz AR, Schubert N, et al: Upperairway collapsibility in snorers and in patients withobstructive hypopnea and apnea. Am Rev Respir Dis143(6):1300–1303, 1991.

138. Rappai M, Collop N, Kemp S, deShazo R: The noseand sleep-disordered breathing: what we know andwhat we do not know. Chest 124(6):2309–2323, 2003.

139. Young T, Palta M, Dempsey J, et al: The occurrenceof sleep-disordered breathing among middle-agedadults. N Engl J Med 328(17):1230–1235, 1993.

140. Wetter DW, Young TB, Bidwell TR, et al: Smoking as arisk factor for sleep-disordered breathing. Arch InternMed 154(19):2219–2224, 1994.

141. Vetrugno R, Provini F, Plazzi G, et al: Catathrenia (noc-turnal groaning): a new type of parasomnia. Neurology56(5):681–683, 2001.

142. Meoli AL, Rosen CL, Kristo D, et al: Nonprescriptiontreatments of snoring or obstructive sleep apnea: anevaluation of products with limited scientific evidence.Sleep 26(5):619–624, 2003.

143. Practice parameters for the treatment of snoring and ob-structive sleep apnea with oral appliances: AmericanSleep Disorders Association. Sleep 18(6):511–513,1995.

144. Stuck BA, Sauter A, Hormann K, et al: Radiofrequencysurgery of the soft palate in the treatment of snoring.A placebo-controlled trial. Sleep 28(7):847–850, 2005.

145. Maurer JT, Hein G, Verse T, et al: Long-term resultsof palatal implants for primary snoring. OtolaryngolHead Neck Surg 133(4):573–578, 2005.

146. Guilleminault C, Stoohs R, Duncan S: Snoring (I).Daytime sleepiness in regular heavy snorers. Chest99(1):40–48, 1991.

147. Lofaso F, Coste A, Gilain L, et al: Sleep fragmentationas a risk factor for hypertension in middle-aged non-apneic snorers. Chest 109(4):896–900, 1996.

148. Gold AR, Dipalo F, Gold MS, O’Hearn D: The symp-toms and signs of upper airway resistance syndrome:a link to the functional somatic syndromes. Chest123(1):87–95, 2003.

149. Lofaso F, Goldenberg F, d’Ortho MP, et al: Arterialblood pressure response to transient arousals fromNREM sleep in nonapneic snorers with sleep fragmen-tation. Chest 113(4):985–991, 1998.

150. Guilleminault C, Poyares D, Palombini L, et al: Varia-bility of respiratory effort in relation to sleep stages innormal controls and upper airway resistance syndromepatients. Sleep Med 2(5):397–405, 2001.

151. Ayappa I, Norman RG, Krieger AC, et al: Non-invasivedetection of respiratory effort-related arousals (REras)by a nasal cannula/pressure transducer system. Sleep23(6):763–771, 2000.

152. Guilleminault C, Stoohs R, Clerk A, et al: A causeof excessive daytime sleepiness. The upper airwayresistance syndrome. Chest 104(3):781–787, 1993.

153. Yoshida K: Oral device therapy for the upperairway resistance syndrome patient. J Prosthet Dent87(4):427–430, 2002.

154. Bao G, Guilleminault C: Upper airway resistance syn-drome—one decade later. Curr Opin Pulm Med10(6):461–467, 2004.

155. Nowbar S, Burkart KM, Gonzales R, et al: Obesity-associated hypoventilation in hospitalized patients: prev-alence, effects, and outcome. Am J Med 116(1):1–7,2004.


156. Kessler R, Chaouat A, Schinkewitch P, et al: Theobesity-hypoventilation syndrome revisited: a prospec-tive study of 34 consecutive cases. Chest 120(2):369–376, 2001.

157. Sullivan CE, Berthon-Jones M, Issa FG: Remission ofsevere obesity-hypoventilation syndrome after short-term treatment during sleep with nasal continuouspositive airway pressure. Am Rev Respir Dis128(1):177–181, 1983.

158. Masa JF, Celli BR, Riesco JA, et al: The obesity hypo-ventilation syndrome can be treated with noninva-sive mechanical ventilation. Chest 119(4):1102–1107,2001.

159. Sugerman HJ, Fairman RP, Sood RK, et al: Long-termeffects of gastric surgery for treating respiratory insuf-ficiency of obesity. Am J Clin Nutr 55(2 Suppl):597S–601S, 1992.

160. Weese-Mayer DE, Silvestri JM, Menzies LJ, et al:Congenital central hypoventilation syndrome: diagno-sis, management, and long-term outcome in thirty-twochildren. J Pediatr 120(3):381–387, 1992.

161. Silvestri JM, Weese-Mayer DE, Flanagan EA: Congeni-tal central hypoventilation syndrome: cardiorespirato-ry responses to moderate exercise, simulating dailyactivity. Pediatr Pulmonol 20(2):89–93, 1995.

162. Paton JY, Swaminathan S, Sargent CW, Keens TG:Hypoxic and hypercapnic ventilatory responses in

awake children with congenital central hypoventilationsyndrome. Am Rev Respir Dis 140(2):368–372, 1989.

163. Paton JY, Swaminathan S, Sargent CW, et al: Ventila-tory response to exercise in children with congenitalcentral hypoventilation syndrome. Am Rev Respir Dis147(5):1185–1191, 1993.

164. Woo MS, Woo MA, Gozal D, et al: Heart rate variabil-ity in congenital central hypoventilation syndrome.Pediatr Res 31(3):291–296, 1992.

165. Gozal D: Congenital central hypoventilation syndrome:an update. Pediatr Pulmonol 26(4):273–282, 1998.

166. Amiel J, Laudier B, Attie-Bitach T, et al: Polyalanineexpansion and frameshift mutations of the paired-likehomeobox gene PHOX2B in congenital central hypo-ventilation syndrome. Nat Genet 33(4):459–461. Epub2003 Mar 17, 2003.

167. Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al:Idiopathic congenital central hypoventilation syndrome:analysis of genes pertinent to early autonomic nervoussystem embryologic development and identification ofmutations in PHOX2b. Am J Med Assoc 123(3):267–278, 2003.

168. Weese-Meyer DE, Shannon DC, Keens TG, SilvestriJM: American Thoracic Society consensus statement.Idiopathic congenital central hypoventilation syn-drome. Diagnosis and management. Am J Respir CritCare Med 160:368–373, 1999.

review of sleep medicine || sleep breathing disorders

Documents