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- v.14(2); Apr-Jun 2021
A comprehensive review of obstructive sleep apnea
Anna abbasi.
1 Maimonides Medical Center, Medicine - Brooklyn - NY - United States.
Sushilkumar Satish Gupta
2 Maimonides Medical Center, Pulmonary and Critical Care Medicine - Brooklyn - NY - United States.
Nitin Sabharwal
Vineet meghrajani, shaurya sharma, stephan kamholz, yizhak kupfer.
Obstructive sleep apnea (OSA) is a complex disorder characterized by collapse of the upper airway during sleep. Downstream effects involve the cardiovascular, pulmonary, and neurocognitive systems. OSA is more prevalent in men than women. Clinical symptoms suggest the diagnosis of OSA but none is pathognomonic of the condition. With rising awareness of OSA and the increasing prevalence of obesity, OSA is increasingly recognized as a major contributor to cardiovascular morbidity including systemic and pulmonary arterial hypertension, heart failure, acute coronary syndromes, atrial fibrillation, and other arrhythmias. Pulmonary manifestations include the development of chronic thromboembolic disease, which can then lead to chronic thromboembolic pulmonary hypertension (CTEPH). Neurocognitive morbidities include stroke and neurobehavioral disorders. Screening for OSA includes the use of symptom questionnaires and the diagnosis is confirmed by polysomnography. Management primarily includes the use of continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) devices during sleep. Alternate options such as mandibular devices and surgical procedures are considered for certain patient populations.
INTRODUCTION
Obstructive sleep apnea (OSA) is a disorder caused by upper airway obstruction (which can be partial or complete) during sleep 1 . The change in airway muscle tone during sleep leads to collapse of the upper airways (predominantly during the inspiratory phase of breathing), which leads to intermittent episodes of hypopnea and/or apnea 2 , 3 . During these episodes the arterial oxygen saturation falls, which can lead to autonomic dysregulation 3 . These acute changes result over time in chronic conditions that affect the cardiovascular, pulmonary, and neurocognitive systems 2 , 3 . In 1956, Bickelmann et al. 4 described obesity hypoventilation syndrome (OHS) in a report regarding an obese business executive who presented to the hospital complaining of excessive daytime sleepiness. These investigators attributed the name “Pickwickian syndrome” to the condition based on the description of a similar fictional character in Charles Dickens’ first novel (1836-37) “The posthumous papers of the Pickwick Club” 4 . Following that, numerous descriptions of the obesity hypoventilation syndrome, central sleep apnea and obstructive sleep apnea were published under the rubric of sleep- disordered breathing (SDB).
Currently, obstructive sleep apnea (OSA) is the most prevalent, clinically significant SDB, and it is known to be associated with numerous diseases including hypertension, atrial fibrillation, heart failure, cerebrovascular accidents, pulmonary hypertension and others 2 , 5 , 6 . The goal of this article is to compile and therefore understand the impact OSA has on other organ systems.
Prevalence and risk factors
OSA is more prevalent in men than women 1 , 2 . Benjafield et al. 7 performed an extensive review to gauge the worldwide prevalence of this disease, which consisted of reliable prevalence data from 16 countries including Brazil, Germany, Spain, China, Switzerland, and USA. The worldwide prevalence of OSA was extrapolated from this data and showed that about 1 billion people aged 30-65 years are affected by OSA, 425 million of those deemed to have moderate to severe OSA 7 . The prevalence of SDB among 30-49-year-old men in North America is 10% compared to 3% among women in the same age bracket, and 17% among 50-70-year-old men, compared to 9% among women in the same age bracket 3 .
Numerous risk factors are associated with OSA that can be detected on physical examination.
- Obesity and high body mass index are the strongest risk factors predisposing OSA. There is a linear correlation between OSA and obesity 1 , 6 ;
- Neck circumference greater than 17 inches (43cm) in men and 15 inches (38cm) in women 8 ;
- Male gender 1 ;
- Age more than 50 years 1 , 2 ;
- Other risk factors include menopause, neuropathy or myopathy that may affect the upper airway muscles (particularly the genioglossus muscle), craniofacial anatomical structure (particularly in the Asian population), family history, smoking, and nasal congestion 2 , 5 , 8 .
- Patients with acromegaly may have OSA due to macroglossia and they develop central sleep apnea due to altered respiratory control 9 .
Clinical symptoms
Clinical symptoms play a key role in identifying patients with OSA but none is pathognomonic of the disease.
Patients usually complain of fatigue, excessive daytime sleepiness, snoring, drooling, nocturnal gasping or choking, headaches and/or falling asleep while driving 10 . Patients with OSA are more likely to be involved in motor vehicle collisions 10 .
The purpose of this article is to review the prevalence, risk factors, clinical presentation, effects of OSA on different organ systems, diagnostic criteria, and to discuss current approaches to the management of patients with OSA.
OSA & cardiovascular disease
OSA is well recognized as a major contributor of cardiovascular disease. Previous studies have not definitively identified the direct link between OSA and cardiovascular disease, since patients with OSA often have other risk factors for cardiovascular disease such as hypertension (HTN), obesity, diabetes, and smoking. Theoretical explanations of the association of OSA and cardiovascular disease include the observations that OSA produces a chronic inflammatory state, which leads to increased atherosclerotic changes in the blood vessels of the patient.
Similar to obesity, which is also considered a low-grade inflammatory state, OSA has been shown to stimulate the white adipose tissue (WAT) leading to the production of inflammatory mediators 11 . OSA leads to sleep fragmentation, intermittent hypoxemia and in some instances, recurrent hypercapnia, which in turn, stimulate increased sympathetic activity, increased systemic inflammation, and increased oxidative stress. The end result of these changes is endothelial dysfunction and metabolic dysfunction which accounts for the increase in cardiovascular disease. Among the aforementioned factors, intermittent hypoxemia has been shown to play a critical role by promoting increased production of inflammatory markers, as depicted in Figure 1 11 - 14 .
Pathogenesis of cardiovascular disease secondary to OSA.
OSA & systemic hypertension
Evidence has been growing steadily for systemic arterial hypertension (HTN) and OSA as cardiovascular disease risk factors. In 1980, Lugaresi et al. 15 associated systemic hypertension with snoring in the general population. In 1985, Fletcher et al. 16 evaluated forty-six middle aged/older men with essential hypertension and thirty-four normotensive, age and weight matched controls for undiagnosed sleep apnea. Thirteen in the study group and three in the control group were found to have undiagnosed sleep apnea. Seven men with hypertension and sleep apnea were treated with protriptyline and one underwent uvulopalatopharyngoplasty (UPPP). A reduction in mean blood pressure (BP) was observed (149/95mmHg to 139/90mmHg) accompanied by a significant decrease in the apnea-hypopnea index (AHI) by 77%. The investigators concluded that OSA could be either the cause or a contributor to systemic arterial hypertension 16 .
Due to the prevalence of obesity as a confounding factor among studied patient populations, the confirmation of the association between OSA and HTN has been challenging 17 , 18 . However, more recently association of nocturnal OSA and daytime hypertension has been demonstrated, even after the adjustment for body mass index 19 - 21 . A prospective longitudinal cohort study with 1889 participants followed for 12.2 years (median) years identified an independent association of OSA and HTN from the confounders including age and obesity. The study demonstrated an increased hazard ratio for incident HTN in patients with OSA compared to the control subjects. Further follow up revealed a dose-response relationship between the severity of OSA and the cumulative incidence of HTN 22 .
The pathophysiology of the association between OSA and HTN is multifactorial. The potential causative factors are summarized in Figure 2 .
Association of OSA and hypertension.
Obesity has been identified as an independent risk factor both for OSA and HTN 22 . Adipose tissue deposition in the oropharyngeal around the upper airway contributes to apnea.
Downstream effects of OSA include physical inactivity, poor dietary habits, insulin resistance, hyperleptinemia, and systemic inflammation. The vicious cycle between obesity and apnea exacerbates HTN 23 - 26 . The nocturnal dipping pattern of BP is a normal physiological phenomenon that is affected by OSA 27 . Intermittent hypoxia and hypercapnia cause autonomic derangements which lead to nighttime increases in BP, and increased catecholamine levels which persist during daytime, worsening HTN 28 . OSA is well known to cause sleep inefficiency, which in itself has been shown to be correlated with several cardiovascular risk factors such as non-dipping of nocturnal BP, endothelial dysfunction, arterial stiffness, and increased sympathetic activity. The renin-angiotensin system (RAS) is known to be activated by obesity and more recently, it is known to be activated by OSA. The presence of OSA has a cumulative effect on obesity-induced activation of RAS, thereby worsening HTN 29 .
Phillips et al performed a randomized controlled trial to compare the change in cardiovascular and neurobehavioral outcomes among patients using CPAP and mandibular advancement devices (MAD). They found that although CPAP was more effective at reducing AHI, patient compliance was better with MADs. They also found that neither treatment improved blood pressure 30 . However, the meta-analysis by Montesi et al. 31 demonstrated a significant reduction in the systolic and diastolic blood pressure of patients when treated with CPAP for their OSA. Reduced nighttime BP and sympathetic traffic can be achieved with effective OSA treatment resulting in more successful BP control 31 .
OSA & heart failure
Sleep-disordered breathing (SDB), (central sleep apnea [CSA] and OSA), was found to be more prevalent in patients with heart failure (HF) 32 . However, OSA often remains as an undiagnosed risk and contributing factor for heart failure. Paulino et al. 33 demonstrated that the prevalence of sleep breathing disorder was 81% (n=256) in 316 patients, 30% of whom were classified as CSA and 70% as OSA. Among this cohort of patients, both CSA and OSA existed together due to certain pathophysiological changes brought on by heart failure leading to SDB.
The interactions of the heart failure and OSA are illustrated in Figure 3 , OSA can lead to intermittent hypoxemia, which activates inflammatory pathways and promotes oxidative stress. Increased inspiratory effort against the high resistance of the upper airway leads to increased arousals and, combined with intermittent hypoxia, leads to sympathetic activation 11 . In addition, the high negative intrathoracic pressure exerted during inspiration through a narrowed or occluded upper airway may increase pulmonary capillary fluid efflux contributing to interstitial edema.
Association of OSA and heart failure.
Increased sympathetic activity leads to increased angiotensin II release which is a potent vasoconstrictor promoting aldosterone production via the adrenal cortex. Aldosterone increases water and salt reabsorption leading to increased intravascular volume, worsening HTN and heart failure 34 . Chronic untreated OSA can lead to persistently elevated BP with absent nighttime dipping of BP, contributing to left ventricular systolic dysfunction 35 .
There are varied mechanisms by which heart failure may worsen OSA and induce apnea. Fluid overload leading to upper airway (UA) narrowing and upper airway edema are important mechanisms leading to worsening OSA 36 . In systolic heart failure patients, nighttime rostral fluid shift from the legs is a contributing pathophysiological mechanism causing worsening of OSA in HF 37 . Overnight rostral leg fluid displacement and an increase in neck circumference have been shown to significantly worsen OSA and CSA. There is a positive correlation with the volume of lower extremity extravascular fluid volume 37 . The brain stem respiratory centers in the medulla and pons receive input from peripheral arteries and the respiratory system. The effectors for the ventilatory center are the respiratory muscles. Heart failure leads to hypoxemia and increased afferent activity from the juxta capillary receptors (due to pulmonary capillary engorgement) which in turn drives the ventilatory center leading to hyperventilation 38 . Hyperventilation leads to decreased PaCO2 levels, resulting in hypopnea and/or apnea.
Also, increased circulation time leads to slower feedback from the chemoreceptors in the peripheral arteries. Pulmonary vascular congestion and edema lead to lower alveolar PAO2 and PACO2 reserve adds to ventilatory instability 39 .
OSA and acute coronary syndrome
OSA is prevalent in patients with preexisting cardiovascular diseases. The plausible factors contributing to the development and maintenance of cardiovascular impairment in patients with OSA include intermittent hypoxemia, development of acidosis, increase in blood pressure and sympathetic vasoconstriction 11 .
The prospective sleep heart health study (SHHS) 40 was done to establish the association between OSA and incident coronary artery disease and heart failure. For the purposes of data collection and analysis regarding incident coronary disease, the first occurrence of myocardial infarction, coronary heart disease (CHD), death, or coronary revascularization procedures were included. The rate of incident CHD was 20.1 events per 1000 person-years of follow-up in men and 8.7 events per 1,000 person-years in women. Event rates increased with severity of OSA in men. When these models were adjusted for age, race, BMI, and smoking status, there was a significant association of apnea/hypopnea index (AHI) with incident CHD in men but not in women. However, this association was not statistically significant after accounting for diabetes mellitus and lipid measures, adjustment for systolic and diastolic blood pressure and anti-hypertensive medication use also diminished the significance of the association.
Other prospective studies have shown an increased association between OSA and CHD. Shah et al. 41 assessed whether OSA increased the risk of cardiovascular events. The outcomes studied included MI, coronary artery revascularization procedures and death from cardiovascular causes. These investigators found that patients with OSA had an increased risk of these outcomes, despite controlling for other cardiovascular risk factors including diabetes, hypertension, hyperlipidemia, tobacco, and alcohol use. A systematic review by Porto et al. 42 supported an association between OSA and MI, which was greater in men.
Another observational study compared cardiovascular outcomes (fatal and non-fatal) in men with OSA who were being treated with CPAP versus untreated men with OSA 43 . Fatal myocardial infarction (MI) and stroke, non-fatal MI, non-fatal stroke, coronary artery bypass surgery, and coronary angiography were the study parameters. Severe OSA significantly increased the risk of fatal and non-fatal cardiovascular outcomes. The study also demonstrated that CPAP treatment in patients with severe OSA reduced the aforementioned adverse outcomes and those patients with mild and moderate OSA, did not exhibit increased risk of these outcomes. Buchner et al. 44 reported that OSA treatment with CPAP had a benefit for patients with all severities of OSA and resulted reduced adverse cardiovascular outcomes. Interestingly the SAVE (sleep apnea cardiovascular endpoints) study 45 , a randomized control trial conducted to assess the effects of CPAP on major cardiovascular events, showed that CPAP use did not prevent cardiovascular events in patients with moderate to severe sleep apnea. It did reduce snoring and daytime sleepiness and improved health-related quality of life and mood. Interestingly the observational study conducted by Anandam et al. 46 showed that CPAPs and MADs may have similar effectiveness in reducing cardiovascular mortality.
OSA and atrial fibrillation
Atrial fibrillation (AF) is the most common arrhythmia linked with OSA. The prevalence of AF in patients with known OSA is 5% 47 . OSA may trigger the onset of and contributes to its persistence 48 . However, OSA is more common and less frequently detected in patients with AF 47 , 49 . The severity of OSA correlated with a higher incidence of AF and may also be a predictor of AF recurrence after cardioversion and/or ablation procedures 50 , 51 . There is limited success of antiarrhythmic therapy in patients with severe OSA 52 . Patients with OSA are more likely to develop AF post coronary artery by-pass graft surgery (CABG) 53 . OSA is associated with an increased incidence of AF in patients with heart failure 54 , coronary artery disease (CAD), and hypertrophic cardiomyopathy (HCM) 55 .
Pathophysiology of developing AF in patients with OSA
Mechanisms linked to the development of AF in patients with OSA include the hemodynamic changes occurring during the apneic episodes. Hypoxemia and hypercapnia during episodes of hypopnea/apnea leads to tachycardia and hypertension. These changes are accompanied by increased myocardial oxygen demand, despite the restricted supply of oxygen during these episodes. This leads to myocardial injury and fibrosis, which promote the development of AF 11 , 47 . Episodes of hypopnea/apnea and post apneic reoxygenation also lead to oxidative stress, which contributes to the remodeling of the myocardium 47 . OSA is associated with higher levels of CRP and IL-6 56 , however the use of CPAP therapy has been shown to decrease these inflammatory markers in patients with OSA 56 .
OSA is also associated with atrial enlargement, conduction abnormalities, and prolonged sinus node recovery time 57 . This structural and electrical remodeling contributes to the development of AF.
Negative intrathoracic pressure during apneic episodes may be associated with the development of AF. The Mueller maneuver was performed on healthy adults to simulate the changes in the upper airway, which occur during OSA 58 and found that the negative intrathoracic pressure led to a decrease in the left atrial volume, increase in left ventricular systolic function and an increase in the ventricular afterload. These dynamic changes can be implicated in the development of AF. Repetitive cycles of negative intrathoracic pressure also lead to atrial stretch, which contributes to the enlargement of the chambers and development of AF 48 . Negative intratracheal pressure causes shortening of the atrial effective refractory period through vagal stimulation, which also predisposes to the development of AF 59 .
Management of AF in OSA
OSA is considered a modifiable risk factor for AF 47 . Current evidence suggests that continuous positive airway pressure is the standard treatment for OSA. Shah et al. 60 showed that CPAP had a beneficial effect on left ventricular remodeling. Use of CPAP is associated with effective lowering of blood pressure, decreased atrial size and ventricular mass, and a lower risk for AF recurrence after ablation 61 . Recurrence of AF after cardioversion is also less frequent in patients being treated with CPAP compared to patients not being treated with 62 . Bayir et al. 63 showed that after 6 months of therapy with CPAP in patients with OSA, there was an improvement in the interatrial, left intra-atrial and right intra-atrial electromechanical delays when compared to pretreatment measurements and possibly a decreased risk for OSA related AF 63 . CPAP can also help reverse left atrial volumetric abnormalities in as little as 12 weeks and improve left atrial remodeling over a period of 24 weeks 64 . Furthermore, it reduces the risk of progression from paroxysmal AF to persistent AF 65 . Drug refractory AF is often treated with catheter ablation (or a convergent procedure); however, screening patients with atrial fibrillation for OSA prior to catheter ablation may be beneficial, and could possibly obviate the need for the procedure 66 .
Renal nerve denervation (RND) is an emerging modality that may be of benefit 66 . Despite the failure of RND in managing drug resistant hypertension, there are new experimental studies suggesting that it may control arrhythmias caused by hyperactivity of the sympathetic nervous system 67 , 68 . Linz et al. 68 studied the effects of RND on anesthetized pigs and determined that RND reduced AF caused by negative intratracheal pressure and reduced shortening of the atrial effective refractory period, in contrast to administration of atenolol which did achieve the same results 68 . They also reported that RND prevented post apneic elevation in blood pressure, decreased plasma renin activity and aldosterone levels 68 .
OSA and other arrhythmias
OSA is associated other arrhythmias including ventricular tachycardia, premature ventricular contractions, ventricular fibrillation, sinus bradycardia and sick sinus syndrome (SSS) 69 , 70 .
OSA is also associated with bradycardia, long pauses and sick sinus syndrome. Simantirakis et al. 71 conducted a study on 23 patients with an established diagnosis of OSA to evaluate their arrhythmias and to determine the effect of CPAP therapy on those arrhythmias. These investigators noted that these patients had multiple episodes of bradycardia and long pauses during sleep. Their study also showed that treatment with CPAP reduced these episodes. In another report, the prevalence of SSS was 31.6% in patients with OSA 72 .
