Med Clin N Am 88 (2004) 611–630
Obstructive sleep apnea syndromes
Christian Guilleminault, MD, BiolDa,*,
Vivien C. Abad, MD, MBAb,c
a
Sleep Disorders Program, Stanford University School of Medicine, 401 Quarry Road,
Suite 3301, Stanford, CA 94305, USA
b
Stanford University Sleep Disorders Center, Stanford University School of Medicine,
Stanford, CA, USA
c
Clinical Monitoring Sleep Disorders Center, Cupertino, CA, USA
The first description of an obstructive sleep apnea (OSA) sufferer is
generally attributed to the novelist Charles Dickens, who described ‘‘Joe’’ in
The Posthumous Papers of the Pickwick Club, published in 1836. Joe was an
excessively sleepy, obese boy who snored loudly and had possible right-sided
heart failure that led to his being called ‘‘young dropsy’’ [1,2]. The first
physician to describe the clinical features of OSA was Broadbent in 1877 [3].
Wells reported in 1898 curing several patients of sleepiness by treating their
upper airway obstruction [3]. Burwell et al studied obese patients with
somnolence, attributed their somnolence to hypercapnia, and coined the
term ‘‘pickwickian’’ in 1956 [2,4]. In 1965, Gastaut et al [5] in France and
Jung and Kuhlo [6] in Germany described sleep apnea and its associated
polysomnographic findings. In 1972, in Rimini, Italy, Lugaresi and Sadoul
organized the first international symposium on ‘‘Hypersomnia with Periodic
Breathing,’’ mostly devoted to the dismemberment of the pickwickian
syndrome, and reports, particularly by Coccagna et al, on hemodynamic
changes associated with abnormal breathing during sleep. Guilleminault
et al [7] reported the presence of sleep apnea in narcolepsy and insomnia at
the 1972 Rimini meeting and characterized insomnia with sleep apnea as
a new syndrome in 1973 [8]. Guilleminault et al coined the terms ‘‘sleep
apnea syndrome’’ and ‘‘obstructive sleep apnea syndrome’’ in 1976 to
emphasize the occurrence of this syndrome in nonobese patients. In the
same year, they reported the existence of this syndrome in children.
Completing the loop of hypersomnolence and insomnia and extending the
spectrum of sleep apnea syndromes, in 1982 Guilleminault et al reported the
* Corresponding author.
E-mail address: cguil@stanford.edu (C. Guilleminault).
0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.01.002
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presence of abnormal respiratory efforts during sleep without apneas in
children and gave the name ‘‘upper airway resistance syndrome’’ (UARS) in
1993 after a similar description in adults [9].
Treatment of sleep apnea advanced significantly when Kuhlo et al [10] in
1969 and Lugaresi et al [11] in 1970 reported that tracheotomy was an
efficacious treatment for sleep apnea. Guilleminault et al [12] confirmed
in 1981 long-term efficacy of tracheotomy in 50 OSA patients who had
complete relief of clinical symptoms, return to full activity, and normal
adaptation to social and familial life. Although Ikematsu popularized
uvulopalatopharyngoplasty (UPPP) for the treatment of snoring in 1964, it
was not until 1981 that Fujita performed the first UPPP as a treatment for
OSA [3]. Sullivan et al [13] devised the first nasal continuous positive airway
pressure (CPAP) machine and in 1981 reported its efficacy in the treatment
of sleep apnea [3]. Riley et al [14] developed new maxillomandibular
procedures in the 1980s for subjects intolerant to nasal CPAP.
Epidemiology
OSA can affect various age groups. The prevalence of adult OSA in the
United States has been reported to be 4% in men and 2% in women between
the ages of 30 and 60 years [15]. The actual prevalence, however, may be
higher. Young et al [16] estimated that among middle-aged adults, 93% of
women and 82% of men with OSA have not been clinically diagnosed [16].
The Wisconsin Sleep Cohort study evaluated the association of premenopause, perimenopause, and postmenopause with sleep-disordered breathing
(SDB) in a group of 589 women [17]. Using multivariate regression analysis
adjusted for age, body habitus, smoking, and other potential confounding
factors, Young et al [17] calculated the odds ratios (95% CI) for apneahypopnea index (AHI) greater than five events per hour of sleep to be 1.2
(range 0.7–2.2) with perimenopause and 2.6 (range 1.4–4.8) with postmenopause. These results suggest that the menopausal transition is
significantly associated with an increased risk of SDB independent of
known confounding factors [17]. After menopause, women develop OSA at
a rate similar to men [18,19]. The maximum prevalence of OSA occurs
between the fifth and seventh decades [18]. Obesity increases the risk of
developing OSA, and race may be a risk factor. The incidence of OSA is
reportedly increased in Pacific Islanders, Mexican-Americans, and blacks
[20–22]. The higher prevalence of OSA among blacks reported by Redline
et al [22] was more pronounced in individuals less than 25 years of age and
was not accounted for by differences in body mass index (BMI) or by
differences in exposure to alcohol and tobacco. Variable age of puberty,
speed of development of secondary characteristics, and mucosal enlargement associated with hormonal surge may have biased these findings [23]. In
contrast, a study in New Zealand comparing sleep apnea severity among
Maori, Pacific Islanders, with Europeans reported that race was not an
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613
important predictor of severity when adjusted for factors, such as neck size,
BMI, and age [24].
Clinical presentation
Adult sleep-disordered breathing
SDB encompasses the spectrum from severe to mild OSA to UARS. The
categorization into two different syndromes is still controversial; the
important issues include recognizing the different signs and symptoms,
adequately exploring respiration during sleep, understanding and choosing
the necessary polygraphic montages, and using the appropriate criteria
to arrive at a valid diagnosis. Diagnostic criteria for SDB include either
excessive sleepiness or insomnia with frequent episodes of obstructed
breathing during sleep and associated features of loud snoring, morning
headaches, and dry mouth on awakening [25].
Daytime sleepiness is the most common complaint among patients with
OSA. It can occur following meals, while sitting as a passenger in a car,
watching television, attending a meeting or a lecture, eating, talking, or even
while driving. Patients may notice difficulty with attention, concentration,
memory, judgment, and impaired performance of tasks requiring dexterity.
Approximately 50% of patients report generalized, dull, morning or
nocturnal headaches [26]. About a third of patients at the Stanford Sleep
Disorders Clinic have reported sexual dysfunction, either decreased libido or
impotence. In a prospective study of 25 OSA patients with AHI greater than
10, Farfulla et al [27] reported abnormal bulbocavernosus reflex (either
prolonged latency or reduced amplitude) in 68% of these patients. These
abnormalities correlated significantly with the severity of OSA and the
severity of gas exchange alterations, but did not vary with age [27].
Nocturnal symptoms in OSA are more specific than daytime symptoms.
