Adult Obstructive Sleep Apnoea

8/12/2019 Adult Obstructive Sleep Apnoea

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Adult obstructive sleep apnoea Amy S Jordan, David G McSharry, Atul Malhotra

Obstructive sleep apnoea is an increasingly common disorder of repeated upper airway collapse during sleep, leadingto oxygen desaturation and disrupted sleep. Features include snoring, witnessed apnoeas, and sleepiness. Pathogenesisvaries; predisposing factors include small upper airway lumen, unstable respiratory control, low arousal threshold,small lung volume, and dysfunctional upper airway dilator muscles. Risk factors include obesity, male sex, age,menopause, uid retention, adenotonsillar hypertrophy, and smoking. Obstructive sleep apnoea causes sleepiness,road traffi c accidents, and probably systemic hypertension. It has also been linked to myocardial infarction, congestiveheart failure, stroke, and diabetes mellitus though not denitively. Continuous positive airway pressure is thetreatment of choice, with adherence of 6070%. Bi-level positive airway pressure or adaptive servo-ventilation can beused for patients who are intolerant to continuous positive airway pressure. Other treatments include dental devices,surgery, and weight loss.

IntroductionObstructive sleep apnoea is a common disorder ofrepetitive pharyngeal collapse during sleep. 1 Pharyngealcollapse could be complete (causing apnoea) or partial(causing hypopnoea). Disturbances in gas exchange leadto oxygen desaturation, hypercapnia, and sleep frag-mentation, which contribute to the consequences ofobstructive sleep apnoeaeg, cardiovascular, metabolic,and neurocognitive effects. Although several treatmentsexist, they are often either poorly tolerated or onlypartially alleviate abnormalities. Thus, improvement ofpatient adherence to existing treatments and developmentof new treatments (or combinations of treatments) areneeded. In view of the obesity pandemic, the propensityfor pharyngeal collapse and therefore the number ofcases of obstructive sleep apnoea are likely to rise.

The landmark study investigating the prevalence ofobstructive sleep apnoea was the 1993 Wisconsin SleepCohort Study. 2 This study reported that the prevalenceof obstructive sleep apnoeadened as more than veapnoeas or hypopnoeas per h of sleep plus excessivedaytime sleepinesswas 4% in middle-aged men and2% in middle-aged women (age 3060 years). Sub-sequent studies suggest that prevalence in high-incomecountries is higher than previously reported (10% inwomen and 20% in men), 3,4 perhaps a result of wor-sening obesity and improving technology over time. 5

Obstructive sleep apnoea is a global health problem;Brazil and several Asian countries have the same, if nothigher, prevalence as the USA and Europe, despite lessoverall obesity.6,7

Diagnosis and denitionsPatients with obstructive sleep apnoea report snoring,witnessed apnoeas, waking up with a choking sensation,and excessive sleepiness. 1 Other common symptoms arenon-restorative sleep, diffi culty initiating or maintainingsleep, fatigue or tiredness, and morning headache. 8 Indi-cators include a family history of the disease or physicalattributes suggestive of obstructive sleep apnoea eg, asmall oropharyngeal airway or markers of obesity (eg,large neck circumference). 9

The best test for obstructive sleep apnoea is overnightpolysomnography in a laboratory with the primary out-come measure of apnoeahypopnoea index (number ofapnoeas plus hypopnoeas per h of sleep). This testinvolves concurrent monitoring of both sleep andrespiration (gures 1, 2). To monitor sleepwake state,electroencephalogram, left and right electro-oculogram,and chin electromyogram are recorded. The respiratoryrecordings should include: respiratory effort measure-ment (eg, respiratory inductance plethysmography bandsplaced around the thorax and abdomen), airow monitor-ing by nasal air pressure and thermal air sensor, andarterial oxygen saturation. Electromyography of theanterior tibialis is also often done to assess limb move-ments that might alter sleep stage or respiration andbody position is monitored because of the position-specicnature of obstructive sleep apnoea in many patients(gure 1).

Table 1 shows the characteristics of each stage of sleepand arousals, and table 2 shows the criteria for respiratoryevents. Several denitions of hypopnoea exist and canlead to different values for apnoeahypopnoea indexbetween laboratories. Ruehland and colleagues 10 showedthat apnoeahypopnoea index could be reckoned as 251,83, or 149 using three different criteria. Denitions ofrespiratory events are based on consensus, 11 althoughdifferent criteria are used around the world. Variability of

denitions can affect patients (eg, the reported severitycan affect eligibility for government-funded treatment)and interpretation of research studies. Although stan-dardised denitions might improve consistency andreproducibility, 12 xed denitions of apnoeahypopnoeaindex might also have limitations. Because obstructivesleep apnoea has different effects on different organsystems, one xed denition is unlikely to predict allnegative outcomes. For example, the different con-sequences of obstructive sleep apnoea are best predictedwith different components of the poly somnography (eg,desaturations by 4% or more in pulse oximetry can bestpredict hypertension, 13 while desaturations of 2% canpredict fasting hyperglycaemia, 14,15 and the frequency ofarousals can predict impaired memory consolidation 16).

Lancet 2014; 383: 73647

PublishedOnlineAugust 2, 2013

http://dx.doi.org/10.1016/S0140-6736(13)60734-5

SeeOnline for a podcastinterview with Amy S Jordan

University of Melbourne,Melbourne, VIC, Australia

(A S Jordan PhD); Institute forBreathing and Sleep,

Melbourne, VIC, Australia (A S Jordan); Brigham and

Womens Hospital and HarvardMedical School, Boston, MA,

USA (D G McSharry MB,Prof A Malhotra MD); University

of California, San Diego, CA,USA(Prof A Malhotra); and

Letterkenny General Hospital,County Donegal, Ireland

(D G McSharry)

Correspondence to:Dr Amy S Jordan, Melbourne

School of Psychological Sciences,The University of Melbourne,Parkville, VIC 3010, Australia

[email protected]
http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(13)60734-5&domain=pdf


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Thus, different denitions of hypopnoea might predictdifferent consequences of obstructive sleep apnoea.Measument of nasal pressure is a recent addition to

polysomnography. Because nasal pressure is moresensitive than thermistor for detection of hypopnoeas,the reported apnoeahypopnoea index (and perhaps thenormal range) increases accordingly. Thus, doctorsshould be aware that subtle differences betweenlaboratories might have a major effect on the reportedapnoeahypopnoea index.

Although polysomnography is usually denitive, theprocedure is cumbersome, expensive, and time con-suming. Thus, home diagnosis and management hasbeen increasingly investigated. Randomised controlledtrials1720 have shown that home-based diagnosis andtreatment are no worse than laboratory diagnosis andtreatment for some patients. All major studies excludedpotentially complicated patients (eg, those with lung

disease, heart failure, or neuromuscular disease), empha-sising that home testing is not appropriate for all patients.However, for some patients, carefully designed home

manage ment procedures can provide timely and cost-effective management of obstructive sleep apnoea. 17 On-going studies focusing on clinical outcomes will help todene optimum management of obstructive sleep apnoea.

Pathophysiology and risk factorsTraditionally, obstructive sleep apnoea was considered tobe primarily a problem of upper airway anatomy, wherecraniofacial structure or body fat decreased the size of thepharyngeal airway lumen, leading to an increasedlikelihood of pharyngeal collapse. 21 During wakefulness,the airway is held open by the high activity of thenumerous upper airway dilator muscles, but after theonset of sleep, when muscle activity is reduced, the airwaycollapses.22,23 Although this sequence probably occurs in

Figure : An example of the signals recorded during overnight polysomnographyShows an obstructive apnoea with cessation of airow for more than 10 s despite persistent respiratory efforts shown on the chest and abdominal respiratory bands.The apnoea is associated with arterial oxygen desaturation and is terminated by arousal from sleep. C4-A1=electroencephalogram. LOC=left electro-oculogram.ROC=right electro-oculogram. CHIN=chin electromyogram. CHEST=respiratory inductance plethysmography bands placed around the thorax. ABDM=respiratoryinductance plethysmography bands placed around the abdomen. PNasal=airow monitoring by nasal air pressure. Therm=airow monitoring by thermal air sensor.SaO2=arterial oxygen saturation. EKG=electrocardiogram.

