European Journal of Internal Medicine 23 (2012) 586593

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review article

Obstructive sleep apnea syndrome

Massimo R. Mannarino , Francesco Di Filippo, Matteo Pirro
Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Obstructive sleep apnea (OSA) syndrome is a common but often unrecognized disorder caused by pharyngeal
Received 6 March 2012 collapse during sleep and characterized by frequent awakenings, disrupted sleep and consequent excessive
Received in revised form 8 May 2012 daytime sleepiness. With the increasing epidemic of obesity, the most important risk factor for OSA, preva-
Accepted 11 May 2012
lence of the disease will increase over the coming years thus representing an important public-health prob-
Available online 24 June 2012
lem. In fact, it is now recognized that there is an association between OSA and hypertension, metabolic
Keywords:
syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension,
Obstructive sleep apnea neurocognitive and mood disorders. Diagnosis is based on the combined evaluation of clinical manifestations
Cardiovascular risk and objective sleep study ndings. Cardinal symptoms include snoring, sleepiness and signicant reports of
Polysomnography sleep apnea episodes. Polysomnography represents the gold standard to conrm the clinical suspicion of OSA
Continuous positive airway pressure syndrome, to assess its severity and to guide therapeutic choices. Behavioral, medical and surgical options are
available for the treatment. Continuous positive airway pressure (CPAP) represents the treatment of choice in
most patients. CPAP has been demonstrated to be effective in reducing symptoms, cardiovascular morbidity
and mortality and neurocognitive sequelae, but it is often poorly tolerated. The results of clinical studies do
not support surgery and pharmacological therapy as rst-line treatment, but these approaches might be use-
ful in selected patients. A better understanding of mechanisms underlying the disease could improve thera-
peutic strategies and reduce the social impact of OSA syndrome.
2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Obstructive sleep apnea (OSA) syndrome is a common sleep disor-
der in which complete or partial airway obstruction, caused by pharyn-
geal collapse during sleep, causes loud snoring or choking, frequent
awakenings, disrupted sleep and excessive daytime sleepiness. When
obstruction of the airway occurs, the inspiratory airow can be either
reduced (hypopnea) or completely absent (apnea). OSA syndrome is
dened as ve or more episodes of apnoea or hypopnoea per hour of
sleep with associated symptoms (e.g., excessive daytime sleepiness,
fatigue, or impaired cognition) or 15 or more obstructive apnea-
hypopnea events per hour of sleep regardless of associated symptoms
[1,2]. It is now recognized that OSA is often associated with severe com-
plications including major cardiovascular disorders, neurocognitive se-
quelae and mood disorders. Indeed, there is a growing body of evidence
that a strong correlation exists between the disease and hypertension,
coronary artery disease, heart failure, arrhythmias and stroke. Cognitive
impairment with changes in attention and concentration, executive
function and ne-motor coordination are common complaints of
patients with OSA. Finally, depression can represent a signicant prob-
lem in the course of the disease.
Corresponding author at: Unit of Internal Medicine, Angiology and Arteriosclerosis,
University of Perugia, Perugia, Italy, Hospital Santa Maria della Misericordia, Piazzale
Menghini, 106129, Perugia, Italy. Tel.: + 39 075 5783172; fax: + 39 075 5784022.
E-mail address: massimo.mannarino@unipg.it (M.R. Mannarino).
With the increasing prevalence of obesity, the most important risk
factor in sleep breathing disorders, the number of patients diagnosed
as suffering from OSA has increased drastically in the last few years
[3] and it will increase over the coming years. Today, OSA syndrome
represents a major public health issue with potential societal conse-
quences and recognition of this syndrome is essential if a signicant
burden of risk is to be prevented.
2. Epidemiology
Population-based studies suggest that 4 percent of men and 2 per-
cent of women aged more than 50 years suffer from symptomatic
OSA [4]. However, OSA is often asymptomatic and the prevalence of
patients with OSA, who do not present clinical syndrome, might be
as high as 2030% in the middle-aged population [5].
