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 b s t r a c ta r t i c l ei n f o
Received 6 March 2012
Received in revised form 8 May 2012
Accepted 11 May 2012
Available online 24 June 2012
Obstructive sleep apnea
Continuous positive airway pressure
Obstructive sleep apnea (OSA) syndrome is a common but often unrecognized disorder caused by pharyngeal
collapse during sleep and characterized by frequent awakenings, disrupted sleep and consequent excessive
daytime sleepiness. With the increasing epidemic of obesity, the most important risk factor for OSA, preva-
lence of the disease will increase over the coming years thus representing an important public-health prob-
lem. In fact, it is now recognized that there is an association between OSA and hypertension, metabolic
syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension,
neurocognitive and mood disorders. Diagnosis is based on the combined evaluation of clinical manifestations
and objective sleep study findings. Cardinal symptoms include snoring, sleepiness and significant reports of
sleep apnea episodes. Polysomnography represents the gold standard to confirm the clinical suspicion of OSA
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 first-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.
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 airflow can be either
reduced (hypopnea) or completely absent (apnea). OSA syndrome is
defined as five 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]. Itisnow recognized that OSA is often associatedwithsevere com-
plications including major cardiovascular disorders, neurocognitive se-
quelaeand mood disorders. Indeed,there is a growingbody of evidence
that a strong correlation exists between the disease and hypertension,
impairment with changes in attention and concentration, executive
function and fine-motor coordination are common complaints of
patients with OSA. Finally, depression can represent a significant prob-
lem in the course of the disease.
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
 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 significant
burden of risk is to be prevented.
Population-based studies suggest that 4 percent of men and 2 per-
cent of women aged more than 50 years suffer from symptomatic
OSA . However, OSA is often asymptomatic and the prevalence of
patients with OSA, who do not present clinical syndrome, might be
as high as 20–30% in the middle-aged population .
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
. 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 .
Postmenopausal women are at higher risk of developing OSA than
are their premenopausal counterparts , an effect that hormone
replacement therapy could prevent or ameliorate .
European Journal of Internal Medicine 23 (2012) 586–593
⁎ Corresponding author at: Unit of Internal Medicine, Angiology and Arteriosclerosis,
University of Perugia, Perugia, Italy, Hospital “Santa Maria della Misericordia”, Piazzale
Menghini, 1‐06129, Perugia, Italy. Tel.: +39 075 5783172; fax: +39 075 5784022.
E-mail address: firstname.lastname@example.org (M.R. Mannarino).
0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
The risk of OSA increases with increasing age. OSA prevalence in-
creases 2–3 times in older persons (>65 years) compared with indi-
viduals aged 30–64 years . Nevertheless, OSA is also described
in children with adenotonsillar hypertrophy . Finally the risk of
developing the disease appears to be related to race. African Ameri-
cans are more frequently affected and develop OSA at a younger age
than white people .
Both anatomic and neuromuscular factors are involved in the de-
velopment of obstruction of the upper airway in OSA. The human
pharynx can be considered as a collapsible tube that serves several
purposes including speech, swallowing and respiration; it is not pro-
vided with a rigid skeletal support and, during normal inhalation, it
undergoes numerous stresses promoting its collapse. Negative pres-
sure within the airway and the presence of soft tissues and bony
structures, which increase extraluminal tissue pressures, can predis-
pose the pharynx to collapse; on the other hand, the tonic and phasic
contractile activity of the dilator muscles of the pharynx contribute to
the maintenance of pharyngeal patency . An imbalance between
these opposite forces is responsible for the upper airway obstructions
that recur in patients with sleep-disordered breathing.
From an anatomic perspective, a narrow upper airway is generally
more prone to collapse than a larger one. Moreover, according to the
Venturi effect, while airflow velocity increases at the site of stricture
in the airway, pressure on the lateral wall of the pharynx decreases
and the likelihood of pharyngeal collapse increases significantly.
A number of imaging studies have demonstrated that during wake-
fulness the cross-sectional area of the upper airway in OSA patients is
reduced compared with control subjects [14,15]. Accordingly, OSA is
frequently associated with a number of alterations in upper airway
ticularly enlarged parapharyngeal fat pads, have been described in pa-
tients with OSA. Thickness of the lateral parapharyngeal muscular
walls also represents a relevant factor causing airway narrowing in ap-
neic subjects .