LOC(V)

ROC(V)

C4-A1(V)

EKG(mV)

Therm

PNasal(cm H2O)

Chest

ABDM

6190 6200 6210 6220 6230

Time (s)

6240 6250 6260

Sa02(%)

CHIN(V)

50

50

0

50

50

0

50

50

0

50

50

0

5

5

0

21

12

0

1

0

025

0250

1

10

98

929496


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obstructive sleep apnoea, several other factors alsocontribute (gure 3). 24 The importance of these non-anatomical and non-neuromuscular factors is shown bypatients with apparently normal upper airway anatomyand very responsive or active upper airway dilator muscleswho still develop obstructive sleep apnoea. 25

One important variable is the stability of the respiratorycontrol system. When the central respiratory output waxesand wanes, the activity of the upper airway dilator musclesvaries accordingly so that periods of low central respiratorydrive are associated with low upper airway dilator muscleactivity, high airway resistance, and a predisposition toairway collapse.26,27 Thus, respiratory control instability(also known as high loop gain) is probably a causativefactor for obstructive sleep apnoea in some patients. 25,28

Another potentially important factor is the propensityto arouse from sleep (the arousal threshold). 29 Afterarousal, most people hyperventilate briey and if thehyperventilation is large enough, CO 2 concentration inblood can fall below the chemical apnoea threshold,resulting in a central apnoea. 30 If hypocapnia is mild,respiratory drive is reduced to just below the eupnoeiclevel when sleep resumes. Because the upper airwaydilator muscles also receive respiratory input, hypo-capnia is expected to reduce the activity of the upperairway dilator muscles and could lead to collapse of theairway. Arousals that halt respiratory events in obstruc-tive sleep apnoea are typically associated with quite largehyperventilation because respiratory drive has risensubstantially during the respiratory event, 30 causing

Figure : An example summary report from an overnight split night polysomnographyTotal time in bed was 4895 min. Half of the night was diagnostic, half therapeutic. The hypnogram shows sleep stages throughout the night. Shortly before midnight,continuous positive airway pressure was started (Pmask increases from 0), which was followed by elimination of respiratory events, normalisation of arterial oxygen saturatioand REM rebound (>2 h of REM). Sleep effi ciency is the proportion of time in bed spent asleep after lights out. Sleep latency is the time from lights out until the rst eposleep. REM latency is the time from lights out until the rst epoch of REM. An epoch is a time window of 30 s. CnA=central apnoea. ObA=obstructive apnoea. MxA=mixapnoea. Hyp=hypnoea. Uns=unclear events. RERA=respiratory event related arousal. PLM=periodic limb movement. TST=total sleep time. REM=rapid eye movement.W=awake. NREM=non-rapid eye movement. R=right. B=back. L=left. F=front. U=upright. AHI=apnoeahypopnoea index. On the hypnogram, 1, 2, and 3 represent NRstages 1, 2, and 3.

Roomlight

On Off

Hypnogram

Total sleep time (min)

Stage 1 (%)

Stage 2 (%)

Stage 3+4 (%)

Stage REM (%)

Sleep efficiency (%)

Sleep latency (min)

REM latency (min)

Arousal index (n per h)

PLM arousal index (n per h)Respiratory summary

Obstructive apnoeas (n)

Mixed apnoeas (n)

Central apnoeas (n)

Hypopnoea (n)

AHI (per h)

AHI NREM (n per h)

AHI REM (n per h)

Lowest SaO2 (%)

Average SaO2 (%)

Desaturations 4% TST (n)

PLM index (n per h)

Baseline

990

111

152

146

258

961

25

750

225

0

CPAP

3815

25

151

96

625

987

15

65

31

0

REMW1234

Arousals

Body positionRBLFU

SpO2

100

50

Respiratory events

CnAObAMxAHypUnsRERA

+5+5+5+5+5+5

Pmask20

0

Heart rate

(beatsper min)

120

20

Time 2200

0 2 4 6 8 101 241 481 721 961 1201

2300 0000 0100 0200 0300 0400 0500 0600 0700

86

0

0

128

1297

1314

1247

49

83

171

0

0

0

0

0

0

0

0

92

97

0

0

HoursEpoch


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hypocapnia in at least some patients. Individuals withlow arousal thresholds might also arouse before thedilator muscles are able to reopen the airway. In suchcases, delay of arousal with non-myorelaxant sedativesmight help to treat the condition if the upper airwaymuscles are suffi ciently responsive to respiratory stimulito stabilise the airway before arousal. 31 Care must betaken with this approach, because sedatives can prolongrespiratory events in some patients (those who cannotre-open the airway without arousal).

Lung volume might also be a causative factor. 32,33 In animals and man, the cross-sectional area of the upperairway increases when lung volume increases (eithernaturally or with passive increases in functional residualcapacity). Conversely, the airway is smaller and collapsesmore easily when lung volume is small. 34 This relationprobably exists because the lower and upper airways aremechanically linked, 35 so that with increased lungvolumes, the mediastinal structures are pulled caudally,resulting in stiffening and dilation of the pharyngealairway. Increased lung volume also probably stabilises

the respiratory control system by increasing the stores ofO2 and CO 2 and thus, buffering the blood gases fromchanges in ventilation. 36 Functional residual capacity fallsbetween waking and sleeping in normal-weight indi-viduals37 and is therefore presumed to contribute to thesleep-related collapse in obstructive sleep apnoea. 33,38,39 However, even when awake, obesity often reduces func-tional residual capacity to residual volume, particularlywhen in the supine position. 40 Therefore, whether lungvolume falls further between wake and sleep in obesepatients with obstructive sleep apnoea remains unclear.

Any factors that impair the upper airway anatomy ormuscle functioneg, dysfunctional upper airwaydilating muscleswill also predispose to obstructivesleep apnoea. 41 The largest and most commonly studied

airway dilator muscle is the genioglossus, which con-stitutes most of the tongue. Adequate contraction of thegenioglossus seems to be necessary and suffi cient tokeep the upper airway open during sleep. 42 Fatigue,

neural injury, and myopathy might cause the genio-glossus to malfunction in people with obstructive sleepapnoea. 4345 Pharyngeal sensory impairment might alsocontribute to collapse of the upper airway. 46,47

Fluid retention and shift of uid overnight from the legsto the neck might also affect airway mechanics. Oedemacan be especially problematic in states of excess extra-cellular uid volumeeg, heart failure, end-stage renaldisease, and hypertension. 48 Treatment with diuretics ormechanical methods to redistribute uid yields someimprovement in obstructive sleep apnoea. 49,50 Accumulationof uid might narrow the pharyngeal airway lumen andcould be a therapeutic target for at least some patients.

Being male and obese are major risk factors forobstructive sleep apnoea. Obesity could increase the

Denition

Apnoea Airow reduced to less than 10% of basel ine for more than 10 s; obstructive ifrespiratory effort is present, central if no respiratory effort is present

Hypopnoea(recommendeddenition)

Airow reduced to less than 30% of baseline for more than 10 s, in association witha 4% oxygen desaturation

Hypopnoea(alternativedenition)

Airow reduced to less than 50% of baseline for more than 10 s, in association witha 3% oxygen desaturation or an arousal from sleep

Respiratory effortrelated arousal

Sequence of breaths lasting more than 10 s that do not meet the standardhypopnoea denition but that are characterised by high upper-airway resistance(snoring and attened inspiratory nasal pressure signal) and that terminate inarousal from sleep

According to AASM scoring manual.

Table : Adult respiratory event scoring

EEG characteristics Relevance to OSA Normal amounts

Wake Low voltage, mixed frequency when eyes are open or alert; activity (813 Hz) while relaxed with eyes closed

Typically increased in OSA 1520% of time in bed

N1 Predominantly low amplitude and relatively fast activity (37 Hz)accompanied by slow rolling-type eye movements

Typically increased in OSA 46%, more in olderpatients

N2 Sleep spindles (1214 Hz bursts lasting >05 s) and K complexes(large negative EEG wave followed immediately by a slower positivewave) on a background of low voltage, mixed frequency EEG

Typically increased in OSA 5065%, more in olderpatients

N3 Slow (75 V) EEG waves for more thanhalf the epoch

Often absent or reduced in OSA, but associatedwith improved severity or complete absence ofOSA when present

1520%, less in olderpatients

REM Low voltage, mixed frequency EEG with periodic runs of sawtoothwaves accompanied by irregular movements of both eyes and lowmuscle tone

Often absent or reduced in OSA; oftenaccompanied by worsening of respiratory eventsand more pronounced desaturation than the non-REM stages

1520%

Arousals 315 s return of waking or faster activity in the EEG; concurrent

increase in EMG must be recorded in REM sleep

Commonly occur at the end of respiratory events,

but also occur spontaneously or as a result of otherstimuli (eg, leg movements)

20 per h of sleep

According to AASM scoring manual. REM=rapid eye movement. OSA=obstructive sleep apnoea. EEG=electroencephalogram. EMG=electromyogram.