Patients with OSA are more frequently male, obese and aged
65 years or more. Obesity is certainly the most important risk factor:
a 10% weight gain increases the risk of developing OSA by six-times
[6]. The androgenic pattern of body fat distribution, in particular
deposition in the trunk, including the neck area, may predispose
men to OSA. Furthermore, sex hormones may affect neurologic
control of the upper airway dilating muscles and ventilation [7].
Postmenopausal women are at higher risk of developing OSA than
are their premenopausal counterparts [8], an effect that hormone
replacement therapy could prevent or ameliorate [9].

0953-6205/$ see front matter 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2012.05.013
 M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586593 587

The risk of OSA increases with increasing age. OSA prevalence in- Finally, ventilatory control instability has been proposed as a poten-
creases 23 times in older persons (>65 years) compared with indi- tial contributing factor for the development of obstructive events [27].
viduals aged 3064 years [10]. Nevertheless, OSA is also described
in children with adenotonsillar hypertrophy [11]. Finally the risk of
4. Clinical features
developing the disease appears to be related to race. African Ameri-
cans are more frequently affected and develop OSA at a younger age
The typical clinical presentation for OSA includes signs of upper air-
than white people [12].
way obstruction during sleep, insomnia and diurnal hypersomnolence.
Symptoms usually begin insidiously and are present for years before
the patient is referred for evaluation. Nocturnal obstructive breathing
3. Pathogenesis
symptoms include snoring, snorting, gasping and choking. Patients
may report intermittent awakenings and insomnia, with reduced total
Both anatomic and neuromuscular factors are involved in the de-
sleep time, fragmented sleep or early morning awakenings [28].
velopment of obstruction of the upper airway in OSA. The human
Nocturia is also frequently reported [29], possibly due to an elevation
pharynx can be considered as a collapsible tube that serves several
in plasma levels of atrial natriuretic peptide secondary to hypoxemia
purposes including speech, swallowing and respiration; it is not pro-
and/or exaggerated intrathoracic pressure swings increasing urine out-
vided with a rigid skeletal support and, during normal inhalation, it
put. Nocturnal symptoms are often under-appreciated by the patient
undergoes numerous stresses promoting its collapse. Negative pres-
leading to a delay in diagnosis until the appearance of more obvious
sure within the airway and the presence of soft tissues and bony
daytime symptoms. Chronic fatigue and daytime sleepiness, secondary
structures, which increase extraluminal tissue pressures, can predis-
to sleep fragmentation, are the most signicant diurnal complaints of
pose the pharynx to collapse; on the other hand, the tonic and phasic
patients suffering from OSA. In the early stages of the disease, the pa-
contractile activity of the dilator muscles of the pharynx contribute to
tient can easily fall asleep during sedentary activities, such as watching
the maintenance of pharyngeal patency [13]. An imbalance between
television; in these phases hypersomnolence, confused with tiredness,
these opposite forces is responsible for the upper airway obstructions
fatigue or lethargy, is often undervalued. Severity of symptoms usually
that recur in patients with sleep-disordered breathing.
progress over years and may increase with weight gain, aging or transi-
From an anatomic perspective, a narrow upper airway is generally
tion to menopause. As the disorder progresses, sleepiness encroaches
more prone to collapse than a larger one. Moreover, according to the
into all daily activities and can become disabling and dangerous. Accord-
Venturi effect, while airow velocity increases at the site of stricture
ingly, OSA represents a signicant cause of motor vehicle crashes
in the airway, pressure on the lateral wall of the pharynx decreases
resulting in a two-fold and up to seven-fold increased risk [30]. Other
and the likelihood of pharyngeal collapse increases signicantly.
common daytime symptoms include morning headaches, dry mouth
A number of imaging studies have demonstrated that during wake-
and sorethroat at waking up time. In women, clinical presentation can
fulness the cross-sectional area of the upper airway in OSA patients is
be rather different from that in men. Particularly, women are less likely
reduced compared with control subjects [14,15]. Accordingly, OSA is
to report symptoms of obstructive breathing and daytime sleepiness
frequently associated with a number of alterations in upper airway
while reporting insomnia, palpitations and ankle edema [31]. Chronic
anatomy that reduce the size of the pharynx. Excessive fat deposits, par-
fatigue syndrome, bromyalgia, irritable bowel syndrome and migraine
ticularly enlarged parapharyngeal fat pads, have been described in pa-
headaches are seen more commonly in women and may be associated
tients with OSA. Thickness of the lateral parapharyngeal muscular
with milder forms of OSA [32,33]. Although all these symptoms are like-
walls also represents a relevant factor causing airway narrowing in ap-
ly to affect the quality of life, the clinical relevance of OSA is mainly due
neic subjects [14].
