Obstructive sleep apnoea–hypopnoea syndrome

Obstructive sleep apnoea–hypopnoea syndrome (OSAHS) is a common chronic disorder affecting ∼10–20% of the adult population in high-income countries [1]. Risk factors include obesity, male sex, older age, menopause, fluid retention, adenotonsillar hypertrophy and smoking [2]. This paper focusses solely on adult OSAHS; however, it should be noted that OSAHS can also manifest in children.

The condition is characterised by repetitive episodes of the complete or partial collapse of the pharyngeal airway during sleep, with a consequent cessation (apnoea) or reduction (hypopnoea) of airflow. Obstructive sleep apnoea (OSA) describes the process of repetitive apnoeas. OSAHS is the condition in which these apnoeas manifest as excessive daytime sleepiness. Disturbances in air flow lead to oxygen desaturation and sleep fragmentation, which contribute to the cardiovascular, metabolic and neurocognitive consequences of OSA [3].

OSAHS pathophysiology includes anatomical narrowing of the upper airways, impairment of muscle responsiveness, low arousal threshold and unstable respiratory drive which all contribute to the upper airway collapse that is the hallmark of the disease [4].

The prevalence of OSAHS is >50% in some countries with almost 1 billion people affected worldwide [5]. Prevalence has been increasing in recent decades due to an ageing population [6,7]. Data suggest that 85% of individuals with OSAHS in the U.K. are undiagnosed [8].

There is a greater prevalence of OSAHS in men, with a 2 : 1 male-to-female ratio [9,10]. There are several factors which may explain this gender difference. Androgens stimulate the collapse of the upper airway, whereas progesterone is believed to have a protective effect, which, in turn, is also likely to explain why the prevalence amongst women increases after menopause [11].

There are anatomical differences in the upper airway between men and women, for example, men have a longer pharyngeal airway length [12]. Gender differences in the comorbidity of depression and in various socioeconomic factors such as income and education level may also impact gender prevalence estimates [13].

An individual's disposition to develop OSAHS depends upon the collapsibility of a segment of the upper airway [14]. The upper airway is predominantly soft tissue without bony structures and is, therefore, collapsible, particularly in the region between the hard palate and the larynx. Obstruction is most often located at the retro-palatal and retro-glossal levels [15].

The degree of collapsibility can be quantified by the balance between occluding or extraluminal pressures of the surrounding tissues versus the dilating positive intraluminal pressure (Figure 1) [2]. The extraluminal pressure increases in patients with skeletal malformations, fat deposition or fluid accumulation in the soft tissue [2]. This load is counterbalanced by dilating upper airway muscles. When awake, the pharynx remains patent due to compensatory neuronal activation of dilator muscles [15]. In all individuals, sleep onset results in decreased upper airway muscle activity, leading in healthy individuals, to small, clinically non-relevant narrowing of the diameter of the airways [16]. In patients with factors lending a greater risk of airway collapse, decreased upper airway muscle activity results in upper airway collapse, causing an apnoea or hypopnoea [3,15].

Multiple patient characteristics place individuals at an increased risk of OSAHS. These include factors which increase occlusive forces, commonly obesity and factors which reduce dilating forces, such as conditions that impair muscular function. Although many patients have anatomic reasons for the development of OSAHS, abnormalities in non-anatomic traits are also present in most patients with OSAHS [4].

Important risk factors contributing to OSAHS include age ≥35 years, BMI ≥ 25 kg/m², alcohol consumption, male sex, post-menopausal state and smoking [17]. There is a higher prevalence of OSAHS in people with certain conditions such as treatment-resistant hypertension, type 2 diabetes, cardiac arrhythmia and stroke [18].

Upper airway collapsibility can be most reliably quantified using the pharyngeal critical closing pressure (Pcrit). This is defined as the level of nasal (upstream) pressure at which the upper airway collapses. The flow is dependent on the upstream (nasal) pressure, the downstream (tracheal) pressure and the pressure of the collapsible segment [19].