Abe et al. 73 performed a study on 1,394 Japanese patients and found that CPAP therapy substantially reduced the incidence of AF, PVCs, sinus bradycardia, and sinus pauses.
OSA and pulmonary hypertension
Pulmonary hypertension (PH) is frequently associated with OSA, and often is a direct consequence of OSA 74 . The prevalence of PH in OSA ranges from 17 to 53% 74 . According the updated guidelines from 6th World Symposium on PH (March, 2019), PH is defined by a mean pulmonary artery pressure (mPAP) >20mmHg rather than >25mmHg, and a pulmonary vascular resistance (PVR) >3 wood units is included to distinguish those with pre-capillary PH 75 .
Figure 4 summarizes the three main factors believed responsible for the increase in the PAP observed in sleep apnea:
Association of OSA and pulmonary vasculature.
- Alveolar hypoxia, causing pulmonary vasoconstriction and endothelial remodeling;
- Mechanical related to increased inspiratory effort resulting in, more negative intrathoracic pressure, variations in heart rate and cardiac output, increased left heart filling pressures;
- Reflex mechanisms directly influencing the vasculature 76 .
Acute pulmonary artery pressure changes during sleep have been reported with obstructive apneas 76 . However, the role of OSA as an independent risk factor for the development of daytime PH is not fully established. Severe OSA frequently causes daytime PH in the absence of significant co-existing cardiopulmonary and vascular diseases, and CPAP therapy significantly reduces the levels of daytime pulmonary artery pressure 77 .
Daytime PH may have a precapillary component related to repetitive hypoxia-reoxygenation 78 leading to both pulmonary vasoconstriction and vascular endothelial remodeling, but there may also be a post capillary component attributable to episodic or permanent elevations in LV filling pressure 79 . The application of nocturnal CPAP therapy can lead to the abolition of both nocturnal hypoxemia and the accompanying sympathetic surges, resulting in improvement in LV diastolic relaxation and decreased LV afterload. This may promote the restoration of the balance among these endothelial vasoactive mediators. Long-term CPAP therapy may avoid irreversible structural pulmonary vascular and right ventricle changes by reducing the pulmonary artery systolic pressure, possibly improving the prognosis 77 .
OSA and CTEPH
OSA promotes the release of inflammatory markers 56 and activates the coagulation cascade, which increase the risk of acute thromboembolic events, and also predisposes patients to the development of Type 4 CTEPH (chronic thromboembolic pulmonary hypertension) 80 .
Evidence supports the pathophysiological association of sleep-disordered breathing as an independent risk factor for venous thromboembolism. There is increased prevalence of sleep apnea in patients with acute pulmonary embolism and/or deep vein thrombosis 80 , 81 .
Obstructive sleep apnea-related hemodynamic alterations may result in venous stasis, increased thrombogenicity (on a vascular and molecular level), increased inflammatory insult and injury, thus fulfilling the criteria for the nomenclature of Virchow’s triad 82 .
The development of CTEPH may be promoted by the persistence of thrombotic material in the circulation, stemming from inadequate/incomplete thrombus resolution 82 , 83 . Chronic hypoxia and hypercapnia in OSA impair thrombus resolution due to inadequate fibrinolysis, persistent inflammation, vascular smooth muscle activation, accelerated adhesion molecule expression and platelet activation 82 - 84 .
OSA and cerebrovascular accidents
Obstructive sleep apnea has been associated with hypoxic-ischemic brain injury (HI-BI), the severity of which depends on the duration and intensity of hypoxemia and ischemia 85 . EEG microarousals and awakenings frequently follow respiratory compromise. Repeated oxyhemoglobin desaturation causes alterations in sympathetic nerve activity, oxidative stress, inflammatory markers and endothelial function, which are associated with decreased vasoreactivity, increased arterial wall stiffness, increased platelet activation and vascular adhesion, resulting in increased risk for cardiovascular and cerebrovascular insults.
Numerous studies have shown the association between OSA and stroke 86 , 87 . A systematic review of 37 studies with 3,242 patients showed a high prevalence of OSA in patients with cerebrovascular disease (61.9%) 88 . A meta-analysis of 16 cohort studies reporting data on 24,308 patients demonstrated that moderate and severe OSA are associated with an increased risk of vascular outcomes, including stroke 11 . Patients with OSA are more likely to have a stroke or die than those without OSA 87 . There is an association between OSA and nocturnal cerebrovascular events 89 - 91 , and a dose-effect relationship has been described between the adjusted risk and OSA severity, as measured by AHI and oxygen desaturation index, viz., the mean number of desaturations of 4% or more per hour of sleep 86 . OSA contributes to ischemic stroke both as a predisposing risk factor and as a triggering factor; there is a statistically significant association between preceding OSA symptoms and wake-up stroke (WUS) 92 . A higher percentage of cerebral white matter disease, radiographic deep grey matter disease or macroangiopathic strokes is noted in individuals with OSA 89 . A study of 61 patients with silent cerebral infarct and 122 without silent lacunar cerebral infarct demonstrated that the presence of severe OSA syndrome was significantly higher in silent cerebral infarct in comparison to patients without lacunar infarcts (55.8% versus 35.7%, p =0.019) 93 . Fluctuations in cerebral blood flow velocity (CBFV) have been documented in OSA, with CBFV increasing along with arterial pressures during OSA episodes. Both CBFV and systemic arterial pressures decrease upon termination of the apneic episode, at the lowest level of oxyhemoglobin desaturation 94 .
Transcranial Doppler imaging has shown decreased cerebrovascular reactivity and increased arterial stiffness, particularly during OSA episodes 95 . An impairment in cerebral autoregulation by means of measurement of the recovery of CBFV and cerebrovascular conductance (CBFV/mean arterial pressure) has been observed after orthostatic challenges, with slower recovery noted in patients with OSA compared to control subjects 96 . A dose-relationship between severity of sleep respiratory disturbance (as measured by AHI) and impaired cerebral autoregulation has also been noted 97 . An impairment in cerebrovascular CO 2 reactivity, measured by the CBF with increasing AHI was demonstrated in one case control study 98 . Global cerebral blood flow increases during episodes of hypoxemia. A study comparing the increase in CBF in patients with OSA compared to that in healthy subjects demonstrated less increase CBF in OSA patients compared to the control subjects, and this difference was not demonstrable after 3 months of treatment with CPAP 99 . Data from other studies suggest that it is possible to normalize cerebral vasoreactivity and cerebral blood flow with CPAP treatment 100 , 101 .
Functional outcomes and long-term mortality of stroke patients with OSA are poor compared to those without OSA. Patients with a higher AHI required longer inpatient rehabilitation and had lower Functional Independence Measure (FIM) scores 102 . Increased mortality 60 months after stroke was observed in those with higher AHI 89 . The nocturnal nadir of oxyhemoglobin saturation is an independent predictor of poor functional outcomes 103 . One study demonstrated that higher severity of SDB correlated with a poorer functional outcome based on the modified Rankin scale score 104 .
There have been concerns about the safety CPAP treatment in patients of acute stroke occurring in the setting of OSA. It is thought that CPAP treatment may reduce cerebral perfusion by altering blood oxygen and carbon dioxide balance. Despite these concerns, current data obtained from prospective and cohort studies suggest no adverse effect of CPAP treatment in patients with OSA during acute stroke 89 , 105 .
The effect of continuous positive airway pressure (CPAP) treatment was evaluated as a primary outcome measure for prevention of new vascular events among OSA patients with stroke. Concurrently, secondary outcome measures were designed to assess post stroke clinical outcomes utilizing the Barthel index and the modified Rankin scale. Measurement of neuropsychological parameters suggested better stroke outcomes and there was a trend toward favorable outcomes vis-a-vis reduced recurrence of vascular events 35 . A meta-analysis of seven randomized controlled trials which included 4,268 patients showed a significant reduction in relative risk or major adverse cardiovascular events and stroke, which correlated with increased CPAP usage time (adherence time >4 hours) 106 . Another systematic review and meta-analysis of 4 randomized clinical trials and 1 prospectively matched observational cohort, (total of 389 patients) showed a mean decrease in National Institutes of Health Stroke Scale scores during the first (≤30) days of acute ischemic stroke in patients treated with non-invasive ventilation (NIV) compared to control subjects (standardized mean difference, 0.38; 95% confidence interval, 0.11-0.66; p =0.007) 107 .
Although several studies have demonstrated the beneficial effect of CPAP on recovery outcomes in stroke patients, including more rapid functional recovery, reduced hospitalization time, and decreased frequency of re-hospitalization, significant challenges remain due to post stroke disability which may lead to limited CPAP adherence in the hospital environment.
Consequently, there has been increased interest in alternate options to treat SDB such as mandibular advancement surgery and supine avoidance. Additional studies are needed to evaluate their efficacy in post-stroke rehabilitation outcomes 108 .
OSA and other neurological disorders
OSA increased the risk of developing optic neuropathy after controlling for comorbidities as demonstrated in a Taiwanese population-based cohort study; however, treatment with CPAP did not reduce the risk of optic neuropathy 109 .
Review performed by Chaitanya et al. 110 highlights OSA as a risk factor for developing glaucoma. Another important point to note is that CPAP therapy can trigger glaucoma damage by raising the intraocular pressure (IOP), which would warrant glaucoma screening in patients on CPAP.
A study to investigate the association between obstructive sleep apnea (OSA) and middle ear acoustic transference/cochlear function demonstrated that severe OSA is associated with cochlear function impairment in patients. Patients with severe OSA presented with significantly lower distortion product otoacoustic emissions (DPOAE) amplitudes when compared to the control, mild, and moderate OSA groups 111 .
Fecal and urinary incontinence has been reported to resolve after treatment with positive airway pressure non-invasive ventilation 112 in a patient with obstructive sleep apnea hypopnea syndrome (OSAHS). Five adults OSA patients who presented with enuresis, enuresis resolved after treatment with continuous positive airway pressure (CPAP) 113 , and similar improvement was noted in another case report 114 .
Patients with OSA demonstrate impairments in behavior, cognition, and physical skills 85 . Excessive daytime sleepiness, as measured by the subjective Epworth sleepiness scale (ESS) and the objective multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) is the most common neurobehavioral consequence of OSA. Other behavioral problems occurring in this patient population include disinhibition, distractibility, and irritability 115 , 116 . Physical skills and cognitive abilities, including selective attention, vigilance, short-term and working memory, and executive and motor functioning are adversely affected by OSA 115 - 121 . Most neurobehavioral deficits, except executive dysfunction, have been found to be reversible with CPAP treatment of OSA 118 , 122 - 124 . CPAP treatment for as little as 2 weeks has been shown to improve daytime sleepiness, including reduction in subjective sleepiness as measured by the ESS, but no significant changes were observed in objective sleepiness measured by MSLT or MWT 125 - 127 . Several key neurobehavioral indices (functional outcomes of sleep questionnaire, Epworth sleepiness scale) failed to normalize despite 3 months of CPAP treatment, even in those who were maximally compliant with treatment. Forty percent of patients in this trial had an abnormal Epworth sleepiness scale score at the conclusion of the trial 128 . Despite this, CPAP treatments have been shown to result in significant improvement in attention, alertness, speed of visual motion perception, vigilance, speed of information processing immediate visual memory, working memory and cognition 122 , 126 , 129 . A prospective 12-month observational study of CPAP treatment of OSA assessed its effects on non-motor symptoms in 67 patients with Parkinson’s disease. Overall improvement in non-motor symptoms, sleep quality, anxiety, and global cognitive function were observed 130 .
Clinical symptoms play a key role in the diagnosis of OSA, although no sign or symptom is specific for the diagnosis of OSA. Once there is a high suspicion questionnaires and symptom- scoring scales can be used to increase the accuracy of diagnosis. Screening questionnaires are used in the outpatient setting, for symptomatic patients, to determine whether a patient should undergo polysomnography. Polysomnography is the standard for diagnostic confirmation, however it is expensive and not always available 2 .
The Mallampati classification (examination of the oropharyngeal inlet) is used to evaluate if tonsillar, uvular, and tongue enlargement are affecting the airway volume 8 .
Pathophysiology
Activation of the pro-inflammatory transcription factor nuclear kappa factor B (NF-kB) by apnea-induced hypoxia is an important pathway linking obstructive sleep apnea with systemic inflammation. It can also stimulate the downstream inflammatory markers resulting in end- organ cardiovascular disease. NF-kB activity is elevated in circulating neutrophils and monocytes in patients with obstructive sleep apnea and studies have revealed decreased activity with continuous positive airway pressure therapy in adults 131 - 133 .
Questionnaires
Questionnaires are sensitive however not very specific, therefore when a patient has low scores, it is helpful to attempt to reduce the diagnostic likelihood of OSA, in some instances avoiding the need to proceed with polysomnography 134 , 135 .
The STOP-bang questionnaire includes questions on snoring, tiredness, observed apneas, blood pressure, BMI, age, neck circumference, and gender. It is one of the most sensitive questionnaires available for use in the clinical setting 135 . Every parameter is scored one point; and a score of >3 indicates a high risk of OSA.
Sleep apnea clinical score (SACS)
It includes data on the neck circumference, hypertension, habitual snoring, and nocturnal gasping or choking. The score ranges from zero to 100 and a score greater than 15 increases the likelihood of being positive for OSA.
Berlin questionnaire
The questionnaire has ten sections distributed in three categories, which include data on snoring, non-restorative sleep, sleepiness while driving, apneas during sleep, hypertension, and BMI. Points are assigned for each category and the patient is identified as high risk or low risk based on the points 135 .
The system assesses five components including neck circumference, BMI, snoring, age, and sex. A cut-off of eight points is used to identify patients with sleep-disordered breathing 136 .
Polysomnography (PSG)
PSG is the standard procedure for the diagnosis of OSA 2 . The preferred approach is to perform overnight PSG in the sleep laboratory; however, it is costly and may not be available (nor approved by third party insurers) at all times. Therefore, home sleep apnea testing (HSAT) can be used for certain patient populations 137 . HSAT can be performed for patients who have a high pre-test probability of OSA and do not have other comorbidities 137 . However, if a HSAT is inconclusive, inadequate or negative, PSG should be performed 137 . Patients with comorbidities such as cardiovascular disease, respiratory muscle weakness secondary to neuromuscular disorders, history of strokes or other ischemic disease, and chronic opioid use should undergo PSG rather than HSAT 137 .
Several parameters are monitored during PSG. Electroencephalography (EEG), chin electromyography (EMG) and electrooculography (EOG) are done to identify episodes of arousal and to determine sleep stage 2 . Respiratory airflow recommended: simultaneous monitoring of two physical variables: air temperature (for thermal airflow) and air pressure (for nasal pressure), respiratory effort, oxyhemoglobin saturation, and ECG are monitored 21 . To diagnose OSA, apnea-hypopnea index (AHI) is measured, i.e., the number of apneic and hypopneic episodes per hour of sleep are tabulated 21 . Apnea is an episode of stoppage of respiratory airflow for a minimum of 10 seconds. Hypopnea is the decrease in airflow, associated with either a drop-in oxyhemoglobin saturation or an episode of arousal 21 . AHI of greater than five is diagnostic of OSA. AHI greater than or equal to five but less than fifteen is classified as mild, greater than or equal to fifteen but less than thirty is classified as moderate, and greater than or equal to thirty is classified as severe OSA 22 .
Management of OSA
CPAP is the primary management strategy for OSA as it decreases symptoms of sleepiness and improves quality of life in patients with moderate and severe disease 2 , 138 . CPAP treatment prevents (or ameliorates) collapse of the upper airways 137 . Change in dietary habits, regular exercise, and weight loss can also contribute to the management of OSA 139 . Bariatric surgery is an option in extreme cases, and may be associated with significant improvement; however, it has not been shown to totally reverse OSA and does not replace the use of CPAP as the primary treatment 140 . However, after surgery and significant weight loss polysomnography should be repeated and CPAP titration should be performed 141 . Other surgical options include tonsillectomy, uvulopalatopharyngoplasty, tongue surgery (to reduce the size) and maxillomandibular advancement surgery 142 . Another alternative is the use of mandibular advancement devices (MAD). The purpose of the device is to expand and stabilize the airway and to lessen the collapse. Although these are not as effective as CPAP in reducing AHI 142 , 143 they can be used in certain circumstances when there is insufficient compliance with CPAP use.
Wojda et al. 144 performed a clinical study with 8 patients, comparing the use of CPAP and MAD and found that the symptoms improved to greater extent with CPAP. In cases where adherence to CPAP is low, these alternative options can be considered. However, CPAP is treatment of choice and has shown the best outcomes, including reduction in all-cause mortality 2 , 138 , 145 . Yearly follow up should be performed after CPAP is initially set up 146 . Oral appliances can be used for patients mild to moderate OSA under certain conditions 146 . Ramar et al. 147 published recommendations based on an extensive review that endorsed the use of oral appliances for patients with snoring (without OSA) and for patients with OSA that are intolerant of CPAP or prefer an alternate treatment. Their guidelines also included the use of custom oral devices for patients with oversight by qualified dentists to monitor for dental side effects, and follow up testing by sleep physicians to check for treatment effectiveness.
OSA affects multiple organ systems. OSA may first present with cardiovascular or neurological morbidity, rather than respiratory symptomatology. It is important to use clinical judgement and to keep a low threshold for diagnosis when patients present with these varied signs and symptoms in order to make a timely diagnosis and to intervene to prevent morbidity and mortality.
