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Obstructive sleep apnoea

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Sophia E. Schiza, Izolde Bouloukaki and Athanasia Pataka

Clinical aspects

OSA is recognised as one of the most prevalent adult chronic respiratory disorders in clinical practice. Due to its high prevalence and its individual and socioeconomic healthcare consequences, improved routine screening and assessment are required. However, the marked heterogeneity of OSA pathogenesis should be taken into account, as this could lead to considerable interindividual variability and dierent clinical presentation between patients.

Clinical symptoms

A detailed sleep history is an essential part of OSA evaluation. Although clinical symptoms may be crucial in identifying OSA, none of them are considered pathognomonic. Snoring is a frequent associated complaint, but a wide variety of nocturnal and daytime symptoms may be present (table 1). Furthermore, symptoms oen begin insidiously and develop progressively over several years before referral for evaluation (table 1).

EDS is one of the most commonly reported symptoms, aecting 40.5–58% of OSA patients. It can have a signiﬁcant impact on quality of life as well as cognition, behaviour and other aspects of daily functioning. Questioning patients and their bed partners about sleepiness typically reveals a pattern of a patient feeling sleepy in boring, passive or monotonous situations. However, special consideration should be given to situations in which the patient’s sleepiness impairs functional abilities, potentially threatening job security, driving safety and negatively impacting interpersonal relationships. EDS may also be masked by activity or caeine consumption. In addition to EDS symptoms, patients oen report nonrestorative sleep and nocturnal restlessness.

Key points

• OSA is a heterogeneous disorder in terms of its pathogenesis (endotypes) and clinical expression (phenotypes).

• Common OSA symptoms are: EDS, snoring, witnessed apnoeas, fatigue, insomnia, headaches and nocturia; however, there are various presentations, depending on the clinical phenotypes.

• Patients with OSA are at increased risk of several adverse clinical outcomes, including cardiovascular, neurocognitive and metabolic complications.

ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

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Table 1. Clinical symptoms of OSA

Nocturnal symptoms Daytime symptoms

Snoring Witnessed apnoeas, interrupting snoring

and ending with a snort

Gasping and choking sensations that may

wake the patient from sleep Restless sleep, with frequent arousals Nocturia Insomnia Nocturnal sweating

EDS during quiet activities; as severity

worsens, patients are sleepy during activities requiring alertness (e.g. work,

driving) Nonrestorative sleep Daytime fatigue/tiredness Morning headache Dry or sore throat Cognitive deﬁcit: memory impairment,

loss of concentration Decreased vigilance Personality and mood changes (depression

and anxiety) Sexual dysfunction (decreased libido,

impotence) Gastro-oesophageal reﬂux

As well as EDS, a signiﬁcant proportion of patients identify lack of energy, exhaustion and fatigue as their main symptoms. Moreover, sleepiness and fatigue frequently coexist. However, as patients oen interchangeably use the terms ‘sleepiness’ and ‘fatigue’, it is critical to distinguish EDS from fatigue. To facilitate this distinction, the ESS can be used to quantify the patient’s perception of sleepiness. Patients with an ESS score of >10 are considered sleepy. Despite being the most widely used questionnaire for EDS assessment, the ESS has not been shown to correlate well with objective measures of sleepiness.

Neurocognitive dysfunction, such as intellectual deﬁciency, memory impairment, lack of concentration, decreased libido, mood disorders and dry mouth, are other common OSA symptoms. Morning headache has also been reported in 10–30% of OSA patients, occurring almost daily and lasting several hours aer waking. Additionally, ∼30–50% of OSA patients report having clinically signiﬁcant insomnia symptoms, mainly sleep maintenance insomnia. This phenomenon is more prominent in females.