Whenever the intraluminal pressures of the upstream nasal segment and downstream tracheal segments exceed the pressure of the collapsible segment, the flow through the airways is unrestricted. However, if the surrounding pressure of the collapsible segment exceeds these pressures, a limitation or cessation of the flow through the upper airway results [20]. Hence, Pcrit is the theoretical value at which there is no ventilation and is the value at which the upper airway collapses [19]. A more positive value represents a higher propensity for collapse [19,20].

The shape of the upper airways influences the upper airway resistance and inspiratory flow. These differences are exacerbated in the presence of factors increasing pressures in the surrounding soft tissues, such as hyoid bone position and fat deposition in obesity [21].

Various skeletal malformations exist that increase the risk of OSAHS. These include brevity or verticalization of the mandible and enlargement of the pharyngeal walls and the tonsils, uvula or tongue. The size of the tongue and the lateral pharyngeal walls are independent risk factors for OSAHS [22]. An inferiorly placed hyoid bone and reduced pharyngeal airway space can both contribute to the presence of OSAHS [21]. Nasal obstruction, for example, in those with chronic rhinitis, can contribute to an increased risk of OSAHS [23].

Several syndromes in which skeletal malformations occur may also be associated with OSAHS. For example, mandibular hypoplasia, such as in Pierre-Robin syndrome, and maxillary hypoplasia in Down syndrome, where there are several overlapping risk factors in addition to the craniofacial differences [24]. In addition, any structural features which can result in increased external pressure to the airway can induce collapse, such as goitre associated with thyroid disorders.

Obesity is associated with the accumulation of fat in the soft tissue of the upper airways, which increases the pressure in the soft tissues surrounding the airway [25]. In OSAHS obesity is the most common anatomical risk factor present, in the development of upper airway obstruction [4,26].

Variation in the volume of the soft tissues surrounding the airway also contributes to the pathophysiology of upper airway obstruction. Fluid shifts in the upper airway tissues occur with the change of position, for example, with the redistribution of fluid from the lower to the upper body upon lying flat [2]. A significant increase in the neck circumference during the night has been correlated with the apnoea–hypopnoea index (AHI) and supports the theory of a fluid shift being relevant to the pathophysiology of OSAHS [27]. Conditions which predispose patients to fluid accumulation, such as congestive cardiac failure and end-stage renal failure, can, therefore, increase the risk of OSAHS [28,29].

Upper airway dilator muscles work to maintain airway patency by responding to changes in ventilation and work to oppose the obstructive forces described above [14,16]. The degree of upper airway obstruction may vary within a single night and with the sleeping position. In patients with increased mechanical load in the upper airway, muscle activity is increased during wakefulness. Individuals with OSA are known to have higher activity of the airway dilator muscles [30].

The upper airway muscles are comprised of the pharyngeal muscles including the geniohyoid muscles and the genioglossus, the latter of which is the largest and most extensively investigated [16]. Innervation is partly derived from the brainstem and the respiratory pattern generator neurones [26]. Nervous supply to upper airway dilator muscles is important both for muscular function, but also sensory characteristics. Negative pressure within the upper airways stimulates a reflexive contraction of the upper airway muscles and ensures stabilisation of the pharyngeal diameter. Nguyen et al. [31] found sensory impairment of this reflex in patients with OSAHS, and an increased threshold for the laryngeal adductor reflex in OSAHS was associated with an increasing severity of OSAHS.

Upon sleep onset, the upper airway dilator muscles have been demonstrated to have reduced activity [32], leading, in healthy people, to small, clinically non-relevant narrowing of the diameter of the airways. Each stage from wakefulness to non-REM (NREM) to rapid eye movement (REM) sleep results in progressively reduced upper airway dilator activity [15]. Local reflex mechanisms, such as mechanical irritation, also influence the muscle tone. However, for a third of individuals with OSAHS, these compensatory mechanisms do not result in increased muscle activity, resulting in upper airway obstruction [4].