The disease has been associated with the presence of tonsillar and
tongue hypertrophy, retrognathia and inferior displacement of the
and accumulation of fat inperipharyngealtissues; moreoveritmay also
increase pharyngeal collapsibility through reduction in lung volumes.
Another anatomically based predisposing factor of pharyngeal collapse
in OSA may be the length of the pharynx . In fact, it has been ob-
with those without OSA .
It is relevant to point out that disordered breathing events occur
only during sleep, emphasising the importance of the sleep state in
the pathogenesis of this disorder; accordingly, in addition to the ana-
tomically imposed mechanical loads on upper airways, the impaired
activity of the pharyngeal dilator muscle during sleep plays a critical
role in determining airway collapse.
In healthy subjects, the phasic activity of some dilator muscles has
been found to decline during rapid eye movement sleep  and the
pharyngeal cross-sectional area has been found to be smaller during
sleep than during wakefulness . Indeed, reflex mechanisms from
both chemoreceptors and mechanoreceptors which control the activ-
ity of pharyngeal dilator muscles are reduced during sleep [23,24].
It has been observed that during wakefulness the activity of pha-
ryngeal dilator muscles in OSA patients is increased to overcome
compromised pharyngeal anatomy . This compensatory mecha-
nism is lost during sleep leading to pharyngeal collapse. Indeed it
has been observed that, in OSA patients, the onset of sleep is associat-
ed with significantly larger decrements in the activity of pharyngeal
dilator muscles' activity compared to controls .
Finally, ventilatory control instability has been proposed as a poten-
tial contributing factor for the development of obstructive events .
4. Clinical features
The typical clinical presentation for OSA includes signs of upper air-
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
symptoms include snoring, snorting, gasping and choking. Patients
may report intermittent awakenings and insomnia, with reduced total
sleep time, fragmented sleep or early morning awakenings .
Nocturia is also frequently reported , possibly due to an elevation
in plasma levels of atrial natriuretic peptide secondary to hypoxemia
and/or exaggerated intrathoracic pressure swings increasing urine out-
put. Nocturnal symptoms are often under-appreciated by the patient
leading to a delay in diagnosis until the appearance of more obvious
daytime symptoms. Chronic fatigue and daytime sleepiness, secondary
to sleep fragmentation, are the most significant diurnal complaints of
patients suffering from OSA. In the early stages of the disease, the pa-
tient can easily fall asleep during sedentary activities, such as watching
television; in these phases hypersomnolence, confused with tiredness,
fatigue or lethargy, is often undervalued. Severity of symptoms usually
progress over years and may increase with weight gain, aging or transi-
tion to menopause. As the disorder progresses, sleepiness encroaches
ingly, OSA represents a significant cause of motor vehicle crashes
resulting in a two-fold and up to seven-fold increased risk . Other
common daytime symptoms include morning headaches, dry mouth
and sorethroat at waking up time. In women, clinical presentation can
be rather different from that in men. Particularly, women are less likely
to report symptoms of obstructive breathing and daytime sleepiness
while reporting insomnia, palpitations and ankle edema . Chronic
fatigue syndrome, fibromyalgia, irritable bowel syndrome and migraine
headaches are seen more commonly in women and may be associated
withmilder forms ofOSA[32,33].Althoughallthesesymptoms are like-
ly to affect the quality of life, the clinical relevance of OSA is mainly due
to its strong association with hypertension, metabolic syndrome, diabe-
tes, heart failure, coronary artery disease, arrhythmias, stroke, pulmo-
nary hypertension, neurocognitive and mood disorders. Cardiovascular
and neurocognitive sequelae of OSA are summarized in Table 1.
5. Cardiovascular sequelae
A growing body of evidence links OSA to cardiovascular disorders
. Several risk factors for OSA such as obesity, age and male gender
are also known risk factors for cardiovascular disease. Moreover, OSA
is associated with additional cardiovascular risk factors, such as hyper-
tension and glucose intolerance. Nevertheless, part of the association
between OSA and cardiovascular diseases is independent of traditional
cardiovascular risk factors.
Cardiovascular and neurocognitive sequelae of OSA.