Table : Adult sleep staging and arousal scoring


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likelihood of airway collapse by directly affecting theanatomy of upper airway as fat is deposited in surround-ing structures. 51 MRI studies suggest that fat is depositedwithin the tongue, which could impair function of thegenioglossus muscle. 52 However, obesity might alsoincrease the risk of obstructive sleep apnoea via effectson lung volumes and therefore stability of respiratorycontrol. How male sex predisposes to obstructive sleepapnoea is less clear. 53 Men tend to gain weight morecentrally than do women, and this pattern probablyresults in men having more fat stored in upper airwaystructures and the abdomen than do women. 54 However,anatomical studies have shown that men tend to have

larger or similar size pharyngeal airway cross-sectionalareas than do women, suggesting that differ ences in fatdeposition might not greatly impair airway anatomy.Several studies 53 suggest that the airway is longer in menthan in women, independent of body height, whichcould explain the increased propensity for airwaycollapse in men. The passive pharyngeal airwaycollapsing pressure provides an overall measure of theanatomy of the upper airway that accounts for allanatomical measures and their interactions, but it doesnot account for neuro muscular reexes. 55,56 The passivepharyngeal airway collapsing pressure is generallyhigher in men than in women for any given body-massindex, suggesting that generally, anatomical factorspredispose men to pharyn geal collapse more than

women. Women also have better respiratory load

responses than do men (eg, higher minute ventilationduring inspiratory resistive loading). 57,58 Finally, the morecentral fat distribution in men might reduce lungvolumes for a given body-mass index.

Age is another major risk factor. 59 Older individualsmight have reduced tethering of the upper airway bylung volume because of loss of elastic recoil in the lung.They might also have a more easily collapsible airwaycaused by loss of collagen or a reduced arousal thresholdcaused by poorer quality of sleep. Finally, the effi ciency ofthe upper airway dilator muscles might fall with age. 6062

Additional risk factors for the development of obstruc-tive sleep apnoea include genetic factors and race, whichaffect craniofacial anatomy, obesity, and perhaps lungvolume. Menopauseindependent of age and body-mass indexis also a risk factor. Menopause could berelated to redistribution of body fat to central regionsand loss of lean muscle mass (with a pro portionateincrease in fat mass). Finally, smoking is also commonlylinked with obstructive sleep apnoea. Although the exactmechanisms of this association are not clear, 4 theymight include increased inammation of the upperairway, nasal stuffi ness, reduced airway sensation, andreduced arousal threshold or frequent arousals becauseof unstable sleep. A more complete understanding ofthe pathogenesis of obstructive sleep apnoea and itsrisk factors could lead to new means to treat or preventthe disease.

ConsequencesRandomised trials have shown that obstructive sleepapnoea causes sleepiness based on signicant improve-ments in symptoms with continuous positive airwaypressure compared with controls. 63 People with obstruc-tive sleep apnoea are more likely to have motor vehicleaccidents (perhaps up to seven-times as many as thosewithout the disease 64 ). This risk might be mitigated, atleast in part, by treatment. 65 Obstructive sleep apnoeaalso affects quality of life and different aspects of healthdomains with improvements noted after treatment withcontinuous positive airway pressure, particularly in

adherent patients. 1Obstructive sleep apnoea leads to systemic hyper-

tension, 66 as shown by animal studies (showing increasedsystemic blood pressure with induction of sleep apnoea,which resolves with relief of apnoea), 67 large cross-sectionaland longitudinal epidemiological studies, 68,69 and severalrandomised trials 70 showing that treatment for obstructivesleep apnoea reduces systemic blood pressure. Treatmentwith continuous positive airway pressure seems to reduceblood pressure, although only by 23 mm Hg, and lessthan the reductions gained by treatment with anti-hypertensive drugs. 71 However, continuous positive air waypressure improves symptoms in addition to hyper tension. 72Results of meta-analyses 70,73 have dened predictors ofimprovement in blood pressure after continuous positive

Figure : Risk factors, pathogenic mechanisms, and possible treatments for obstructive sleep apnoeaRisk factors for obstructive sleep apnoea probably act through one or more pathogenic mechanisms. One or two ofthe pathogenic mechanism might predominate in each patient and give rise to the disorder. Although CPAP treatsobstructive sleep apnoea irrespective of underlying cause, treatments based on tackling individual pathogenicmechanisms might prove a successful alternative approacheg, uid accumulation outside the airway could makethe upper airway lumen smaller and might respond to diuretic treatment. CPAP=continuous positive airwaypressure. MAD=mandibular advancement device. HGNS=hypoglossal nerve stimulation.

Risk factors

Pathogenicmechanisms

Possibletreatments

Genetics andethnic origin

Craniofacialstructure

Small upperairway lumen

Respiratoryinstability

Low arousalthreshold

Poor upperairway muscle

function

Nasalcongestion

Obesity

Unknown O2 or drugs HGNS SedativesMAD

CPAP

Surfacant

Route of breathing

Surfaceforces

Low lungvolume

Sex Age

Treatment of obstructive sleep apnoea


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airway pressure, including adherence, young age, baseline

blood pressure (ie, blood pressure can fall greatly inhypertensive patients), daytime sleepiness (ie, larger fallsin sleepier patients), and severity of obstructive sleepapnoea. However, proponents of theories on centralregulation of blood pressure would argue that largechanges in blood pressure are unlikely to occur ifcontinuous positive airway pressure simply reducedvasoconstriction; 74 various counter-regulatory mechanisms(eg, baroreexes) would stabilise blood pressure, at least inthe short term. Nonetheless, some patients given con-tinuous positive airway pressure do have large improve-ments in blood pressure as well as reductions in surges innocturnal blood pressure associated with obstructive sleepapnoea. However, this link is still controversial; somestudies have shown that the connection between obstruc-tive sleep apnoea and hypertension is weak when covariatesare adequately considered. 7577

The relation between hard cardiovascular outcomesand obstructive sleep apnoea is unproven. 78 Marin andcolleagues79 reported results of a prospective observationalcohort study in which severe untreated obstructive sleepapnoea was associated with an increased incidence ofboth fatal and non-fatal cardiovascular events comparedwith patients with treated obstructive sleep apnoea andvarious control groups. Although these data accord withthe idea that treatment of obstructive sleep apnoeaprevents cardiovascular events, the result might becaused by a treatment biasie, patients who adhere tocontinuous positive airway pressure might also bemotivated to adhere to diet and exercise advice and toadhere to drugs. 80 Other epidemiological studies 72,81 havelinked obstructive sleep apnoea with myocardial infarc-tion, congestive heart failure, and stroke. Post-hocsubgroup analyses suggest that obstructive sleep apnoeahas a bigger effect on cardiovascular outcomes in youngmen compared with old men. Asymptomatic patientsoften do not adhere to treatment and so do not improvemuch in randomised trials. Several observational studieshave assessed the effect of obstructive sleep apnoea onoverall mortality and cancer risk, although large, con-trolled, randomised trials are needed to draw denitive

conclusions. 82,83No clear data show that continuous positive airway

pressure prevents myocardial infarction, congestiveheart failure, or stroke, although this topic is beinginvestigated. 72,78 Among patients with heart failure,continuous positive airway pressure improves cardiacfunction, although the existing studies are small. 84 Toshow that obstructive sleep apnoea increases the chanceof cardiovascular events, studies in high-risk patients areneeded. Assessing changes in surrogate outcomemeasures or biomarkers might also be informative. 85