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Diagnosis and Management of Obstructive Sleep Apnea : A Review
- 1 Medical Service, VA Boston Healthcare System, Boston, Massachusetts
- 2 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
- 3 Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts
- 4 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
- Original Investigation Oral Appliance Therapy in Patients With Snoring or Moderate Sleep Apnea Marie Marklund, PhD, DDS; Bo Carlberg, MD, PhD; Lars Forsgren, MD, PhD; Tommy Olsson, MD, PhD; Hans Stenlund, PhD; Karl A. Franklin, MD, PhD
- US Preventive Services Task Force USPSTF Evidence Report: Screening for OSA in Adults Daniel E. Jonas, MD, MPH; Halle R. Amick, MSPH; Cynthia Feltner, MD, MPH; Rachel Palmieri Weber, PhD; Marina Arvanitis, MD, MPH; Alexander Stine, BA; Linda Lux, MPA; Russell P. Harris, MD, MPH
- US Preventive Services Task Force USPSTF Recommendation: Screening for Obstructive Sleep Apnea in Adults US Preventive Services Task Force; Kirsten Bibbins-Domingo, PhD, MD, MAS; David C. Grossman, MD, MPH; Susan J. Curry, PhD; Karina W. Davidson, PhD, MASc; John W. Epling Jr, MD, MSEd; Francisco A. R. García, MD, MPH; Jessica Herzstein, MD, MPH; Alex R. Kemper, MD, MPH, MS; Alex H. Krist, MD, MPH; Ann E. Kurth, PhD, RN, MSN, MPH; C. Seth Landefeld, MD; Carol M. Mangione, MD, MSPH; William R. Phillips, MD, MPH; Maureen G. Phipps, MD, MPH; Michael P. Pignone, MD, MPH; Michael Silverstein, MD, MPH; Chien-Wen Tseng, MD, MPH, MSEE
- JAMA Patient Page Screening for Obstructive Sleep Apnea in Adults Jill Jin, MD, MPH
- JAMA Clinical Guidelines Synopsis Diagnostic Testing for Obstructive Sleep Apnea in Adults Babak Mokhlesi, MD, MSc; Adam S. Cifu, MD
- Original Investigation Association Between Unrecognized OSA and Cardiovascular Events After Major Noncardiac Surgery Matthew T. V. Chan, MBBS, PhD; Chew Yin Wang, MBChB; Edwin Seet, MBBS, MMed; Stanley Tam, MD; Hou Yee Lai, MBBS; Eleanor F. F. Chew, MBBS; William K. K. Wu, PhD; Benny C. P. Cheng, MBBS; Carmen K. M. Lam, MBBS; Timothy G. Short, MD; David S. C. Hui, MD; Frances Chung, MBBS; for the Postoperative Vascular Complications in Unrecognized Obstructive Sleep Apnea (POSA) Study Investigators
- Original Investigation Association of Obstructive Sleep Apnea With the Risk of Affective Disorders Jong-Yeup Kim, MD, PhD; Inseok Ko, MS; Dong-Kyu Kim, MD, PhD
- Original Investigation Development of a Sleep Apnea–Specific Health State Utility Algorithm Jonathan R. Skirko, MD, MPH; Kathryn T. James, PA-C, MPH; Louis P. Garrison, PhD; Edward M. Weaver, MD, MPH
- Comment & Response Benefits of Treating Obstructive Sleep Apnea Mahadevappa Hunasikatti, MD
- Comment & Response Benefits of Treating Obstructive Sleep Apnea—Reply Daniel J. Gottlieb, MD, MPH; Naresh M. Punjabi, MD, PhD
- JAMA Diagnostic Test Interpretation Home Sleep Apnea Testing for the Diagnosis of Obstructive Sleep Apnea Scott Hoff, MD; Nancy Collop, MD
Importance Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA.
Observations The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events.
Conclusions and Relevance OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.
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Gottlieb DJ, Punjabi NM. Diagnosis and Management of Obstructive Sleep Apnea : A Review . JAMA. 2020;323(14):1389–1400. doi:10.1001/jama.2020.3514
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Open Access
Peer-reviewed
Research Article
Obstructive sleep apnea: A sharp increase in the prevalence of patients treated with nasal CPAP over the last decade in France
Roles Formal analysis, Methodology, Validation, Writing – original draft
Affiliation Santé Publique France, The French National Public Health Agency, Saint-Maurice, France
Roles Methodology, Validation, Writing – original draft, Writing – review & editing
Affiliation EA 7330 VIFASOM and APHP-Hôtel Dieu, Centre du Sommeil et de la Vigilance, Université de Paris, Paris, France
Roles Conceptualization, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing
* E-mail: [email protected]
- Laurence Mandereau-Bruno,
- Damien Léger,
- Marie-Christine Delmas
- Published: January 12, 2021
- https://doi.org/10.1371/journal.pone.0245392
- Reader Comments
Introduction
Obstructive sleep apnea (OSA) is a frequent condition. In the absence of treatment, OSA is associated with a higher risk of traffic accidents and a large variety of diseases. The objectives of this study were to describe the characteristics of patients treated for OSA in France and assess the time trends in treatment.
The French National Health Data System is an individual database with data on all healthcare reimbursements for the entire French population. Based on this database, we included all patients aged 20 years or over who were treated with continuous positive airway pressure (CPAP) or mandibular advancement splint (MAS) between 2009 and 2018. Negative binomial models, adjusted for age, were used to assess time trends in treatment prevalence and incidence rates.
In 2017, 2.3% of French adults aged ≥20 years were treated with CPAP (men: 3.3%; women: 1.3%). The highest prevalence was observed in people aged 70–74 years (5.0%). From 2009 to 2018, the annual prevalence of CPAP increased 3-fold and the annual incidence 1.9-fold. During the same period, the rate of patients reimbursed for MAS (first prescription or renewal) was multiplied by 7.6. The proportion of patients treated with CPAP in 2017 who were no longer treated in the subsequent year was 6.9%.
The sharp increase in the incidence of OSA treatment probably reflects a better recognition of the disease in France. However, the prevalence of OSA treatment remains lower than expected based on the international literature. Further studies are needed to identify the obstacles to an optimal management of individuals with OSA in France.
Citation: Mandereau-Bruno L, Léger D, Delmas M-C (2021) Obstructive sleep apnea: A sharp increase in the prevalence of patients treated with nasal CPAP over the last decade in France. PLoS ONE 16(1): e0245392. https://doi.org/10.1371/journal.pone.0245392
Editor: James Andrew Rowley, Harper University Hospital, UNITED STATES
Received: July 28, 2020; Accepted: December 29, 2020; Published: January 12, 2021
Copyright: © 2021 Mandereau-Bruno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: According to French law, only a few public institutions have permanent access to the individual data from the SNDS. For other researchers, data are available from the “Plateforme des données de santé” (Health Data Hub, https://www.health-data-hub.fr ) upon request.
Funding: The authors received no specific funding for this work.
Competing interests: Dr Damien Léger declares that in the past 5 years, he has been a consultant or investigator in studies sponsored by Actellion, Agence Spatiale Européenne, Bioprojet, iSommeil, Jazz, Vanda, Merck, Philips, Rythm, Sanofi, Vitalaire, and Resmed. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
It is well known that obstructive sleep apnea (OSA) may interfere with numerous metabolic and cardiovascular risks [ 1 ]. OSA is also associated with a higher risk of road accidents due to daytime sleepiness as well as cognitive disorders. OSA is defined as a combination of clinical symptoms, dominated by excessive daytime sleepiness not explained by other factors, a feeling of non-restorative sleep, and at least five apneas or hypopneas per hour of sleep [ 2 ].
The estimated prevalence of OSA varies greatly from one study to another due to differences in the criteria used to define it (method of diagnosis, apnea/hypopnea threshold, presence of symptoms) as well as variations in the populations studied, especially in terms of body mass index (BMI) and age, which are major risk factors for OSA. On the basis of a single threshold of five apneas/hypopneas per hour, studies observe rates in adults ranging from 9% to 38% [ 3 ]. Although an awareness of OSA is growing among health professionals and the general population, it remains underdiagnosed. There is also a reticence among many patients and health professionals to accept the recommended treatment.
The treatment of OSA is adapted to the symptoms and severity of the syndrome, measured by the apnea-hypopnea index (AHI) [ 4 ]. In France, the Health Authority recommends treating patients with moderate or severe OSA defined as AHI≥15/hr and at least three of the following symptoms: daytime sleepiness, habitual loud snoring, feeling of choking or suffocation during sleep, daytime fatigue, nocturia, and morning headaches. The choice of medical device–nocturnal continuous positive airway pressure (CPAP) or mandibular advancement splint (MAS)–depends on the severity of symptoms. CPAP is recommended as first-line treatment when the AHI exceeds 30/hr, or when the AHI is between 15 and 30/hr and is associated with poor-quality sleep (at least 10 microarousals per hour of sleep) or concomitant severe cardiovascular disease. In all circumstances, MAS is an alternative if CPAP is refused or poorly tolerated by the patient. MAS is recommended as first-line treatment when the AHI is between 15 and 30 and there is no associated severe cardiovascular disease. In all cases, irrespective of OSA severity, lifestyle and dietary advice is offered, irrespective of OSA severity.
The purpose of our analysis was to describe the characteristics of patients treated for OSA in France and to assess the time trends in the prevalence and incidence of OSA treatment over the last decade.
Source of data
Data are drawn from the French National Health Data System (SNDS) [ 5 ]. The SNDS comprises a database of anonymized individual data known as the DCIR, which includes all reimbursements for care delivered on an outpatient basis (medical acts, laboratory tests, medical devices, medicinal products) as well as social and demographic data (age, sex, entitlement to complementary universal health insurance (CMU-C), area of residence, date of death) for the recipients of these services and information about the health professionals consulted. Medical diagnoses are not stipulated unless they are provided as the reason for exemption from a co-payment relating to a long-term condition (affection de longue durée, ALD), an occupational illness, a workplace accident, or a disability. To date, the DCIR collects data from all health insurance schemes except for the National Assembly and Senate schemes. CPAP devices and, since late 2008, MAS are on the list of reimbursable products and services. For a CPAP device to be covered by the patient’s health insurance in France, a prior agreement is required based on the patient’s clinical and polygraphic/polysomnographic evaluation: i) AHI≥30/hr; or ii) if AHI≥15 and <30, then severe daytime sleepiness, accident risk, or severe cardiovascular or respiratory comorbidity. Hypopnea is defined as at least a 30% reduction in airflow amplitude lasting for at least 10 seconds and associated with a 3% or more oxygen desaturation. This agreement for a CPAP device must be renewed every year. MAS renewal is covered every 2 years.
Study population
The analysis focused on health insurance beneficiaries aged 20 or older and residing in France who received at least one reimbursement for the use of a CPAP or MAS between 2009 and 2018. We examined all the codes for reimbursable products and services relating to CPAP, irrespective of whether CPAP use was associated with oxygen therapy, as well as all the codes relating to MAS.
Data analysis
A patient was considered to have been treated with CPAP in a given year if CPAP treatment was delivered during the year (prevalent case), and as newly treated (incident case) if CPAP treatment was delivered in a given year but not in the previous year. After excluding patients who deceased in years N or N+1, patients treated in year N who did not receive treatment in the following year were considered to have stopped treatment. Regarding MAS, the annual numbers of reimbursed patients, including both patients who were newly treated and MAS renewals, were calculated.
The annual rates of prevalence and incidence of CPAP and MAS treatment were calculated using population data provided by the French National Institute for Statistics and Economic Studies (INSEE). For the analysis of socioeconomic disparities (based on the entitlement to CMU-C and the French deprivation index of the area of residence (FDep) [ 6 ], the annual number of patients was divided by the population of health insurance beneficiaries who received at least one reimbursement for care in the year under consideration. The FDep covers mainland France and only applies to beneficiaries of the general health insurance scheme, the scheme for self-employed workers (RSI), and the scheme for agricultural workers (MSA), representing around 85% of the population covered by health insurance.
To eliminate the effect of age in the comparisons, age-standardized annual prevalence and incidence rates were calculated using the European population as a reference for the age structure [ 7 ]. Time trends from 2009 to 2018 were assessed after excluding four health insurance schemes (accounting for less than 2% of health insurance beneficiaries) that were incorporated into the SNDS after 2009. The average annual percent changes were estimated using negative binomial regression models adjusted for age and sex. Interaction terms were added to the models to test for differences in time trends by sex or age. The analysis was performed using SAS software (SAS Institute Inc., Cary, NC, USA).
Prevalence of CPAP treatment
In 2017, 1,152,539 patients aged 20 years or older received treatment with CPAP, which corresponds to an annual prevalence of 2.3% (3.3% in men, 1.3% in women). The mean age of patients was 63 years. For all age ranges, prevalence was higher in men than in women ( Fig 1 ). The age-specific rate increased regularly with age to reach a maximum in the age range of 70–74 years (5.0% for both sexes combined, 7.4% in men, 2.9% in women). In patients treated with CPAP in 2017 who belonged to the general health insurance scheme, 22.5% had a diagnosis of diabetes, 9.4% coronary heart disease, 8.4% another heart disease, and 2.5% a stroke-related disability (all ages combined).
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https://doi.org/10.1371/journal.pone.0245392.g001
Significant variations in the prevalence of CPAP treatment were observed in different French regions ( Fig 2 ). The highest rates, after standardization for age, were in Martinique and Guadeloupe followed by the North and North-East in mainland France.
https://doi.org/10.1371/journal.pone.0245392.g002
Among health insurance beneficiaries aged between 20 and 59 years, the standardized prevalence of CPAP treatment was similar for those with and without CMU-C (1.3% for both). In mainland France, the differences based on the deprivation index (FDep) were more marked in women than in men (the prevalence ratio of the most disadvantaged quintile to the least was 1.40 in women and 1.10 in men) ( Fig 3 ).
https://doi.org/10.1371/journal.pone.0245392.g003
Between 2009 and 2018, in adults aged 20 years or older, the standardized prevalence of CPAP treatment tripled (+16.0% per year on average) ( Fig 4 and Table 1 ). The increase was statistically more marked in women and, by age group, in the youngest and oldest groups.
https://doi.org/10.1371/journal.pone.0245392.g004
https://doi.org/10.1371/journal.pone.0245392.t001
Incidence of CPAP treatment
A total of 213,635 CPAP-treated patients were newly treated, leading to an annual incidence of 4.2 per 1,000. Between 2010 and 2018, the standardized annual incidence of CPAP treatment increased 1.9-fold, with an average annual increase of 11.4% (+10.0% in men and +13.9% in women).
Discontinuation of CPAP treatment
Among the 1,121,260 patients aged 20 years or older treated with CPAP in 2017 who did not die in 2017 or 2018, 77,040 (6.9%) stopped treatment in 2018. Only 2,140 (2.8%) of these 77,040 patients were managed with a MAS in 2017 or 2018. The proportion of patients who stopped CPAP was higher among women (8.4%) than among men (6.2%). In terms of age group, this figure fell gradually from 20.4% in the 20–24 age range to 5.1% in the 65–69 age range and then increased to reach 13.0% in those aged 90 years and older.
Treatment with MAS
In 2017, 15,584 patients aged 20 years or older were reimbursed for a MAS, which corresponds to a rate of 0.3 per 1,000. Between 2009 and 2018, the standardized annual rate of MAS reimbursement increased 7.6-fold, representing an average annual increase of 19.7% (+17.5% in men and +23.1% in women).
Our study shows a high prevalence of treatment for OSA in France. In 2017, 2.3% of adults aged 20 years or older were treated with CPAP, rising to 5% among those aged 70–74 years. Moreover, the number of treated patients has risen considerably over the last decade. Between 2009 and 2018, the prevalence of CPAP treatment tripled, while the rate of patients reimbursed for a MAS (first prescription or renewal) increased almost 8-fold over the same period.
To our knowledge, this is the first study to estimate the prevalence of treatment for moderate to severe OSA in the French adult population based on exhaustive data. However, due to the underdiagnosis of OSA, our findings represent only part of the disease burden. In Canada, health administrative data were poorly accurate in identifying OSA patients [ 8 ]. For the algorithm based on PSG followed by receipt of a CPAP device, although the specificity was high (98%), the sensitivity was low (19%). In a study conducted in the French general population in 2008, only 15% of individuals with symptoms suggestive of OSA reported undergoing a sleep study [ 9 ]. A similar figure (19%) was reported in the USA in 2007 based on a questionnaire on symptoms suggestive of OSA and the electronic medical records of respondents [ 10 ]. In France, there are no estimates for the prevalence of OSA in the general population. In the international literature, prevalence surveys are scarce, with varying results depending on the definition of OSA. A literature review published in 2013 showed that prevalence ranged from 9% to 17% based on the AHI threshold of at least five apneas or hypopneas per hour [ 11 ]. With a threshold of 15, prevalence was 6%. In Europe, the largest prevalence survey was carried out in Switzerland in around 2,000 individuals, observing a much higher prevalence of moderate to severe OSA: 49.7% in men and 23.4% in women [ 12 ]. A very high prevalence of moderate to severe OSA was also found in two other studies: 14.2% of men and 7.0% of women in Spain and 24.8% of men and 9.6% of women in Brazil [ 13 , 14 ]. These results cannot be extrapolated to the French population given the different study populations, notably in terms of BMI, which is a major risk factor for OSA. However, they raise questions about the scale of the disease in France. Our rate of CPAP-treated patients (2.3% in 2017) is far below these OSA prevalence estimates. From the disease to the treatment, there is a long way, which may explain part of this low rate. We may also hypothesize that OSA remains undiagnosed, because patients and health professionals minimize snoring or are unaware of excessive daytime sleepiness, which is often confused with fatigue. It is also possible that sleep examinations are not readily available in France, as sleep experts and centers are not common. In the last decade, under the authority of the French Sleep Research and Medicine Society, more than 1,000 doctors (about 100 per year) graduated in Sleep Medicine, which was recognized as a medical subspecialty in 2017.
The second important issue of our study is the marked increase in the rates of prevalence and incidence of CPAP treatment (+16% and +11% per year respectively). The rate of patients covered for a MAS also increased significantly (+20% per year). These trends took into account changes in the age structure of the French population. Changes in obesity are unlikely to explain all of the increase in CPAP treatment observed in our study. Following the sharp rise in the prevalence of self-reported obesity in adults between 1997 and 2000, this rise then slowed significantly, and between 2009 and 2012, a non-statistically significant increase of 3% was observed [ 15 ]. Surveys conducted in 2006 and 2015 based on anthropometric data did not observe any significant change in the prevalence of obesity in adults [ 16 ]. The most recent data on diabetes show a fall in the incidence of this disease between 2012 and 2017 (–2.6% per year) [ 17 ]. One explanation for the sharp increase in CPAP incidence might be the better recognition and management of OSA in France, which is in keeping with data from North America that show a 15-fold increase in OSA diagnoses between 1993 and 2010 [ 18 ]. In France, efforts have been made over the last decades to raise awareness about sleep disorders among general practitioners and the general population.
The prevalence of CPAP treatment was higher in men, which is consistent with the literature showing a prevalence of OSA that is two to three times higher in men than in women [ 19 , 20 ]. In our study, in both men and women, the prevalence of CPAP treatment was the highest in the 70–74 year age group. Studies show that the prevalence of moderate to severe OSA increases with age up to 55–60 years, but this rise is followed by a plateau if OSA is defined by AHI alone and by a decrease if sleepiness is incorporated [ 21 , 22 ]. These studies also show a higher severity of OSA in the youngest age group, suggesting that the lower prevalence in the oldest group could relate to a “survivor” effect, with severe OSA patients dying prematurely.
The increase in the prevalence of CPAP treatment was more marked in women. This may reflect the differential evolution of OSA risk factors by sex, such as that observed for obesity [ 16 ]. Prevalence trends in CPAP treatment may also reflect the greater reduction of underdiagnosis of OSA in women. Comparing the sex ratio of patients managed for OSA in specialized centers with those identified in general population surveys, studies suggest that OSA might be diagnosed less frequently in women [ 23 , 24 ].
We found significant regional variations in the prevalence of CPAP treatment, which are consistent with those observed for the prevalence of obesity [ 15 , 25 ]. Nonetheless, regional disparities in OSA diagnosis and management cannot be excluded.
