Definisi Obstructive SLeep APne

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

Article history:

Received 6 March 2012

Received in revised form 8 May 2012 Accepted 11 May 2012

Available online 24 June 2012

Keywords:

Obstructive sleep apnea Cardiovascular risk Polysomnography

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, prevalence of the disease will increase over the coming years thus representing an important public-health problem. 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 studyfindings. 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 asfirst-line treatment, but these approaches might be useful in selected patients. A better understanding of mechanisms underlying the disease could improve therapeutic strategies and reduce the social impact of OSA syndrome.

1. Introduction

Obstructive sleep apnea (OSA) syndrome is a common sleep disorder in which complete or partial airway obstruction, caused by pharyngeal 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]. It is now recognized that OSA is often associated with severe complications including major cardiovascular disorders, neurocognitive sequelae 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 fine-motor coordination are common complaints of patients with OSA. Finally, depression can represent a significant problem 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 [3]and it will increase over the coming years. Today, OSA syndrome represents a major public health issue with potential societal consequences and recognition of this syndrome is essential if a signiﬁcant burden of risk is to be prevented.

2. Epidemiology

Population-based studies suggest that 4 percent of men and 2 percent 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 20–30% 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].

⁎ 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:[email protected](M.R. Mannarino).

doi:10.1016/j.ejim.2012.05.013

Contents lists available atSciVerse ScienceDirect

European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j i m

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The risk of OSA increases with increasing age. OSA prevalence increases 2–3 times in older persons (>65 years) compared with individuals aged 30–64 years[10]. Nevertheless, OSA is also described in children with adenotonsillar hypertrophy[11]. 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[12].

3. Pathogenesis

Both anatomic and neuromuscular factors are involved in the development 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 pressure within the airway and the presence of soft tissues and bony structures, which increase extraluminal tissue pressures, can predispose 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[13]. 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 wakefulness 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 anatomy that reduce the size of the pharynx. Excessive fat deposits, particularly enlarged parapharyngeal fat pads, have been described in patients with OSA. Thickness of the lateral parapharyngeal muscular walls also represents a relevant factor causing airway narrowing in apneic subjects[14].

The disease has been associated with the presence of tonsillar and tongue hypertrophy, retrognathia and inferior displacement of the hyoid bone[16–18]. Obesity can cause elevations in neck circumference 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 in OSA may be the length of the pharynx[19]. In fact, it has been observed that OSA patients have a greater length of the pharynx compared with those without OSA[20].

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 anatomically 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[21]and the pharyngeal cross-sectional area has been found to be smaller during sleep than during wakefulness[22]. Indeed, reﬂex mechanisms from both chemoreceptors and mechanoreceptors which control the activity of pharyngeal dilator muscles are reduced during sleep[23,24].

It has been observed that during wakefulness the activity of pharyngeal dilator muscles in OSA patients is increased to overcome compromised pharyngeal anatomy[25]. This compensatory mechanism is lost during sleep leading to pharyngeal collapse. Indeed it has been observed that, in OSA patients, the onset of sleep is associated with signiﬁcantly larger decrements in the activity of pharyngeal dilator muscles' activity compared to controls[26].

Finally, ventilatory control instability has been proposed as a potential contributing factor for the development of obstructive events[27].

4. Clinical features

The typical clinical presentation for OSA includes signs of upper airway 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 [28].

Nocturia is also frequently reported[29], 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 patient 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 into all daily activities and can become disabling and dangerous. Accord- ingly, OSA represents a significant cause of motor vehicle crashes resulting in a two-fold and up to seven-fold increased risk[30]. 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[31]. Chronic fatigue syndrome,fibromyalgia, irritable bowel syndrome and migraine headaches are seen more commonly in women and may be associated with milder forms of OSA[32,33]. Although all these symptoms are likely to affect the quality of life, the clinical relevance of OSA is mainly due to its strong association with hypertension, metabolic syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension, neurocognitive and mood disorders. Cardiovascular and neurocognitive sequelae of OSA are summarized inTable 1.