Obstructive sleep apnoea has been linked with diabetesmellitus. Foster and colleagues 5,86 showed that 87% ofobese patients with type 2 diabetes had clinically importantobstructive sleep apnoea, although because obesity is a

common risk factor for both obstructive sleep apnoea and

diabetes mellitus, the association could simply be acorrelation. Diabetes can lead to neuromyopathy, whichmight impair reexes in the upper airway, increasing thelikelihood of obstructive sleep apnoea. 1 However, few datasupport this contention. Furthermore, because of therelease of counter-regulatory hormones during obstructiveapnoea, glycaemic control might be expected to be worsein patients with diabetes if obstructive sleep apnoea is leftuntreated. 87,88 However, most data show no major improve-ment in glycaemic control with treatment of obstructivesleep apnoea. 89 A potential explanation for this ndingrelates to adherence to continuous positive airwaypressure. A study from India 90 showed improvement inmetabolic syndrome in a setting where adherence tocontinuous positive airway pressure was high. Addition-ally, because standard of care in type 2 diabetes requiresfairly good glycaemic control, the incremental benets ofcontinuous positive airway pressure beyond standarddiabetes treatment might be small. Moreover, theinteractions between obstructive sleep apnoea and obesityand their effects on glucose regulation are probablycomplex.91,92 Finally, obstructive sleep apnoea and diabetesmellitus could affect vascular function through dif-ferent pathways, 93,94 therefore treatment of obstructivesleep apnoea could improve vascular outcomes indiabetes. Standard therapeutic targets for diabeteseg,hypercholesterolaemia, blood pressure, and glycaemiccontrolhave probably been exploited as much aspossible, suggesting the need for new therapeutic targets.Efforts are ongoing to assess the effect of continuouspositive airway pressure in patients with diabetes.

Randomised controlled trials of continuous positiveairway pressure are diffi cult to do for both ethical andlogistical reasons. 22 Symptomatic patients will benetfrom continuous positive airway pressure, makinglong-term assignment to an untreated control groupchallenging. Conversely, adherence of asymptomaticpatients is often poor, reducing any potential benet ofassignment to continuous positive airway pressure. 72,95 Comparative effectiveness research might be feasible, inwhich two active treatments are compared to one another

(eg, continuous positive airway pressure vs oralappliance); 96,97 however, obtaining denitive data willrequire improved identication of patients likely togreatly benet from continuous positive airway pressure(or combinations of treatments).

ManagementNasal continuous positive airway pressure is thetreatment of choice for adults with obstructive sleepapnoea. 98 It was rst reported as an effective means ofpreventing collapse of the pharyngeal airway in 1981. 99 The mechanism of continuous positive airway pressure isdebated, but probably involves maintenance of a positivepharyngeal transmural pressure so that the intraluminalpressure exceeds the surrounding pressure. 33 Continuous


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positive airway pressure also increases end-expiratorylung volume, which stabilises the upper airway throughcaudal traction. 100 The decision to start treatment withcontinuous positive airway pressure should include adiscussion with the patient about the potential alleviationof symptoms and possible cardiovascular protection. 73,95,98Continuous positive airway pressure has substantialbenets for some patients and adherence is roughly6070%, much the same as adherence to inhalers inpatients with asthma, anti-convulsant drugs in thosewith epilepsy, and maintenance of good glyceamiccontrol in diabetes. 98 It is also highly cost effective when

considering its effects on neurocognitive and cardio-vascular sequelae. 101

Patients likely to maintain long-term adherence includethose who snore heavily, have severe sleep apnoea,and have substantial excessive daytime sleepiness. 102,103 Because short-term adherence and early perceivedbenets are the best predictors of long-term adherence,efforts to optimise adherence are best done before orshortly after starting treatment.

Several points should be considered when managingpatients who are struggling to adhere to continuouspositive airway pressure (gure 4). First, intensivesupport can be benecial according to some studies. 104 Education and support can improve adherence: patientswho understand the benets of treatment and who are

helped to troubleshoot diffi culties are likely to respond

favourably. Second, some patients have nasal diffi cultiesthat limit their ability to tolerate nasal treatment withcontinuous positive airway pressure. Nasal decongestantsand heated humidication can be benecial for suchpatients. In rare cases, nasal surgery can improve adher-ence. Third, although randomised trials have not shownone type of mask to be better than another, some patientsprefer a full face mask to a nasal mask, while othersprefer a nasal pillow device. Fourth, some patientsrespond to hypnotherapy if they develop insomnia orfrequently wake when using continuous positive airwaypressure. 105 Some data support the use of eszopiclone inpatients who are starting continuous positive airwaypressure. Our clinical experience suggests that consoli-dating sleep (stabilising or preventing fragmented sleep)can enable adherence so that hypnotherapy is no longerneeded once the patient has habituated to the newequipment. Sedatives should be used cautiously inpatients with obstructive sleep apnoea.

Several alternative options are available for patients inwhom continuous positive airway pressure is unsuccess-ful. Bi-level positive airway pressure can be used (andmight be preferred by some patients who have expiratorypressure discomfort), although randomised trials 106 haveshown no major benet compared with continuouspositive airway pressure. Second, expiratory pressurerelief strategieseg, C-Flex (Philips Respironics;Murraysville, PA, USA) or EPR (Resmed; San Diego, CA,USA)can improve discomfort during expiration insome patients. Most data 107 suggest that such treatmentsoffer no major benet compared with standard continuouspositive airway pressure. Third, autotitration positiveairway pressure has been used to vary pressure on an ad-hoc basis to maintain stable ventilation. Some patientswho need different pressures to be applied (eg, based onbody posture or sleep stage) might benet from variablepressure devices that can lower the applied pressure whenappropriate. However, most randomised trials 108 haveshown no improvement in adherence with autotitrationcompared with standard continuous positive airwaypressure. Some data 109 suggest that autotitration positive

airway pressure worsens outcomes, seemingly becausechanges in intrathoracic pressure lead to arousal fromsleep and haemodynamic instability. Thus, the datasupporting new technologies to improve adherence arenot compelling, 110 but occasional benets are seen inclinical practice.

For patients in whom positive airway pressure isunsuccessful, alternatives include oral devices, upperairway surgery, positional therapy, and other conservativemeasures. Different oral devices work in different waysbut generally they apply pressure to the jaw to preventretroglossal collapse. Oral devices are preferable tocontinuous positive airway pressure in some patients,particularly those with mild-to-moderate disease. 111,11However, the effi cacy of oral devices varies and little data

Figure :Suggested steps for management of patients struggling with CPAPCPAP=continuous positive airway pressure.

CPAP intolerant

Assess patient motivation andeducation and extent of previousattempts

Intensive support andencouragement

Assess nasal pathologyConsider nasal decongestants,steroids, or septoplasty orpolypectomy

Assess mask leak or discomfortTry different masks, respiratorytherapist assessment

Assess for inability to sleep with

CPAP

Consider eszopiclone and address

any sleep hygiene problems

Highly variable pressurerequirement

Consider autotitration positiveairway pressure

Assess for expiratory pressurediscomfort

Consider expiratory pressure reliefof bi-level positive airway pressure

Failed positive airway pressuretreatment

Consider oral appliance, upperairway surgery, or experimentaltreatment


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on outcomes have been collected. 113116 One challenge with

such devices is that several visits to a dentist are neededwith satisfactory outcome diffi cult to judge until after69 months of gradual titration. Although the device,plus repeated visits to the dentist, can be costly, oraldevices are likely to be cost effective if they successfullytreat obstructive sleep apnoea.

Some simple surgeries can be done to the soft palate(somnoplasty, laser-assisted uvulopalatopharyngo plasty),but the resulting improvements in symptoms aregenerally small at best. Fewer than 50% of patients havemajor improvements in apnoeahypopnoea index withuvulopalatopharyngoplasty, therefore many doctorsrecommend against this procedure. However, becausesurgical procedures obviate the diffi culties of patientadherence, some researchers recommend surgicaltreatments. 117120 Aggressive surgerieseg, maxilla-man-dibular advancementare probably more effective thansimple surgeries, but many patients would rather avoidmajor surgery for obstructive sleep apnoea. Tracheostomyeliminates obstructive sleep apnoea but it can sub-stantially reduce quality of life. Prediction of whichpatients will respond to a particular procedure is poor atpresent, although research is ongoing. 121 Experimentalsurgeries such as hypoglossal nerve stimulation arebeing studied, but denitive data are not available. 122124 Thus, further study is needed to dene the best treatmentfor obstructive sleep apnoea.