to its strong association with hypertension, metabolic syndrome, diabe-
The disease has been associated with the presence of tonsillar and
tes, heart failure, coronary artery disease, arrhythmias, stroke, pulmo-
tongue hypertrophy, retrognathia and inferior displacement of the
nary hypertension, neurocognitive and mood disorders. Cardiovascular
hyoid bone [1618]. Obesity can cause elevations in neck circumference
and neurocognitive sequelae of OSA are summarized in Table 1.
and accumulation of fat in peripharyngeal tissues; moreover it may also
increase pharyngeal collapsibility through reduction in lung volumes.
Another anatomically based predisposing factor of pharyngeal collapse 5. Cardiovascular sequelae
in OSA may be the length of the pharynx [19]. In fact, it has been ob-
served that OSA patients have a greater length of the pharynx compared A growing body of evidence links OSA to cardiovascular disorders
with those without OSA [20]. [34]. Several risk factors for OSA such as obesity, age and male gender
It is relevant to point out that disordered breathing events occur are also known risk factors for cardiovascular disease. Moreover, OSA
only during sleep, emphasising the importance of the sleep state in is associated with additional cardiovascular risk factors, such as hyper-
the pathogenesis of this disorder; accordingly, in addition to the ana- tension and glucose intolerance. Nevertheless, part of the association
tomically imposed mechanical loads on upper airways, the impaired between OSA and cardiovascular diseases is independent of traditional
activity of the pharyngeal dilator muscle during sleep plays a critical cardiovascular risk factors.
role in determining airway collapse.
In healthy subjects, the phasic activity of some dilator muscles has Table 1
been found to decline during rapid eye movement sleep [21] and the Cardiovascular and neurocognitive sequelae of OSA.
pharyngeal cross-sectional area has been found to be smaller during Cardiovascular sequelae Neurocognitive sequelae
sleep than during wakefulness [22]. Indeed, reex mechanisms from
Systemic hypertension Impaired vigilance
both chemoreceptors and mechanoreceptors which control the activ- Coronary heart disease Decit in executive functioning
ity of pharyngeal dilator muscles are reduced during sleep [23,24]. Heart failure Impaired ne-motor coordination
It has been observed that during wakefulness the activity of pha- Cardiac arrhythmias Depression
ryngeal dilator muscles in OSA patients is increased to overcome Atrial brillation
Supraventricular tachycardia
compromised pharyngeal anatomy [25]. This compensatory mecha-
Ventricular tachycardia/brillation
nism is lost during sleep leading to pharyngeal collapse. Indeed it Sinus bradycardia
has been observed that, in OSA patients, the onset of sleep is associat- Heart block
ed with signicantly larger decrements in the activity of pharyngeal Pulmonary hypertension
Stroke
dilator muscles' activity compared to controls [26].
588 M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586593
Clinical and experimental evidences have shown the role of OSA in
atherosclerosis progression. In Apolipoprotein E-decient (ApoE/)
mice, intermittent hypoxia is associated with accelerated atherosclerotic
plaque growth [35], and in humans a signicant correlation between
OSA severity and carotid-artery intima-media thickness was found
[36]. In addition to the development of chronic vascular damage it
should be noted that acute hypoxaemia during obstructive events can
activate pathophysiological responses that might also lead to acute noc-
turnal cardiac events [37,38]. The pathogenesis of cardiovascular com-
plications in OSA is not completely understood. Proposed mechanisms
include increased sympathetic activity, endothelial dysfunction, meta-
bolic dysregulation, oxidative stress and inammation. OSA has also
been associated with increased platelet activation, increased brinogen
and other potential markers of thrombotic risk [39]. Repetitive hypoxia
due to intermittent airway obstruction results in heightened sympathet-
ic drive which persists even during normoxic daytime wakefulness [40].