5. Cardiovascular sequelae

A growing body of evidence links OSA to cardiovascular disorders [34]. 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 hypertension and glucose intolerance. Nevertheless, part of the association between OSA and cardiovascular diseases is independent of traditional cardiovascular risk factors.

Table 1

Cardiovascular and neurocognitive sequelae of OSA.

Cardiovascular sequelae Neurocognitive sequelae

Systemic hypertension Impaired vigilance

Coronary heart disease Deﬁcit in executive functioning

Heart failure Impairedﬁne-motor coordination

Cardiac arrhythmias Depression

• Atrial ﬁbrillation

• Supraventricular tachycardia

• Ventricular tachycardia/ﬁbrillation

• Sinus bradycardia

• Heart block Pulmonary hypertension Stroke

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Clinical and experimental evidences have shown the role of OSA in atherosclerosis progression. In Apolipoprotein E-deficient (ApoE−/−) mice, intermittent hypoxia is associated with accelerated atherosclerotic plaque growth[35], and in humans a significant 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 nocturnal cardiac events[37,38]. The pathogenesis of cardiovascular complications in OSA is not completely understood. Proposed mechanisms include increased sympathetic activity, endothelial dysfunction, metabolic dysregulation, oxidative stress and inflammation. OSA has also been associated with increased platelet activation, increasedfibrinogen and other potential markers of thrombotic risk[39]. Repetitive hypoxia due to intermittent airway obstruction results in heightened sympathetic drive which persists even during normoxic daytime wakefulness[40].

Accordingly, animals exposed to intermittent hypoxia developed hypertension that was prevented by sympathectomy[40]. In healthy men, exposure to intermittent hypoxia, has been associated with increased blood pressure levels[41]. OSA is also associated with abnormal cardiovascular regulation during resting normoxic daytime wakefulness, with a faster heart rate, higher blood pressure variability and lower RR variability[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 endothelial 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 inﬂammation is relevant in the pathogenesis of atherosclerosis[48]; elevated C-reactive protein (CRP) is associated with increased cardiovascular risk [49]. 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 [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 cardiovascular 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, intrathoracic 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[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 identiﬁed 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 hypertension with an estimated prevalence of 64% among subjects with resistant 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 pulmonary 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 hypertension[64]. Percentages of prevalence of pulmonary hypertension in patients suffering from OSA ranging from 17% to 42%[65–68]and improvement 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 associated with a 2.38 increase in the likelihood of having heart failure, independent 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 signiﬁcantly greater mortality than patients without OSA[73]. Accordingly, OSA might promote the progression of cardiac dysfunction through several mechanisms, including an increased 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 prospective analysis from the Sleep Heart Health Study, after adjustment for confounding factors, OSA remains a signiﬁcant predictor of coronary 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 atrialfibrilla- tion is increased 4-fold in patients with sleep-disordered breathing even after adjusting for confounding factors[78]. Other clinically relevant arrhythmias such as ventricular tachycardia orfibrillation, 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 present 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]. Significant rhythm disturbances often occur only during the nighttime and a positive correlation between OSA severity and the severity of rhythm disturbance has been observed[83]. Guilleminault and colleagues monitored 400 patients 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-

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disordered breathing[85]. The association between OSA and hypertension, 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[86]and a reduction of up to 20% in the middle cerebral artery bloodflow has been observed [87]. Cross- sectional data from the Sleep Heart Health Study showed a greater odds ratio of prevalent stroke among subjects with OSA[78]. 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[88].

6. Neurocognitive sequelae

OSA is associated with impaired neurocognitive function. All cognitive domains are affected, including attention and concentration, vi- suospatial and verbal memory, executive function, constructional abilities and psychomotor functioning[89]. Magnetic resonance imaging has revealed diminished grey matter correlated with OSA severity[90]. In a meta-analysis of 1092 patients with OSA, Beebe[91]

found that vigilance was markedly impaired; accordingly, patients with OSA often have difﬁculty in concentrating and sustaining attention 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 forﬁne-motor coordination.