Loud snoring with brief gasps alternating with episodes of silence lasting from
20 to 30 seconds occurs frequently [26,28]. Seventy-five percent of spouses
report apneic episodes terminated by gasps, choking sounds, snorts,
vocalizations, or brief awakenings [29]. Diaphoresis in the neck and upper
chest area and restlessness manifested as tossing and turning, probably caused
by increased respiratory effort related to upper airway obstruction, has been
described in about half of the patients. Eighteen percent to 31% of patients
with OSA syndrome report a sensation of choking or dyspnea interrupting
sleep [26,28,30,31]. Dyspnea may be caused by increased pulmonary wedge
pressure resulting from increased venous return from the extremities
secondary to decreased intrathoracic pressure during episodes of upper
airway obstruction. Other nocturnal symptoms include nocturia (28%);
esophageal reflux; dryness of the mouth (74%); and drooling (36%) [26,28].
Physical examination findings in OSA include obesity (BMI >28 kg/m2);
neck circumference greater than 40 cm (Kushida et al [32] reported
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sensitivity of 61% and specificity of 93% for OSA regardless of gender);
nasal turbinate hypertrophy; septal deviation; high and narrow hard palate;
elongated low-lying uvula; redundant and low-lying soft palate; crowding
of the oropharynx with enlarged tonsils and adenoids; prominent tonsillar
pillars; macroglossia; narrow maxilla; narrow mandible; overjet and
retrognathia; cross-bite; and dental malocclusion.
Adult upper airway resistance syndrome
In a series of 400 UARS patients, Guilleminault et al [33,34] reported that
56% were women, 32% were of East Asian origin, and the mean age was 38
14 years. This sex, race, and age distribution varies from that typically
seen in OSA. Unlike OSA patients, who usually complain of daytime
sleepiness, UARS patients frequently complain of insomnia, sleep fragmentation, and fatigue, and their psychologic profile reveals high anxiety. Other
clinical features of UARS patients include cold extremities; postural
hypotension; history of fainting; low mean systemic arterial blood pressure;
orthostasis on tilt table testing; myalgias (sometimes corresponding to the
characteristic pain points associated with fibromyalgia); and functional
somatic complaints [35]. During sleep, the arousal threshold in UARS
patients is lower than OSA patients, thereby allowing the patient to awaken
in response to small increases in inspiratory effort, compared with OSA
patients, whose arousal thresholds require higher inspiratory pressures up to
ÿ40 to ÿ80 cm H2O and decrease in oxygen saturation. During sleep,
UARS patients demonstrate an increase in alpha rhythm and a relative
increase in delta sleep, whereas OSA patients show a predominance of stage
1 and 2 non–rapid eye movement (REM) sleep with a decrease in delta sleep.
The difference between UARS and OSA patients is hypothesized to be
caused by genetically predetermined and environmentally altered pharyngeal receptors, particularly mechanoreceptors: patients with UARS may
have intact, sensitive, peripheral pharyngeal function, whereas OSA patients
may have primary pharyngeal receptor dysfunction [35].
Sleep-disordered breathing syndromes and insomnia
OSA and more often UARS patients may present with complaints of
insomnia (problems with sleep maintenance or unrefreshing sleep) similar to
patients with primary insomnia, such as psychophysiologic insomnia. Other
SDB-associated manifestations, however, such as snoring, choking-gaspingsnorting, frank apneic episodes, nocturia, reflux, and hypertension, together
with objective findings suggestive of upper airway obstruction may provide
clues to the presence of disordered breathing during sleep as the underlying
etiology. History of trying too hard to sleep, conditioned arousal to
bedroom or sleep-related activities, evidence of increased somatized tension
(agitation, muscle tension, or increased vasoconstriction), or prolonged
wake after sleep onset associated with racing thoughts and heightened
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arousal, together with normal physical examination, may suggest psychophysiologic insomnia, despite the fact that conditioned sleep-onset insomnia
may developed secondary to the nocturnal sleep disruption induced by the
SDB.
Syndromes criteria and severity classification
SDB is characterized by transient upper airway resistance, repetitive
reduction or cessation of airflow caused by partial or complete occlusion of
the upper airway during sleep, associated with fragmentation of sleep,
arousals, bradytachycardia, and more or less oxygen desaturation, despite
the presence of increasing respiratory effort. Apnea in adults is defined as
the cessation of airflow for greater than or equal to 10 seconds. Various
criteria have been utilized to define hypopnea, including (1) greater than
50% reduction in the amplitude of breathing from baseline during sleep, or
(2) less than 50% reduction in the amplitude of breathing during sleep
associated with either greater than 3% oxygen desaturation or an arousal,
or (3) greater than 30% reduction in the amplitude of breathing during sleep
or 30% reduction in the nasal cannula-pressure transducer curve associated
with oxygen desaturation greater than or equal to 4%, and (4) event
duration greater than or equal to 10 seconds [35,36]. Respiratory eventrelated arousals consist of limitation of flow greater than or equal to 10
seconds and terminating in an arousal associated with snoring. Introduction
of the nasal cannula–pressure transducer system and esophageal pressure
(Pes) monitoring has led to recognition of various patterns of increased
respiratory effort that disrupt sleep but are not apneas or hypopneas, such
as Pes crescendo (a progressive increase in Pes) and sustained continuous
effort (a persistent increase in Pes without any crescendo, over several
epochs). These events terminate in Pes reversal (an abrupt drop in Pes) that
occurs independently of the electroencephalogram pattern, which may be an
alpha electroencephalogram arousal, a burst of delta activity, or no visually
seen change in electroencephalogram pattern.
Although the authors believe that UARS clearly represents a syndrome
distinct from OSA, in evaluating SDB the American Academy of Sleep
Medicine Task Force in 1999 included UARS in the OSA-hypopnea
syndrome and defined it as the demonstration of five or more obstructive
apneas-hypopneas or respiratory event-related arousals per hour of sleep
and none of the new patterns easily identified with appropriate recording
techniques have been integrated well [35,36]. This deficiency means that
minutes of increased respiratory effort with unstable sleep are currently not
tabulated in many clinical polysomnograms, and real impairment of subjects
is underestimated, particularly in UARS subjects. OSA can be classified
based on the apneas plus hypopneas per hour of sleep index (AHI)
or respiratory disturbance index ([RDI] apneas plus hypopneas plus
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respiratory event-related arousals per hour of sleep) into mild (5\ AHI or
RDI \15); moderate (15\ AHI or RDI \30); or severe (AHI or RDI >30).
UARS has been defined as having a RDI less than 4 and arterial oxygen
saturation (SaO2) greater than 93%.
Polysomnography and other tests
Overnight pulse oximetry has occasionally been used as a screening test
to identify patients with sleep apnea, but it is not a substitute for
polysomnography because of its inability to detect UARS and apneas or
hypopneas with arousal but unassociated with significant desaturation
[37,38]. Full-night polysomnography is routinely indicated for patients
suspected of having OSA syndrome [37–39]. Pes monitoring during
polysomnography recording is the reference standard in detecting respiratory effort [36,37]. Pulse transit time measures the transmission time for
the arterial pulse pressure wave to travel from the aortic valve to the
periphery and increases during inspiratory falls in blood pressure and
decreases during arousal-induced increases in blood pressure. Pulse transit
time has a high sensitivity and specificity in distinguishing between central
and obstructive apnea-hypopnea [37] and may be used if Pes monitoring is
not available. Polysomnography monitoring in adult OSA demonstrates
greater than five obstructive apneas per hour of sleep, lasting at least 10
seconds and associated with one or more of the following: (1) frequent
arousals from sleep; (2) bradytachycardia; and (3) arterial oxygen desaturation [25]. Fig. 1 depicts the polysomnographic findings in a patient
with OSA.