Accordingly, animals exposed to intermittent hypoxia developed hyper-
tension that was prevented by sympathectomy [40]. In healthy men, ex-
posure to intermittent hypoxia, has been associated with increased
blood pressure levels [41]. OSA is also associated with abnormal cardio-
vascular regulation during resting normoxic daytime wakefulness, with
a faster heart rate, higher blood pressure variability and lower RR vari-
ability [42]. Recurrent hypoxemic stress might promote release of vaso-
constrictors such as endothelin [43]. Repetitive cycles of hypoxia and
reoxygenation promote the production of reactive oxygen species and
increase oxidative stress [44].
OSA is known to be associated also with endothelial dysfunction
[45]. An imbalance between endothelial injury and repair has been
proposed as a novel theory for atherosclerosis. In particular endothe-
lial fragmentation and increased endothelial microparticles on the
one hand, and impaired endothelium repair by endothelial progenitor
cells on the other, might promote atherosclerosis development [46].
In sixteen patients with OSA, Jelic and colleagues found an increased
number of endothelial microparticles and a reduced mobilization of
endothelial progenitor cells compared to healthy controls, suggesting
that the disease can cause an imbalance between endothelial injury
and repair [47].
Chronic inammation is relevant in the pathogenesis of athero-
sclerosis [48]; elevated C-reactive protein (CRP) is associated with in-
creased cardiovascular risk [49]. Chronic intermittent hypoxia can
activate the nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-B) pathway which, in turn, can stimulate the production
of proinammatory mediators [50]. Accordingly, OSA is associated
with elevated CRP levels which are correlated with disease severity
[51]. Plasma levels of cytokines, adhesion molecules [52] and serum
amyloid-A have been found to be increased in OSA [53]. Metabolic
dysregulation may also play a role in the pathogenesis of cardiovascu-
lar diseases in OSA. Metabolic syndrome is more common in patients
with OSA than in the general population [54] and patients with OSA
have a higher prevalence of insulin resistance and glucose intolerance
even after adjusting for body weight [55].
Finally, a role in the development of cardiovascular diseases in
OSA may be played by repetitive intrathoracic pressure changes. Dur-
ing forced inspiration against the obstructed upper airway, intratho-
racic pressure signicantly decreases; these intrathoracic pressure
swings probably exert a deleterious effect on intrathoracic blood ves-
sels. OSA patients were found to have a greater thoracic aortic size
than healthy subjects [56] and a higher prevalence of severe OSA
was observed in patients with thoracic aorta dissection [57].
5.1. OSA and hypertension
About of patients with one half OSA are affected by hypertension
[58] and a linear relationship was identied between the severity of
sleep-disordered breathing and prevalence of hypertension [59]. Del-
eterious effects of OSA on blood pressure appear to be more relevant
in middle-aged compared with older subjects and are predominantly
associated with increased systolic blood pressure [60]. Moreover, OSA
is the most common condition associated with drug-resistant hyper-
tension with an estimated prevalence of 64% among subjects with re-
sistant hypertension [61]. OSA and hypertension share several risk
factors such as age, male gender, obesity, alcohol intake and smoking
[62]. The Wisconsin Sleep Cohort Study found that the adjusted odds
ratio for developing hypertension was 2.9 in the group of patients
with moderate to severe OSA compared to controls [63].
Not only systemic hypertension, but also high blood pressure in pul-
monary circulation may complicate the course of the disease. In the
most recent pulmonary hypertension guidelines, sleep-disordered
breathing is included among the causes of secondary pulmonary hyper-
tension [64]. Percentages of prevalence of pulmonary hypertension in
patients suffering from OSA ranging from 17% to 42% [6568] and im-
provement in pulmonary hemodynamics have been observed after
CPAP therapy [69].