Patients with OSAHS are also more likely to have muscle atrophy abnormalities compared with controls, which was found in studies to be correlated with the severity of respiratory disturbances [33]. Stål et al. [34]. also found capillary density reduction in the upper airway muscles of patients with OSAHS, in addition to reduced mitochondria numbers in both patients with OSAHS and snorers.

Airway collapse and the resultant lack of or reduction in airflow (apnoea and/or hypopnoea) results in hypoxia and hypercapnia. This is identified by chemoreceptors and leads to activation of upper airway motor neurones and phrenic motor neurones, leading to increased ventilatory effort and arousal from sleep [35]. It can also lead to excretion of stress hormones. Restoration of the upper airway muscle activity de-occludes the airway and restores airflow, reducing carbon dioxide levels and increasing oxygen levels [15]. The patient then returns to sleep and the cycle repeats. However, not all respiratory events leading to a reduction in airflow require arousal to restore normal airflow; arousals are likely to increase the severity of the disorder by promoting greater ventilatory instability [36].

Re-opening of the upper airways after an apnoea or hypopnoea is characteristically associated with an extensive increase in ventilation, even above the baseline level of stable respiration [14,37]. This hyperventilation can be associated with arousal, or not. It is thought that respiratory drive continuously increases during the obstructive event due to hypoxia, hypercapnia and upper airway resistive load. The combination of these factors is thought to increase respiratory drive during obstructive events [38]. The longer the event takes, the higher the increases in respiratory drive and the higher the overshoot of ventilation at the opening of the upper airways. High overshoot of ventilation after reopening reduces CO₂ which dampens ventilation and muscle activity [39].

Loop gain is the individual response of the ventilatory system to changes in the CO₂ level and is understood to be a key contributor to the pathophysiology of OSAHS [4,14]. It quantifies the sensitivity of the negative feedback system controlling ventilation and is the reaction of the upper airway tone and respiratory effort to insufficient ventilation. Loop gain is defined as the size of a corrective ventilator response divided by the size of the ventilatory disturbance that elicits the correction [26]. A large response to a small disturbance represents a system with a high loop gain, which indicates an unstable system prone to ventilator oscillation. This is particularly important in those individuals with a lower propensity for upper airway collapse, compared with those with near inevitable upper airway collapse [4]. Low loop gain indicates a stable ventilator control system [40].

Upper airway obstruction events are usually terminated by a cortical arousal leading to the opening of the closed airway and resumption of ventilation [26]. The arousal from sleep is followed by rapid activation of inspiratory motor neurones causing a hyperventilation which can reduce CO₂ levels to below the threshold that is necessary to generate respiratory drive during sleep. This can result in a central apnoea and may also reduce the upper airway dilator activity, predisposing to the subsequent upper airway collapse. Consequently, arousals are important to reopen the airway, but can also destabilise ventilatory control and cause repetitive apnoea in these patients.

Arousal threshold, the propensity of the brain to arouse from sleep, is important in the development of OSAHS. High arousability means the individual will only awake at very low negative intrathoracic pressures or high levels of respiratory drive; low arousability is the converse. This mechanism shortens the obstructive event and thus reduces the ventilatory overshoot [26]. It minimises insufficient ventilation and therefore minimises CO₂ accumulation. However, low arouseability, can impede deep sleep, destabilise ventilation and is present in over a third of patients with OSAHS [25].

Symptoms of OSAHS include snoring, unrefreshing sleep, witnessed apnoeas, waking with a choking sensation and excessive sleepiness [41]. Other common symptoms include non-restorative sleep, difficulty initiating or maintaining sleep, fatigue or tiredness and morning headaches [42]. However, many patients do not report excessive daytime sleepiness or fatigue, with some patients reporting only minimal symptoms [43–45].

The STOP-BANG questionnaire, designed to predict OSAHS risk, is a screening tool which has been validated for use in various settings, including in the sleep clinic [45,46]. It involves four symptoms and signs (snoring, tiredness, observed apnoea, hypertension) and four demographic questions (body mass index, age, neck circumference, gender) [47]. The Epworth Sleepiness Scale (ESS) is a validated scoring system to evaluate subjective sleepiness; comprising of a series of scenarios, patient rating their likelihood of falling asleep [48]. Although ESS is validated as a measure of excessive daytime sleepiness, it correlates poorly with the severity of OSAHS and is open to reporting bias [45,49–52].