Conservative measures can also be helpful. Avoidance ofdepressants including alcohol can be helpful since suchsubstances can worsen symptoms. Sleeping for 78 h pernight can reduce sleepiness. Avoidance of a supine posturecan also help patients whose apnoea is caused by sleepposition, although such patients often prefer continuouspositive airway pressure to positional treatment. 125 Additionally, positional treatment can be diffi cult tomonitor at home and thus, clinical outcomes are variable.Positional treatment can also be used in combination withother treatments when interventions such as oral devicesor surgery give incomplete responses. Weight loss throughdiet and exercise can also be helpful. 5 Few patients achievelong-term maintenance of reduced bodyweight, but

education and support can be helpful. Some data 126 suggestthat bodyweight increases after treatment with continuouspositive airway pressure, emphasising the need for dietand exercise advice for all patients. Epidemiological data 127 suggest that exercise might have other benets forobstructive sleep apnoea in addition to weight loss;however, the mechanism of this improvement is unclear.Similarly, neuromuscular exer cises are benecial for somepatients, 128 although the data are not denitive.

Sleepiness persists in some patients despite goodadherence to continuous positive airway pressure. 129,130 The mechanism underlying this nding is unclear, butmight result from consequences of apnoea that areirreversible. Such patients are managed supportivelywith efforts to improve adherence and sleep duration as

much as possible. Several randomised trials have been

done to test the usefulness of stimulants such asmodanil to treat residual sleepiness in patients whoadhere to continuous positive airway pressure. In moststudies, patients benet from stimulants, although somestudies 131 suggest that use of continuous positive airwaypressure is compromised. Thus, patient education isimportant to emphasise that stimulants can provide anadjunctive treatment for sleepiness but do not treat theunderlying apnoea: ongoing adherence to continuouspositive airway pressure is needed.

Central apnoeas develop in roughly 10% of patientswho start treatment with continuous positive airwaypressure. 132 These apnoeas are also known as complexapnoea and have been the subject of debate. 133 Althoughthe mechanisms are unclear, 134 various theories havebeen suggested, 133 including lung stretch reexesreducing ventilatory motor output, improvement in CO 2 clearance with relief of upper airway obstruction yieldinga partial pressure of CO 2 below the chemical apnoeathreshold, and reduction of anatomical deadspace bywashout of CO 2 from the upper airway. Irrespective ofthe underlying mechanism, most results 134 suggest thatthese central apnoeas resolve spontaneously with on-going continuous positive airway pressure treatment.Even so, some researchers advocate for the use of newdeviceseg, adaptive servo-ventilationto treat suchapnoeas. 135 If breathing normalises spontaneously overtime, then the use of expensive new devices might notbe justied. Conversely, if a patients rst experienceof continuous positive airway pressure treatment isunpleasant (perhaps because of repeated centralapnoeas), then long-term adherence to treatment mightbe poor as a result. 135 Thus, early intervention to treatcentral apnoeas could improve long-term adherence topositive airway pressure. Treatment-emergent centralapnoeas seem to have no effect on outcomes or long-termadherence 133 and thus, efforts at early intervention withnew devices have been unsuccessful. As a resulttreatment-emergent central apnoea can be considered aminor problem.

PreventionAlthough many risk factors for obstructive sleep apnoeaare xed, weight loss (though diet and exercise), andavoidance of cigarettes, alcohol, and other myorelaxantdrugs can be benecial. 5,86 Results of a randomisedcontrolled trial 5,86 show that a 10 kg reduction in body-weight can yield a reduction in apnoeahypopnoea indexof roughly ve events per h. Obstructive sleep apnoearesolved in 63% of patients with mild disease, whereasonly 13% of patients with severe obstructive sleep apnoeahad remission. Although bariatric surgery is highlyeffective at causing weight loss, long-term elimination ofapnoea varies. 136 Several studies 40,137140 have shown thatobstructive sleep apnoea re-emerges or persists aftersurgical or non-surgical weight loss.


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Future directions

Future treatments for obstructive sleep apnoea are likelyto be targeted to the cause of disease since the diseaseoccurs for different reasons in different patients(gure 3). For patients with a low arousal threshold,sedatives or hyp notics might be useful, whereas forpatients with un stable ventilatory control, oxygen oracetazolamide might improve obstructive sleepapnoea. 28 Palate surgery will probably help patients withanatomical problems at the level of the velopharynx. 141 For patients with upper airway muscle dysfunction,treatments such as hypoglossal nerve stimulation, 122 muscle training exercises, 128 or strategies to increasehypoglossal output might be useful. For patients withmultifactorial disease, combination treatment might benecessary. Further research into disease mechanismsshould focus on new treatment strategies. 24 Ultimately,drugs might be developed to either block apnoea orattenuate its consequences.ContributorsAll authors wrote and edited the seminar. ASJ and AM made the gures.

Conicts of interestAM has received consulting and research income from Philips, SleepGroup Solutions, Pzer, Apnex Medical, and Apnicure but hasrelinquished all outside personal income since May, 2012. DGM hasreceived funding from the American Heart Association. ASJ is fundedby the Australian Research Council and NHMRC Australia. Before 2010,she received consulting income from Apnex Medical.

References1 Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;

360: 23745.2 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S.

The occurrence of sleep-disordered breathing among middle-agedadults. N Engl J Med 1993;32: 123035.

3 Sforza E, Chouchou F, Collet P, Pichot V, Barthelemy JC, Roche F.Sex differences in obstructive sleep apnoea in an elderly Frenchpopulation. Eur Respir J 2011;37: 113743.

4 Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM.Increased prevalence of sleep-disordered breathing in adults.Am J Epidemiol 2013;177: 100614.

5 Foster GD, Borradaile KE, Sanders MH, et al. A randomized studyon the effect of weight loss on obstructive sleep apnea among obesepatients with type 2 diabetes: the Sleep AHEAD study. Arch Intern Med 2009; 169: 161926.

6 Sharma SK, Ahluwalia G. Epidemiology of adult obstructive sleepapnoea syndrome in India. Indian J Med Res 2010;131: 17175.

7 Ip MS, Lam B, Lauder IJ, et al. A community study of

sleep-disordered breathing in middle-aged Chinese men inHong Kong. Chest 2001;119: 6269.8 Chervin RD. Sleepiness, fatigue, tiredness, and lack of energy in

obstructive sleep apnea. Chest 2000; 118: 37279.9 Davies RJ, Ali NJ, Stradling JR. Neck circumference and other

clinical features in the diagnosis of the obstructive sleep apnoeasyndrome. Thorax 1992;47: 10105.

10 Ruehland WR, Rochford PD, ODonoghue FJ, Pierce RJ, Singh P,Thornton AT. The new AASM criteria for scoring hypopneas:impact on the apnea hypopnea index. Sleep 2009; 32: 15057.

11 Silber MH, Ancoli-Israel S, Bonnet MH, et al. The visual scoring ofsleep in adults. J Clin Sleep Med 2007; 3: 12131.

12 Grigg-Damberger MM. The AASM scoring manual four years later. J Clin Sleep Med 2012;8: 32332.

13 Foster GE, Hanly PJ, Ahmed SB, Beaudin AE, Pialoux V, Poulin MJ.Intermittent hypoxia increases arterial blood pressure in humansthrough a renin-angiotensin system-dependent mechanism.Hypertension 2010;56: 36977.

14 Lindberg E, Theorell-Haglow J, Svensson M, Gislason T, Berne C,Janson C. Sleep apnea and glucose metabolism: a long-termfollow-up in a community-based sample. Chest 2012;142: 93542.

15 Stamatakis K, Sanders MH, Caffo B, et al. Fasting glycemia in sleepdisordered breathing: lowering the threshold on oxyhemoglobindesaturation. Sleep 2008; 31: 101824.

16 Djonlagic I, Saboisky J, Carusona A, Stickgold R, Malhotra A.Increased sleep fragmentation leads to impaired off-lineconsolidation of motor memories in humans. PLoS One 2012;7: e34106.

17 Mulgrew AT, Fox N, Ayas NT, Ryan CF. Diagnosis and initialmanagement of obstructive sleep apnea without polysomnography:a randomized validation study. Ann Intern Med 2007;146: 15766.