A number of nocturnal symptoms may also be present, such as snoring, choking, witnessed apnoeas, gasping, waking with a dry mouth and nocturia (table 1). The most common symptom is snoring, which has a sensitivity of 80–90% for OSA diagnosis but a speciﬁcity of <50%. OSA severity appears to be positively correlated with snoring intensity, although not all studies replicate this association. However, the absence of snoring reduces the likelihood of OSA diagnosis, particularly where associated risk factors are absent. Taken together, disruptive snoring and witnessed apnoeas have a speciﬁcity of 94% for predicting OSA. It is usually beneﬁcial to have the patient’s bed partner or family present at the interview as they oen have greater insight than the patient into the severity and frequency of these symptoms during sleep. It is also important to note that patients sometimes report symptoms that relate to OSA-associated diseases or complications, such as chest pain due to angina pectoris or palpitations due to atrial ﬁbrillation (AF), as well as neuropsychiatric symptoms.

75ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

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Risk factors and associated conditions

Several risk factors and a variety of medical conditions, evaluated in many studies worldwide, are associated with an increased risk of OSA, with obesity and male sex being the most signiﬁcant (table 2). The prevalence of OSA increases with age; nevertheless, OSA is under-recognised in elderly patients due to the absence of typical symptoms of self-reported breathing pauses and snoring.

Physical examination

Physical examination of a patient presenting with a history that is indicative of OSA should include assessment of associated risk factors, such as BMI and waist-to-hip ratio, cardiorespiratory auscultation, BP measurement and identiﬁcation of peripheral oedema. The patient’s history may also guide focused neurological examination. Comorbidities associated with OSA should also be evaluated.

In all patients, and particularly in non-obese patients with symptoms that are compatible with OSA, it is essential to evaluate the upper airway for potential craniofacial abnormalities and to examine the nasal and oral cavities, including tonsil size, tongue size and architecture of the hard palate and faucial pillars. A simple way of quantifying airway narrowing is by using Mallampati and Friedman scoring of the oropharynx. Both oropharynx evaluation techniques predict OSA severity

Table 2. Risk factors and conditions associated with OSA

Risk factors at clinical examination

Obesity, high BMI Neck circumference of >43 cm in men and >38 cm in women Male sex Age >50 years Postmenopausal state Pregnancy/pregnancy-induced hypertension Ethnicity (African-Americans, Asian populations) Smoking and alcohol consumption Nasal obstruction Craniofacial anatomical structure (retrognathia, macroglossia, increased or modiﬁed

Mallampati score, Friedman tongue position, high-arched palate)

Neuropathy or myopathy of the upper airway (i.e. the genioglossus muscle)

Conditions associated with OSA

Hypertension (particularly resistant), ‘non-dipping’ pattern AF Stroke and transient ischaemic attacks CHF PH OHS Metabolic syndrome Type 2 diabetes mellitus Polycystic ovary syndrome Acromegaly Hypothyroidism Chronic lung disease (asthma, COPD, IPF) End-stage kidney disease Parkinson disease Down syndrome, Pierre Robin syndrome

IPF: idiopathic pulmonary ﬁbrosis.

ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

https://t.me/medicina_free

satisfactorily, with the Friedman score correlating more strongly with OSA severity than the Mallampati score. Fibreoptic nasopharyngoscopy with Mueller’s manoeuvre is an alternative method of observing pharyngeal structures. This method is widely used in upper airway evaluation ahead surgery, in order to improve patient selection and predict outcome and postoperative changes in the upper airway.

Parameters from clinical examination, as well as symptoms, demographics (sex and age) and the presence of comorbidities, have been used to develop clinical questionnaires for OSA prediction. However, there is signiﬁcant variability in the sensitivity and speciﬁcity of these OSA-screening tools. Nevertheless, these tools may assist in early identiﬁcation of high risk OSA patients and prioritisation of diagnostic testing.