5.2. OSA and heart failure
In the Sleep Heart Health Study, the presence of OSA was associat-
ed with a 2.38 increase in the likelihood of having heart failure, inde-
pendent of confounders [70]. OSA might induce deterioration of left
ventricular function mostly by raising blood pressure levels. Accord-
ingly, hypertension represents a risk factor for cardiac hypertrophy
and failure [71]. Particularly, it should be noted that left ventricular
hypertrophy is more closely linked to blood pressure levels during
sleep than during wakefulness [72]. Patients with heart failure and
OSA were found to have a signicantly greater mortality than patients
without OSA [73]. Accordingly, OSA might promote the progression of
cardiac dysfunction through several mechanisms, including an in-
creased risk of ischemic heart disease. Several cross-sectional and
longitudinal studies have reported an association between OSA and
coronary heart disease [7476,34]. However in a more recent pro-
spective analysis from the Sleep Heart Health Study, after adjustment
for confounding factors, OSA remains a signicant predictor of coro-
nary events only in men younger than 70 years and not in older
men or in women [77].
5.3. OSA and arrhythmias
A wide spectrum of conduction disturbances have been described
in patients with OSA, ranging from premature ventricular contrac-
tions to life-threatening arrhythmias. The likelihood of atrial brilla-
tion is increased 4-fold in patients with sleep-disordered breathing
even after adjusting for confounding factors [78]. Other clinically rel-
evant arrhythmias such as ventricular tachycardia or brillation, com-
plex ventricular ectopy and supraventricular tachycardia have been
described [79]. The increase in vagal tone during apneic events
might represent the underlying mechanism in the development of
bradyarrhythmias [80]. Bradycardia during sleep apnea is often pre-
sent in patients with OSA [81] and various degrees of heart block
have been observed in up to 10% of patients, particularly during
rapid eye movement sleep [82]. Signicant rhythm disturbances
often occur only during the nighttime and a positive correlation be-
tween OSA severity and the severity of rhythm disturbance has
been observed [83]. Guilleminault and colleagues monitored 400 pa-
tients with OSA during a single night of sleep; in this time interval,
48% had cardiac arrhythmias including ventricular tachycardia, sinus
arrest and second-degree atrioventricular conduction block [84].
5.4. OSA and stroke
There is also evidence that links OSA to cerebrovascular diseases.
OSA seems to be a risk factor for stroke. Conversely it is also true
that stroke appears to be a risk factor in the development of sleep-
 M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586593 589

disordered breathing [85]. The association between OSA and hyper- Table 2
tension, accelerated atherosclerosis and atrial brillation certainly History and physical examination ndings that should raise suspicion for OSA
syndrome.
plays a role in the development of cerebrovascular diseases, but
other mechanisms may be implicated. In particular, some observa- History Physical examination
tions suggest that OSA may also acutely impair the cerebral blood Daytime symptoms Obesity
ow supply. An increase in intracranial pressure has been reported Hypersomnolence Large neck circumference
during obstructive apneas [86] and a reduction of up to 20% in the Morning headaches Retrognathia
Dry mouth, sorethroat on waking Micrognathia
middle cerebral artery blood ow has been observed [87]. Cross-
Moodiness, irritability Macroglossia
sectional data from the Sleep Heart Health Study showed a greater Forgetfulness, difcult to concentrate Crowded airway appearance
odds ratio of prevalent stroke among subjects with OSA [78]. More re- Depression
cently, analysis of prospective data from the Sleep Heart Health Study Nocturnal symptoms
suggests that severe OSA is an independent risk factor for stroke only Snoring
Choking
in men [88].
Snorting
Gasping
Insomnia, fragmented sleep
6. Neurocognitive sequelae Nocturia

OSA is associated with impaired neurocognitive function. All cog-

nitive domains are affected, including attention and concentration, vi-
suospatial and verbal memory, executive function, constructional
abilities and psychomotor functioning [89]. Magnetic resonance im-
aging has revealed diminished grey matter correlated with OSA se-
verity [90]. In a meta-analysis of 1092 patients with OSA, Beebe [91]
found that vigilance was markedly impaired; accordingly, patients
with OSA often have difculty in concentrating and sustaining atten-
tion for extended periods. The disease also substantially impairs the
domain of executive functioning, the ability to develop and sustain
an organized approach to problem situations, and it is deleterious
for ne-motor coordination.