In some circumstances, split-night full-night polysomnography may be
considered [37–40]. During split-night full-night polysomnography recordings, the first half of the night is spent in diagnostic recording, with the
second half of the night used for CPAP titration. In a consensus statement,
Loube et al [40] formulated these guidelines: split-night studies may be
considered in patients with RDI greater than 40 events per hour during the
first 2 hours of a diagnostic polysomnography, of which the final portion is
used to titrate CPAP; patients with RDI between 20 and 40 events per hour
may undergo a split-night study based on the occurrence of obstructive
respiratory events of prolonged duration or associated with severe oxygen
desaturation; a minimum of 3 hours of sleep is recommended for adequate
titration; the split-night study requires the recording and analysis of the
same parameters as a standard diagnostic full-night polysomnography; and
an additional full-night CPAP titration may be required if the split-night
study does not allow for abolishment of most obstructive events or if the
prescribed CPAP treatment does not control clinical symptoms. Split-night
studies can potentially underestimate the severity of OSA, however, because
breathing abnormalities are usually worse during REM sleep in overweight
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C3-A2
O1-A2
EMG
ROC-A1
LOC-A2
L/RAT
EKG
MIC
SpO2
+100.0
+90.0
+80.0
+70.0
+60.0
Cannula
Airflow
Chest
Abd
PES
-20.0
-25.0
-30.0
-35.0
Fig. 1. Polysomnogram of a patient with OSA. The cannula and airflow channels demonstrate
reduction in oronasal airflow consistent with a hypopnea. Paradoxical respiration is noted on
the chest and abdominal effort channels. Esophageal pressure crescendo with Pes reversal
associated with an arousal is seen.
patients, and the longest REM sleep periods are in the second half of the
night. In addition, CPAP titration during split-night recordings may be
suboptimal because of the shorter time spent on titration.
Limited-channel diagnostic full-night polysomnography (cardiorespiratory sleep studies) may be adequate [40–42] in patients who have a high
pretest probability of OSA based on validated screening algorithms [30,32].
Minimum parameters recorded and measured in limited-channel full-night
polysomnography are oronasal airflow, chest wall respiratory effort,
electrocardiogram, and oxyhemoglobin saturation [42]. These limited sleep
studies, however, cannot effectively distinguish sleep from wake or
determine sleep stage, are less accurate than standard full-night polysomnography in determining the number of obstructive respiratory events,
and are unable to detect co-existing non-OSA sleep disorders. They cannot
recognize UARS. They recognize subjects with severe problems [40,43].
Multiple sleep latency testing, which consists of four to five daytime naps
during which sleep latency is measured, provides an objective measure of
sleepiness and propensity to sleep. OSA patients may or may not
demonstrate a mean sleep latency of less than 10 minutes (normal >10
minutes) [25]. Maintenance of Wakefulness Test is preferred by some to
evaluate the propensity of subjects to stay alert.
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Comorbid conditions
Hypertension
OSA is an independent risk factor for hypertension, and hypertension is
a frequent comorbid condition with sleep apnea [44–47]. About 30% of
patients with systemic hypertension have sleep apnea, whereas 50% or more
of patients with sleep apnea have systemic hypertension [26,48]. Moller et al
[49] performed 24-hour blood pressure monitoring and measured plasma
levels of vasoactive hormones (renin, angiotensin II, aldosterone, atrial
natriuretic peptide, brain natriuretic peptide, vasopressin, and endothelin-1)
in 24 OSA patients and 18 control subjects. Compared with controls, OSA
patients had significantly higher blood pressure and heart rate, and the
sleep-related nocturnal blood pressure drop was reduced. Moreover,
angiotensin II and aldosterone levels were significantly higher in OSA
subjects compared with controls, with angiotensin II correlating positively
with daytime blood pressure recordings. Thirteen OSA patients re-examined
after 14 months of CPAP therapy demonstrated reduction in blood
pressure, which correlated with a decrease in both plasma renin and plasma
angiotensin II concentrations.
Brachial artery diameter and brachial artery flow-mediated dilation,
which are surrogates of endothelial dysfunction, were measured in elderly
participants in the Wisconsin Sleep Heart Health/Cardiovascular Health
Study cohort (N = 1037; age >68 years; 56% women) [50]. After
adjustment for BMI and other confounders, a statistically significant linear
association between the hypoxemia index and baseline diameter was noted.
This association was stronger among participants less than 80 years and
among hypertensives. Nieto et al [50] suggested that vascular dysfunction
may partially explain the relationship between OSA, hypertension, and
cardiovascular disease. In another study, Sin et al [51] reported that 40% of
301 patients with congestive heart failure had OSA and systemic hypertension. After controlling for other risk factors, including obesity, OSA
patients were 2.89 times (95% CI, range 1.25–6.73) more likely to have systolic hypertension (blood pressure 140 mm Hg) than those without OSA,
and the degree of systolic blood pressure elevation was directly related to the
frequency of obstructive apneas and hypopneas [51].
Hypertension associated with OSA may be generated by sympathetic
overactivity triggered by intermittent hypoxemia, large negative fluctuations
in intrathoracic pressure, and arousal from sleep [52,53]. Several studies
have demonstrated reversal of sustained daytime hypertension by effective
treatment of apnea through surgery [54,55] or nasal CPAP [56,57].
Cardiovascular disease
The Sleep Heart Health Study reported that OSA is associated with
relative odds of 2.38 for heart failure, independent of other known risk
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factors [58,59]. OSA has also been implicated in the pathogenesis of
pulmonary hypertension, nocturnal cardiac ischemia, nocturnal arrhythmias, and atherosclerosis [46,48,60–64]. OSA patients demonstrate transient
fluctuations in pulmonary artery pressure and pulmonary wedge pressure
coincident with apneas, which may lead to progressive increase in
pulmonary artery pressure. Permanent precapillary pulmonary hypertension
at rest has been observed in some OSA patients and is reported to be poorly
reversible after OSA treatment [63]. Various studies have demonstrated that
OSA can precipitate nocturnal angina in patients with coronary artery
disease [65–69]. Myocardial ischemia associated with OSA is postulated to
result from a combination of increased left ventricular afterload, sympathoadrenal stimulation, and postapneic tachycardia [48]. In a study of 400
OSA patients conducted by Guilleminault et al [70], cardiac arrhythmias
consisting of nonsustained ventricular tachycardia (N = 8), sinus arrest
lasting 2.5 to 3 seconds (N = 43), second-degree atrioventricular conduction
block (N = 31), and premature ventricular contractions (N = 75) were
noted in 193 (48%) of subjects. A relationship between low SaO2 (\75%)
and presence of severe arrhythmias was shown. A prospective study of 147
consecutive patients demonstrated significantly higher prevalence of
nocturnal paroxysmal asystole in OSA patients and increased episodes of
bradycardia and pauses that correlated with the severity of the sleep apnea
[61]. OSA has been linked to other risk markers for cardiovascular disease,
including leptin, C-reactive protein, homocysteine, and insulin-resistance
syndrome [71]. The independent role of OSA in these overweight and obese
subjects is unclear.