The clinical phenotypes of OSA and their relationship with underlying pathophysiology

OSA is a heterogeneous disorder in terms of its pathogenesis and clinical expression. One approach to addressing this heterogeneity is to cluster symptoms and comorbidities, and to identify clinical phenotypes with distinct characteristics. The term ‘phenotype’ is dierentiated from ‘endotype’, which is a subtype of the disease deﬁned by a distinct functional or pathophysiological mechanism. Potential pathophysiological endotypes that play an important role in the pathogenesis of OSA include a narrow or collapsible upper airway (‘impaired anatomy’), impairment in pharyngeal dilator muscle control and function during sleep, increased propensity for waking during airway narrowing (low respiratory arousal threshold) and respiratory control instability (high loop gain). All of these endotypes may interact dierently according to sex, age and ethnicity.

Currently there is no agreement on how to categorise OSA into dierent phenotypes. Dierent methodologies of cluster analysis have tried to identify clearly distinct subgroups of OSA, with minimal dierences between two patients within the same phenotype and evident dierences between two patients with distinct phenotypes. Figure 1 illustrates the classiﬁcation of potential clinically relevant OSA phenotypes, based on symptom, sex, age and ethnicity, and presents their correlation with their corresponding predominant endotype.

The symptom-based phenotype

For decades, dierent presenting symptoms have been used to phenotype OSA patients. Initially, three dierent symptom-based phenotypes were subjectively reported: patients experiencing insomnia-related symptoms, relatively asymptomatic patients and excessively sleepy patients. Similar OSA symptom phenotypes appear to be associated with a varying CVD risk. Up to 60% of OSA patients present with EDS, associated with impaired concentration, mood changes and other neurocognitive diculties. EDS phenotypes also seem to be associated with the incidence of hypertension, CVD, glucose metabolism and mortality. With this in mind, it was proposed that OSA with EDS is a distinct phenotype from other OSA subtypes, with important clinical implications. However, the phenotypes of patients with minimal symptoms and insomnia also appear to be linked to adverse clinical outcomes.

The sex-speciﬁc phenotype

The lower prevalence of OSA in females may be the result of dierences in ageing, hormones, upper airway anatomy, fat distribution and respiratory stability between the sexes. Speciﬁcally, the upper airways in females are less collapsible and more

77ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

Asian

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Anatomical

Male phenotype

Anatomical

(android obesity)

Rostral ﬂuid shi

Sex-speciﬁc

Age-speciﬁc

Elderly phenotype

Low arousal threshold

Rostral ﬂuid shi

Hyporesponsive genioglossus

Anatomical

(abnormal fat distribution)

phenotype

OSA clinical

phenotypes

Sleepy

Non-speciﬁc

endotype identiﬁed

Ethnic

phenotype

Symptom-based

phenotypes

Insomnia

Non-speciﬁc

endotype identiﬁed

(abnormal craniofacial

morphology)

African-American

Anatomical

(obesity)

Caucasian

Anatomical

(both obesity and abnormal

craniofacial morphology)

Low arousal threshold

symptomatic

Non-speciﬁc

Figure 1. OSA clinical phenotypes and their corresponding predominant endotypes.

Minimally

endotype identiﬁed

stable during sleep than in males. This is due to a number of mechanisms, including sex hormones (protection is provided by female-speciﬁc hormones), a more ecient active response of the upper airways during respiratory events, dierent body fat distribution (more central in men, more peripheral in women) and lower instability of respiratory drive aer arousals. Furthermore, the pharyngeal airway is longer in males than in females. The android pattern of fat deposition around the abdomen contributes to lung volume reduction in males and increases the upper airways’ susceptibility to collapse as a result of diminished longitudinal caudal traction on the trachea.

Females are less likely to report snoring or witnessed apnoeas, but are more likely to complain of daytime fatigue, lack of energy, morning headaches, insomnia and mood disturbances. Female sex was also found to be an independent predictor of restless leg syndrome, frequent awakenings and nocturia. Females oen present a lower AHI, a lower proportion of supine AHI and a shorter respiratory event duration, with predominance during REM sleep. The relatively higher REM AHI in women is clinically signiﬁcant given the growing evidence of an association between adverse cardiovascular outcomes and REM-related OSA.