Cardiovascular sequelae Neurocognitive sequelae
Coronary heart disease
• Atrial fibrillation
• Supraventricular tachycardia
• Ventricular tachycardia/fibrillation
• Sinus bradycardia
• Heart block
Deficit in executive functioning
Impaired fine-motor coordination
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
Clinical and experimental evidences have shown the role of OSA in
atherosclerosis progression. In Apolipoprotein E-deficient (ApoE−/−)
plaque growth , and in humans a significant correlation between
OSA severity and carotid-artery intima-media thickness was found
. 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 inflammation. OSA has also
been associated with increased platelet activation, increased fibrinogen
and other potential markers of thrombotic risk . Repetitive hypoxia
ic drive which persists even duringnormoxic daytimewakefulness .
posure to intermittent hypoxia, has been associated with increased
blood pressure levels . 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 . Recurrent hypoxemic stress might promote release of vaso-
constrictors such as endothelin . Repetitive cycles of hypoxia and
reoxygenation promote the production of reactive oxygen species and
increase oxidative stress .
OSA is known to be associated also with endothelial dysfunction
. 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 .
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 .
Chronic inflammation is relevant in the pathogenesis of athero-
sclerosis ; elevated C-reactive protein (CRP) is associated with in-
creased cardiovascular risk . Chronic intermittent hypoxia can
activate the nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-κB) pathway which, in turn, can stimulate the production
of proinflammatory mediators . Accordingly, OSA is associated
with elevated CRP levels which are correlated with disease severity
. Plasma levels of cytokines, adhesion molecules  and serum
amyloid-A have been found to be increased in OSA . 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  and patients with OSA
have a higher prevalence of insulin resistance and glucose intolerance
even after adjusting for body weight .
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 significantly 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  and a higher prevalence of severe OSA
was observed in patients with thoracic aorta dissection .
5.1. OSA and hypertension
About of patients with one half OSA are affected by hypertension
 and a linear relationship was identified between the severity of
sleep-disordered breathing and prevalence of hypertension . 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 . 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 . OSA and hypertension share several risk
factors such as age, male gender, obesity, alcohol intake and smoking
. 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 .
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 . Percentages of prevalence of pulmonary hypertension in
patients suffering from OSA ranging from 17% to 42% [65–68] and im-
provement in pulmonary hemodynamics have been observed after
CPAP therapy .
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 . 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 . Particularly, it should be noted that left ventricular
hypertrophy is more closely linked to blood pressure levels during
sleep than during wakefulness . Patients with heart failure and
OSA were found to have a significantly greater mortality than patients
without OSA . 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 [74–76,34]. However in a more recent pro-
spective analysis from the Sleep Heart Health Study, after adjustment
for confounding factors, OSA remains a significant predictor of coro-
nary events only in men younger than 70 years and not in older
men or in women .
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 fibrilla-
tion is increased 4-fold in patients with sleep-disordered breathing
even after adjusting for confounding factors . Other clinically rel-
evant arrhythmias such as ventricular tachycardia or fibrillation, com-
plex ventricular ectopy and supraventricular tachycardia have been
described . The increase in vagal tone during apneic events
might represent the underlying mechanism in the development of
bradyarrhythmias . Bradycardia during sleep apnea is often pre-
sent in patients with OSA  and various degrees of heart block
have been observed in up to 10% of patients, particularly during
rapid eye movement sleep . Significant 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 . 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 .
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) 586–593
disordered breathing . The association between OSA and hyper-
tension, accelerated atherosclerosis and atrial fibrillation certainly
plays a role in the development of cerebrovascular diseases, but
other mechanisms may be implicated. In particular, some observa-
tions suggest that OSA may also acutely impair the cerebral blood
flow supply. An increase in intracranial pressure has been reported
during obstructive apneas  and a reduction of up to 20% in the
middle cerebral artery blood flow has been observed . Cross-
sectional data from the Sleep Heart Health Study showed a greater
odds ratio of prevalent stroke among subjects with OSA . More re-
cently, analysis of prospective data from the Sleep Heart Health Study
suggests that severe OSA is an independent risk factor for stroke only
in men .
6. Neurocognitive sequelae
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 . Magnetic resonance im-
aging has revealed diminished grey matter correlated with OSA se-
verity . In a meta-analysis of 1092 patients with OSA, Beebe 
found that vigilance was markedly impaired; accordingly, patients
with OSA often have difficulty 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 fine-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 .