Cerebrovascular disease
The relationship between OSAS and cerebrovascular disease is bidirectional. Habitual snoring increases the risk of cerebrovascular disease
with odds ratios (95% CI) ranging from 2.1 to 3.3 [72–75]. Sixty-nine
percent to 95% of patients with acute strokes or transient ischemic attacks
has OSA [76,77]. One hundred fourteen male snorers, 40 to 65 years of age,
with complaints of disturbed sleep underwent ultasonographic examination
of both carotid arteries to evaluate intima-media thickness and the presence
of plaque. The study revealed significantly higher intima-media thickness
values in OSA patients compared with habitual snorers. Age and BMI were
significantly associated with intima-media thickness, whereas age and RDI
were most predictive for plaque [78]. Kaynak et al [78] suggested that SDB
may be a predisposing factor for atherosclerosis and may precipitate plaque
formation. Proposed mechanisms underlying increased risk of stroke in
OSA patients are multifactorial and include hypertension, reduction in
cerebral blood flow, altered cerebral autoregulation, impaired endothelial
function, accelerated atherogenesis, thrombosis, and paradoxic embolism
[79].
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Obesity-metabolic syndrome
Approximately 60% to 90% of OSA patients are obese [80]. Obesity is
the most common metabolic abnormality seen with sleep apnea and is
predominantly central in pattern. BMI, body weight, and the sum of fat skin
folds are good predictors for the degree of OSA [80,81]. The percentage of
body fat and BMI are good predictors of AHI greater than 10, with high
sensitivity (95.5%) but low specificity (46.2%) [81]. A review of MRI scans
demonstrated a significant correlation between AHI and intra-abdominal
and subcutaneous abdominal fat, but no correlation was established with
subcutaneous fat in the neck region or parapharyngeal fat in the airway
vicinity [81]. Leptin concentrations correlate with AHI and with biochemical
markers of the metabolic syndrome (lipoproteins, glucose) [81]. Vgontzas et al
[82] have demonstrated elevations of interleukin-6, tumor necrosis factoralpha, leptin, and insulin levels in sleep apnea, independent of obesity [82].
Upper body obesity is linked to increased risk of diabetes, hyperlipidemia,
insulin resistance and hyperinsulinemia, hyperuricemia, hypertension, and
cardiovascular or cerebrovascular disease [83,84]. OSA has been implicated
as an independent risk factor for insulin resistance, a known risk factor for
atherogenesis [9], but this independence has been challenged by other data.
Treatment
Treatment for symptomatic OSA syndromes is influenced by the severity
of sleep apnea, relative efficacy of treatment options, the presence of
comorbid conditions, and patient and physician preference. For mild forms
of OSAS, nonsurgical options include (1) weight loss; (2) avoidance of sleep
deprivation, alcohol, nicotine, and sedatives; (3) positional therapy
(avoidance of the supine posture); and (4) treatment of comorbid conditions, such as hypothyroidism. Pharmacologic treatment of sleep apnea
has not been very successful [85,86]. The use of stimulants, however, such as
modafinil, 200 to 400 mg/d, may be useful as adjunctive therapy for daytime
sleepiness that persists despite optimization of CPAP therapy. Oral
appliances are useful for mild OSA and for patients with moderate or
severe OSA who are unable or unwilling to tolerate CPAP and who have
failed surgery or are not surgical candidates. Oral appliances work by
increasing airway space, providing a stable anterior position of the
mandible, advancing the tongue or soft palate, and possibly by changing
genioglossus muscle activity [87,88]. These devices are not well tolerated by
patients with significant temporomandibular joint symptoms.
Positive airway pressure therapy (continuous, bilevel, and autotitrating)
CPAP therapy can be used for all categories of OSA and represents firstline therapy for moderate to severe OSA. Based on the risk of increased
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hypertension documented in the Wisconsin sleep cohort data, Loube et al
[40] recommend CPAP therapy for all OSA patients with RDI of 30 events
per hour. Similarly, based on documented improvement in symptoms and
daytime function in CPAP-treated patients, Loube et al [40] recommend
CPAP therapy for patients with RDI of 5 to 30 events per hour associated
with symptoms of excessive daytime sleepiness; impaired cognition; mood
disorders; insomnia; documented cardiovascular diseases (including hypertension and ischemic heart disease); or stroke. For Loube et al [40],
treatment with CPAP is not indicated for asymptomatic, mild OSA patients
without evidence of cardiovascular disease.
Effective CPAP therapy reduces nocturnal respiratory disturbances and
improves nocturnal oxygenation, sleep architecture, daytime sleepiness,
neurocognitive performance, driving performance, and perceived health
status [89,90]. Cardiovascular end points, such as hypertension, cardiac
arrhythmia, nocturnal ischemia, left ventricular function, and mortality,
may also improve with CPAP therapy [89]. Health care use is also reduced in
OSA patients on CPAP therapy compared with untreated patients.
Seventy-six percent of OSA patients who were offered a trial of CPAP
took their machines home [91]. In addition to patients declining CPAP,
patient compliance and adherence remain major issues. Compliance refers
to the proportion of patients using CPAP machines that are delivering
a preset level of pressure, whereas adherence refers to the proportion of
patients prescribed CPAP who report continued usage [92]. Compliance
rates assessed through patient self-reported usage of CPAP nightly range
from 63% to 90% [90,92]. In one study when compared with objective
measures, patients overestimated the number of hours of use by 69
minutes 110 minutes, and 14% of subjects erroneously reported nightly
usage of CPAP [93]. Kribbs et al [93] defined CPAP failure as usage of
CPAP less than 4 hours per night on 70% of the nights or lack of
symptomatic improvement. Objectively measured CPAP usage adjusted to
reflect mask-on time demonstrated average nightly use to be only 4.97 hours
(range 2.8–6.9) [90]. The hallmark for eventual nonadherence and rejection
of CPAP is use of CPAP less than 4 hours per night [90]. Reasons for
nonadherence cited by patients at the Stanford Sleep Disorders Clinic are
similar to those reported by others [90,92]: (1) nuisance factors (noise,
partner intolerance, inconvenience); (2) mask problems (leaking mask, mask
rubbing, skin rash or abrasion, conjunctivitis); (3) side effects (nasal
congestion, rhinorrhea, epistaxis, sinus discomfort, oronasal dryness, chest
discomfort, aerophagia, claustrophobia, difficulty exhaling, pneumothorax
[rare], pneumocephaly [rare]); and (4) incomplete resolution of symptoms
(frequent awakening, persistent fatigue or sleepiness). CPAP pressure has
not been found to be a determinant of long-term use [89].
Interventions to improve CPAP use are based on patient education and
behavioral principles of positive reinforcement. These include providing
literature addressing sleep apnea and good sleep habits; disseminating
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information on CPAP use, benefits, and potential side-effects; organizing
group educational sessions and support groups (eg, AWAKE groups);
teaching adaptation skills to the patient and bed partner; scheduling regular
clinic follow-up to monitor CPAP meter readings, discuss patient-perceived
problems, and initiate treatment plans addressing identified problems; and
implementing regular follow-up telephone calls (initially weekly, then
monthly). Interventions mostly involve spending time with patients to
determine the best nasal interface with least amount of sleep disruption,
having common sense, and taking into consideration age and health status
of the patient.