OSA has also been linked to a number of comorbidities in women, including asthma, depression and thyroid disease, and it may increase the risk of diabetes and coronary heart disease.

The dierences in OSA predisposing factors, PSG characteristics, symptom proﬁle and comorbidities for OSA between the sexes suggest that OSA in women appears to be a distinct phenotype.

Importantly, sex dierences in OSA prevalence appear to be attenuated in the postmenopausal years. During menopausal transition, the respiratory drive decreases, whereas so tissue collapsibility and arousals increase, predisposing to OSA.

ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

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The elderly phenotype

Elderly OSA patients may have vague symptoms as a result of comorbidities and lifestyle changes, whereas younger OSA patients are likely to present with behavioural and cognitive disturbances. It is well known that the severity of EDS decreases with age. Notably, with increasing age, the distribution of pathophysiological endotypes may change, and the inﬂuence of a low arousal threshold may increase, whereas loop gain decreases. Moreover, the pathogenesis of OSA in the elderly may even be more strongly inﬂuenced by a rostral volume shi from the lower body extremities to the upper airways. These ﬁndings support the speculation that OSA in the elderly is a distinct physiological phenotype.

The ethnic phenotype

OSA phenotypes vary according to ethnicity. This can be partly explained by dierences in adiposity, particularly upper body fat distribution, craniofacial anatomy and respiratory arousal threshold. More speciﬁcally, Caucasians are usually more obese compared to Asians who exhibit more craniofacial restriction. Furthermore, despite having less severe anatomical compromise, Caucasians exhibit signs of a lower respiratory threshold, which is not typically the case in Asian patients. Obesity and enlarged upper airway so tissues, as well as exposure to unfavourable social and physical environments, may also predispose African-Americans to OSA. Interestingly, symptom proﬁle, including sleepiness and snoring, seems to vary according to ethnicity, with African-Americans more likely to report EDS than any other ethnic group.

Multiple-feature phenotypes

Although the above clinical phenotypes may serve as an intermediate step towards personalised medicine in OSA, more complex phenotypes have been identiﬁed, which combine anatomic characteristics, symptoms, polysomnographic indices and comorbidities. This approach has been applied to numerous single and multinational datasets, with identiﬁable phenotypes comprising of three or more distinct subtypes, based on the dierent selections and combinations of variables included in the clustering analysis. The most commonly used combination is comorbidities and symptoms.

As well as dierent clinical presentations, varying cardiovascular outcomes and levels of treatment adherence have been noted. Generally, it should be kept in mind that such dierences could not be found in the typical classiﬁcation of OSA based on AHI severity scores.

Clinical phenotypes may facilitate the early identiﬁcation of OSA and lead to the development of personalised therapies.

Consequences

Evidence supports a causal association between OSA and the development of several adverse outcomes, which may lead to impaired quality of life and increased mortality over time. However, these adverse eects extend beyond the margin of a patient’s quality of life and may have an impact on family environment, professional performance, healthcare costs and the community as a whole.

Neurobehavioural: sleepiness, cognitive and psychiatric

Recent studies have conﬁrmed that OSA is associated with a deﬁcit in multiple cognitive domains, including vigilance and attention, visuospatial abilities, executive function and some components of memory. Intermittent hypoxia, oxidative stress

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and alterations in sleep architecture that are associated with OSA may predispose to small vessel disease, micro-infarction, stroke and changes in the brain’s white and grey matter. EDS in an OSA patient can manifest as irritability or mood swings, which can harm a couple’s relationship and inﬂuence their quality of life.

OSA is a well-recognised risk factor for work accidents, especially accidents that relate to occupational driving. This association has signiﬁcant implications for public safety, as accidents involving patients with OSA are more likely to result in serious injuries. It is important to note that both the severity of subjective sleepiness and the actual objective OSA severity increase the likelihood of driving risk.