A recent systematic review pointed to low socioeconomic status as a risk factor for OSA [ 26 ]. In line with this finding, we observed a greater prevalence of CPAP treatment in areas with a higher deprivation index, which probably reflects the higher prevalence of obesity in more disadvantaged areas [ 27 , 28 ]. Nonetheless, we did not find any difference in CPAP prevalence according to entitlement to the CMU-C, which is free supplementary health insurance based on income. By contrast, the prevalence of diabetes was found to be twice as high in CMU-C beneficiaries than in other people [ 29 ]. These results may suggest the lower diagnosis and/or treatment of OSA in the most socioeconomically disadvantaged people. A lower adherence to CPAP treatment in socioeconomically disadvantaged patients could also play a role [ 30 ].
Regarding comorbidities, we analyzed specific chronic diseases in patients treated for OSA through the frequency of individuals who were exempt from a co-payment due to a long-term condition (ALD). This analysis focused on beneficiaries of the general health insurance scheme, irrespective of age, so that the results could be compared with published data [ 31 ]. In 2017, the proportion of patients treated with CPAP and categorized under ALD due to a post-stroke disability, heart disease, or diabetes were between 3 and 5 times higher than those seen for all beneficiaries of the general scheme. The relationship between OSA and diabetes is well known. OSA is associated with changes in glucose metabolism and is a risk factor for type 2 diabetes, whereas diabetes is a risk factor for sleep-related respiratory disorders [ 32 ]. Regarding cardiovascular diseases, OSA causes hypertension and is associated with a higher incidence of stroke, heart failure, heart rhythm disorders, and coronary heart disease [ 33 ]. However, these comorbidities may also complicate CPAP adherence [ 30 ].
In our study, 7% of patients treated with CPAP in 2017 were not reimbursed in the following year, and among them, only 2.8% were managed with a MAS in 2017 or 2018. These results are difficult to interpret. Some patients may have recovered (weight loss, surgical treatment). Among patients who continued treatment, some of them do not correctly use the CPAP. A systematic review from 2016 estimated overall treatment nonadherence to be 34.1%, with no significant improvement over the past 20 years [ 34 ].
The main strength of our study is its use of an exhaustive database covering all healthcare reimbursements for the entire French population. Our study has several limitations. Due to the substantial underdiagnosis of OSA, health insurance reimbursement data only gives a partial view of the OSA burden in France. Moreover, our data do not consider other OSA treatments (i.e., other types of ventilation, positional therapy) or OSA cases that are resolved following surgical treatment or weight loss, while they include treated patients who do not comply with treatment. Another limitation is the lack of information about the reasons for CPAP treatment discontinuation.
In conclusion, our study shows a sharp increase in treatment for OSA in France. The prevalence of CPAP treatment tripled between 2009 and 2018, while the incidence increased 1.9-fold between 2010 and 2018. The marked increase in the incidence of CPAP treatment may reflect the better recognition of OSA in France. However, the prevalence of CPAP treatment remains below the expected prevalence of moderate to severe OSA according to international data. Further studies should identify the obstacles to the optimal management of patients with OSA and the factors determining treatment failure.
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- Published: 04 July 2019
Long term management of obstructive sleep apnea and its comorbidities
- Marta Marin-Oto 1 ,
- Eugenio E. Vicente 2 , 4 &
- Jose M. Marin 3 , 4
Multidisciplinary Respiratory Medicine volume 14 , Article number: 21 ( 2019 ) Cite this article
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Obstructive sleep apnea (OSA) is a worldwide highly prevalent disease associated with systemic consequences, including excessive sleepiness, impairment of neurocognitive function and daytime performance, including driving ability. The long-term sequelae of OSA include and increase risk for cardiovascular, cerebrovascular and metabolic syndrome disorders that ultimately lead to premature death if untreated. To ensure optimal long-term outcomes, the assessment and management of OSA should be personalized with the involvement of the appropriate specialist. Most studies have demonstrated inmediate improvement in daytime somnolence and quality of life with CPAP and other therapies, but the effect of long-term treatment on mortality is still under debate. Currently, the long-term management of OSA should be based on a) identifying physiological or structural abnormalities that are treatable at the time of patient evaluation and b) comprehensive lifestyle interventions, especially weight-loss interventions, which are associated with improvements in OSA severity, cardiometabolic comorbidities, and quality of life. In long-term management, attention should be paid to the clinical changes related to a potential reoccurrence of OSA symptoms and it is also necessary to monitor throughout the follow up how the main associated comorbidities evolve.
Introduction
We define obstructive sleep apnea (OSA) as an entity characterized by repeated collapses of the pharynx during sleep that reduce or eliminate airflow completely for at least 10 s and in a number of 5 episodes or more every hour of sleep (Apnea-Hipopnea Index, −AHI-). These episodes are associated with sympathetic activation, exaggerated negative swings in intrathoracic pressure, intermittent oxyhemoglobin desaturation, hypercapnia and arousal from sleep. These physiological changes seem to act as intermediate mechanisms responsible for the accelerated development of new comorbidities. This topic has been reviewed extensively in Multidisciplinary Respiratory Medicine by MR Bonsignore et al. [ 1 ]. In this chapter we will review three relevant questions: 1) the available information on the natural history of OSA and its relationship with incident comorbidities, particularly cardiovascular ones, 2) how the available treatment for patients with OSA does impact the evolution of OSA and 3) how the OSA treatment can modify the health outcomes of the comorbidities associated with OSA. Unfortunately, there is little information in the literature on both subjects. This is so, because since the appearance of continuous positive airway pressure (CPAP) as an effective treatment to reverse OSA symptomatology, it would not be ethical to study the natural history of symptomatic patients with OSA for a long time of period without offering them an effective treatment.
Clinical course of obstructive sleep apnea
OSA is actually part of a “continuous” patho-physiological process in which the upper airway (UA), mainly the pharynx, shows a high resistance to air flows (Fig. 1 ). Initially this dysfunction is asymptomatic or manifested by snoring: “stage of susceptibility”. Predisposed subjects probably have a genetic load of susceptibility that we are largely unaware of. With adulthood and in parallel with weight gain, environmental and epigenetic factors aggravate the collapsibility of the UA. In this “pre-symptomatic” stage, snoring is usually aggravated, nocturnal apneas appear but the subject may not report a diurnal limitation in his/her activities. Without solution of continuity, the patient evolves towards a “stage of clinical illness” in which morbidities develop at younger ages with respect to the non-OSA population in what we could consider in some way an accelerated aging. If patients are not identified and treated, the natural evolution is towards disability and premature death mainly due to cardiovascular events.
Natural history of obstructive sleep apnea (see text for details)
In current medicine, knowledge about the natural evolution of diseases is based on the descriptions made by doctors in the last century. It is not possible with current treatments to validate these descriptions through observational cohort studies and much less with randomized controlled trials (RCT). In OSA it happens the same thing. The first detailed descriptions of OSA were made by European authors. However, these reports did not describe the long-term evolution of the disease [ 2 , 3 ]. Before the description by Sullivan et al of the efficacy of CPAP for the treatment of OSA [ 4 ], physicians who treated these patients only had upper airway surgery (including tracheotomy). Early clinical descriptions of OSA included substantial disability and health care utilization, largely reflecting the limited management options available at the time. Many patients evolved towards the development of heart failure and respiratory failure or dying in various accidents. The majority of these patients were young adults. In the last 30 years, many studies on the evolution and short- and long-term management of OSA have been published. We review here briefly the most significant studies grouping them according to their study design: clinical based cohort, community-based cohort and RCT (Table 1 ).
Cohort studies
The first clinical-based and retrospective studies seemed to indicate that patients with severe OSA treated with tracheotomy and CPAP had better survival than those treated with uvulo-palato-pharyngoplasty (UPPP) or by conservative measures [ 5 , 6 ]. Mortality rates were around 6% per 5–8 years among the untreated patients, being cardiovascular events the most frequents causes of death. What was interesting about these early studies is that, despite their methodological limitations, it appears that the “complete” suppression of apneas/hypopneas with treatments such as tracheotomy or CPAP could improve the survival of patients with OSA, while other “partial” efficacy techniques (e.g. the UPPP) did not influence the health outcomes of the patients, therefore cannot be recommended to treat the most severe cases of OSA. There were another four prospective studies with three of them only including elderly population with contradictory results [ 7 , 8 , 9 , 10 ]. All six studies had many methodologic limitations because they failed adequately to take into account important confounding risk factors for cardiovascular diseases, such as obesity, smoking, dyslipemia, or hypertension. As stated in a systematic review published in 1997 by Wright et al., the results of those studies showed inconsistent results with limited evidence to link OSA with an excess of mortality [ 11 ].
Since the Wright's paper was published, many well designed longitudinal studies have confirmed increased mortality in OSA patients. In Israel, Lavie and colleagues collected mortality information among a very large cohort of 14,589 men referred to the sleep clinics with suspected sleep apnea [ 12 ]. After a median follow up of 4.6 years, Cox proportional analysis revealed that both BMI and RDI were independently associated with mortality. Unfortunately, no other potential risk of mortality, clinical status at diagnosis, or therapy was controlled. In USA, among patients without pre-existing cardiovascular diseases who were referred to a Sleep Center for the evaluation of sleep-disordered breathing, Yaggi and colleagues reported an increased risk for death or stroke in OSA patients and a dose-effect relationship between OSA severity and risk [ 13 ]. Unfortunately, use of nasal CPAP was not evaluated and the short duration of follow up (3 years) and the small number of observed events did not allow the specific assessment of the effects of therapy. In 2005, we reported the long-term cardiovascular outcomes in men with OSA referred to our sleep unit between January 1, 1992, and December 31, 1994 [ 14 ]. During the recruitment period, 1,465 patients had polysomnography and treatment with CPAP was recommended to 667 patients. Patients attended the clinic yearly. During these visits, compliance with CPAP therapy was assessed by the timer built into each CPAP device. A mean daily use of more than 4 h per day was considered necessary to maintain the CPAP prescription. After a mean of 10.1 years, Patients with untreated severe OSA had a higher incidence rate of fatal events (1.06 events per 100 person-years) than untreated patients with mild-moderate OSA (0.55 events, < 0.02); simple snorers (0.34 events, p < .0005); patients treated with nasal CPAP (0.35 events, p < .005); and healthy subjects (0.3 events, p < .005). Multivariate analysis adjusted for potential confounders showed that untreated severe OSA increased significantly the risk of fatal cardiovascular events (odds ratio 2.87; 95% CI, 1.17–7.51) compared with healthy subjects (Table 2 ). At the time, this study was very relevant because it contributed not only to the knowledge of the natural history of OSA, but also to establish AHI > 30 as a defining reference value for severe OSA. It was also the first paper to report that CPAP therapy reduces the risk of fatal and non-fatal cardiovascular outcomes in OSA.
Some population studies have confirmed the results of these clinical-based cohort studies. In a 18-year mortality follow up conducted on the Wisconsin Sleep Cohort sample ( n = 1522), the adjusted hazard ratio (95% CI) for all-cause mortality with severe OSA (AHI > 30) versus no OSA was 3.8 (1.6,9.0) irrespective of symptoms of sleepiness [ 15 ]. The Busselton study confirms this finding in a relatively young population in Australia [ 16 ], while in a somewhat older population such as Sleep Health Heart Study, the excess mortality associated with OSA was only shown in men [ 17 ]. The problem with these three epidemiological studies is that the effect of OSA treatment on health outcomes could not be adequately evaluated.
In addition with mortality, in cohort studies, OSA has been linked with incident cardiovascular outcomes such as hypertension [ 18 ], coronary artery disease [ 19 ], myocardial infarction [ 20 ] and stroke [ 13 ]. Given the increased cardiovascular morbidity and mortality in patients with OSA, the possibility that OSA was also a risk factor for developing other cardiovascular risk factors such as diabetes or dyslipidemia, has been investigated in these cohort studies. A recent meta-analysis that includes a total of 64,101 participants reveals that OSA is associated with incident diabetes, with an unadjusted pooled relative risk of 1.62 (95% CI, 1.45–1.80) [ 21 ]. There are, however, no reports that have specifically explored the development of dyslipidemia in longitudinal studies. Patients with OSA commonly experience memory problems, and neurocognitive disfunction [ 22 ], however, there are no data that allow associating OSA and incident dementia. As part of the cognitive disfunction and daytime sleepiness, it is well known that patients with OSA are at higher risk for motor vehicle accidents [ 23 ]. Finally, excess mortality in patients with OSA could also be justified by an increased incidence of all types of malignancies, especially in young adults with severe OSA [ 24 , 25 ].
Randomized studies
Long-term randomized controlled trials (RCTs) with the aim of evaluating the effect of treatment on morbidity and mortality in OSA are difficult to carry out due to the insurmountable ethical problems that supposed to stop treating patients with significant diurnal symptoms. However, some RCTs have been carried out to assess the effect of treatment on diurnal symptoms and quality of life during relatively short time. Most studies have evaluated the effect of CPAP on excessive daytime sleepiness (EDS) [ 26 , 27 ] and health status [ 27 ]. Additionally, these studies immediately showed that the positive effects of CPAP required a minimum effective use of more than 4 h a day.
As an alternative for patients intolerant to CPAP, mandibular advancement oral appliance therapy (MAT) can be considered. Some short-term (3 months) RCT have shown similar improvement in somnolence, vigilance, and neurocognitive performance with MAT, compared with CPAP in patients with mild-to-moderate OSA [ 28 ]. Upper airway surgery as a treatment option for OSA has been extensively reviewed and meta-analyzed [ 29 ], however, until now, RCTs that have demonstrated their efficacy on the symptomatology and quality of life of patients with OSA have not been carried out.
Weight-loss intervention is effective to improve the cardiovascular risk-factor profile in obese patients with or without OSA. In addition, all bariatric surgery procedures achieve improvement in their sleep apnea however, OSA can persist in after substantial weight loss [ 30 ] so follow up sleep study needs to be done to determine whether further OSA therapy is needed despite weight loss. In RCT, the combined therapy of CPAP with weight-loss intervention resulted in a larger reduction in blood pressure than either CPAP or weight loss alone [ 31 ]. There are no RCT head to head studies to compare the effect of bariatric surgery versus CPAP, MAT or other therapies.
Role of OSA in the evolution of other comorbid diseases
Given that the majority of patients with OSA present some comorbidity, especially cardiovascular or metabolic, it is relevant to know how the most prevalent and relevant comorbidities, mainly cardiovascular risk factors, will evolve depending on the treatment applied to control apneas.
- Hypertension
Arterial hypertension in patients with OSA should be treated according to the current guidelines regardless of the specific treatment that is to be applied for sleep apnea. Nevertheless, three circumstances must be considered in the relationship hypertension - OSA.
In the normotensive patient with OSA who consults for the first time, what is the future risk of developing hypertension? Put it in another way, is the treatment of OSA effective for the primary prevention of hypertension? There are data that suggest it. After considering confounding factors, the odds of developing incident hypertension over 4 years in non-hypertensive OSA patients that received no treatment, was threefold greater for those with an AHI > 15 at baseline in population studies [ 32 ], and twofold in clinical studies [ 33 , 34 ] compared with participants without OSA. However, in the latter study, compared with controls, the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy (1.33; 95% CI, 1.01–1.75), among those who declined CPAP therapy (1.96; 95% CI, 1.44–2.66), and among those nonadherent to CPAP therapy (1.78; 95% CI, 1.23–2.58), whereas the HR was lower in patients with OSA who were treated with CPAP therapy (0.71; 95% CI, 0.53–0.94) [ 33 ]. These results were confirmed in a post hoc analysis of a RCT performed during 4 years with normotensive patients with OSA and without excessive daytime sleepiness. In this multicentric study, CPAP treatment reduce the incidence of hypertension or cardiovascular events in patients with CPAP adherence of 4 h/night or longer [ 35 ].
In patients with OSAS and associated hypertension, how do the blood pressure (BP) figures in treated and untreated subjects behave? This has been one of the most studied topics of sleep medicine related to OSA. From several recent RCTs and meta-analyzes, it can be concluded that: in patients treated with CPAP that show good compliance, diurnal systolic and diastolic BP are reduced by an average of − 2.58 mmHg (95% CI, − 3.57 to − 1.59 mmHg) and − 2.01 (95% CI, − 2.84 to − 1.18 mmHg) compared to patients with untreated OSA. The effects were stronger in younger and sleepier patients and more severe OSA [ 36 ]. It should always be borne in mind that the reduction of BP is a collateral effect of CPAP and that, this treatment should not be used with the specific objective of reducing the BP Figs.
In a patient with arterial hypertension, when should the co-existence of OSA and its potential role in the pathogenesis of hypertension be suspected? Since more than 80% of OSA patients have a non-dipping BP profiles in a sample of untreated patients with mild to severe OSA [ 37 ], hypertensive subjects that demonstrate a BP drop < 10% of daytime values (non-dippers) during a 24 h ambulatory blood pressure monitoring (ABPM), should have a sleep study to rule out OSA. These hypertensive non-dippers are at higher risk of incident cardiovascular events, and increased risk of renal disease progression as compared to nocturnal dippers [ 38 ]. Another very important group of hypertensive patients in whom a sleep study is needed to rule out the coexistence of OSA are those with resistant hypertension (RH) defined as an office BP ≥140/90 mmHg despite the use of 3 or more antihypertensive agents [ 39 ]. In this subgroup, the prevalence of OSA is reported to be 70–83% [ 40 ] and the treatment with CPAP showed a favorable reduction of BP in RCT [ 41 ]. In summary, since among hypertensive patients there was a dose-dependent reduction in blood pressure and incident cardiovascular diseases [ 42 ], those patients with comorbid OSA who receive effective treatment with CPAP are also receiving a treatment that helps them stabilize their blood pressure and reduce their cardiovascular morbidity and mortality.
It is recognized that the prevalence of diabetes among patients with OSA is greater than that in the non-OSA population, and exhaustive reviews of the relationship between OSA and diabetes have recently been published [ 43 ]. On the other hand, based on clinical and population-based observational cohort studies, patients with severe OSA (eg AHI > 30), without initial diabetes mellitus (DM), are considered to have an increased risk of developing DM in the future. [ 44 , 45 ]. There is no information on the role played by the long-term treatment of OSA in reducing or not the risk of developing diabetes.
Conversely, in observational studies of diabetic subjects with OSA, effective treatment of OSA tend to improve indicators of glycemic status [ 46 ]. A recent systematic review and meta-analysis concluded that CPAP does not improve glycemic control measure as HbA1c [ 47 ]. However, the studies reviewed included mostly non-sleepy patients, were of short duration (12 to 24 weeks) and in most of them, the daily use of CPAP was lower than 4 h. Again, the selection of patients with OSA that are included in the RCTs, is in itself a bias that does not reflect the reality of the patients we see in the clinics on a daily basis. For example, it is known that the effect of CPAP on glucose metabolism is more effective when patients are drowsier [ 48 ]. The clinician must manage their diabetic patients with OSA based on the clinical guidelines and should focus primarily on weight reduction. as a target treatment for both the management of diabetes and OSA.