Bilevel positive airway pressure allows independent adjustment of
inspiratory and expiratory pressures. Indications for a trial of bilevel
positive airway pressure may include OSA patients who cannot tolerate
CPAP because of persistent massive nasal mask air leak or discomfort
exhaling against positive pressure, or have concomitant nocturnal breathing
disorders, such as restrictive thoracic disorders, chronic obstructive
pulmonary disease, or nocturnal hypoventilation [40].
Autotitrating positive airway pressure devices detect snoring, apneas,
hypopneas, flow limitation, and changes in airway resistance or impedance,
which are then interpreted by a central processing unit based on specific
diagnostic algorithms to determine the resultant voltage for the autotitrating
positive airway pressure blower in response to these signals [89,94]. The 2002
American Academy of Sleep Medicine practice parameters on autotitrating
positive airway pressure indicate that (1) the diagnosis of OSA must be
established by an acceptable method; (2) autotitrating positive airway
pressure may be used during attended titration to identify a single effective pressure for use with standard CPAP; (3) autotitrating positive airway
pressure may be used in self-adjusting mode for unattended treatment of
OSA after an initial successful attended CPAP or autotitrating positive
airway pressure titration; (4) patients being treated with fixed CPAP on the
basis of an autotitrating positive airway pressure titration or being treated
with autotitrating positive airway pressure require follow-up to determine
treatment efficacy and safety; and (5) if symptoms do not resolve or if
autotitrating positive airway pressure therapy is inefficacious, re-evaluation
should be performed, and if needed, a standard CPAP titration should be
done [94]. Autotitrating positive airway pressure devices are not recommended for split-night studies or for patients with congestive heart failure;
significant lung disease (chronic obstructive pulmonary disease); daytime
hypoxemia; respiratory failure; or prominent nocturnal oxygen desaturation
other than from OSA [94]. Autotitrating positive airway pressure devices
that rely on vibration or sound in the device’s algorithm should not be used
in patients who snore [94].
Surgical therapy of OSA is directed toward site-specific obstruction in the
upper airway. The three major anatomic regions of obstruction for OSA are
(1) the nose; (2) the palate (oropharynx); and (3) the base of the tongue
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
623
(hypopharynx). Fujita classified the sites of obstruction as follows: Fujita
type I (palate with normal base of the tongue; Fujita type II (palate and base
of the tongue obstruction); and Fujita type III (base of the tongue
obstruction with normal palate).
Surgical techniques involve either extirpation of soft tissue, secondary soft
tissue repositioning through primary skeletal mobilization, or bypass of the
pharyngeal airway [95–97]. Procedures resulting in extirpation of soft tissue
include UPPP; modified UPPP-extended uvulopalatal flap (discussed under
the Stanford protocol later in this article); uvulopalatopharyngoglossoplasty; laser midline glossectomy; and lingualplasty [95]. UPPP, the most
commonly used technique, enlarges the retropalatal airway through
tonsillectomy (if present); trimming and reorientation of the posterior and
anterior tonsillar pillars; and excision of the uvula and the posterior portion
of the palate [95]. UPPP has a surgical response rate (defined as 50%
reduction in AHI or RDI and a RDI below 20) ranging from 40% to 65%
[95,97]. Analyzing 37 papers with a total of 640 patients, Sher and Goldberg
[95] reported the following complications of UPPP: velopharyngeal insufficiency greater than 1 month (14 of 640); postoperative bleeding (7 of 640);
nasopharyngeal stenosis (5 of 640); voice change (4 of 640); vague foreign
body sensation (1 of 640); successfully managed airway obstruction (2 of
640); and death secondary to upper airway obstruction (1 of 640). UPPP
has reported success rates ranging from 43% to 67% [95,98]. Powell et al
[99] have described a modification of UPPP called uvulo-flap, which is less
traumatic with less complication and at least similar success rate (see later).
Surgical techniques involving primary skeletal mobilization include
transpalatal advancement pharyngoplasty, mandibular advancement, maxillomandibular advancement, genioglossal advancement, and hyoid myotomy and suspension [95]. Transpalatal advancement pharyngoplasty
involves resection of the posterior hard palate with anterior advancement
of the soft palate into the bony defect, thereby enlarging the retropalatal
airway; it is used for persistent retropalatal obstruction after UPPP, but
its role in the surgical armamentarium is still vague [95]. Mandibular
advancement uses sagittal mandibular osteotomies to mobilize the tongue
anteriorly and advance its insertion at the genioid tubercle; this procedure is
beneficial for a small group of patients with class II dental occlusion and
significant mandibular deficiency [95,96]. Maxillomandibular advancement
involves Le Fort I maxillary and sagittal-split mandibular osteotomies with
simultaneous advancement of both maxilla and mandible, thereby producing maximal enlargement of the retrolingual airway and some
enlargement of the retropalatal airway [95,96].
Tracheotomy may be used to bypass the pharyngeal airway in OSA
patients with morbid obesity; severe facial skeletal deformity (mandibular
deficiency) with excessive daytime somnolence; hypoxemia (SaO2 \70%); or
significant cardiac arrhythmias [95,97]. The tracheotomy tube is plugged
when the patient is awake to allow speech and swallowing. Although
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tracheotomy is easy to perform and is effective for OSA, inconvenience and
hygiene issues preclude its more widespread use.
The Stanford Protocol (Riley-Powell) surgical approach consists of a twophased approach to direct surgical treatment of suspected regions of
obstruction [95–97]. In conjunction with the clinical evaluation, patients
undergo lateral cephalometry and fiberoptic endoscopy with Müller’s
maneuver. Phase I surgical intervention includes nasal reconstruction,
UPPP or uvulopalatal flap, and limited mandibular osteotomy with
genioglossus advancement. Nasal reconstruction is performed for patients
with significant obstruction of the nasal airway (deviated septum, collapsed
ala, or enlarged turbinates) [96]. In a series of 33 patients who underwent the
modified UPPP-extended uvulopalatal flap surgery, the reported success
rate was 81.8% [100], compared with the overall reported success rate of
60% for phase I surgery. Phase II surgery involves maxillomandibular
advancement osteotomy to treat refractory hypopharyngeal (base of the
tongue) obstruction by advancing the mandible at least 10 mm. The reported success rate for phase II surgery in 350 patients was 90% [96,97]. In
a subgroup of 175 patients who underwent maxillomandibular advancement
between 1998 and 1995, the mean age was 43.5 years, the cure rate was 97%,
the mean hospital stay was 2.4 days, and the mean postoperative RDI was
7.2 compared with mean preoperative RDI of 72.3 [97].
Radiofrequency volumetric tissue reduction has been used for the treatment of turbinate hypertrophy and to reduce the base of the tongue [97,101].