OSA can promote cognitive impairment mainly through intermit-
tent hypoxia. An animal model of chronic episodic hypoxia developed
neurodegenerative changes in the hippocampus and cortex with im-
paired performance during acquisition of a cognitive spatial task [92].
Some studies in humans reported a signicant correlation between
hypoxemia severity and neuropsychological impairment [9395].
Findley and colleagues [96] found that patients who have sleep apnea
with associated hypoxemia have more severe cognitive impairment
than those without hypoxemia. Hypersomnolence due to sleep frag-
mentation may also play a role in the development of neurocognitive
impairment [97,98].
The relationship between OSA and depression is not completely
clear. In a prospective cohort study of 1408 patients Peppard [99]
found that patients with mild sleep breathing disorders have a 2-fold in-
creased risk of developing depression. Other reports did not nd any
signicant relationship between OSA and depression [100,101]. In a
systematic review of the literature McMahon and colleagues observed
that continuous positive airway pressure (CPAP) had a signicant and
positive impact on depression [102].
questionnaire which measures an individual's likelihood of falling
asleep in routine life situations [103].
The Multiple Sleep Latency Test and the Maintenance of Wakeful-
ness Test can be used for objectively measuring sleepiness and alert-
ness. The rst measures the number of minutes it takes the patient to
fall asleep while lying down in a dark room [104]. The second is used
to assess a patient's ability to maintain wakefulness during specic
conditions such as sitting in a dimly lit room [105].
Objective sleep studies are necessary to conrm the clinical suspi-
cion of OSA, to assess its severity and to guide therapeutic choices.
One method used to screen obstructive sleep apnea is the continuous
recording of oxygen saturation during sleep. This method is economic
and easily practicable; however, it is often not sufciently sensible or
specic and its utility in clinical practice is poor [106].
Polysomnography remains the gold standard for the diagnosis.
During polysomnographic studies several physiological variables are
measured and recorded while the patient sleeps including pulse ox-
imetry, electroencephalogram, an electro-oculogram, nasal and oral
air ow measurements, chest wall movements, electromyogram and
electrocardiogram. An obstructive apnea is dened as a cessation of
airow for at least 10 seconds despite ongoing inspiratory effort; an
hypopnea is dened by one of the following three features: more
than 50% airow reduction, moderate airow reduction (b50%) asso-
ciated with oxyhemoglobin desaturation and moderate airow re-
duction with electroencephalographic evidence of awakening [1].
Diagnostic criteria of OSA syndrome are summarized in Table 3 [1,2].
The apnea-hypopnea index (AHI), calculated by dividing the num-
ber of events by the number of hours of sleep, is the most useful and
objective way of classifying the severity of the disease (Table 3).
Using the AHI, OSA can be classied as mild (AHI 514), moderate
(AHI 1529) or severe (AHI 30) [107].

7. Diagnosis Table 3
Diagnostic criteria and classication of severity of OSA syndrome.
Medical history and physical examination are the cornerstones of
A Excessive daytime sleepiness that is not better explained by other factors
clinical diagnosis (Table 2). Patients should be asked about both their B Two or more of the following that are not better explained by other factors:
nocturnal and daytime symptoms and interviewing the bedpartner Choking or gasping during sleep
can provide important information about the patient's sleep. Given Recurrent awakenings from sleep
the close association between OSA and cardiovascular disease, OSA Unrefreshing sleep
Daytime fatigue
should be suspected in those individuals who have systemic or pul-
Impaired concentration
monary hypertension, metabolic syndrome, heart failure or arrhyth- C Overnight monitoring demonstrates 5 obstructed breathing events per hour
mias. Physical examination includes evaluation for obesity, neck during sleep.
circumference, retrognathia, micrognathia, macroglossia, and inferior Diagnosis of OSA syndrome is conrmed by the presence of criterion A or B, plus
displacement of the hyoid bone. Hypothyroidism, acromegaly and criterion C or by the presence of 15 or more obstructed breathing events per
hour of sleep regardless of symptoms.
Marfan's syndrome should always be considered as possible underly-
ing causes for OSA and thyroid function tests are often indicated. Classication of severity of OSA on the basis of apnea-hypopnea index (AHI).