Dyslipidemia
Several observational studies [ 49 ] and a meta-regression analysis [ 50 ] support the existence of a link between OSA and dyslipidemia. No studies have been conducted to establish whether the treatment or not of OSA is associated with a reduction in the risk of developing dyslipidemia in subjects without lipid alterations at baseline. On the other hand, there are RCTs that have evaluated the response of CPAP in terms of blood lipids in patients with OSA and dyslipidemia with mixed results [ 51 , 52 ]. Again, it should be emphasized that the results of the RCTs do not exactly reflect the usual patient attended at sleep clinics. For example, the improvement of hypersomnolence could be associated with increased physical activity and caloric output, which can also contribute towards improving dyslipidemia. Therefore, it is difficult to identify in the context of an integral management of the patient with OSA (e.g hygienic-dietetic measures, promotion of exercise, abstinence from tobacco and alcohol, CPAP, upper-airway surgery, etc. ...), which of the therapeutic measures on an individual basis is more effective to improve the lipid profile and health outcomes.
Cardiovascular diseases
The acute and chronic cardiovascular effects of sleep apnea are well known and have been extensively studied [ 53 ]. On the other hand, among patients with OSA, the prevalence of diseases promoted by atherosclerosis (eg, stroke, ischemic heart disease, aneurysms, etc.) is higher. The evidence of an increased risk of cardiovascular morbidity and mortality among patients with untreated OSA is consistent but comes from long-term clinical and population studies [ 14 , 15 , 16 , 17 ]. There are also epidemiological studies that have indicated a reduction in cardiovascular risk in patients with OSA treated correctly with CPAP or with tracheostomy [ 14 , 54 ]. The development of RCT studies that confirm a causal relationship will not be possible for reasons indicated above. Based on this evidence and in parallel with how we inform our smokers, the doctor must communicate to their patient with severe OSA the risk and potential benefit of the treatment of their underlying disease.
Another different problem is the influence it has on the clinical course of an already established cardiovascular disease (eg coronary atherosclerotic disease, stroke, aneurysm), suffering from OSA as an associated morbidity. In the cardiovascular literature it is well established that treating, for example, hypertension or dyslipidemia of a patient with established coronary disease will ultimately reduce the likelihood of new cardiovascular events (secondary prevention). The effect of treating OSA in this type of patients is not so clear. RCTs done in patients recruited in cardiac clinics, mostly with already cardiovascular or cerebrovascular events, did not show an improving in morbi-mortality compared to those treated with CPAP. Nevertheless, a significant improvement was reported in daytime sleepiness, quality of life, mood, and work productivity in patients who received CPAP [ 55 , 56 ]. From the practical point of view and until we know the results of more RCT currently underway, we must act with patients with cardiovascular disease and suspected OSA, following the same strategy as with the “non-cardiovascular” patients. That is, based on a good sleep history, ordering the appropriate sleep study and designing the personalized treatment for each case based on the current guidelines. For our part, we would add that the sleep studies in this type of patients should always be “attended” to specify the dominant type of breathing-sleep disorder (eg, obstructive apneas, central apneas) and if positive pressure ventilation is required, its titration should always be done manually in a second sleep study.
The present strategy in the long-term management of OSA
There is no worldwide consensus about the management of OSA. Several scientific societies have clinical management guidelines for the initial treatment of OSA [ 57 , 58 , 59 ]. Figure 2 shows our strategy for the prescription of CPAP. Currently sleep specialist are moving to treat their patients from a mechanistic perspective grouping patient into phenotypic traits that cause OSA such upper airway anatomic compromise, high loop gain, low respiratory arousal threshold and poor pharyngeal muscle responsiveness during sleep [ 60 ]. However, there is no specific recommendation on how the patient’s long-term follow up process should be, what specialist should initiate the patient’s diagnostic and therapeutic process, how often and until when a patient’s course should be followed after being diagnosed or when should a new sleep study be carried out.
Treatment algorithm for obstructive sleep apnea (OSA). This flow diagram shows a general approach to the management of patients with suspected OSA. See Box 61–2 for the Epworth Sleepiness Scale. AHI, apnea-hypopnea index; PAP, positive airway pressure
In addition to an intervention to increase the upper airway lumen with pharyngeal surgery or to prevent the collapsibility of the upper airway with the application of CPAP, the management of OSA should always include lifestyle intervention. A comprehensive lifestyle intervention (CLI) program includes a reduced-calorie diet, exercise/increased physical activity, and behavioral counseling. A seminal RCT of a CLI demonstrated significant improvement in AHI parallel with weightloss [ 61 ]. CLI is particularly effective in overweight and obese patients with OSA. A CLI program that effectively achieves a weight reduction, not only improves the AHI, but simultaneously impacts on the prognosis of a coexisting diabetes [ 62 ], hypertension and cardiovascular diseases [ 63 ]. A recent Clinical Practice Guideline document from the American Thoracic Society summarizes the principles and recommendations of CLI in the management of OSA [ 64 ].
The current trend is that any recommendation included in the guidelines must be strictly evidence-based. However, in many real-world situations, evidence is not available. In our opinion, when irrefutable evidence is lacking on certain aspects of clinical management, common sense and good practices should prevail. Some recommendations in the field of sleep-breathing disorders should be implemented without the need for large randomized trials. Indeed, there is no randomized trial supporting the benefit of smoking cessation, yet it is recommended in all guidelines. One of the responsibilities of a physician is to interpret their patients’ individual problems. We have brought in our Sleep Clinic the recommendations derived from scientific knowledge in the area of OSA, and, following the worthy example of a passage from the Old Testament that has served humanity for thousands of years, have set them down in 10 OSA commandments (Table 3 ). This simple guideline constitutes an attractive, easy and practical approach to the management of COPD in all its variations and will give physicians the freedom to provide the best possible care to their patients.
Conclusions
The current knowledge about the clinical course or natural history of the disease in the case of obstructive sleep apnea, comes largely from the clinical experience of the physicians who have handled this type of patients for decades. In support of this knowledge, we only have some clinical-base and populational observational studies. Unlike other areas of medicine, in the case of OSA, we will not be able to have large long-term RCTs that help us to define the management of our patients. At present, the initial treatment of patients with OSA should focus on eliminating apneas with personalized therapy for each subject with the ultimate goal of normalizing the quality of life and control or delay the occurrence of comorbidities. To help achieve this goal, we must include the patient in lifestyle improvement programs with the ultimate goal of reducing weight and increasing physical activity, especially in overweight or obese subjects.
Abbreviations
Ambulatory blood pressure monitoring
Apnea hypopnea index
Body mass index
Blood pressure
Continuous positive airway pressure
Diabetes mellitus
Oral appliance therapy
- Obstructive sleep apnea
Randomized controlled trial
Respiratory disturbance index
Resistant hypertension
Upper airways
Uvulopalatopharyngoplasty
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This work has been funded by Instituto Salud Carlos III (PI18/01524), Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
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Marta Marin-Oto
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Eugenio E. Vicente
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Jose M. Marin
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Marin-Oto, M., Vicente, E.E. & Marin, J.M. Long term management of obstructive sleep apnea and its comorbidities. Multidiscip Respir Med 14 , 21 (2019). https://doi.org/10.1186/s40248-019-0186-3
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Challenges and perspectives in obstructive sleep apnoea
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Obstructive sleep apnoea (OSA) is a major challenge for physicians and healthcare systems throughout the world. The high prevalence and the impact on daily life of OSA oblige clinicians to offer effective and acceptable treatment options. However, recent evidence has raised questions about the benefits of positive airway pressure therapy in ameliorating comorbidities.
An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field, and proposed topics for future research on epidemiology, phenotyping, underlying mechanisms, prognostic implications and optimal treatment of patients with OSA.
The group concluded that a revision to the diagnostic criteria for OSA is required to include factors that reflect different clinical and pathophysiological phenotypes and relevant comorbidities ( e.g. nondipping nocturnal blood pressure). Furthermore, current severity thresholds require revision to reflect factors such as the disparity in the apnoea–hypopnoea index (AHI) between polysomnography and sleep studies that do not include sleep stage measurements, in addition to the poor correlation between AHI and daytime symptoms such as sleepiness. Management decisions should be linked to the underlying phenotype and consider outcomes beyond AHI.
Clinical and pathophysiological phenotyping and personalised diagnostic and therapeutic procedures remain challenges in obstructive sleep apnoea management http://ow.ly/OhNU30jOCr3
- Introduction
Breathing disturbances during sleep present in the clinical entities of obstructive sleep apnoea (OSA), central sleep apnoea, including periodic breathing, and hypoventilation disorders [ 1 ]. These labels describe imprecisely the variety of phenotypes. Many patients suffer from different and often variable amounts of obstructive and central disturbances. The clinical entities can best be described by the definition of the pathophysiological components relevant to the individual patient, i.e. the obstruction of the upper airways, disturbances of central regulation and arousal threshold. This pathophysiological approach allows selection of optimum therapeutic options, focusing on the stabilisation of the upper airways or influencing breathing regulation and manipulating the arousal threshold. New insights in the pathophysiology of OSA and central sleep apnoea, the variety of the symptoms, and the heterogeneous treatment approaches require extensive discussion and evaluation.
Due to the high prevalence and both individual and socioeconomic healthcare issues involved, this report focuses on OSA [ 2 ]. Although already high, the prevalence of OSA is expected to further increase due to ageing of societies and the global obesity epidemic. This very high prevalence of OSA represents a challenge for diagnosis, especially as current diagnostic criteria require overnight monitoring of sleep disordered breathing, which is often limited by financial constraints. The diagnosis is further complicated by the poor association between daytime symptoms ( e.g. excessive sleepiness) and the severity of OSA recorded in a sleep study [ 3 ].
Although OSA is widely recognised as an independent risk factor for cardiovascular and metabolic diseases, beneficial effects of continuous positive airway pressure (CPAP) therapy on cardiovascular outcomes in patients with established cardiovascular disease have recently been challenged [ 4 – 8 ]. The major early success of CPAP in the symptomatic treatment of OSA may have inhibited scientific research in many aspects of the disorder, including the complex pathophysiology and genetics, the variety of clinical presentations, and the effects and outcomes of different therapeutic options. Consequently, the diagnosis and treatment may have become oversimplified in many patients, focusing principally on the number of respiratory events during sleep and resulting in inadequate clinical characterisation. This may contribute to unclear and unexpected outcomes. Recent concepts on pathophysiology and differing clinical phenotypes of OSA provide opportunities for a better understanding and individualised therapy of the disorder [ 9 ].
At present, many patients with OSA are managed by clinicians who are not expert in sleep disorders, such as respiratory physicians who treat OSA patients as only one component of general respiratory practice, and may not have undertaken specific training in sleep disorders. This practice is facilitated by the lack of recognition of sleep medicine as a distinct speciality in many jurisdictions.
These challenges have been discussed by a group of sleep medicine specialists from the European Respiratory Society (ERS) and the European Sleep Research Society (ESRS). The aims of the process were to: 1) focus on current limitations in the diagnosis and treatment of OSA, 2) provide questions on current clinical practice, and 3) highlight future research priorities for the next decade.
This report emanates from the deliberations of an ad hoc expert group initiated by the ERS group “Sleep and Control of Breathing” and the Alpine Sleep Summer School ( sleep-summer-school.ch ), a European Forum for postgraduate education and think tank activities in sleep research and medicine in the ESRS [ 10 ]. The group activities included teleconferences to coordinate actions and priorities, and literature reviews to identify the most up-to-date information on diagnosis and management, and culminated in a “Think Tank” style conference held in Baveno, Italy over 3 days in October 2016.
26 European experts were invited to participate and 19 actually attended the Baveno conference. Participants were invited based on recent activities in Task Forces of the Sleep Apnoea group of the ERS, ESRS and the Alpine Summer School, and represented a spectrum of pneumologists, neurologists and psychiatrists, in addition to basic and translational scientists. All European regions were represented to reflect a variety of healthcare systems.
In a first Delphi process performed at the outset of the project, eight major topics were defined to address the most important clinical questions and challenges: clinical phenotyping of OSA; assessment of disease severity; diagnostic algorithms/new tools; excessive daytime sleepiness (EDS) and related driving risk; OSA and neuropsychiatric disorders (NPDs); outcomes of sleep apnoea; comorbid conditions in OSA; and optimum treatment. A focus was placed on adults and on OSA. Individual topics established the task for eight working groups, each consisting of between eight and 13 participants, with individual group members contributing to several working groups.
In the next step, each expert was asked to define the most relevant papers on the respective topic during the previous 5 years. Each had to describe the most important clinical challenges and research priorities in the field of OSA for the next 5–10 years.
During the meeting in Baveno, each subgroup intensively discussed the materials gathered during the initial stages, prepared a document on their respective topics that synthesised the best current available evidence on clinical practice, and prioritised evidence gaps and research priorities to best fill these gaps. The overall output of the subgroup discussions was finally reviewed and agreed in a plenary session of all experts ( figure 1 ).
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Delphi process performed at the outset of the project to select topics addressing the most important clinical questions and challenges in obstructive sleep apnoea.
- Findings and discussion
Phenotyping of OSA
Current status and limitations of existing clinical practice, the need for an individualised approach.
OSA is increasingly recognised as involving a clinical spectrum that far surpasses the classical picture of the male, obese and sleepy patient. A range of varying phenomena are now recognised that affects many aspects of the disorder:
Pathophysiology, especially relating to pathogenesis of upper airway obstruction, loop gain and arousal threshold.
Clinical presentation, i.e. heterogeneity of symptoms ( e.g. daytime sleepiness, insomnia and mood disturbances); some patients have only minimal symptoms.
Associated biomarkers such as inflammation, microRNA, vascular and polysomnographic parameters predicting prognosis and response to treatment.
Comorbidities recognised to be highly associated with OSA ( e.g. arterial hypertension and nondipping nocturnal blood pressure).
Current diagnostic criteria are inadequate to describe the variety of relevant subgroups, and new diagnostic tools are required to meet the increasing demand for personalised diagnosis and treatment of OSA. For personalised management, demographic factors such as age and sex must be considered, as they have a major impact in determining the clinical presentation of this disorder.
Conventional diagnostic procedures
Polysomnography (PSG) is the reference method for the diagnosis of OSA and its differential diagnosis or co-occurrence with other sleep disorders [ 11 , 12 ]. However, conventional measures of OSA severity ( e.g. the apnoea–hypopnoea index (AHI)), do not correlate well with the severity of clinical symptoms. This observation evokes some concerns regarding the assessment of OSA based on PSG:
PSG measures of severity such as AHI may need recalibration by which new cut-off limits may be established.
Other markers than AHI could have better predictive power for disease severity.
PSG may be inadequate, as it may fail to demonstrate individual susceptibility for systemic effects of OSA.
A new conceptual framework for assessing disease severity of OSA may be elaborated. OSA may be conceived as a model of chronic recurrent strain in which the outcomes are defined by the presence of pathological stressors, on the one hand, and the tolerance to these effects, on the other hand ( figure 2 ).
Graphic representation of a three-dimensional model of obstructive sleep apnoea (OSA) disease severity. The first dimension ( x -axis) represents the amount of respiratory events (A) in an overnight sleep period. Usually this number is expressed in relation to total sleep time ( e.g. the apnoea–hypopnoea index (AHI)), which, as such, is a measure of the “density” of the respiratory events in the overnight sleep period. The second dimension ( y -axis) represents an acute systemic effect (E) induced by respiratory events ( e.g. a certain degree of oxygen desaturation ( x %)). Respiratory pressure swings, arousals, changes in blood pressure, recurrent sympathetic activation and other phenomena are also part of the constellation of acute bodily effects caused by respiratory events. The shaded area A×E represents a combination of both dimensions. Combined measures, such as x % oxygen desaturation index, contain information of both frequency and amplitude of the specific effect, and may indicate the “intensity” of OSA. Such combined measures may better predict disease severity than the unidimensional AHI. The third dimension ( z -axis) represents a chronic end-organ impact (O) of OSA ( e.g. chronic arterial hypertension, vascular damage, insulin resistance, etc. ). This impact is variable among OSA patients, even when OSA is stratified for density or intensity. The enclosed volume A×E×O represents the relation between intensity and the observed end-organ impact. This relationship may reflect individual susceptibility, and may comprise a spectrum between low intensity/high impact and high intensity/low impact. The dashed aspect of the boundaries indicates that the end-organ impact of OSA is as-yet difficult to assess, because of the confounding influence of other disease processes. Specific biomarkers of end-organ damage in OSA need to be developed and validated in this research area.
Polygraphy, while having the advantage over PSG of being more suitable for ambulatory studies, lacks the recording of neurophysiological signals. As such, polygraphy is not specifically a sleep study, as sleep stages and electroencephalogram (EEG) arousals cannot be documented. Assessment of AHI is intrinsically imprecise [ 13 ]. Coexisting sleep disorders such as insomnia, periodic limb movements and parasomnias go undetected. In conclusion, polygraphy is a relatively crude diagnostic method and unsuited for the differentiation of clinical OSA subtypes in a significant number of cases.
Pathophysiological phenotypes
For many years the pathogenesis of OSA was deemed to be the result of anatomical factors associated with an imbalance of forces acting on the upper airway, whereby a narrowed oropharyngeal airway results in increased closing pressures that overcome the ability of the upper airway dilating muscles to maintain a patent airway. Anatomical factors that contribute to upper airway narrowing include retrognathia and adenotonsillar hypertrophy, but in many patients there is a nonspecific narrowing that can be clinically evaluated by the Mallampati score. The net result of this disparity is an increased critical closing pressure, which is representative of the anatomical status. Recently, the relevance of physiological, nonanatomical factors has been investigated and several additional factors identified [ 14 ]:
Inadequate responsiveness of the genioglossus dilating muscle.
Decreased arousal threshold.
Instability of the respiratory control system.
These additional nonanatomical factors have clinical relevance as they may be amenable to specific treatment approaches [ 9 , 15 ]. Different morphological changes ( e.g. enlargement of upper airway soft tissue structure, craniofacial structures and the variable interaction between these structures) may define different anatomical phenotypes. Three-dimensional imaging of the upper airway anatomy may help in selecting specific treatment modalities [ 16 ]. Novel techniques have recently been reported that facilitate the evaluation of these nonanatomical factors ( e.g. loop gain in the ambulatory setting). It is currently unknown whether these findings are reproducible over time and between different research groups. Therefore, more studies by independent investigators are needed.
Clinical phenotypes
The clinical manifestations of OSA are very diverse, and reflect anthropometric features, comorbid conditions and environmental factors, including smoking habits, and a sedentary lifestyle. Clustering of symptoms and comorbidities allows discrimination between clinical phenotypes that include different characteristics:
Paucity of symptoms versus EDS.
Complaints of sleep disturbance versus undisturbed sleep.
Presence or absence of arterial hypertension, cardiometabolic complications or severe obesity.