In 18 patients treated with radiofrequency tongue-base reduction under
local anesthesia with a mean of 5.5 sessions, mean RDI improved from
39.5 32.7 to 17.8 15.6 at 2.6 0.7 months postoperatively [97]. Longterm follow-up (mean 28 4 months) showed increase of RDI to 28.7
29.4, with persistent improvement of the mean apnea index but with worsening hypopnea index and with mean weight increase of 3.1 7.9 kg [97].
Performance of extra sessions improved results.
In the recent past orthognathic surgery has been performed. Maxillary
expansion is routinely performed orthodontically, when there is constriction
of the maxilla where posterior crossbite often exists. Although the width of
the maxilla can be improved by expansion [102], it usually remains narrowed
after expansion because the extent of expansion is limited by the width of the
mandible, and mandibular constriction often coexists. Distraction osteogenesis, a process of bone lengthening by gradually separation of bone
segments performed by simple osteotomy, has improved the ability to
expand the mandible simultaneously with the maxilla. It has been performed
by Li and Guilleminault [103] in six patients, improvement of SDB based on
polysomnography and clinical results were seen in all six patients following
maxillo-mandibular expansion, and no complications were encountered. The
ideal candidate for this treatment may be an adolescent and young adult with
isolated SDB who may be contemplating or are already in orthodontic
treatment where lifelong CPAP treatment seems a limited alternative.
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
625
Surgery remains a viable alternative to nasal CPAP in OSA patients. The
indications, risks, and complications of surgery, the possibility of multiple
and staged procedures, and alternative forms of therapy need to be
discussed with the patient. The selection of surgical procedures should be
driven by the site of obstruction and the patient’s airway anatomy, medical
status, severity of sleep apnea, overall clinical status, age, patient preference,
relative efficacy of the surgery, and the surgeon’s experience and skill.
Summary
OSA syndromes afflict various age groups. OSA is reported to be more
prevalent in middle-aged men (4%) compared with women (2%) in the
United States, but the true prevalence may be higher, because OSA
syndromes are underdiagnosed. This article reviews the history of sleep
apnea, discusses the clinical presentation of OSA-hypopnea and UARS, and
presents the pertinent physical examination findings and the results of sleep
laboratory testing. Associated significant comorbid conditions (hypertension,
cardiovascular and cerebrovascular disease, obesity-metabolic syndrome) are
reviewed. Treatment options, both nonsurgical and surgical, are reviewed.
References
[1] Dickens C. The posthumous papers of the pickwick club. London: Chapman and Hall;
1836.
[2] Dement W. History of sleep physiology and medicine. In: Kryger M, Roth T, Dement W,
editors. Principles and practice of sleep medicine. 3rd edition. Philadelphia: WB
Saunders; 2000. p. 1–14.
[3] Thorpy M. Historical perspective on sleep and man. In: Culebras A, editor. Sleep
disorders and neurological disease. New York: Marcel Dekker; 2000. p. 1–36.
[4] Bickelmann AG, Burwell CS, Robin ED, Whaley RD. Extreme obesity associated with
alveolar hypoventilation: a pickwickian syndrome. Am J Med 1956;21:811–8.
[5] Gastaut H, Tassinari CA, Duron B. Polygraphic study of diurnal and nocturnal (hyponic
and respiratory) episodal manifestations of pickwick syndrome. Rev Neurol (Paris) 1965;
112:568–79.
[6] Jung R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the
pickwickian syndrome. Prog Brain Res 1965;18:140–59.
[7] Guilleminault C, Eldridge FE, Dement WC. Insomnia, narcolepsy and sleep apneas. Bull
Pathophysiol Resp 1972;8:1127–38.
[8] Guilleminault C, Eldridge FL, Dement WC. Insomnia with sleep apnea: a new syndrome.
Science 1973;181:856–8.
[9] Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime
sleepiness: the upper airway resistance syndrome. Chest 1993;104:781–7.
[10] Kuhlo W, Doll E, Franck MD. Successful management of pickwickian syndrome using
long-term tracheostomy. Dtsch Med Wochenschr 1969;94:1286–90.
[11] Lugaresi E, Coccagna G, Mantovani M, Brignani F. Effects of tracheotomy in
hypersomnia with periodic respiration. Rev Neurol 1970;123:267–8.
[12] Guilleminault C, Simmons FB, Motta J, Cummiskey J, Rosekind M, Schroeder JS, et al.
Obstructive sleep apnea syndrome and tracheostomy: long-term follow-up experience.
Arch Intern Med 1981;141:985–8.
626
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
[13] Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnea by
continuous positive airway pressure applied through the nares. Lancet 1981;1:862–5.
[14] Riley R, Powell N, Guilleminault C. Maxillofacial surgery and obstructive sleep apnea:
a review of 80 patients. Otalaryngol Head Neck Surg 1989;101:353–61.
[15] Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep
disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5.
[16] Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of
sleep apnea syndrome in middle-aged men and women. Sleep 1997;20:705–6.
[17] Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing
in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167:1181–5.
[18] Coleman RM, Roffwarg HP, Kennedy SJ, Guilleminault C, Cinque J, Cohn MA, et al.
Sleep wake disorders based on a polysomnographic diagnosis: a National cooperative
study. JAMA 1982;247:997–1003.
[19] Tishler PV, Larkin EU, Schluchter MD, Redline S. Incidence of sleep-disordered
breathing in an urban adult population: the relative importance of risk factors. JAMA
2003;289:2230–7.
[20] Grunstein RR, Lawrence S, Spies JM. Snoring in paradise: the Western Samoa Sleep
Survey. Eur Respir J 1989;2(Suppl 5):4015.
[21] Schmidt-Nowara WW, Coultas DB, Wiggins C, Skipper BE, Samet JM. Snoring in
Hispanic-American population: risk factors and association with hypertension and other
morbidity. Arch Intern Med 1990;150:597–601.
[22] Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial differences in
sleep-disordered breathing in African-Americans and Caucasians. Am J Respir Crit Care
Med 1997;155:186–92 [erratum in Am J Respir Crit Care Med 1997;155:1820].
[23] Robinson A, Guilleminault C. Obstructive sleep apnea syndrome. In: Chokroverty S,
editor. Sleep disorders medicine: basic science, technical considerations, and clinical
aspects. 2nd edition. Boston: Butterworth Heinemann; 1999. p. 331–54.
[24] Baldwin DR, Kolbe J, Troy K, Belcher J, Gibbs H, Frankel A, et al. Comparative clinical
and physiological features of Maori, Pacific Islanders and Europeans with sleep related
breathing disorders. Respirology 1998;3:253–60.
[25] American Academy of Sleep Medicine. International classification of sleep disorders,
revised: diagnostic and coding manual. Rochester, MN: American Academy of Sleep
Medicine; 2000. p. 27–8.
[26] Bassiri A, Guilleminault C. Clinical features and evaluation of obstructive sleep apneahypopnea syndrome. In: Kryger M, Roth T, Dement W, editors. Principles and practice
of sleep medicine. 3rd edition. Philadelphia: WB Saunders; 2000. p. 869–78.
[27] Farfulla F, Malaguti S, Montagna T, Salvini S, Bruschi C, Crotti P, et al. Erectile
dysfunction in men with obstructive sleep apnea: an early sign of nerve involvement. Sleep
2000;23:1–6.