18 Rosen CL, Auckley D, Benca R, et al. A multisite randomized trialof portable sleep studies and positive airway pressure autotitrationversus laboratory-based polysomnography for the diagnosis andtreatment of obstructive sleep apnea: the HomePAP study. Sleep 2012;35: 75767.

19 Kuna ST, Gurubhagavatula I, Maislin G, et al. Noninferiority offunctional outcome in ambulatory management of obstructive sleepapnea. Am J Respir Crit Care Med 2011;183: 123844.

20 Masa JF, Corral J, Pereira R, et al. Therapeutic decision-making forsleep apnea and hypopnea syndrome using home respiratorypolygraphy: a large multicentric study. Am J Respir Crit Care Med 2011;184: 96471.

21 Schwab R, Pasirstein M, Pierson R, et al. Identication of upperairway anatomic risk factors for obstructive sleep apnea withvolumetric magnetic resonance imaging. Am J Respir Crit Care Med 2003; 168:52230.

22 Malhotra A, Loscalzo J. Sleep and cardiovascular disease:an overview. Prog Cardiovasc Dis 2009; 51: 27984.

23 Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal EMGin sleep apnea patients versus normal controls (a neuromuscularcompensatory mechanisms). J Clin Invest 1992;89: 157179.

24 Saboisky JP, Chamberlin NL, Malhotra A. Potential therapeutictargets in obstructive sleep apnoea. Expert Opin Ther Targets 2009;13: 795809.

25 Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control andairway anatomy in obstructive sleep apnea.Am J Respir Crit Care Med 2004; 170: 122532.

26 Strohl K, Butler J, Malhotra A. Mechanical properties of the upperairway. Compr Physiol 2012; 2: 185372.

27 Badr MS, Roiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol 1995;78: 180615

28 Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improvesloop gain but not the other physiological traits causing obstructivesleep apnoea. J Physiol2012;590: 1199211.

29 Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increasesthe respiratory arousal threshold and lowers the apnoea/hypopnoeaindex in obstructive sleep apnoea patients with a low arousalthreshold. Clin Sci (Lond) 2011;120: 50514.

30 Dempsey JA, Veasey SC, Morgan BJ, ODonnell CP.Pathophysiology of sleep apnea. Physiol Rev 2010;90: 47112.

31 Heinzer RC, White DP, Jordan AS, et al. Trazodone increases arousalthreshold in obstructive sleep apnoea. Eur Respir J 2008; 31: 130812.

32 Begle RL, Badr S, Skatrud JB, Dempsey JA. Effect of lung inationon pulmonary resistance during NREM sleep. Am Rev Respir Dis 1990;141: 85460.

33 Owens RL, Malhotra A, Eckert DJ, White DP, Jordan AS.The inuence of end-expiratory lung volume on measurements ofpharyngeal collapsibility. J Appl Physiol 2010;108: 44551.

34 Heinzer RC, Stanchina ML, Malhotra A, et al. Lung volume andcontinuous positive airway pressure requirements in obstructivesleep apnea. Am J Respir Crit Care Med 2005; 172: 11417.

35 Van de Graaff WB. Thoracic inuence on upper airway patency. J Appl Physiol 1988;65: 212431.

36 Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W.Chemical control stability in patients with obstructive sleep apnea.Am J Respir Crit Care Med 2001;163: 118190.

37 Ballard R, Irvin CG, Martin RJ, Pak J, Pandey R, White DP.Inuence of sleep on lung volume in asthmatic patients andnormal subjects. J Appl Physiol 1990;68: 203441.


10/13

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38 Owens RL, Edwards BA, Sands SA, et al. Upper airway collapsibilityand patterns of ow limitation at constant end-expiratory lungvolume. J Appl Physiol 2012;113: 69199.

39 Stadler DL, McEvoy RD, Bradley J, Paul D, Catcheside PG. Changesin lung volume and diaphragm muscle activity at sleep onset inobese obstructive sleep apnea patients vs. healthy-weight controls. J Appl Physiol 2010;109: 102736.

40 Malhotra A, Hillman D. Obesity and the lung: 3. Obesity,respiration and intensive care. Thorax 2008; 63: 92531.

41 Saboisky JP, Butler JE, Gandevia SC, Eckert DJ. Functional role ofneural injury in obstructive sleep apnea. Front Neurol 2012;3: 95.

42 Jordan AS, White DP, Lo YL, et al. Airway dilator muscle activityand lung volume during stable breathing in obstructive sleep apnea.Sleep 2009; 32: 36168.

43 Eckert DJ, Lo YL, Saboisky JP, Jordan AS, White DP, Malhotra A.Sensorimotor function of the upper-airway muscles and respiratorysensory processing in untreated obstructive sleep apnea. J Appl Physiol 2011;111: 164453.

44 McSharry D, OConnor C, McNicholas T, et al. Genioglossus

fatigue in obstructive sleep apnea. Respir Physiol Neurobiol 2012;183: 5966.45 Friberg D, Ansved T, Borg K, Carlsson-Nordlander B, Larsson H,

Svanborg E. Histological indications of a progressive snorersdisease in an upper airway muscle. Am J Respir Crit Care Med 1998;157: 58693.

46 Kimoff R, Sforza E, Champagne V, Oara L, Gendron D. Upperairway sensation in snoring and obstructive sleep apnea.Am J Respir Crit Care Med 2001;160: 25055.

47 Jobin V, Champagne V, Beauregard J, Charbonneau I,McFarland DH, Kimoff RJ. Swallowing function and upper airwaysensation in obstructive sleep apnea. J Appl Physiol 2007;102: 158794.

48 Yumino D, Redol S, Ruttanaumpawan P, et al. Nocturnal rostraluid shift: a unifying concept for the pathogenesis of obstructiveand central sleep apnea in men with heart failu re. Circulation 2010;121: 1598605.

49 Redol S, Arnulf I, Pottier M, et al. Attenuation of obstructive sleep

apnea by compression stockings in subjects with venousinsuffi ciency. Am J Respir Crit Care Med 2011;184: 106266.50 Hanly P, Pierratos A. Improvement in sleep apnea in patients with

chronic renal failure who undergo nocturnal hemodialysis.N Engl J Med 2001;344: 10207.

51 Patil S, Schneider H, Gladmon E, et al. Obesity and upper airwaymechanical control during sleep. Am J Respir Crit Care Med 2004;169: A435.

52 Chi L, Comyn FL, Mitra N, et al. Identication of craniofacial riskfactors for obstructive sleep apnoea using three-dimensional MRI.Eur Respir J 2011;38: 34858.

53 Malhotra A, Huang Y, Fogel R, et al. The male predisposition topharyngeal collapse: the importance of airway length.Am J Respir Crit Care Med 2002; 166: 138895.

54 Whittle AT, Marshall I, Mortimore IL, Wraith PK, Sellar RJ,Douglas NJ. Neck soft tissue and fat distribution: comparisonbetween normal men and women by magnetic resonance imaging.Thorax 1999;54: 32328.

55 Kirkness JP, Schwartz AR, Schneider H, et al. Contribution of malesex, age, and obesity to mechanical instability of the upper airwayduring sleep. J Appl Physiol 2008; 104: 161824.

56 Kirkness JP, Peterson LA, Squier SB, et al. Performancecharacteristics of upper airway critical collapsing pressuremeasurements during sleep. Sleep 2011;34: 45967.

57 Chin CH, Kirkness JP, Patil SP, et al. Compensatory responses toupper airway obstruction in obese apneic men and women. J Appl Physiol 2012;112: 40310.

58 Pillar G, Malhotra A, Fogel R, Beauregard J, Schnall R, White D.Airway mechanics and ventilation in response to resistive loadingduring NREM sleep: the inuence of gender.Am J Respir Crit Care Med 2000; 162: 162732.

59 Edwards BA, ODriscoll DM, Ali A, Jordan AS, Trinder J,Malhotra A. Aging and sleep: physiology and pathophysiology.Semin Respir Crit Care Med 2010;31: 61833.

60 Malhotra A, Huang Y, Fogel R, et al. Aging inuences on

pharyngeal anatomy and physiology: the predisposition topharyngeal collapse. Am J Med 2006; 119: e914.