A prevalence of depressive and anxiety symptoms is also frequently seen in OSA patients. Numerous studies have shown that patients in whom OSA coexists with severe depression have the lowest quality of life and suer the most from EDS and fatigue. Potential factors that underlie depressive symptoms in OSA are sleep fragmentation and oxygen desaturation. Importantly, OSA may eventually lead to treatment-resistant depression and therefore, clinicians should have a high clinical suspicion in these patients for OSA.

CVD

Although the cardiovascular consequences of OSA were recognised early on, there are still uncertainties and controversial ﬁndings in this ﬁeld, particularly regarding the eect of OSA treatment on cardiovascular outcome.

Systemic hypertension

There is consistent epidemiological evidence that OSA and systemic arterial hypertension are strongly connected, with the prevalence of arterial hypertension in OSA patients ranging 35–80%. Several potential mechanisms support this relationship, including hypoxaemia, increased sympathetic/decreased parasympathetic tone, nocturnal rostral ﬂuid shi, impaired renin-angiotensin-aldosterone system (RAAS) and poor sleep quality (ﬁgure 2). The nocturnal BP dip observed in healthy subjects is oen absent in OSA patients, probably due to an increase in nocturnal sympathetic activity, which can extend to the daytime. However, this pattern may be associated with le ventricular systolic dysfunction and poor prognosis.

Sleep fragmentation

Sympathetic activity

Parasympathetic

activity

Angiotensin II release

Aldosterone production

Figure 2. Pathophysiological mechanisms of the cardiovascular eects of OSA.

OSA

Arousals Intermittent hypoxia

Oxidative stress Inﬂammation Endothelial dysfunction Prothrombotic state

Hypertension (systemic-pulmonary) Atherosclerosis – myocardial ischaemia Cardiac arrhythmias Cerebrovascular disease stroke Le ventricular hypertrophy and HF

Negative

intrathoracic pressure

Pulmonary

capillary ﬂuid

ERS Handbook: Respiratory Sleep Medicine

Le heart

ﬁlling pressures

Obstructive sleep apnoea

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OSA has also been linked to a higher risk of developing resistant hypertension. Given that patients with OSA and resistant hypertension represent a distinct high-risk phenotype for experiencing a cardiovascular event, more aggressive screening for OSA is recommended in these patients.

Not all studies conﬁrm the causal role of OSA on hypertension development, aer accounting for confounders, such as BMI. However, these results must be interpreted with caution due to the heterogeneity of the populations studied and the dierent diagnostic methods used for OSA diagnosis.

Many questions remain unanswered about the relationship between OSA and hypertension, both from a pathophysiological perspective, and with regard to the eect of OSA treatment on BP.

Coronary artery disease

OSA has been linked to development of atherosclerosis and coronary artery disease (CAD). OSA is also considered a risk factor for a worse outcome in patients with established CAD. The pathophysiological mechanisms involved include increased sympathetic nervous system activity, oxidative stress, and poorly controlled or resistant hypertension, endothelial dysfunction and promotion of a procoagulable state. Subclinical markers of atherosclerosis such as coronary artery calciﬁcation and increased concentrations of high-sensitivity troponin-I have also been associated with increasing OSA severity, potentially contributing to low-grade myocardial injury.

Cardioprotective eects of OSA have also been shown, as recurrent nocturnal oxygen desaturations might support the formation of coronary collaterals, which may help to attenuate the myocardial damage in the context of myocardial infarction.

Randomised trials have failed to show a clear beneﬁt of OSA treatment on cardiovascular death, myocardial infarction, stroke or transient ischaemic attack.

Stroke

There is an association between OSA and cerebrovascular events during the night, with a dose–eect relationship with OSA severity. Importantly, the Sleep Heart Health Study demonstrated that the relationship of OSA with stroke was stronger than other CVDs. The coexistence of OSA and stroke is associated with poorer recovery from stroke, reduced quality of life, cognitive dysfunction and longer hospitalisation.