[28] Kales A, Cadieux RJ, Bixler EO, Soldatos CR, Vela-Bueno A, Misoul CA, et al. Severe
obstructive sleep apnea. I: onset, clinical course, and characteristics. J Chron Dis 1985;38:
419–25.
[29] Hoffstein V, Szalai JP. Predictive value of clinical features in diagnosing obstructive sleep
apnea. Sleep 1993;16:118–22.
[30] Maislin G, Pack AI, Kribbs NB, Smith PL, Schwartz AR, Kline LR, et al. A survey
screen for prediction of apnea. Sleep 1995;18:158–66.
[31] Coverdale SG, Read DJ, Woolcock AJ, Schoeffel RE. The importance of suspecting sleep
apnea as a common cause of excessive daytime sleepiness: further experience from the
diagnosis and management of 19 patients. Aust N Z J Med 1980;10:284–8.
[32] Kushida C, Efron B, Guilleminault C. A predictive morphometric model for the
obstructive sleep apnea syndrome. Ann Intern Med 1997;127(8 pt 1):581–7.
[33] Guilleminault C, Stoohs R, Kim YD, Chervin R, Black J, Clerk A. Upper airway sleep
disordered breathing in women. Arch Intern Med 1995;122:493–501.
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
627
[34] Guilleminault C, Black J, Palombini L, Ohayon M. A clinical investigation of obstructive
sleep apnea syndrome and upper airway resistance syndrome patients. Sleep Med 2000;1:
51–6.
[35] Guilleminault C, Chowdhuri S. Upper airway resistance syndrome is a distinct syndrome.
Am J Respir Crit Care Med 2000;161:1412–3.
[36] American Academy of Sleep Medicine Task Force. Sleep related breathing disorders in
adults: recommendations for syndrome definition and measurement techniques in clinical
research. Sleep 1999;22:667–89.
[37] Lee-Chiong T. Monitoring respiration during sleep. In: Lee-Chiong T, Sateia M,
Carskadon M, editors. Sleep medicine. Philadelphia: Hanley & Belfus; 2002. p. 639–46.
[38] Chesson AL, Ferber RA, Fry JM, Grigg-Damberger M, Hartse KM, Johnson S, et al.
The indications for polysomnography and related procedures. Sleep 1997;20:423–87.
[39] Standards of Practice Committee of the American Sleep Disorders Association. Practice
parameters for the indications for polysomnography and related procedures. Sleep 1997;
20:406–22.
[40] Loube D, Gay P, Strohl K, Pack A, White D, Collop N. Indications for positive airway
pressure treatment of adult obstructive sleep apnea patients. Chest 1999;115:863–6.
[41] Standards of Practice Committee of the American Sleep Disorders Association. Practice
parameters for the use of portable recording in the assessment of obstructive sleep apnea.
Sleep 1994;17:372–7.
[42] Ferber R, Millman R, Coppola M, Fleetham J, Murray CF, Iber C, et al. Portable
recording in the assessment of obstructive sleep apnea. ASDA standards of practice. Sleep
1994;17:378–92.
[43] Phillips BA, Anstead MI, Gottlieb DJ. Monitoring sleep and breathing methodology.
Clin Chest Med 1998;19:203–12.
[44] Dart RA, Gregoire JR, Gutterman DD, Woolf SH. The association of hypertension and
secondary cardiovascular disease with sleep-disordered breathing. Chest 2003;123:244–60.
[45] Pepperell JC, Davies RJ, Stradling JR. Systemic hypertension and obstructive sleep
apnoea. Sleep Med Rev 2002;6:157–73.
[46] Lattimore JD, Celermajer DS, Wilcox I. Obstructive sleep apnea and cardiovascular
disease. J Am Coll Cardiol 2003;41:1429–37.
[47] Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between
sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84.
[48] Somers V, Fletcher E. Mechanisms of hypertension in obstructive sleep apnea. In: Pack
A, editor. Sleep apnea pathogenesis diagnosis and treatment. New York: Marcel Dekker;
2002. p. 353–76.
[49] Moller DS, Lind P, Strunge B, Pedersen EB. Abnormal vasoactive hormones and 24-hour
blood pressure in obstructive sleep apnea. Am J Hypertens 2003;16:274–80.
[50] Nieto FJ, Harrington DM, Redline S, Benjamin EJ, Robbins JA. Sleep apnea and
markers of vascular endothelial function in a large community sample of older adults.
Am J Respir Crit Care Med 2004;169:354–60. Epub 2003 Oct 09.
[51] Sin DD, Fitzgerald F, Parker JD, Newton GE, Logan AG, Floras JS, et al. Relationship
of systolic blood pressure to obstructive sleep apnea in patients with heart failure. Chest
2003;123:1536–43.
[52] Fletcher EC. Sympathetic over activity in the etiology of hypertension of obstructive sleep
apnea. Sleep 2003;26:15–9.
[53] Richert A, Ansarin K, Baran AS. Sleep apnea and hypertension: pathophysiologic
mechanisms. Semin Nephrol 2002;22:71–7.
[54] Shibata N, Nishimura T, Hasegawa K, Hattori C, Suzuki K. Influence of sleep
respiratory disturbance on nocturnal blood pressure. Acta Otolaryngol Suppl 2003;550:
32–5.
[55] Guilleminault C, Eldridge FL, Simmon FB, Dement WC. Sleep apnea syndrome: can it
induce hemodynamic changes? West J Med 1975;123:7–16.
628
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
[56] Logan AG, Tkacova R, Perlikowski SM, Leung RS, Tisler A, Floras JS, et al. Refractory
hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur
Respir J 2003;21:241–7.
[57] Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, von Wichert P. Blood pressure
and sleep apnea: results of long term nasal continuous positive airway pressure therapy.
Cardiology 1991;79:84–92.
[58] Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, et al. Sleepdisordered breathing and cardiovascular diseases: cross-sectional results of the Sleep
Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25.
[59] Javaheri S. Heart failure and sleep apnea: emphasis on practical therapeutic options. Clin
Chest Med 2003;24:207–22.
[60] Wolk R, Somers VK. Cardiovascular consequences of obstructive sleep apnea. Clin Chest
Med 2003;24:195–205.
[61] Roche F, Xuong AN, Court-Fortune I, Costes F, Pichot V, Duverney D, et al.
Relationship among the severity of sleep apnea syndrome, cardiac arrhythmias, and
autonomic imbalance. Pacing Clin Electrophysiol 2003;26:669–77.
[62] Weitzenblum E, Krieger J, Apprill M, Vallee E, Ehrhart M, Ratomaharo J, et al. Daytime
pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev
Respir Dis 1988;138:345–9.
[63] Marrone O, Bonsignore MR. Pulmonary haemodynamics in obstructive sleep apnoea.
Sleep Med Rev 2002;6:175–93.
[64] Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics
in the obstructive sleep apnea syndrome: results in 220 consecutive patients. Chest 1996;
109:380–6.
[65] Franklin KA, Nilsson JB, Sahlin C, Naslund U. Sleep apnoea and nocturnal angina.
Lancet 1995;345:1085–7.
[66] Philip P, Guilleminault C. ST segment abnormality, angina during sleep and obstructive
sleep apnea [letter]. Sleep 1993;16:558–9.