61 Eikermann M, Jordan AS, Chamberlin NL, et al. The inuence ofaging on pharyngeal collapsibility during sleep. Chest 2007;131: 170209.

62 Marcus CL. Obstructive sleep apnea syndrome: differences betweenchildren and adults. Sleep 2000; 23 (suppl 4): S14041.

63 Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison oftherapeutic and subtherapeutic nasal continuous positive airwaypressure for obstructive sleep apnoea: a randomised prospectiveparallel trial. Lancet 1999;353: 210005.

64 Teran-Santos J, Jimenez-Gomez, A, Cordero-Guevara, J. Theassociation between sleep apnea and the risk of traffi c accidents.Cooperative Group Burgos-Santander. N Engl J Med 1999;340: 84751.

65 Strohl KP, Brown DB, Collop N, et al, ATS Ad Hoc Committee onSleep Apnea, Sleepiness, and Driving Risk in NoncommercialDrivers. An offi cial American Thoracic Society clinical practiceguideline: sleep apnea, sleepiness, and driving risk in noncommercialdrivers. Am J Respir Crit Care Med 2013;187: 125966.

66 Parati G, Lombardi C, Hedner J, et al. Position paper on themanagement of patients with obstructive sleep apnea andhypertension: joint recommendations by the European Society ofHypertension, by the European Respiratory Society and by themembers of European COST (COoperation in Scientic andTechnological research) ACTION B26 on obstructive sleep apnea. J Hypertens 2012;30: 63346.

67 Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA.Obstructive sleep apnea as a cause of systemic hypertension.Evidence from a canine model. J Clin Invest 1997;99: 10609.

68 Lavie P, Here P, Hoffstein, V. Obstructive sleep apnea syndrome asa risk factor for hypertension. BMJ 2000; 320: 47982.

69 Peppard P, Young T, Palta M, Skatrud J. Prospective study of theassociation between sleep disordered breathing and hypertension.N Engl J Med 2000; 342: 137884.

70 Montesi S, Edwards BA, Malhotra A, Bakker J. The effect ofcontinuous positive airway pressure treatment on blood pressure:a systematic review and meta-analysis of randomized controlledtrials. J Clin Sleep Med 2012;8: 58796.

71 Pepin JL, Tamisier R, Barone-Rochette G, Launois SH, Levy P,

Baguet JP. Comparison of continuous positive airway pressure andvalsartan in hypertensive patients with sleep apnea.Am J Respir Crit Care Med 2010;182: 95460.

72 Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. Effect ofcontinuous positive airway pressure on the incidence of hypertensionand cardiovascular events in nonsleepy patients with obstructivesleep apnea: a randomized controlled trial. JAMA 2012;307: 216168.

73 Barbe F, Duran-Cantolla, J, Sanchez-de-la-Torre M, et al. Effect ofcontinuous positive airway pressure on the incidence ofhypertension and cardiovascular events in nonsleepy patients withobstructive sleep apnea: a randomized controlled trial. JAMA 2012,307: 216168.

74 Guyenet PG. The sympathetic control of blood pressure.Nat Rev Neurosci 2006; 7: 33546.

75 OConnor GT, Caffo B, Newman AB, et al. Prospective study ofsleep-disordered breathing and hypertension: the Sleep HeartHealth Study. Am J Respir Crit Care Med 2009; 179: 115964.

76 Cano-Pumarega I, Duran-Cantolla J, Aizpuru F, et al. Obstructivesleep apnea and systemic hypertension: longitudinal study in thegeneral population: the Vitoria Sleep Cohort.Am J Respir Crit Care Med 2011;184: 1299304.

77 Marin JM, Agusti A, Villar I, et al. Association between treated anduntreated obstructive sleep apnea and risk of hypertension. JAMA 2012;307: 216976.

78 Kohler M, Stradling JR. Mechanisms of vascular damage inobstructive sleep apnea. Nat Rev Cardiol 2010;7: 67785.

79 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-termcardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positiveairway pressure: an observational study. Lancet 2005; 365: 104653.

80 Platt AB, Kuna ST, Field SH, et al. Adherence to sleep apneatherapy and use of lipid-lowering drugs: a study of the healthy-usereffect. Chest 2010;137: 10208.

81 Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study ofobstructive sleep apnea and incident coronary heart disease andheart failure: the sleep heart health study. Circulation 2010;122: 35260.


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82 Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathingand mortality: a prospective cohort study. PLoS Med 2009; 6: e1000132.

83 Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre R.Sleep-disordered breathing and cancer mortality: results from theWisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2012;186: 19094.

84 Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects ofcontinuous positive airway pressure in patients with heart failureand obstructive sleep apnea. N Engl J Med 2003; 348: 123341.

85 Montesi SB, Bajwa EK, Malhotra A. Biomarkers of sleep apnea.Chest 2012;142: 23945.

86 Foster GD, Sanders MH, Millman R, et al. Obstructive sleep apneaamong obese patients with type 2 diabetes. Diabetes Care 2009;32: 101719.

87 Aronsohn RS, Whitmore H, Van Cauter E, Tasali E. Impact ofuntreated obstructive sleep apnea on glucose control in type 2diabetes. Am J Respir Crit Care Med 2010;181: 50713.

88 Punjabi NM, Beamer BA. Alterations in glucose disposal insleep-disordered breathing. Am J Respir Crit Care Med 2009;

179: 23540.89 Weinstock TG, Wang X, Rueschman M, et al. A controlled trial ofCPAP therapy on metabolic control in individuals with impairedglucose tolerance and sleep apnea. Sleep 2012;35: 61725B.

90 Sharma SK, Agrawal S, Damodaran D, et al. CPAP for themetabolic syndrome in patients with obstructive sleep apnea.N Engl J Med 2011;365: 227786.

91 Hoyos CM, Killick R, Yee BJ, Phillips CL, Grunstein RR, Liu PY.Cardiometabolic changes after continuous positive airway pressurefor obstructive sleep apnoea: a randomised sham-controlled study.Thorax 2012;67: 108189.

92 Sivam S, Phillips CL, Trenell MI, et al. Effects of 8 weeks ofcontinuous positive airway pressure on abdominal adiposity inobstructive sleep apnoea. Eur Respir J 2012;40: 91318.

93 Yim-Yeh S, Rahangdale S, Nguyen AT, et al. Obstructive sleep apneaand aging effects on macrovascular and microcirculatory function.Sleep 2010;33: 117783.

94 Yim-Yeh S, Rahangdale S, Nguyen AT, et al. Vascular dysfunction inobstructive sleep apnea and type 2 diabetes mellitus.Obesity (Silver Spring) 2011;19: 1722.

95 Craig SE, Kohler M, Nicoll D, et al. Continuous positive airwaypressure improves sleepiness but not calculated vascular risk inpatients with minimally symptomatic obstructive sleep apnoea:the MOSAIC randomised controlled trial. Thorax 2012;67: 109096.

96 Deane SA, Cistulli PA, Ng AT, Zeng B, Petocz P, Darendeliler MA.Comparison of mandibular advancement splint and tonguestabilizing device in obstructive sleep apnea: a randomizedcontrolled trial. Sleep 2009; 32: 64853.

97 Ferguson KA, Ono T, Lowe AA, Keenan SP, Fleetham JA.A randomized crossover study of an oral appliance vs nasal-continuous positive airway pressure in the treatment ofmild-moderate obstructive sleep apnea. Chest 1996;109: 126975.

98 Weaver TE, Mancini C, Maislin G, et al. CPAP treatment of sleepypatients with milder osa: results of the CATNAP randomizedclinical trial. Am J Respir C rit Care Med 2012, 186: 67783.

99 Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal ofobstructive sleep apnoea by continuous positive airway pressureapplied through the nares. Lancet 1981;1: 86265.

100 Squier SB, Patil SP, Schneider H, Kirkness JP, Smith PL,Schwartz AR. Effect of end-expiratory lung volume on upper airwaycollapsibility in sleeping men and women. J Appl Physiol 2010;109: 97785.

101 Ayas NT, FitzGerald JM, Fleetham JA, et al. Cost-effectiveness ofcontinuous positive airway pressure therapy for moderate to severeobstructive sleep apnea/hypopnea. Arch Intern Med 2006; 166: 97784.