The diagnosis of OSAHS should be confirmed with a sleep study. Polysomnography (PSG) is the reference-standard diagnostic tool for OSAHS, however, is complex, time consuming and is typically completed in-hospital [53,54]. A randomised control examining the efficacy of PSG compared with home cardio-respiratory polygraphy demonstrated non-inferiority of home cardio-respiratory polygraphy testing [55]. In the U.K., the usual practice is for home cardio-respiratory polygraphy in the first instance, or consideration of home oximetry in centres where there is limited access to home cardio-respiratory polygraphy [18]. Cardio-respiratory polygraphy involves concurrent monitoring of both sleep and respiration without neurophysiologic recordings. The respiratory recordings assess respiratory effort measurement, for example, thorax and abdomen respiratory inductance plethysmography bands, nasal pressure and thermal airflow monitoring and transcutaneous arterial oxygen saturation. Body position is monitored due to the position-specific nature of OSAHS in many patients, Heart rate and snoring can also be monitored. In-hospital cardio-respiratory polygraphy may also include electrocardiograph and electromyography of the anterior tibialis to assess limb movements [3]. PSG is used if respiratory polygraphy is negative, but symptoms continue [18]. Home respiratory polygraphy is more cost effective than inpatient respiratory polygraphy and home oximetry [18].

The primary sleep study outcome measure is the AHI (the number of apnoeas plus hypopnoeas per hour of sleep). American Academy of Sleep Medicine diagnostic criteria define a diagnosis of OSAHS if a respiratory polygraphy demonstrates >15 predominantly obstructive respiratory events per hour of sleep; or >5 predominantly obstructive respiratory events per hour of sleep with associated symptoms of sleepiness, choking, snoring or secondary features such as hypertension or atrial fibrillation [54]. OSAHS severity is graded via the AHI; an AHI of <5 events per hour is considered normal; 5–14 events per hour is considered mild OSAHS; 15–29 events per hour moderate OSAHS and 30 or more events per hour is defined as severe OSAHS [18].

Some centres perform oximetry as the initial screening test for OSAHS. The oxygen desaturation index (ODI) may be a stronger and more reliable predictor of adverse cardiovascular outcomes than the AHI [44] and is easier to measure. Furthermore, the ODI and other variables of oxygen desaturation, such as the cumulative time spent below oxygen saturation levels such as 90% (CT90), minimal oxygen saturation, and mean oxygen desaturation also provide important clinical information to better address disease severity and risk of comorbidity in patients with comparable AHI [56]. However, pulse oximetry has significant rates of both false negatives and false positives, and cannot reliably distinguish between obstructive and central apnoeas, therefore, some centres prefer not to use this as a diagnostic modality [57].

OSAHS, particularly when unmanaged, has significant health and relationship consequences for the individual, in addition to societal, financial and healthcare implications. Bed partners of patients living with OSAHS often report a lower quality of life than the patient and experience an impact on their physical and mental health [58,59]. Patients with OSAHS are at greater risk of death from any cause [60]. It is associated with many conditions, and due to shared risk factors, there is a clustering of some comorbidities in patients with high-risk profiles, such as those with physical inactivity, obesity and tobacco smoking. Chronic obstructive pulmonary disease (COPD) and its relationship with OSAHS-termed COPD–OSAHS overlap syndrome are being increasingly referenced [61].

OSAHS alters sleep architecture by accelerating the decay of non-REM and REM sleep phases, reflecting sleep fragmentation [62]. Sleep fragmentation, chronic intermittent hypoxia and fluctuations in intrathoracic pressure are features of OSAHS. They promote cellular and molecular mechanisms such as sympathetic nervous system activation, oxidative stress and systemic inflammation [42]. These processes then trigger metabolic and endothelial dysfunction, including atherosclerosis and elevated arterial stiffness which results in OSA-related cardio-metabolic comorbidities [63–65].