The severity of daytime hypersomnolence can be quantied using Mild Moderate Severe
questionnaires and objective tests. One of the most widely used tests
AHI 514 AHI 1529 AHI 30
to screen for sleepiness is the Epworth Sleepiness Scale, a self-report
590 M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586593
8. Treatment options
Management of OSA requires a long-term multidisciplinary ap-
proach. Behavioral, medical and surgical options are available for
the treatment. An algorithm for the treatment of OSA is proposed in
Fig. 1. The most effective behavioral measure is weight loss. In a pro-
spective, randomized controlled study [108] a weight loss of 10.7 kg
was paralleled by 40% reduction in AHI in patients with mild disease.
Low energy diet was followed by signicant clinical improvement
in obese men with moderate to severe sleep apnea; in this study a
67% reduction of the AHI was observed and patients with severe
OSA beneted most from the intervention [109]. In sedentary over-
weight/obese adults, exercise may be benecial for the treatment of
OSA beyond simply facilitating weight loss [110]. A rise in respiratory
drive and stabilized muscle tone in the upper airway might explain
the benecial inuence of physical exercise on OSA severity [111].
CPAP is the treatment of choice in most patients with OSA because
of its remarkable effectiveness in reducing symptoms and the possi-
ble sequelae of the disease [112114].
CPAP acts as a physical pressure splint to prevent partial or com-
plete collapse of the upper airway during sleep. Polysomnographic
studies have demonstrated that treatment with CPAP is able to re-
store patency of the airway throughout the respiratory cycle and to
reverse apnea and hypopnea [115]. Daytime sleepiness and
neurocognitive performance can be signicantly improved by CPAP
therapy.
In an observational study in men with OSA a reduced incidence of
fatal and non-fatal cardiovascular events was observed in patients
treated with nasal CPAP [34]. In a recent placebo-controlled trial in
patients with metabolic syndrome, a three months CPAP treatment
improved blood pressure control and metabolic abnormalities [116].
Weight loss and reduction in intra-abdominal fat are observed after
CPAP therapy, probably as a consequence of decreased daytime hyp-
ersomnolence and of increased physical activity.
Patients' failure to adhere to the therapy represents a major limi-
tation of CPAP. Adverse effects of CPAP include irritation, pain, rash
and skin breakdown at mask contact points; dryness or irritation of
Fig. 1. Flow-chart for the treatment of OSA syndrome. Weight reduction by diet and increased physical activity should be recommended to all overweight patients. Patients should
be advised to avoid alcohol and sedatives before bedtime. CPAP is the treatment of choice in mild, moderate and severe OSA and should be offered to every patient. If CPAP is refused
or adherence is poor, alternative therapies including oral appliance, surgery and pharmacotherapy can be considered. When the results of treatment are satisfactory, the patient is
started on longterm followup.
the nasal and pharyngeal membranes, nasal congestion and
rhinorrhea, and eye irritation from air leakage are also common.
Claustrophobia, gastric and bowel distension and ear and sinus infec-
tions are less common adverse effects [117]. Provision of heated hu-
midication together with a systematic educational program is
suggested for improving patient adherence to CPAP [118].
Pharmacological treatments have been proposed in patients with
OSA with the aim of improving pharyngeal dilator muscle tone (tricy-
clic antidepressant, serotonergic agents), of increasing ventilatory
drive (methylxanthine derivatives, opioid antagonists), of reducing
airway resistance (oximethazoline or steroid nasal spray) and of im-
proving pharyngeal surface tension forces (soft tissue lubricants)
[119]. In a systematic review of 26 studies of 21 drugs, the authors
concluded that there is still insufcient evidence to recommend any
systemic pharmacological treatment for OSA [120].
Although less effective than CPAP, oral devices designed for the
advancement of the mandible or tongue retainment have given posi-
tive results in the treatment of obstructive sleep apnea [121,122].
These devices have potential advantages over CPAP in that they are
unobtrusive, make no noise, do not need a power source and are, po-
tentially, less costly. When directly compared in randomized trials,
oral appliances are generally preferred by patients over CPAP
[123,124]. Thus, oral appliances should be considered for patients
who refuse CPAP treatment.