102 Kohler M, Smith D, Tippett V, Stradling JR. Predictors of long-termcompliance with continuous positive airway pressure. Thorax 2010;65: 82932.

103 Engleman HM, Asgari-Jirhandeh N, McLeod AL, Ramsay CF,Deary IJ, Douglas NJ. Self-reported use of CPAP and benets ofCPAP therapy: a patient survey. Chest 1996;109: 147076.

104 Hoy CJ, Vennelle M, Kingshott RN, Engleman HM, Douglas NJ.Can intensive support improve continuous positive airway pressure

use in patients with the sleep apnea/hypopnea syndrome?Am J Respir Crit Care Med 1999;159: 1096100.

105 Lettieri CJ, Shah AA, Holley AB, Kelly WF, Chang AS, Roop SA.Effects of a short course of eszopiclone on continuous positiveairway pressure adherence: a randomized trial. Ann Intern Med 2009; 151: 696702.

106 Reeves-Hoche MK, Hudgel DW, Meck R, Witteman R, Ross A,Zwillich CW. Continuous versus bi level positive airway pressurefor obstructive sleep apnea. Am J Respir Crit Care Med 1995;151: 44349.

107 Vennelle M, White S, Riha RL, Mackay TW, Engleman HM,Douglas NJ. Randomized controlled trial of variable-pressure versusxed-pressure continuous positive airway pressure (CPAP)treatment for patients with obstructive sleep apnea/hypopneasyndrome (OSAHS). Sleep 2010;33: 26771.

108 Ayas NT, Patel SR, Malhotra A, et al. Auto-titrating versus standardcontinuous positive airway pressure for the treatment ofobstructive sleep apnea: results of a meta-analysis. Sleep 2004;27: 24953.

109 Ip S, DAmbrosio C, Patel K, et al. Auto-titrating versus xedcontinuous positive airway pressure for the treatment of obstructivesleep apnea: a systematic review with meta-analyses. Syst Rev 2012;1: 20.

110 Powell ED, Gay PC, Ojile JM, Litinski M, Malhotra A. A pilot studyassessing adherence to auto-bilevel following a poor initialencounter with CPAP. J Clin Sleep Med 2012;8: 4347.

111 Cistulli PA, Grunstein RR. Medical devices for the diagnosis andtreatment of obstructive sleep apnea. Expert Rev Med Devices 2005; 2: 74963.

112 Almeida FR, Henrich N, Marra C, et al. Patient preferences andexperiences of CPAP and oral appliances for the treatment ofobstructive sleep apnea: a qualitative analysis. Sleep Breath 2012;published online July 26. DOI:10.1007/s11325-012-0739-6.

113 Mostaz W, Dalci O, Sutherland K, et al. Inuence of oral andcraniofacial dimensions on mandibular advancement splinttreatment outcome in patients with obstructive sleep apnea. Chest 2011;139: 133139.

114 Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral appliance therapyimproves symptoms in obstructive sleep apnea: a randomized,

controlled trial. Am J Respir Crit Care Med 2002; 166: 74348.115 Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G. The effectsof 1-year treatment with a herbst mandibular advancement splinton obstructive sleep apnea, oxidative stress, and endothelialfunction. Chest 2007; 131: 74049.

116 Holley AB, Lettieri CJ, Shah AA. Effi cacy of an adjustable oralappliance and comparison with continuous positive airway pressurefor the treatment of obstructive sleep apnea syndrome. Chest 2011;140: 151116.

117 Weaver EM, Maynard C, Yueh B. Survival of veterans with sleepapnea: continuous positive airway pressure versus surgery.Otolaryngol Head Neck Surg 2004; 130: 65965.

118 Kezirian EJ, Hussey HM, Brietzke SE, et al. Hypopharyngealsurgery in obstructive sleep apnea: practice patterns, perceptions,and attitudes. Otolaryngol Head Neck Surg 2012;147: 96471.

119 Weaver EM. Judging sleep apnea surgery. Sleep Med Rev 2010;14: 28385.

120 Weaver TE, Maislin G, Dinges DF, et al. Relationship betweenhours of CPAP use and achieving normal levels of sleepiness anddaily functioning. Sleep 2007;30: 71119.

121 Kezirian EJ, White DP, Malhotra A, Ma W, McCulloch CE,Goldberg AN. Interrater reliability of d rug-induced sleep endoscopy.Arch Otolaryngol Head Neck Surg 2010;136: 39397.

122 Eastwood PR, Barnes M, Walsh JH, et al. Treating obstructive sleepapnea with hypoglossal nerve stimulation. Sleep 2011;34: 147986.

123 Schwartz AR, Barnes M, Hillman D, et al. Acute upper airwayresponses to hypoglossal nerve stimulation during sleep inobstructive sleep apnea. Am J Respir Crit Care Med 2012;185: 42026.

124 Van de Heyning PH, Badr MS, Baskin JZ, et al. Implanted upperairway stimulation device for obstructive sleep apnea. Laryngoscope 2012;122: 162633.

125 Oksenberg A, Khamaysi I, Silverberg DS. Apnoea characteristicsacross the night in severe obstructive sleep apnoea: inuence ofbody posture. Eur Respir J 2001;18: 34046.

126 Redenius R, Murphy C, ONeill E, Al-Hamwi M, Zallek SN. DoesCPAP lead to change in BMI? J Clin Sleep Med 2008; 4: 20509.


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127 Awad KM, Malhotra A, Barnet JH, Quan SF, Peppard PE. Exerciseis associated with a reduced incidence of sleep-disorderedbreathing. Am J Med 2012;125: 48590.

128 Guimaraes KC, Drager LF, Genta PR, Marcondes BF,Lorenzi-Filho G. Effects of oropharyngeal exercises on patients withmoderate obstructive sleep apnea syndrome.Am J Respir Crit Care Med 2009; 179: 96266.

129 Pack AI, Black JE, Schwartz JRL, Matheson JK. Modanil as adjuncttherapy for daytime sleepiness in obstructive sleep apnea.Am J Respir Crit Care Med 2001;164: 167581.

130 Pepin JL, Viot-Blanc V, Escourrou P, et al. Prevalence of residualexcessive sleepiness in CPAP-treated sleep apnoea patients:the French multicentre study. Eur Respir J 2009; 33: 106267.

131 Kingshott RN, Vennelle M, Coleman EL, Engleman HM,Mackay TW, Douglas NJ. Randomized, double-blind,placebo-controlled crossover trial of modanil in the treatment ofresidual excessive daytime sleepiness in the sleep apnea/hypopneasyndrome. Am J Respir Crit Care Med 2001;163: 91823.

132 Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea:pathophysiology and treatment. Chest 2007;131: 595607.

133 Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isntreally a disease. J Clin Sleep Med 2008; 4: 40608.

134 Javaheri S, Smith J, Chung E. The prevalence and natural history ofcomplex sleep apnea. J Clin Sleep Med 2009; 5: 20511.

135 Morgenthaler TI, Gay PC, Gordon N, Brown LK. Adaptiveservoventilation versus noninvasive positive pressure ventilation forcentral, mixed, and complex sleep apnea syndromes. Sleep 2007;30: 46875.

136 Pillar G, Peled R, Lavie P. Recurrence of sleep apnea withoutconcomitant weight increase 75 years after weight reductionsurgery. Chest 1994;106: 170204.

137 Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructivesleep apnea after surgical weight loss. J Clin Sleep Med 2008;4: 33338.

138 Sugerman HJ, Fairman RP, Sood RK, Engle K, Wolfe L, Kellum JM.Long-term effects of gastric surgery for treating respiratoryinsuffi ciency of obesity. Am J Clin Nutr 1992;55 (2 suppl) : 597S601S.

139 Marien H, Rodenstein D. Morbid obesity and sleep apnea. Is weightloss the answer? J Clin Sleep Med 2008; 4: 33940.

140 Smith PL, Gold AR, Meyers DA, Haponik EF, Bleecker ER. Weightloss in mildly to moderately obese patients with obstructive sleepapnea. Ann Intern Med 1985;103: 85055.

141 Kezirian EJ, Malhotra A, Goldberg AN, White DP. Changes inobstructive sleep apnea severity, biomarkers, and quality of life aftermultilevel surgery. Laryngoscope 2010;120: 148188.


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Adult Obstructive Sleep Apnoea

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