OSA can promote cognitive impairment mainly through intermittent hypoxia. An animal model of chronic episodic hypoxia developed neurodegenerative changes in the hippocampus and cortex with impaired performance during acquisition of a cognitive spatial task[92].

Some studies in humans reported a signiﬁcant correlation between hypoxemia severity and neuropsychological impairment [93–95]. 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 fragmentation 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 increased risk of developing depression. Other reports did notfind 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[102].

7. Diagnosis

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 pulmonary hypertension, metabolic syndrome, heart failure or arrhythmias. 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 underlying 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[103].

The Multiple Sleep Latency Test and the Maintenance of Wakeful- ness Test can be used for objectively measuring sleepiness and alertness. Theﬁrst 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 speciﬁc conditions such as sitting in a dimly lit room[105].

Objective sleep studies are necessary to conﬁrm the clinical suspicion 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[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 oximetry, electroencephalogram, an electro-oculogram, nasal and oral airflow 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%) associated with oxyhemoglobin desaturation and moderate airflow reduction with electroencephalographic evidence of awakening [1].

Diagnostic criteria of OSA syndrome are summarized inTable 3 [1,2].

The apnea-hypopnea index (AHI), calculated by dividing the number 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)[107].

Table 2

History and physical examination ﬁndings that should raise suspicion for OSA syndrome.

History Physical examination

Daytime symptoms • Obesity

• Hypersomnolence • Large neck circumference

• Morning headaches • Retrognathia

• Dry mouth, sorethroat on waking • Micrognathia

• Moodiness, irritability • Macroglossia

• Forgetfulness, difﬁcult to concentrate • Crowded airway appearance

• Depression Nocturnal symptoms

• Snoring

• Choking

• Snorting

• Gasping

• Insomnia, fragmented sleep

• Nocturia

Table 3

Diagnostic criteria and classiﬁcation of severity of OSA syndrome.

A Excessive daytime sleepiness that is not better explained by other factors B Two 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

C Overnight monitoring demonstrates≥5 obstructed breathing events per hour during sleep.

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).

Mild Moderate Severe

AHI 5–14 AHI 15–29 AHI≥30

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8. Treatment options

Management of OSA requires a long-term multidisciplinary approach. 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 prospective, 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 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[109]. In sedentary overweight/obese adults, exercise may be beneficial 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 beneficial influence 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 possible sequelae of the disease[112–114].

CPAP acts as a physical pressure splint to prevent partial or complete 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 signiﬁcantly 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 hypersomnolence 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

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- midiﬁcation 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 improving 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 insufﬁcient 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 positive 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, potentially, 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 therapeutic success. Surgical options include several procedures, with different degrees of invasiveness, that aim to reduce anatomical airway obstruction. 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.

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this surgical procedure and adverse events were uncommon[125].

This type of intervention is particularly suitable in patients with skeletal hypoplasia and retrognathia[126]. This procedure is technically demanding and requires full anesthesia and inpatient treatment.

Less invasive palatal and pharyngeal surgery gave contrasting results. Uvulopalatopharyngoplasty that involves resection of the ton- sils (if present), uvula, and posterior palate and reorientation of the tonsillar pillars [127], has shown a signiﬁcant 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 reduction in AHI and little or no reduction in daytime symptoms[128].

Radiofrequency ablation aims to modify the anatomic site of the obstruction 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 therapy[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 improve the criteria for patient selection as well as processes for matching appropriate surgery to individual patients with OSA taking into account its efﬁcacy 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 identification of patients with OSA syndrome, definition of the stage of the disease and tailoring of effective therapies. Weight reduction and lifestyle measures are effective asfirst line treatment in mild to moderate OSA. On the basis of randomized trials, CPAP is considered 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 selected patients, but its long-term benefits are still not supported by a consistent body of evidence in large populations. A better understanding of the mechanisms that underlie obstructive sleep apnea could lead to an improvement of therapeutic strategies and to a reduction 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 excessive 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 treatment of choice in mild, moderate and severe OSA, being effective in reducing symptoms, cardiovascular morbidity and mortality and neurocognitive sequelae.

Conﬂict of interest statement

None of the authors has any conﬂict of interest.

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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