Surgery may represent an effective therapeutic alternative. Surgi-
cal modications of the upper airway have been performed for de-
cades as a treatment for OSA. The use of such treatments, however,
remains controversial mainly because of the lack of controlled studies
and of standardized criteria to dene the surgical efcacy. Appropri-
ate patient selection and surgeon experience are crucial for therapeu-
tic success. Surgical options include several procedures, with different
degrees of invasiveness, that aim to reduce anatomical airway ob-
struction. Maxillo-mandibular advancement osteotomy is designed
to enlarge the velo-orohypopharyngeal airway by advancing the an-
terior pharyngeal tissues (soft palate, tongue base, and suprahyoid
musculature) attached to the maxilla, mandible, and hyoid bone. Sub-
stantial and consistent reductions in the AHI were observed following
 M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586593
this surgical procedure and adverse events were uncommon [125].
This type of intervention is particularly suitable in patients with skel-
etal hypoplasia and retrognathia [126]. This procedure is technically
demanding and requires full anesthesia and inpatient treatment.
Less invasive palatal and pharyngeal surgery gave contrasting re-
sults. Uvulopalatopharyngoplasty that involves resection of the ton-
sils (if present), uvula, and posterior palate and reorientation of the
tonsillar pillars [127], has shown a signicant reduction in AHI
[128]. Laser Assisted Uvulopalatoplasty is an outpatient surgical tech-
nique that involves a series of laser incisions and vaporizations
designed to shorten the uvula and modify and tighten the soft palatal
tissue. In most studies such a procedure resulted in a modest reduc-
tion in AHI and little or no reduction in daytime symptoms [128].
Radiofrequency ablation aims to modify the anatomic site of the ob-
struction acting on nasal turbinates, tongue base and palate, with
minimal invasiveness and very few risks [129]. These procedures
may be considered for patients whose main complaint is snoring,
with little or no apnea.
Innovative procedures are constantly being explored for OSA ther-
apy [130]. Novel surgical techniques and evolving technology may
offer less invasive treatment modalities with broader patient accep-
tance and improvement in results. Further studies are needed to im-
prove the criteria for patient selection as well as processes for
matching appropriate surgery to individual patients with OSA taking
into account its efcacy and safety.
9. Conclusions
OSA syndrome is a common but often unrecognized condition
with potentially serious complications, mainly due to its important
cardiovascular and neurocognitive sequelae. As the obesity epidemic
is rising, the prevalence of this condition is likely to increase, thus
representing an important public-health problem. Adequate history
and proper use of diagnostic tests, such as polysomnography, enable
accurate identication of patients with OSA syndrome, denition of
the stage of the disease and tailoring of effective therapies. Weight re-
duction and lifestyle measures are effective as rst line treatment in
mild to moderate OSA. On the basis of randomized trials, CPAP is con-
sidered the most effective treatment aimed at reducing symptoms
and cardiovascular and neurocognitive complications. However,
CPAP is often poorly tolerated by patients. Surgery is suitable for se-
lected patients, but its long-term benets are still not supported by
a consistent body of evidence in large populations. A better under-
standing of the mechanisms that underlie obstructive sleep apnea
could lead to an improvement of therapeutic strategies and to a re-
duction of the social impact of this condition.
Learning points
Obstructive sleep apnea (OSA) syndrome is a common, but often
unrecognized, sleep disorder associated with serious cardiovascular
and neurocognitive consequences.
OSA should always be suspected in obese patients referred with ex-
cessive daytime sleepiness particularly when associated with refrac-
tory hypertension, congestive heart failure, nocturnal arrhythmias,
glucose intolerance and pulmonary hypertension.
Polysomnography is the gold standard for the diagnosis and the as-
sessment of OSA syndrome severity.
Continuous positive airway pressure (CPAP) represents the treat-
ment of choice in mild, moderate and severe OSA, being effective
in reducing symptoms, cardiovascular morbidity and mortality
and neurocognitive sequelae.
Conict of interest statement
None of the authors has any conict of interest.
591
Acknowledgments
The authors thank Mrs. Shriyani Worsley and Mr. Peter Worsley for
their useful comments and suggestions in preparing the manuscript.
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