Newer evidence is emerging that OSAHS impacts upon glymphatic system function, a clearance system which rids the brain of metabolic wastes such as beta-amyloid and phosphorylated tau. The impairment in this function contributes to an increased risk of Alzheimer's disease, with the increased burden of beta-amyloid more pronounced in groups with moderate and severe OSAHS. Studies have suggested that OSAHS treatments which reduce the severity of OSAHS could relieve beta-amyloid and phosphorylated tau burden and delay progression to mild cognitive impairment or dementia [66,67].

OSAHS commonly coexists with other sleep conditions such as restless legs, insomnia and parasomnias. Management of coexistent OSAHS is an important component of managing these sleep conditions. OSAHS coexistent with insomnia is known as COMISA (co-morbid insomnia and sleep apnoea) [68]. The conditions interact to amplify an overall greater illness severity: COMISA is associated with higher rates of hypertension and cardiovascular disease (CVD), and increased risk of all-cause mortality compared with no insomnia or OSAHS [69,70]. Furthermore, insomnia can impact upon an individual's ability to tolerate OSAHS treatments. Emerging evidence has demonstrated cognitive behavioural therapy for insomnia to be effective in the presence of comorbid OSA, to improve the use of continuous positive airway pressure (CPAP) therapy in COMISA and to lead to improvements to AHI [71–73].

Patients with OSAHS have an increased risk of CVD comorbidities and of worse CVD outcomes [7]. Patients with OSAHS are more likely to have atrial fibrillation and heart failure, and are three times more likely to be hypertensive [74]. OSAHS is also an independent risk factor for stroke, stroke recurrence, mortality, and poor functional and cognitive outcomes [7].

Patients with OSAHS have high vascular sympathetic tone which results in elevated systemic resistance and therefore elevated blood pressure (BP). Hypertension in OSAHS is primarily nocturnal and diastolic, with a high proportion of refractory hypertension [65]. Increased sympathetic outflow to the kidney stimulates renin release leading to renin-angiotensin-aldosterone system activation and increases the risk of renal disease [75]. The fluid overload of patients with chronic renal disease plays a role in the pathogenesis of OSAHS as described above; fluid removal by ultrafiltration leads to marked improvements in sleep apnoea severity [28,29]. Arterial stiffness is a predictor of late cardiovascular events and is associated with an increased risk of stroke; data suggest arterial stiffness in OSAHS is related to comorbidities rather than hypoxic burden or OSA severity however [76].

OSAHS has an independent association with the different components of metabolic syndromes, particularly visceral obesity, hypertension, insulin resistance and abnormal lipid metabolism [15,77]. Multiple pathways contribute to the unbalanced plasma glucose and insulin homeostasis found in individuals with OSAHS which increases the risk of the development of diabetes [77,78]. Furthermore, diabetic-related neuropathy is thought to affect the collapsibility of the upper airway by impairing pharyngeal sensitivity and the protective pharyngeal reflexes [78,79]. Intermittent hypoxia leads to increased serum cholesterol and phospholipid levels and inhibition of triglyceride uptake by the liver [15,77]. Hypoxia is also associated with lipoprotein lipase inhibition in adipose tissue which could favour the progression of atherosclerosis. Insulin resistance and dyslipidaemia are key factors in the occurrence and progression of non-alcoholic fatty liver disease [80].

All patients with OSAHS, regardless of severity, should be counselled on lifestyle modification, including weight loss, smoking cessation, sleep hygiene and alcohol reduction [18].