[67] Hanly P, Sasson Z, Zuberi N, Lunn K. ST-segment depression during sleep in obstructive
sleep apnea. Am J Cardiol 1993;71:1341–5.
[68] Mooe T, Franklin KA, Wiklund U, Rabben T, Holmstrom K. Sleep-disordered breathing
and myocardial ischemia in patients with coronary artery disease. Chest 2000;117:1597–602.
[69] Koehler U, Dubler H, Glaremin T, Junkermann H, Lubbers C, Ploch T, et al. Nocturnal
myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and
without coronary artery disease. Klin Wochenschr 1991;69:474–82.
[70] Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction
disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol
1983;52:490–4.
[71] Phillips BG, Somers VK. Sleep disordered breathing and risk factors for cardiovascular
disease. Curr Opin Pulm Med 2002;8:516–20.
[72] Palomaki H, Partinen M, Erkinjuntti T, Kaste M. Snoring, sleep apnea syndrome, and
stroke. Neurology 1992;42(7 Suppl 6):75–81.
[73] Neau JP, Meurice JC, Paquereau J, Chavagnat JJ, Ingrand P, Gil R. Habitual snoring as
a risk factor for brain infarction. Acta Neurol Scand 1995;92:63–8.
[74] Partinen M. Ischaemic stroke, snoring, and obstructive sleep apnea. J Sleep Res 1995;4:
156–9.
[75] Bassetti C, Chervin R. Cerebrovascular diseases. In: Kryger M, Roth T, Dement W,
editors. Principles and practice of sleep medicine. 3rd edition. Philadelphia: WB Saunders;
2000. p. 1072–86.
[76] Bassetti C, Aldrich MS, Chervin RD, Quint D. Sleep apnea in patients with transient
ischemic attack and stroke: a prospective study of 59 patients. Neurology 1996;47:1167–73.
[77] Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmermann MB. Investigating the
relationship between stroke and obstructive sleep apnea. Stroke 1996;27:401–7.
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
629
[78] Kaynak D, Goksan B, Kaynak H, Degirmenci N, Daglioglu S. Is there a link between the
severity of sleep-disordered breathing and atherosclerotic disease of the carotid arteries?
Eur J Neurol 2003;10:487–93.
[79] Yaggi H, Mohsenin V. Sleep-disordered breathing and stroke. Clin Chest Med 2003;24:
223–37.
[80] Benumof J. Obstructive sleep apnea in the adult obese patient: implications for airway
management. Anesthesiol Clin North America 2002;20:789–811.
[81] Schafer H, Pauleit D, Sudhop T, Gouni-Berthold I, Ewig S, Berthold HK. Body fat
distribution, serum leptin, and cardiovascular risk factors in men with obstructive sleep
apnea. Chest 2002;122:829–39.
[82] Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep
apnoea: the importance of visceral obesity and insulin resistance. J Intern Med 2003;254:
32–44.
[83] Grunstein R. Neuroendocrine changes in sleep apnea. In: Pack A, editor. Sleep apnea
pathogenesis diagnosis and treatment. New York: Marcel Dekker; 2002. p. 411–41.
[84] Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is
independently associated with insulin resistance. Am J Respir Crit Care Med 2002;165:
670–6.
[85] Veasey S. Pharmacotherapeutic trials for sleep-disordered breathing. In: Pack A, editor.
Sleep apnea pathogenesis diagnosis and treatment. New York: Marcel Dekker; 2002.
p. 607–22.
[86] Hudgel D, Thanakitcharu S. Pharmacologic treatment of sleep-disordered breathing. Am
J Respir Crit Care Med 1998;158:691–9.
[87] Lowe A. Oral appliances for sleep breathing disorders. In: Kryger M, Roth T, Dement W,
editors. Principles and practice of sleep medicine. 3rd edition. Philadelphia: WB Saunders;
2000. p. 929–39.
[88] Lowe A, Schmidt-Nowara W. Oral appliance therapy for snoring and sleep apnea. In:
Pack A, editor. Sleep apnea pathogenesis diagnosis and treatment. New York: Marcel
Dekker; 2002. p. 555–73.
[89] Roux F, Hilbert J. Continuous positive airway pressure: new generations. Clin Chest Med
2003;24:315–42.
[90] Weaver T. Adherence to continuous positive airway pressure treatment and functional
status in adult obstructive sleep apnea. In: Pack A, editor. Sleep apnea pathogenesis
diagnosis and treatment. New York: Marcel Dekker; 2002. p. 523–54.
[91] Pieters T, Collard P, Aubert G, Dury M, Delguste P, Rodenstein DO. Acceptance and
long-term compliance with nCPAP in patients with obstructive sleep apnoea syndrome.
Eur Respir J 1996;9:939–44.
[92] Grunstein R, Sullivan C. Continuous positive airway pressure for sleep breathing
disorders. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep
medicine. 3rd edition. Philadelphia: WB Saunders; 2000. p. 894–912.
[93] Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, et al. Objective
measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea.
Am Rev Respir Dis 1993;147:887–95.
[94] Berry RB, Parrish JM, Hartse KM. The use of auto-titrating continuous positive airway
pressure for treatment of adult obstructive sleep apnea: an American Academy of Sleep
Medicine review. Sleep 2002;25:148–73.
[95] Sher A, Goldberg A. Upper airway surgery for obstructive sleep apnea. In: Pack A,
editor. Sleep apnea pathogenesis diagnosis and treatment. New York: Marcel Dekker;
2002. p. 575–605.
[96] Riley R, Powell N, Li K, Guilleminault C. Surgical therapy for obstructive sleep apneahypopnea syndrome. In: Kryger M, Roth T, Dement W, editors. Principles and practice
of sleep medicine. 3rd edition. Philadelphia: WB Saunders; 2000. p. 913–28.
[97] Li KK. Surgical management of obstructive sleep apnea. Clin Chest Med 2003;24:365–70.
630
C. Guilleminault, V.C. Abad / Med Clin N Am 88 (2004) 611–630
[98] Miljeteig H, Tvinnereim M. Uvulopalatopharyngoglossoplasty (UPPGP) in the treatment
of the obstructive sleep apnea syndrome. Acta Otolaryngol Suppl 1992;492:86–9.
[99] Powell N, Riley R, Guilleminault C, Troell R. A reversible uvulopalatal flap for snoring
and sleep apnea syndrome. Sleep 1996;19:593–9.
[100] Li HY, Li KK, Chen NH, Wang PC. Modified uvulopalatopharyngoplasty: the extended
uvulopalatal flap. Am J Otolaryngol 2003;24:311–6.
[101] Riley RW, Powell NB, Li KK, Weaver EM, Guilleminault C. An adjunctive method of
radiofrequency volumetric tissue reduction of the tongue for OSAS. Otolaryngol Head
Neck Surg 2003;129:37–42.
[102] Cistulli PA, Palmisano RG, Poole MD. Treatment of obstructive sleep apnea syndrome
by rapid maxillary expansion. Sleep 1998;21:831–5.
[103] Guilleminault C, Li KK. Maxillomandibular expansion for the treatment of sleepdisordered breathing: preliminary result. Laryngoscope, in press.