To date, several cluster analyses have been performed, which show mixed results [ 17 – 22 ]. The generalisability of available studies on clinical phenotypes is limited due to methodological differences, and prospective studies will be required to assess 1) the optimal cluster techniques and 2) the validity of cluster analysis in terms of clinical outcomes.
While EDS is a key symptom in many OSA patients, a working definition of this phenomenon is still lacking in clinical practice and clinical tools for its assessment are insufficient. More specifically, a question regarding fitness to drive should be implemented in the assessment.
Assessing target organ consequences
The link between the frequency of OSA (as measured by AHI) and clinical manifestations of OSA has proved elusive. Patients with a high AHI may be low on symptom scales and vice versa [ 3 ]. This diversity may be explained by differences in individual susceptibility to the systemic effects of OSA ( e.g. intermittent hypoxia, intrathoracic pressure swings, variations in sympathetic tone and haemodynamic instability). Substances from molecular pathways that are triggered by these mechanisms may be identified that could serve as biomarkers reflecting the end-organ strain or damage inflicted by OSA. Biomarkers, either single or clustered, could serve as surrogate end-points for disease severity and susceptibility, as well as individual responsiveness to treatment [ 23 ]. While data on the presence of certain biomarkers in OSA have been published and the effect of treatment has been explored, research into this area is still at an early stage [ 24 – 28 ].
Priorities for future research
Although recent investigations have demonstrated promising results, phenotyping of OSA is not yet ready for daily practice. Remaining problems include:
Re-definition of the optimum role of PSG.
Clinical importance of pathophysiological traits in OSA.
Confirmation of the current findings regarding cluster analysis in prospective cohorts.
Clarification of the purported end-organ susceptibility for systemic effects of OSA.
Translation of the OSA subtypes into personalised medicine.
Assessment of severity of adult OSA
The clinical definition of OSA based on the combination of AHI and daytime symptoms [ 29 ], particularly EDS, is compromised by the high prevalence of elevated AHI in the general population and by the poor correlation of EDS with AHI [ 30 , 31 ]. AHI as a measure of OSA is limited by the inclusion of arousal in the definition, making PSG the optimum modality for assessment, which does not reflect the trend towards ambulatory monitoring in clinical practice, although some ambulatory monitoring systems do include monitoring of the EEG [ 32 ]. The oxygen desaturation index (ODI) may be a stronger and more reliable predictor of adverse cardiovascular outcomes than AHI [ 33 , 34 ], and is easier to measure, although current guidelines continue to refer to AHI as the primary measure of OSA severity. A consensus on how to assess EDS (and other daytime consequences) in patients with OSA is lacking.
Current severity grading of OSA based on AHI [ 29 ] is influenced by the inclusion of sleep staging in the test [ 13 ] and studies that do not include sleep staging ( e.g. cardiorespiratory polygraphy) give a lower AHI compared with the calculation based on PSG where periods of wakefulness during the sleep study are excluded in the calculation of AHI [ 13 ]. This difference is particularly important in the assessment of patients with mild/moderate OSA [ 35 ]. However, technological developments in electrode placement and automated analysis have facilitated the use of PSG in ambulatory recordings [ 36 ]. Multiple night studies may provide a more accurate assessment than a single night [ 37 ], which may be more feasible with the development of newer technologies utilising minimal contact devices suitable for home studies that do not include sleep staging. Technical differences ( e.g. thermistor and nasal prongs) influence the assessment of respiratory disturbances and differences in hypopnoea definition may also influence the assessment of severity. The choice of 3% or 4% oxygen desaturation with or without arousal in the definition of hypopnoea [ 38 , 39 ] has recently been demonstrated in a Spanish community-based study to substantially influence OSA prevalence and severity classification, and also affect the association with cardiovascular outcomes [ 40 ]. Oxygen desaturation is more pronounced during apnoea compared with hypopnoea and is also more pronounced with longer event duration. Severity of oxygen desaturation events differs between hypopnoea and obstructive apnoea events, and is modulated by their duration in OSA [ 41 , 42 ].
The Epworth Sleepiness Scale (ESS) is the most widely used clinical tool to evaluate subjective sleepiness, but correlates poorly with AHI [ 43 ] and with objective tests of EDS, and is also open to reporting bias. Questionnaires such as the ESS may provide more accurate results with additional input from a partner. Focused questions by the clinician on core features of sleepiness ( e.g. the presence of sleepiness when alone and inactive, when mentally or physically active in company, and when performing high-risk activities such as driving) may be more reliable than the ESS. Daytime symptoms in OSA are influenced by age, sex and the presence of other comorbidities [ 2 ], particularly depression and insomnia, and other symptoms such as fatigue and tiredness may be equally important in certain groups.
Anthropometric and other objective variables such as age, sex, body mass index, neck circumference and comorbidities may be more reliable than subjective variables such as snoring and EDS in predicting OSA [ 44 ]. The identification of clinically significant OSA may be improved by the inclusion of relevant comorbidities, particularly systemic hypertension, and the loss of nocturnal blood pressure dipping may add to the clinical significance of OSA ( figure 3 ) [ 45 ].
Proposal of a multicomponent grading system for obstructive sleep apnoea (OSA) severity. ESS: Epworth Sleepiness Scale. Prerequisite for the following grading system is the evidence of obstructive sleep-related breathing disturbances (apnoea–hypopnoea index ≥15 events·h −1 ). The proposal combines the symptomatology based on the patient's history, the ESS, episodes of dozing off during daytime and results of objective vigilance tests. In addition, it includes the impact of OSA on the cardiovascular system and metabolism and any accompanying comorbidities. The patient is considered to suffer from mild symptoms if all conditions (ESS <9, no dozing episodes, no self-assessed hypersomnia, normal vigilance test) are fulfilled, whereas symptoms are considered severe if any of these parameters are positive. Patients with mild symptoms are classified as group A or C depending on the presence of comorbidities or end-organ damage. If there is no or well-controlled arterial hypertension, no or non-recurrent atrial fibrillation, no heart failure, no diabetes, or no history of a stroke, the disease is classified as minor end-organ impact leading to group A or B; if any of these factors are fulfilled, the disease is classified as major end-organ impact leading to group C or D.
Definition of most appropriate diagnostic criteria to evaluate a suspected patient with OSA.
Revision of OSA severity grading to supersede the original “Chicago criteria” and subsequent updates [ 29 , 38 ].
Definition of the relative strengths of AHI and ODI in assessing OSA severity, particularly relating to comorbidities.
Revision of the grading of OSA severity to reflect the presence or absence of sleep assessment/staging in the diagnostic test.
Definition of the role of comorbidities ( e.g. nondipping blood pressure) and of biomarkers in assessing the clinical significance of OSA.
Definition of surrogates of neurovegetative activity and cardiovascular variability to detect the harmful effects of OSA.
Diagnostic algorithms/new tools
At present, an elevated AHI remains the principal objectively measured variable in diagnosis, although patients are referred for different reasons relating to daytime and/or night-time symptoms such as snoring and/or EDS, existing cardiometabolic risk, and driving or work safety issues. According to the pre-test probability of OSA, different diagnostic pathways can be applied, which may vary between centres. Currently available screening questionnaires may assist in patient pre-selection for sleep studies, but should not replace the individual patient clinical assessment [ 46 ].
There is unanimous consensus among the expert group that AHI alone is insufficient to answer three key questions:
Who suffers from a clinically significant OSA?
Who should be treated?
What is the optimal therapy?
Challenges of existing technologies and patient care
Respiratory variables other than AHI, such as flow limitation or other nonapnoeic events, might allow a more accurate assessment of OSA and new technologies may simplify the assessment of flow limitation without measuring AHI [ 47 ]. ODI and other variables of oxygen desaturation, such as cumulative sleep time with oxygen saturation below 90%, 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 [ 48 ].
New measurements and technologies may better assess the various pathophysiological mechanisms underlying OSA ( e.g. loop gain, arousal threshold and anatomical factors). Reliable techniques to monitor sleep structure and arousals outside the conventional EEG ( e.g. arterial tonometry) require further evaluation and development, in addition to assessment of autonomic state and cardiovascular events associated with OSA events ( e.g. ECG algorithms, heart rate variability, arterial tonometry and capnography), which are currently omitted from conventional PSG [ 49 ]. Further development of existing signals such as cordless portable acoustic devices will allow enhanced diagnostic potential [ 50 , 51 ]. There is a need to identify and validate physiological signals during wakefulness or sleep that may be useful in predicting cardiovascular risk. Tools to evaluate sleepiness, including objective vigilance and performance tests, can also be considered in populations such as individual clinic patient assessment or targeted populations ( e.g. those at potential driving risk). Signals in sleep studies that may better relate to EDS are required, and could include measures of sleep fragmentation, micro sleeps and/or arousal, but these require further development and validation.
Treatment responses are difficult to predict from existing diagnostic variables ( e.g. AHI) and current diagnostic algorithms, which are typically one dimensional, are not adapted to the heterogeneous patient populations that include symptomatic patients, screening high-risk groups with cardiometabolic disease or patients with neuropsychiatric diseases. The potential role of new technologies ( e.g. smartphone-based applications and telemedicine) is not yet sufficiently elaborated and healthcare systems often do not integrate objective information provided by the patient from self-made home recordings such as from smartphone applications.
New technologies
The following promising modalities for improved sleep diagnostics are identified, most of which require further evaluation and validation:
Peripheral arterial tonometry to assess OSA and other sleep disorders.
Overnight pulse wave analysis to assess autonomic and cardiovascular function/risk.
Indwelling ear sensor to monitor the EEG.
Capnometry for new areas in assessing sleep function and autonomic dysfunction.
Alternative OSA screening technology, including noncontact sensor technology, acoustic breath analysis and smartphone-based applications.
Smartphone-based diagnostic applications for sleep disorders and OSA.
Assessment of OSA based on ambulatory Holter ECG devices or thoracic impedance from implantable devices.
New algorithms for snoring detection, quantification and characterisation.
Novel algorithms for the quantification of loop gain and arousal threshold.
Biomarkers ( e.g. exhaled breath analysis or RNA microarray).
Relevant role of new technologies on existing diagnostic algorithms for OSA and targets of therapy.
Evaluation of different diagnostic algorithms in different populations ( e.g. patients with cardiovascular or other diseases, or with predominant sleepiness).
Development of a composite OSA score, including AHI, symptoms and comorbidities/complications, to customise treatment and predict treatment responses.
Evaluation of physiological markers of autonomic and cardiovascular function in the identification of increased cardiometabolic risk.
Evaluation of OSA-related biomarkers in the identification of clinically relevant OSA.
Evaluation of new digital technology ( e.g. smartphone-based diagnostic technologies and treatment surveillance by telemedicine) to change sleep medicine procedures and models of care.
OSA, excessive daytime sleepiness and driving
Sleepiness is a physiological subjective sensation linked to the inner sleep need, and is influenced by circadian and homeostatic factors, external conditions, and individual features. EDS is a pathological disabling condition with important influences relating to sex, age and comorbidities such as depression and other disorders commonly associated with fatigue [ 52 , 53 ]. EDS is associated with a subjective feeling and may also be associated with impaired psychomotor performance that may compromise driving safety.
OSA frequently causes EDS, the latter being possibly influenced by other comorbidities and masked sleep disorders, and the strength of the association is clearly related both to the operational definition of EDS itself and to the studied population [ 22 , 54 ]. Most of the available literature applied the ESS, a subjective trait sleepiness assessment questionnaire on individual dozing-off attitudes in active and passive conditions. Despite its simple and wide application, the ESS is limited by a poor correlation with OSA presence and severity at the individual level, while other subjective tools addressing vigilance recently gave more promising results [ 55 , 56 ].
Subjective EDS assessment should include partner-assisted reports, and an extensive clinical interview on habitual sleep patterns and core symptoms frequency in passive and active situations at different circadian times [ 57 , 58 ]. Objective tools include in-laboratory approaches (maintenance of wakefulness test (MWT) and multiple sleep latency test (MSLT)) validated for specific diagnostic (MSLT to characterise suspected hypersomnias of central origin) or safety-related (MWT to address individual ability to resist sleep in monotonous conditions) purposes and several nonvalidated psychomotor tests including simulated driving [ 59 , 60 ]. EDS is indeed an intrinsic marker of OSA severity, and might be a useful marker of cardiovascular and mortality outcomes [ 61 , 62 ]. EDS is rapidly resolved by appropriate OSA treatment, but sometimes persists. In such cases depression, inappropriate lifestyles or other undiagnosed sleep disorders should be carefully explored [ 52 ].
Pro-inflammatory cytokines (interleukin-6) appear to promote sleepiness, while cortisol promotes vigilance. It has been demonstrated that objective EDS (as measured by the MSLT), but not subjective EDS, is associated with significantly elevated 24-h interleukin-6 levels and significantly decreased daytime cortisol levels in patients with OSA [ 63 ]. Data on orexin are inconsistent in OSA, while it is an important biomarker in narcolepsy–cataplexy [ 64 ]. EDS has been recognised as an important cause in the multifactorial car accident risk in OSA patients [ 65 ]. Patients with OSA show an average 2.5-fold risk for car accidents compared with healthy controls [ 66 ]. An ESRS survey in 19 countries reported that 17% of respondents had fallen asleep at the wheel in the previous 2 years [ 67 ]. Younger age, male sex, driving at least 20 000 km per year, higher EDS and high risk for OSA as assessed by questionnaires predicted EDS at the wheel. As shown in the European Sleep Apnea Database (ESADA) cohort, driving accident risk increased with OSA severity [ 68 ].
OSA treatment significantly reduced the risk, although whether treated OSA patients have a car accident risk comparable to the general population is strongly suggested but still under debate [ 69 ]. Prediction of individual car accident risk in OSA is the challenge. There is established evidence linking self-reported near-miss accidents with increased car accident risk [ 65 , 70 ], while other factors such as sleepiness at the wheel and driving habits need further verification and should be addressed. In the experimental settings (on the road and simulated), driving performance was best correlated with objective vigilance (MWT) and was improved by effective OSA treatment [ 69 ], as well as by vigilance-promoting medications [ 71 , 72 ]. Given the key role of individual behaviour while driving, OSA patients should understand their personal responsibility if driving while feeling sleepy, in order to avoid dangerous behaviours [ 59 ]. Recently introduced regulations by the European Union (EU) relating to driving among patients with OSA recognise that disease severity measured by both AHI and sleepiness are relevant to the question of driving licence restriction in such patients [ 73 ]. CPAP treatment significantly reduces EDS and driving risk in OSA patients. The EU Directive mandates objective assessment of compliance to CPAP in OSA patients. The reassessment of fitness to drive and compliance to treatment is mandatory at 3-year intervals in noncommercial drivers and every year in commercial drivers [ 32 , 73 ]. More strict rules are allowed in the individual EU member states.
Short-term priorities
Definition and evaluation of subjective tools to reliably assess EDS in the general population.
Identification of subjective and objective tools for reliable EDS and fitness to drive assessment in OSA patients.
Identification of educational strategies to adequately improve OSA patient awareness on sleepiness-related accident risk.
Identification of appropriate driving risk prediction in OSA.
Long-term priorities
Evaluation of patient-tailored interventions for adequate risk management.
Assessment of functional biomarkers for EDS assessment in OSA patients.
Identification of causes and evaluation of adequate treatments of residual EDS in well-treated OSA patients.
Integration of OSA and EDS comprehension into transportation and industrial development standards.
OSA and neuropsychiatric disorders
There is growing evidence for an increased frequency of OSA in a variety of NPDs, including stroke, neurodegenerative/muscular disorders, major depression and post-traumatic stress disorder [ 10 , 74 – 77 ]. Age, sex and criteria of sleep recording/scoring partially explain some of the discrepancy in the literature. However, the awareness of NPDs in OSA, and of OSA in NPDs, is not very high among specialists treating these patients [ 10 , 78 ].
Several studies suggest that OSA may not only be frequent, but also represents an (independent) risk factor for the subsequent development of NPDs such as stroke, dementia and depression [ 76 , 78 – 82 ].
Concerning the relationship between OSA and neurodegenerative diseases, recent studies suggest that hypoxic events can be either neuroprotective or neurotoxic, depending on several factors, including time, severity and duration of hypoxia [ 83 , 84 ]. Chronic intermittent hypoxia has been associated with increased neurodegeneration related to elevated oxidative stress, as well as with neuroinflammation in animal models of sleep apnoea. Elevated oxidative stress and inflammation are hallmarks of neurodegenerative diseases [ 85 , 86 ]. In humans, intermittent hypoxia may play a role in Alzheimer's pathology. It has been associated with a cerebral increase of phosphorylated\total tau and amyloid β1–42 concentrations in cognitively healthy adults [ 87 , 88 ].
OSA was shown to be associated not only with EDS and fatigue, but also with an impairment of neurocognitive functions ( e.g. memory and attention), psychiatric disturbances and changes of cerebral structures [ 10 , 83 , 89 , 90 ].
The origin of such complex relationships between OSA, NPDs, cognitive and psychiatric disturbances is unclear, and may include such factors as sleep fragmentation, recurrent hypoxias, shared signalling pathways, cerebral hypoperfusion/microvascular changes, comorbidities (obesity, insomnia and EDS), medications and psychoreactive factors [ 91 ].
The clinical relevance of the link between untreated OSA and NPDs stems from the observation of a negative effect of OSA on the evolution of NPDs such as stroke, epilepsy, dementia and depression [ 78 , 92 ].
Data on the effect of OSA treatment ( e.g. CPAP) on NPDs is limited and contradictory [ 78 , 93 – 97 ]. The difficulty in consistently showing an effect of OSA treatment on NPDs and their progression may be related to a variety of factors, including their chronicity, patient selection based only on AHI, heterogeneity of OSA and different outcome tools.
Identification of neurophysiological and molecular mechanisms underlying the bidirectional link between OSA and NPDs.
Identification and evaluation of screening tools for NPDs in the management of patients with OSA.
Identification and evaluation of screening tools for OSA in patients with NPDs.
Evaluation of short- or long-term benefits in treating OSA in patients with NPDs.
Identification of causes and possible treatment options for patients with persisting EDS and NPDs despite efficient OSA therapy.
Comorbid conditions in OSA
Osa is highly prevalent in cardiovascular and metabolic diseases.
Intermittent hypoxia, the hallmark of OSA, causes oxidative stress, and consequently promotes inflammation, sympathetic hyperactivity and endothelial dysfunction, which in turn lead to cardiometabolic comorbidities [ 4 ]. As demonstrated by epidemiological data in the general population and clinical cohort studies, OSA prevalence is up to 50% in arterial hypertension, refractory arrhythmias, stroke, coronary heart disease and cardiac failure [ 2 , 85 , 98 , 99 ]. There is an independent association of OSA with components of the metabolic syndrome [ 100 ], particularly visceral obesity, insulin resistance and abnormal lipid metabolism [ 5 , 26 ]. OSA is independently associated with alterations in glucose metabolism and increased risk of developing type 2 diabetes, with more than 50% of patients with type 2 diabetes exhibiting OSA [ 101 , 102 ]. Nonalcoholic fatty liver disease is a highly prevalent condition increasing in parallel with the epidemic of obesity and type 2 diabetes. There is now evidence both in adults and children [ 103 – 105 ] for a link between nonalcoholic fatty liver disease and the presence of OSA, with a dose–response relationship between the severity of nocturnal hypoxia and liver injury [ 106 , 107 ]. Comorbidities are of major importance, because they have a significant impact on healthcare use and mortality in patients with OSA [ 108 , 109 ].