Some studies in humans reported a significant correlation between
hypoxemia severity and neuropsychological impairment [93–95].
Findley and colleagues  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
The relationship between OSA and depression is not completely
clear. In a prospective cohort study of 1408 patients Peppard 
creased risk of developing depression. Other reports did not find any
significant 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 significant and
positive impact on depression .
Medical history and physical examination are the cornerstones of
clinical diagnosis (Table 2). Patients should be asked about both their
nocturnal and daytime symptoms and interviewing the bedpartner
can provide important information about the patient's sleep. Given
the close association between OSA and cardiovascular disease, OSA
should be suspected in those individuals who have systemic or pul-
monary hypertension, metabolic syndrome, heart failure or arrhyth-
mias. Physical examination includes evaluation for obesity, neck
circumference, retrognathia, micrognathia, macroglossia, and inferior
displacement of the hyoid bone. Hypothyroidism, acromegaly and
Marfan's syndrome should always be considered as possible underly-
ing causes for OSA and thyroid function tests are often indicated.
The severity of daytime hypersomnolence can be quantified using
questionnaires and objective tests. One of the most widely used tests
to screen for sleepiness is the Epworth Sleepiness Scale, a self-report
questionnaire which measures an individual's likelihood of falling
asleep in routine life situations .
The Multiple Sleep Latency Test and the Maintenance of Wakeful-
ness Test can be used for objectively measuring sleepiness and alert-
ness. The first measures the number of minutes it takes the patient to
fall asleep while lying down in a dark room . The second is used
to assess a patient's ability to maintain wakefulness during specific
conditions such as sitting in a dimly lit room .
Objective sleep studies are necessary to confirm 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 sufficiently sensible or
specific and its utility in clinical practice is poor .
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 flow measurements, chest wall movements, electromyogram and
electrocardiogram. An obstructive apnea is defined as a cessation of
airflow for at least 10 seconds despite ongoing inspiratory effort; an
hypopnea is defined by one of the following three features: more
than 50% airflow reduction, moderate airflow reduction (b50%) asso-
ciated with oxyhemoglobin desaturation and moderate airflow re-
duction with electroencephalographic evidence of awakening .
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 classified as ‘mild’ (AHI 5–14), ‘moderate’
(AHI 15–29) or ‘severe’ (AHI≥30) .
History and physical examination findings that should raise suspicion for OSA
• Morning headaches
• Dry mouth, sorethroat on waking
• Moodiness, irritability
• Forgetfulness, difficult to concentrate
• Insomnia, fragmented sleep
• Large neck circumference
• Crowded airway appearance
Diagnostic criteria and classification of severity of OSA syndrome.
A Excessive daytime sleepiness that is not better explained by other factors
BTwo or more of the following that are not better explained by other factors:
• Choking or gasping during sleep
• Recurrent awakenings from sleep
• Unrefreshing sleep
• Daytime fatigue
• Impaired concentration
COvernight monitoring demonstrates ≥5 obstructed breathing events per hour
Diagnosis of OSA syndrome is confirmed by the presence of criterion A or B, plus
criterion C or by the presence of 15 or more obstructed breathing events per
hour of sleep regardless of symptoms.
Classification of severity of OSA on the basis of apnea-hypopnea index (AHI).
AHI 5–14AHI 15–29AHI≥30
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
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  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 significant 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 benefited most from the intervention . In sedentary over-
weight/obese adults, exercise may be beneficial for the treatment of
OSA beyond simply facilitating weight loss . A rise in respiratory
drive and stabilized muscle tone in the upper airway might explain
the beneficial influence of physical exercise on OSA severity .
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 [112–114].
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 apneaand hypopnea
neurocognitive performance can be significantly improved by CPAP
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 . In a recent placebo-controlled trial in
patients with metabolic syndrome, a three months CPAP treatment
improved blood pressure control and metabolic abnormalities .
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
. Daytime sleepinessand
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 . Provision of heated hu-
midification together with a systematic educational program is
suggested for improving patient adherence to CPAP .
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)
. In a systematic review of 26 studies of 21 drugs, the authors
concluded that there is still insufficient evidence to recommend any
systemic pharmacological treatment for OSA .
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 modifications 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 define the surgical efficacy. 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
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 long‐term follow‐up.
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593