Patients may require CPAP therapy [18,35,81]. This therapy provides positive pressure to splint open a patient's airway, limiting hypopnoea and apnoea. This can be considered for patients with mild OSAHS who have symptoms that affect their quality of life or daytime activities and have a relevant comorbidity such as unstable CVD or pregnancy, or have an occupation where vigilance is critical for safety or is a vocational driver [18]. Individuals with moderate or severe OSAHS are recommended to use CPAP [18]. Long-term observational studies have reported a lower mortality rate in OSAHS patients treated with CPAP compared with those refusing or with poor adherence to CPAP. Historically, CPAP usage of 4 h per night represented adherence, however, a dose dependence has been subsequently shown and patients are encouraged to wear the device for as many hours as they sleep [35,82]. CPAP adherence of above 5.5 h per night is required to obtain the greatest BP reduction. CPAP can significantly reduce snoring and daytime sleepiness and improve health-related quality of life and mood [35]. Randomised control trials have not demonstrated a cardiovascular benefit of CPAP over standard care; however, many of these studies have not been completed in real-world cohorts with excessive sleepiness, and adherence in trials has been low [83].

Whilst CPAP is the most researched and evidenced treatment, alternatives exist. This includes mandibular advancement devices, which are intra-oral devices designed to bring the lower jaw and tongue forward in sleep, to increase the pharyngeal airway diameter and thereby reduce the risk of apnoeas and hypopneas. European and U.K. guidelines advocate their first-line use in patients with symptomatic mild OSAHS or as an alternative for patients who have been unable to tolerate CPAP [18,81]. Whilst there is a growing evidence base for their use, mandibular advancement devices (MADs) currently achieve an inferior reduction in AHI compared with CPAP use [81]; however, there is also evidence supporting greater patient adherence resulting in greater hours of use compared with CPAP [84].

Positional modifiers are devices that can treat positional OSAHS by reducing time spent sleeping in the supine position. Various devices exist, all with the goal of dissuading the individual to sleep supine. Positional modifiers do not seem to have detrimental effects on sleep quality nor is there evidence of adverse effects; however, evidence is limited, and their use is advised only in those who have mild-moderate position-dependent OSA [81,84]. Novel treatments such as radiofrequency ablation and hypoglossal nerve stimulation have more limited referral criteria, more limited access and a smaller evidence base at the current time [81]. Hypoglossal nerve stimulators (HNSs), which provide upper airway stimulation, have been trialled with improvements in sleepiness and quality of life [85,86]. HNS aims to decrease upper airway collapsibility by stimulating the genioglossus muscle [86]. Both U.K. and European guidelines currently only recommend this avenue of treatment for those individuals with moderate to severe OSA who are unable to tolerate CPAP therapy [81,87].

Some patients require expediting through services, such as those who are pregnant or are occupational drivers — there is a requirement for patients to inform the DVLA of their diagnosis if they have at least moderately severe OSAHS and excessive sleepiness, having, or likely to have, an adverse effect on driving [18].

Some surgical treatments, such as tonsillectomy or bariatric surgery, may augment OSAHS therapy [81]. Coexistent conditions should also be managed effectively, to limit the organ-damaging sequelae [7] and to decrease healthcare costs [88]. Meta-analyses have demonstrated significant positive health impacts following effective treatment of OSAHS, for example, decreases in BP [89], improvements in cardiac dysfunction [90], and reductions in fatal and non-fatal cardiovascular outcomes [91].

• OSAHS is an increasingly common condition and is a significant cause of morbidity, contributing to mortality.

• The pathophysiology includes narrowing of the upper airway, impairment of muscle responsiveness, a low arousal threshold and an unstable respiratory drive, all of which result in repetitive episodes of reduction/cessation in airflow, oxygen desaturation and sleep fragmentation.

• OSAHS is diagnosed on sleep studies, which also helps to grade the severity of the condition.

• Management includes lifestyle measures, in particular weight loss, and strategies to maintain upper airway patency overnight, including CPAP, mandibular advancement devices and positional modifiers.

The authors declare that there are no competing interests associated with the manuscript.

AHI

apnoea–hypopnoea index

BP

blood pressure

COMISA

co-morbid insomnia and sleep apnoea

CPAP

continuous positive airway pressure

CVD

cardiovascular disease

HNS

hypoglossal nerve stimulators

ODI

oxygen desaturation index

OSA

obstructive sleep apnoea

OSAHS

obstructive sleep apnoea–hypopnoea syndrome

PSG

polysomnography