Arrhythmias

Patients with severe OSA have a two- to four-fold increased risk of arrhythmias. AF, the most common cardiac arrhythmia, has been strongly associated with OSA, independently of obesity and other confounding factors. Furthermore, OSA has been correlated with the risk of AF recurrence aer cardioversion or ablation.

As well as AF, OSA has been associated with other arrhythmias, such as bradycardia, atrioventricular block and asystole, premature ventricular contractions, ventricular tachycardia or ﬁbrillation, and sick sinus syndrome. Potential direct mechanisms linking OSA and arrhythmias are changes in sympathetic and parasympathetic tone, intermittent hypoxia, large shis in intrathoracic pressure that lead to atrial stretch, systemic inﬂammation and oxidative stress, hypercapnia and an enhanced prothrombotic state that may contribute to cardiac structural and electrical remodelling. Indirect mechanisms include the development of CVDs, such as hypertension and CAD, which alter the structure of the heart and form the underlying substrate for arrhythmiogenesis.

81ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

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OSA itself appears to contribute considerably to the development and progression of HF, especially in men. Additionally, in both HF with reduced ejection fraction and HF with preserved ejection fraction, OSA is more prevalent than in the general population. Although OSA patients with HF usually report less subjective daytime sleepiness, the excessively sleepy OSA phenotype was found to be associated with an increased risk incident HF. OSA can, in many ways, promote the development of HF. During apnoeas there is increased inspiratory eort against the high upper airway, increasing the arousals and, along with intermittent hypoxia and sympathetic activation, promoting oxidative stress. High negative intrathoracic pressure during a respiratory event may increase pulmonary capillary ﬂuid contributing in interstitial oedema. Increased sympathetic activity increases angiotensin II release, which promotes aldosterone production, further worsening hypertension and HF (ﬁgure 2).

Pulmonary hypertension and thromboembolism

Pulmonary hypertension (PH) and OSA are closely associated, and OSA may contribute to PH pathophysiology. PH is a concerning OSA complication that is thought to aect ∼20% of OSA patients. Potential factors that are implicated include: alveolar hypoxia, leading to pulmonary vasoconstriction and endothelial remodelling; increased inspiratory eort, leading to more negative intrathoracic pressure; increased le heart ﬁlling pressures; and variations in cardiac output and heart rate. Patients with coexistent OSA and PH tend to have a worse cardiovascular outcome.

There is growing evidence that OSA is also a risk factor for acute pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Data from pathophysiological studies suggest that the OSA-induced pro-inﬂammatory state combined with intermittent hypoxia is linked to blood hypercoagulability, venous stasis and endothelial dysfunction, leading to DVT and PE.

Cancer

Studies in both animals and humans have found an association between OSA and cancer. Hypoxia plays an important role in regulating various stages of tumour formation and progression, and intermittent hypoxia seems to trigger transcriptional responses in a dierent way to continuous hypoxia. According to epidemiological studies, OSA may inﬂuence each type of cancer dierently, with the eects of age and sex remaining controversial.

Type 2 diabetes and metabolic syndrome

OSA has been independently associated with an increased risk of insulin resistance as well as type 2 diabetes and diabetes complications. The complex relationship between OSA and type 2 diabetes may be mediated by the eect of intermittent hypoxia, repeated arousals, altered sleep architecture, as well as with resulting increases in sympathetic activation and activation of the hypothalamic-adrenal axis on insulin resistance and β-cell function.

Growing evidence suggests that there is a signiﬁcant association between OSA and metabolic syndrome, independently of BMI. Nocturnal intermittent hypoxia, one of the pathogenic mechanisms in OSA, has been found to play a potential role in this association.

ERS Handbook: Respiratory Sleep Medicine

Obstructive sleep apnoea

https://t.me/medicina_free