OSA is commonly associated with inflammatory lung disorders
In recent years, asthma and idiopathic pulmonary fibrosis (IPF) have been identified as significant comorbidities of OSA. The prevalence of OSA is higher in asthmatic patients than in the general population, and OSA has been associated with daytime sleepiness, poor asthma control and reduced quality of life [ 110 – 114 ]. Experimental studies indicate that chronic intermittent hypoxia may promote allergen-induced airway inflammation and airflow limitation [ 115 ], suggesting a detrimental effect of coexisting asthma and OSA. Both diseases considerably increase the economic burden of care [ 116 ].
Several studies on small patient samples have highlighted that mild/moderate OSA frequently occurs in IPF patients [ 117 ] and may contribute to worsen prognosis, especially when associated with significant nocturnal hypoxaemia [ 118 ]. Chronic intermittent hypoxia has been reported to exacerbate bleomycin-induced lung fibrosis in rats [ 119 ]. However, it has been hypothesised that OSA may introduce subclinical alveolar injury due to mechanical alveolar stretch, supported by increased plasma KL-6 [ 120 ].
Oxygen desaturation in patients with OSA and IPF was found to be more severe during sleep than during exercise [ 121 ]. To better understand whether OSA treatment may positively affect symptoms and prognosis of asthma or of IPF, randomised controlled studies in well-characterised samples are still needed.
The combination of COPD and OSA (the so-called “overlap syndrome”) [ 122 , 123 ] is favoured by upper airway inflammation consecutive to smoking, rostral fluid shift, upper airway muscle weakness and inhaled corticosteroids, while the predominant COPD emphysema phenotype protects against OSA. Overlap syndrome is characterised by more pronounced nocturnal hypoxaemia, oxidative stress and systemic inflammation, such that COPD patients with comorbid OSA are at increased risk for repeated exacerbations and death. Overlap also represents a major burden in survivors from acute hypercapnic respiratory failure, with a higher risk of death and early readmission [ 124 ]. CPAP treatment may improve the prognosis of patients with overlap syndrome and decrease exacerbations [ 125 ].
Epidemiological studies and animal trials suggest a link between OSA and cancer mortality and incidence [ 126 ]. A large cohort of 4910 subjects identified a significant association between overnight hypoxia and all-type cancer incidence [ 127 ]. However, a recent meta-analysis did not find a significant relationship, and studies are limited particularly for the inadequate control for obesity and the limited differentiation between different types of cancers [ 128 ].
Association of OSA and comorbidities may magnify the cardiometabolic risk aggravating morbidity and mortality
Optimal blood pressure control is more difficult to achieve in hypertensive OSA patients [ 129 , 130 ] and there is a high prevalence of drug-resistant hypertension in the OSA population. Among the deleterious consequences of OSA, the most alarming are arrhythmias and sudden cardiac death. Rates of atrial fibrillation with poor response to medications or exhibiting recurrence of atrial fibrillation after electrical cardioversion or ablation are higher in patients with OSA [ 131 ]. Poorly controlled type 2 diabetes is also more frequent in the presence of severe OSA [ 132 ]. The number of hospitalisations and the mortality rate increase in cardiac failure patients with associated OSA [ 133 ]. In stroke patients, sleep apnoea has a negative impact on long-term outcome [ 78 ]. The comorbid condition of COPD and OSA is characterised by heightened inflammation and increased cardiovascular risk, reflecting the synergistic deleterious impact of both diseases [ 134 ].
Evaluation of the relevance of obesity and OSA on cancer, and the specific relevance of intermittent hypoxia and sleep fragmentation in humans based on large epidemiological studies coupled with pre-clinical models.
Evaluation of an independent cardiometabolic risk factor in OSA.
Evaluation of the risk associated with OSA compared with sedentary behaviour, obesity, smoking and other factors.
Evaluation of the inclusion of OSA in integrated cardiometabolic risk reduction management.
Evaluation of the epidemiology of the comorbid condition of COPD and OSA, considering stratification for OSA and COPD severity.
Evaluation of a specific COPD–OSA overlap syndrome based on pathophysiological or prognostic factors.
Relevance of OSA/intermittent hypoxia on outcomes and relative biomarkers in COPD patients.
Definition of subgroups benefitting from CPAP treatment, especially resistant hypertension, atrial fibrillation, poorly controlled type 2 diabetes, overlap syndrome (COPD–OSA), bronchial asthma and IPF.
Evaluation of the effect of CPAP on cardiometabolic risk in primary prevention.
Treatment and outcomes
Osa treatment has limited impact in reducing cardiometabolic risk.
CPAP and other therapies for OSA have been viewed as benefitting sleepiness and other aspects relating to quality of life, in addition to reducing risk of comorbidity and mortality [ 135 – 138 ]. As OSA is clearly associated with metabolic and cardiovascular conditions, an effective treatment of OSA may then represent an important target for improving cardiometabolic risk. The impact of CPAP, the first-line therapy of OSA, on cardiovascular or metabolic consequences is limited and still under debate [ 42 , 139 ]. The impact of CPAP or oral appliance on blood pressure is small (−2 mmHg for mean 24 h blood pressure) [ 137 ], being clinically relevant only in the resistant hypertension population [ 138 ]. Reported benefits are best in CPAP-compliant patients and especially compliance sufficient to cover rapid eye movement periods at the end of the night [ 140 , 141 ]. Whereas earlier reports indicated that fixed CPAP was superior to autoadjusting CPAP in reducing blood pressure, a recent report indicates that fixed CPAP has equal effects to autoadjusting CPAP in lowering blood pressure levels [ 142 – 144 ]. Mandibular advancement device (MAD) therapy has also been reported to benefit blood pressure on OSA patients [ 145 ].
CPAP does not appear to improve lipid profile or metabolic syndrome in unselected OSA populations [ 26 ]. Regarding glucose control, improvements were reported only in subgroups with suboptimally controlled type 2 diabetes [ 140 ] and prolonged nocturnal CPAP use allowing to cover REM sleep periods at the end of the night [ 141 ]. It is not realistic to expect a clinically relevant decrease in cardiometabolic mortality in secondary prevention with sole CPAP therapy as suggested by the SAVE study [ 6 ]. It did not report any benefit from CPAP therapy in reducing the incidence of future cardiovascular and cerebrovascular events in OSA patients with established cardiovascular and cerebrovascular disease, but was compromised by poor treatment compliance and low EDS, while other reports indicate that CPAP improves cardiovascular outcomes in patients with established cardiovascular disease who adequately comply with therapy [ 6 , 22 ]. The recent data demonstrating lack of efficacy of CPAP in the secondary prevention of cardiovascular disease do not exclude the possibility of benefit in the primary prevention of cardiovascular disease, although very large patient numbers may be required to evaluate this aspect. In the face of limited resources for future trials, carefully designed registries with "big data", based on real-life observations ( e.g. ESADA), could be a more pragmatic approach. In trials, to overcome poor adherence leading to poor outcome, a run-in phase to optimise adherence could be justified. The negative findings of the SAVE trial may also justify prospective randomised controlled studies of more symptomatic patients with moderate/severe OSA, where treatment compliance may be expected to be higher.
A major issue is that some patients show huge CPAP treatment effects, while others do not benefit at all, with no way for clinicians to distinguish between likely responders and nonresponders [ 27 ]. The identification of responder phenotypes, including a set of predictive biomarkers, would be particularly helpful for asymptomatic or only minimally sleepy OSA patients who will not accept CPAP treatment, unless some other major benefits, such as an improvement in cardiometabolic risk, can be predicted [ 146 ].
Regarding comorbidities overall, CPAP has little efficacy in the secondary prevention of cardiovascular and metabolic comorbidities, but the possibility of benefit remains in highly compliant patients and in some patient subgroups that remain poorly defined.
One area of CPAP therapy that is growing in clinical practice is its role as part of the diagnostic pathway to establish the relationship between symptom profile and OSA, especially in highly symptomatic patients with mild OSA [ 147 , 148 ]. Lack of symptom improvement in CPAP-compliant patients indicates that reported symptoms may be the result of other factors such as restless legs syndrome or other sleep disturbance. However, symptomatic improvement with CPAP supports the relationship of daytime symptoms such as EDS to OSA and may increase the likelihood of benefit from other therapies such as MADs, although this possibility has not been validated in prospective studies.
Combined therapeutic strategies for individualised treatment of OSA and comorbidities
Usual antihypertensive agents are less effective in reducing blood pressure in OSA patients, especially at night and in the morning, although recent evidence indicates that morning administration of antihypertensive therapy is superior to evening [ 149 ]. Combining CPAP with medications reduces blood pressure in a clinically relevant way in CPAP-compliant patients [ 130 ]. A recent meta-analysis revealed that CPAP is associated with a gain in weight of 0.5 kg compared with control therapy [ 150 ]. As many OSA patients are obese, CPAP treatment should be combined with weight loss and recent evidence indicates that baseline oropharyngeal calibre influences the degree of benefit [ 151 , 152 ]. Lifestyle modifications, including physical activity, through a wide variety of secondary prevention programmes substantially reduced mortality, recurrent heart attacks and blood pressure [ 153 ]. In OSA, only one study evaluated CPAP coupled with weight loss, which when combined was superior in improving blood pressure, insulin resistance and lipid profile than either treatment alone [ 152 ]. There is a strong rationale for future mechanistic and clinical research into treatment strategies combining CPAP with comprehensive risk factor management, and to identify personalised therapies for addressing cardiovascular and metabolic risk factors of OSA patients.
Opportunities and challenges of telemedicine
The quality of care a sleep centre provides is mainly determined by individual patient management over the long term, including continuing efforts to maintain optimal CPAP therapy, rapid detection of low compliance and personalised consideration of alternatives to CPAP where appropriate [ 154 , 155 ]. Telemedicine offers possibilities to diagnose and follow-up OSA patients [ 156 – 166 ], but several open questions, including ethics, data ownership, prescription, storage, usage and reimbursement issues, slow down its implementation [ 156 ]. It remains unclear if telemedicine can replace direct patient–nurse contact and/or permit better treatment customisation [ 167 – 169 ]. Critical aspects must be clarified, including the respective role of companies and physicians in patient care, and the risk of unauthorised use of “big data” [ 170 ].
Alternative treatment options for OSA
Several alternative treatment options to CPAP and weight loss are available for selected patient populations, which focus on specific target groups and recognise the increasing demand for tailored treatment [ 155 , 171 ]. Open questions regarding alternatives to CPAP include the prediction of success, long-term outcomes and health economics [ 24 ]. There is an urgent need to define reliable predictors of treatment success and long-term outcomes [ 172 – 176 ].
Mandibular advancement devices
Although less effective in reducing AHI, evidence supports the use of MADs in mild/moderate OSA, even in positional OSA, with associated symptom improvement [ 142 , 177 , 178 ]. In severe cases, MADs are clearly inferior to CPAP [ 179 ]. As there is a large variety of MADs, scientific data cannot be translated from one device to another. Standardisation of MADs is needed to guide therapeutic recommendations and comparison of total costs [ 145 , 180 ].
Ablative surgery
Most ablative surgical options cannot be recommended as single interventions and should only be considered in highly selected patients [ 177 , 181 – 183 ]. Tonsillectomy, which is a common therapy in paediatric OSA, also benefits adult patients with enlarged tonsils [ 184 ]. Maxillomandibular osteotomy appears as effective as CPAP in selected patients refusing conservative treatment [ 177 , 185 ]. Bariatric surgery may be particularly effective in selected obese OSA patients [ 177 , 186 ].
Positional therapy
Positional therapy is as effective as CPAP in reducing AHI in positional OSA, but sleep disturbance is a major concern and long-term compliance is poorly documented [ 187 – 189 ]. Devices to assess long-term compliance with positional therapy are needed. Socially disturbing snoring often persists in the nonsupine positions. Substantial nonresponse, partial improvement, patient selection and treatment costs remain significant concerns.
Hypoglossal nerve stimulation
Results from randomised controlled trials of hypoglossal nerve stimulation are promising [ 190 ], but data on long-term outcomes are limited, given evidence is based on the same nonrandomised clinical trial (STAR trial), characterised by an unexplained large dropout rate (28%) after 48 months of follow-up [ 191 – 194 ]. Being a responder or nonresponder is partly explained by the resulting tongue protrusion or retrusion after hypoglossal nerve stimulation and related to the stimulation of proximal or more distal nerval branches [ 195 ]. Only a minority of patients are eligible for this intervention [ 196 ]. There is a need for a more precise description of treatment responders based on outcome parameters equivalent to CPAP and for a better understanding of the underlying pathophysiology relating to treatment response [ 197 , 198 ]. The use of predictor techniques for hypoglossal stimulation response ( e.g. drug-induced sleep endoscopy) is not supported by conclusive prospective studies.
Pharmacological therapy
Pharmacological therapy for OSA has shown disappointing results in earlier studies, but pharmacotherapy for selected patients is still under debate [ 199 ]. Pharmacological therapy typically targets certain aspects of pathophysiology such as pharyngeal collapsibility, obesity, arousal threshold and loop gain, which supports a personalised approach to treatment [ 15 , 200 – 202 ]. Liraglutide is the first pharmaceutical compound having an indication for OSA, by targeting weight reduction in selected populations, although its effect is weak, resulting in a decline in AHI of only 30% [ 203 ]. Desipramine has been demonstrated to reduce pharyngeal collapsibility in healthy subjects during sleep [ 204 ] and to lower AHI in selected OSA patients [ 205 ], but its use is hampered by significant side-effects. The combination of supplemental oxygen and a hypnotic has been reported to benefit OSA patients with mild/moderate pharyngeal collapsibility [ 206 ], presumably by beneficial effects on arousal and loop gain, and could be considered in highly selected patients where insomnia is a prominent feature. Hypnotic use in such patients needs to be carefully considered, given the adverse events associated with hypnotics (fall risk, memory impairment, progression of OSA and the fact that most patients never stop them). Oxygen supplementation may be considered in patients with persisting hypoxaemia despite CPAP therapy, which has been reported to improve perceived physical functioning [ 207 ]. Finally, a recent report indicates benefit from acetazolamide therapy in OSA and comorbid hypertension with reductions in both AHI and blood pressure levels [ 208 ].
Integrated approach to patient management
While CPAP remains the treatment of choice for most patients with moderate/severe OSA, alternative and/or additional treatment options can be considered, depending on the clinical and pathophysiological phenotypic traits [ 15 , 209 ]. Clinical variables include body mass index, EDS, insomnia, upper airway anatomical factors ( e.g. micrognathia or adenotonsillar hypertrophy), in addition to comorbidities, especially arterial hypertension. Pathophysiological variables include upper airway collapsibility and dilator muscle function, arousal threshold, and loop gain. Where upper airway collapsibility predominates, CPAP is the most appropriate management option, but where other factors play a major role, additional or alternative treatment options could be considered, such as pharmacological therapy or hypoglossal nerve stimulation (where upper airway dilating muscle response is inadequate) and other pharmacological agents with oxygen supplementation (where arousal threshold and loop gain play a significant role). Surgical approaches can be considered where a correctable anatomical abnormality is identified and in bariatric surgery for major obesity. A schematic illustration of the complex role of phenotypes in management considerations of OSA is given in figure 4 . Categorising and treating patients based on clinical and pathophysiological phenotypic traits is an attractive theoretical concept, but nevertheless, very little data are available supporting such an approach in daily practice.
Role of clinical and pathophysiological traits in treatment selection for obstructive sleep apnoea (OSA). Schematic illustration of the potential impact of phenotypic traits on treatment options in OSA. Individual treatment options are given different emphasis, based on their relative importance in the overall management of OSA, although the evidence to support the use of drug therapy and O 2 supplementation in modifying arousal threshold and loop gain is limited. EDS: excessive daytime sleepiness; CPAP: continuous positive airway pressure; O 2 : oxygen.
Evaluation of predictors of treatment outcome.
Evaluation of the concept of “diagnostic treatment”.
Evaluation of phenotypes predisposing to benefit from surgery, MADs and drugs.
Identification of potential benefits of surgical interventions.
Inclusion of objective evaluation of snoring and cardiovascular outcome parameters in outcome studies.
Identification of treatment options focusing on pathophysiological aspects (loop gain and arousal threshold) and sleep stages (reduction in rapid eye movement sleep).
Evaluation of the additional long-term effect of oxygen in insufficient positive airway pressure response.
Evaluation of the combination of OSA treatment with other interventions.
Validation of biomarkers predicting CPAP responses.
Identification of the most appropriate therapeutic strategy in OSA patients without symptoms, given their limited acceptance of CPAP.
- Conclusions
The heterogeneity of breathing disturbances associated with OSA, daytime or night-time symptoms and end-organ damage advocates against a simple approach focusing mainly on AHI. There is an urgent need for the definition of phenotypes, based on polysomnographic, clinical and outcome parameters. The diagnostic work-up should integrate this multifactorial approach, define severity, not only based on AHI, but include EDS, NPDs ( e.g. cognitive impairment and depression), associated sleep disturbances ( e.g. insomnia), consequences and prognosis. This may facilitate an individualised and critical use of positive airway pressure and emerging new therapies. These considerations indicate that adequate training and expertise are required of clinicians treating patients with OSA, and support the implementation of speciality training and certification in sleep medicine for sleep practitioners, as advocated by both the ERS and ESRS [ 210 , 211 ].
Conflict of interest: W. Randerath reports grants and personal fees (travel grants and speaking fees) from Heinen & Löwenstein, Weinmann, ResMed, Inspire and Philips Respironics, outside the submitted work. L. Ferini-Strambi reports personal fees from Philips Respironics (honoraria for a lecture and for chairing a scientific meeting in 2015–2016, none of which involved promotion of company products and there was no influence on lecture content) and ResMed (honoraria for participating in an advisory board), outside the submitted work. R. Farre reports other fees from ResMed (a contract between the company and the University of Barcelona (Fundació Bosch Gimpera) for assessing automatic CPAP devices in a bench test) and other fees from ANTADIR (a contract between the company and the University of Barcelona (Fundació Bosch Gimpera) for assessing automatic CPAP devices in a bench test), outside the submitted work. L. Grote reports grants and personal fees (speakers’ bureau) from ResMed and Philips, personal fees from Breas Mecical (consultancy), personal fees and nonfinancial support from Heinen & Löwenstein (consultancy), and grants from the ERS, during the conduct of the study; and personal fees (speakers’ bureau) from AstraZeneca, outside the submitted work. In addition, L. Grote has a patent on pharmacological treatment of OSA pending. J. Hedner has together with the ESADA study group received grants from ResMed and Philips Respironics to enable the ESADA database. He has also received personal speaker bureau fees from AstraZeneca, Takeda and Bayer. M. Kohler reports personal fees from Bayer (advisor fees), outside the submitted work. J-L. Pepin reports unrestricted research grants from Philips, ResMed, Fisher & Paykel, Fondation de la recherche medicale, Direction de la recherche Clinique du CHU de Grenoble and Fond de dotation “Agir pour les maladies chroniques”, and personal fees (travel grants and lecture fees) from Perimetre, Philips, Fisher & Paykel, ResMed, AstraZeneka, SEFAM, Agiradom and Teva, during the conduct of the study. J. Verbraecken reports other fees (sponsoring courses) from Koninklijke Philips Respironics, ResMed, Fisher & Paykel, NightBalance, Heinen & Löwenstein, AirLiquide, Accuramed, OSG, Medidis, MediqTefa, Wave Medical, Vivisol, TotalCare, SomnoMed, UCB Pharma, Olympus Belgium, Takeda, Masimo and Linde Healthcare, outside the submitted work. W.T. McNicholas reports personal fees from Philips Respironics (honoraria for lectures, but none of these lectures related to promotion of company products and the lecture content was not in any way influenced by the company), outside the submitted work.
Support statement: The Think Tank meeting was funded by unrestricted grants from the European Sleep Foundation (former Alpine Sleep Summer School) Sleep and Health (Lugano, Switzerland), Respironics GmbH (Herrsching, Germany) and ResMed EPN Ltd (Vimercate, Italy). Role of the funding source: none.
- Received December 16, 2017.
- Accepted April 25, 2018.
- Copyright ©ERS 2018
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Related Articles
- Vol 7, No 8 (August 28, 2015) /
- Obstructive sleep apnea is a common disorder in the population—a review on the epidemiology of sleep apnea
Obstructive sleep apnea is a common disorder in the population—a review on the epidemiology of sleep apnea
Karl A. Franklin 1 , Eva Lindberg 2
1 Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden ; 2 Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden
Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: Not applicable; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Abstract: The prevalence of obstructive sleep apnea (OSA) defined at an apnea-hypopnea index (AHI) ≥5 was a mean of 22% (range, 9-37%) in men and 17% (range, 4-50%) in women in eleven published epidemiological studies published between 1993 and 2013. OSA with excessive daytime sleepiness occurred in 6% (range, 3-18%) of men and in 4% (range, 1-17%) of women. The prevalence increased with time and OSA was reported in 37% of men and in 50% of women in studies from 2008 and 2013 respectively. OSA is more prevalent in men than in women and increases with age and obesity. Smoking and alcohol consumption are also suggested as risk factors, but the results are conflicting. Excessive daytime sleepiness is suggested as the most important symptom of OSA, but only a fraction of subjects with AHI >5 report daytime sleepiness and one study did not find any relationship between daytime sleepiness and sleep apnea in women. Stroke and hypertension and coronary artery disease are associated with sleep apnea. Cross-sectional studies indicate an association between OSA and diabetes mellitus. Patients younger than 70 years run an increased risk of early death if they suffer from OSA. It is concluded that OSA is highly prevalent in the population. It is related to age and obesity. Only a part of subjects with OSA in the population have symptoms of daytime sleepiness. The prevalence of OSA has increased in epidemiological studies over time. Differences and the increase in prevalence of sleep apnea are probably due to different diagnostic equipment, definitions, study design and characteristics of included subjects including effects of the obesity epidemic. Cardiovascular disease, especially stroke is related to OSA, and subjects under the age of 70 run an increased risk of early death if they suffer from OSA.
Keywords: Epidemiology; population-based; sleep apnea; prevalence
Submitted Nov 27, 2014. Accepted for publication Jun 14, 2015.
doi: 10.3978/j.issn.2072-1439.2015.06.11
Introduction
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial and complete airway obstructions during sleep with repetitive apneas and hypopneas as a result ( 1 ). The disease severity is measured using the apnea-hypopnea index (AHI), i.e., the mean number of apneas and hypopneas per hour of sleep. OSA is defined when the AHI is ≥5 and OSA syndrome when AHI ≥5 is accompanied with daytime sleepiness ( 1 ). The American Association of Sleep Medicine defined daytime sleepiness as mild, moderate and severe in relation to impact on social life during the daytime ( 1 ). The Epworth Sleepiness Scale (ESS) is, however, the most often used measure to define daytime sleepiness ( 2 , 3 ). Diagnostic equipment and definitions of oxygen desaturations, apnea, hypopnea, OSA and daytime sleepiness has, changed over time, which in turn affects estimates of the prevalence of sleep apnea.
In the first prevalence surveys when sleep apnea was considered a rare disorder, sleep recordings were only performed in sub-samples with a high risk of OSA in a first-stage screening procedure, and the estimated prevalence in the whole population was based on the assumption that there was no OSA at all among the remaining participants. The estimated prevalence of OSA syndrome in these studies ranged from 0.7% to 3.3% ( 4 - 8 ).
Patients in sleep clinic cohorts have all been referred for the diagnostic sleep test because of symptoms suggestive of the diagnosis and they are most frequently heavy snorers suffering from daytime sleepiness. Epidemiological studies on sleep apnea will identify all subjects with OSA defined as AHI ≥5. However, only part of them will have symptoms such as snoring and daytime sleepiness reflecting subjects eligible for sleep apnea investigation on clinical grounds. This article reviews the epidemiology of OSA on prevalence and associated factors including possible risk factors and consequences.
Prevalence of OSA
We identified eleven population-based epidemiological studies from US, Chine, Spain, India, Korea, Japan and Sweden published between 1993 and 2013. All eleven studies were done in two stages. In stage one, they send postal questionnaires to a random sample of the population. In stage two, they investigated a random sample of responders from stage one, with oversampling of subjects who reported snoring and daytime sleepiness and then weighted their results to the population. The prevalence of OSA defined at an AHI ≥5 were a mean of 22% (range, 9-37%) in men and 17% (range, 4-50%) in women ( Table 1 , Figure 1 ) ( 3 , 8 - 17 ). OSA syndrome defined as apnea-hypopnea index ≥5 and excessive daytime sleepiness occurred in 6% (range, 3-18%) of men and in 4% (range, 1-17%) of women ( Figure 1 ). The prevalence in different studies has increased with time and OSA in the last studies was reported in 37% of men and in 50% of women ( 3 , 16 ). The differences over time could be due to different equipment and definitions for the apnea-hypopnea scoring. There are also differences in study design and populations. The results may also be affected by an increased amount of obese subject due to the obesity epidemic.
Associated factors with OSA
OSA is more common in men than women. The male-to-female ratio is estimated to about 2:1 in the general population ( Table 1 , Figure 1 ) and the prevalence of snoring shows similar gender differences ( 18 - 20 ). The male predominance is higher in clinical populations ( 21 , 22 ). Possible explanations for the male predominance include hormonal effects on upper airway muscles and collapsibility, gender differences in body fat distribution and differences in pharyngeal anatomy and function. Hormonal influences could play an important role in the pathogenesis of OSA, as the prevalence seems to be higher in post- versus pre-menopausal women ( 17 , 23 ). The pathophysiological roles of hormones are, however, unclear and the gender differences in prevalence remained also in the elderly ( 24 ).
A recent study, by Franklin et al ., reported that sleep apnea occurs in as much as 50% of females aged 20-70 years old in the population ( 3 ). There was no relationship between OSA and daytime sleepiness in this study. Instead hypertension, obesity and age were associated with sleep apnea in females. It is, thus, possible that sleep apnea has not been observed as a public heath problem in females, as they have other signs of sleep apnea than males.
Snoring frequency increases with age up to 50 to 60 years old and then decrease in both men and women ( 6 , 18 , 25 , 26 ). The prevalence of OSA also increases with age independent of other risk factors including obesity ( 3 , 8 , 27 , 28 ). On the contrary to snoring, the prevalence of OSA still increases also after the age of 60 years ( 3 , 8 , 10 ). Bixler et al. reported an increase in OSA after 65 years but the frequency of OSA syndrome declined ( 8 ). The above findings indicate that self-reported snoring and doctor-diagnosed OSA syndrome display similar age distributions with a decline at older ages in contrast to the age distribution of OSA with an AHI over five that increase with age also in the elderly.
Several studies have reported little or no association between sleep-disordered breathing and morbidity and mortality at older ages, and it has been suggested that sleep apnea in seniors represents a specific entity compared with middle-aged adults ( 29 ).
Obesity is a major risk factor for snoring and sleep apnea and a majority of patients with OSA are overweight ( 3 , 30 - 32 ). Caloric restriction or bariatric surgery reduces the severity of sleep apnea ( 28 , 33 - 36 ). One randomized controlled study reported a decrease in AHI using very low calorie diet ( 37 ). Another recent study reported that despite an effect of diet on AHI compared with continuous positive airway pressure (CPAP), patients were still better off with the combination of diet and CPAP than with CPAP alone ( 38 ). Men are more likely than women to increase their AHI at a given weight gain regardless of starting weight, waist circumference, age, or ethnicity ( 39 ).
Obesity is believed to predispose to OSA because of mass loading in the upper airway ( 40 ). Controversy remains whether specific measures of body habitus, such as neck or waist circumference, are better predictors of sleep-disordered breathing as compared with body mass index (BMI) alone. Neck circumference was in a population-based sample more important as a risk factor for snoring with increasing BMI in obese than in lean women ( 26 ).
Young et al. estimated that 58% of moderate to severe cases of OSA is due to a BMI of ≥25 kg/m 2 ( 34 ). This highlights the need for effective strategies to implement long-term weight-loss programs to prevent OSA and the ongoing epidemics of obesity. Not only subjects with obesity and fat necks suffer from sleep apnea, but also lean subject and about one-third of OSA syndrome patients are non-obese ( 41 ). Franklin et al. reported that 39% of normal weighted women had OSA but only 0.1% of them had severe sleep apnea ( 3 ).
Several cross-sectional epidemiological surveys observed significant associations between cigarette smoking and snoring or sleep apnea ( 18 , 19 , 42 - 46 ). Possible underlying mechanisms include airway inflammation and sleep instability from overnight nicotine withdrawal ( 47 ). Never-smokers who have been exposed to passive smoking on a daily basis display an increase in the odds of being a habitual snorer of 1.6 (95% CI, 1.2-2.1) after adjusting for age and BMI according to the Respiratory Health in Northern Europe Study ( 44 ). In a Swedish longitudinal study, smoking predicted the development of snoring in men younger than 60 years old but not in older ones ( 25 ).
Wetter et al. found a dose-response relationship between smoking and the severity of sleep apnea. Heavy smokers ran the greatest risk, while former smoking was unrelated to snoring and sleep-disordered breathing after adjustment for confounders ( 46 ). Smoking is, however, not an established risk factor for OSA. In the analysis from the Sleep Heart Health Study, smokers actually displayed less sleep apnea than non-smokers and there are still no available data on the impact of smoking on the incidence and remission of sleep apnea ( 48 ).
Alcohol intake reduces motor output to the upper airways with hypotonia of the oropharyngeal muscles as a result ( 49 ). In studies performed in the laboratory, alcohol increases both the number of apneas and the duration of apnea ( 50 , 51 ). The results did, however, diverge, when the relationship between chronic alcohol use and snoring or sleep apnea was analyzed in epidemiological studies and an association was found by some but not by others ( 13 , 25 , 30 , 52 - 54 ). Svensson et al. reported that alcohol dependence was only related to snoring in lean women with a BMI of <20 kg/m 2 ( 26 ). It is thus possible that the alcohol-induced reduction in motor output to the upper airways is more important in lean women without compromised upper airways from fat deposits and overweight.
Excessive daytime sleepiness
Excessive daytime sleepiness is regarded as the most common and most important symptom of OSA. Numerous randomized controlled trials have demonstrated a significant improvement in daytime sleepiness when such patients are effectively treated with CPAP as compared to sham CPAP or oral placebo ( 55 - 60 ).
Daytime sleepiness is related to OSA and snoring in the general population studies ( 9 , 61 - 63 ). In the Wisconsin Sleep Cohort Study, about 23% of the women with an AHI of ≥5 reported excessive daytime sleepiness compared with only 10% of non-snoring women ( 9 ). The corresponding prevalence in men was 16% and 3% respectively. Similar findings were reported from the Sleep Heart Health Study using the ESS with a significant, progressive increase in sleepiness with increasing AHI in both older and younger subjects and independent of gender, age and BMI ( 61 ).
The evidence of apnea induced daytime sleepiness is, however, weak as only a fraction of patients with OSA in the population report daytime sleepiness. Attempts to find the suggested association between the arousals and sleepiness have also failed ( 64 , 65 ). Daytime sleepiness can be due to a number of factors and OSA patients may have suffered from other disorders of sleepiness than sleep apneas. Svensson et al. reported that snoring, but not sleep apnea (AHI >15) was related to excessive daytime sleepiness ( 63 ). The association between OSA and sleepiness is also less evident in patients with chronic disease such as in patients with congestive heart failure who report less daytime hypersomnolence regardless of whether they have OSA or not ( 66 ). Sleepiness is also frequently reported in the absence of OSA in elderly people and in patients with end-stage renal disease ( 67 , 68 ).
Hypertension
Sleep apnea and hypertension are both prevalent in the community and many individuals suffer from both. Several large population-based, cross-sectional studies reported an independent association between the two conditions ( 3 , 10 , 69 - 72 ). Self-reported snoring is also a predictor of developing hypertension in both males and females ( 43 , 73 , 74 ). Peppard et al. analyzed the odds ratios for the presence of hypertension at a 4-year follow-up among 709 middle-aged participants in the Wisconsin cohort, all of who had been investigated with polysomnography at baseline. Compared with subjects with no OSA, the adjusted odds ratio for prevalent hypertension at follow-up was 2.03 (95% CI, 1.29-3.17) for mild OSA (AHI, 5-14.9) and 2.89 (95% CI, 1.46-5.64) for moderate to severe OSA (AHI ≥15) ( 75 ). The same group also provided data from a sub-group who were followed-up after a mean of 7 years using 24-hour blood pressure studies. Regardless of confounders including baseline blood pressure and progress of sleep apnea, there was a significant dose-response relationship between the severity of sleep apnea at baseline and the risk of developing systolic non-dipping blood pressure during sleep ( 76 ).
The impact of snoring and OSA on hypertension is less pronounced in overweight and obese subjects when compared with normal-weights in population-based samples ( 43 , 69 , 71 ). Analyzed by age group, there is an independent relationship of snoring or OSA on hypertension among young and middle-aged participants, but not in the elderly ( 71 - 73 , 77 , 78 ). An AHI of ≥15 was independently associated with hypertension in subjects aged <60 years, with an adjusted odds ratio of 2.38 (95% CI, 1.30-4.38), among 6,120 participants in the Sleep Heart Health Study, while no such relationship was found between sleep apnea and hypertension among subjects above that age ( 72 ).
Although observational studies indicate a causal relationship between OSA and hypertension the effectiveness of reducing blood pressure by treating OSA is less clear and intervention studies using CPAP have produced mixed results ( 79 ).
Coronary artery disease
OSA frequently coexists, but is usually being undiagnosed in patients with cardiovascular disease and several cross-sectional studies support a strong association between OSA and prevalent coronary artery disease, defined as myocardial infarction and/or angina pectoris ( 80 - 82 ). However, sleep apnea was assessed after coronary artery disease was established in the cited studies and thereby limits the conclusion on an etiologic relationship. Cross-sectional epidemiologic studies on self-reported coronary artery disease and snoring or objectively measured OSA have reported a positive association, although of considerably smaller magnitude than that observed in case-control studies ( 18 , 83 ). Among 6,424 participants who underwent in-home polysomnography in the Sleep Heart Health Study, Shahar et al. reported that subjects with the highest quartile of AHI >11 had an adjusted odds ratio of 1.27 of self-reported coronary artery disease after adjusting for confounders including hypertension ( 84 ). The relative high age with a mean of 64 years old of participants at study start could be an explanation to the rather modest association.
Patients with OSA had a higher incidence of coronary artery disease (16.2%) compared with snorers without OSA (5.4%) in a prospective study over 7 years ( 85 ). Efficient treatment with CPAP significantly reduced the risk of adverse cardiovascular outcomes both when it comes to primary and secondary prevention ( 85 - 87 ).
Population-based prospective studies on sleep apnea and incidence of coronary artery disease are still lacking.
Clinical cohorts suggest an important link between sleep apnea and stroke. Spriggs et al. followed patients with recent stroke until death or 6 months and found that previous stroke and regular snoring were the only two risk factors that adversely affected mortality ( 88 ). Yaggi et al. followed 1,022 patients being investigated on clinical grounds an concluded that OSA syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension ( 89 ). Valham et al. found a dose-response relationship between AHI at baseline among patients with coronary artery disease and the incidence of stroke during a 10-year follow-up after adjusting for potential confounders ( 90 ). Moreover, in stroke survivors, the occurrence of OSA, but not central sleep apnea, was a significant predictor of early death ( 91 ).
Population based studies also support the evidence of stroke due to OSA. Munoz et al. reported that severe sleep apnea (AHI ≥30) at baseline was associated with a significantly increased risk of developing an ischemic stroke (adjusted hazard ratio 2.52, 95% CI, 1.04-6.01) from a 6-year longitudinal study of a population-based cohort, initially event-free subjects aged 70-100 years ( 92 ). Arzt et al. investigated a younger population-based cohort of 1,189 subjects, mean age 47 years with polysomnography. During the following 4 years, 14 subjects suffered a first-ever stroke and this was related to sleep apnea defined as an AHI of ≥20 at baseline, although the association did not reach statistical significance after adjusting for age, gender and BMI (adjusted OR 3.08, 95% CI, 0.74-12.81) ( 93 ).
Diabetes mellitus
Sleep-disordered breathing and diabetes mellitus share several risk factors. Insulin resistance and/or type 2 diabetes mellitus coexist with snoring or sleep apnea in general population cross-sectional studies independent of obesity and other confounders ( 94 - 101 ). Furthermore, an independent association between self-reported snoring and incident diabetes is reported in both males and females ( 102 , 103 ).
Longitudinal studies on OSA as a risk factor for future diabetes mellitus have not been conclusive. Among 1,387 participants in the Wisconsin Sleep Cohort, subjects with an AHI ≥15 did not differ significantly from those with an AHI of <5 when it came to the risk of developing diabetes mellitus over a 4-year period (OR 1.62; 95% CI, 0.7-3.6) when adjusting for age, gender, and body habitus ( 99 ). Similar findings were reported from the Busselton health study ( 104 ). On the contrary, Botros et al. found an independent association between sleep apnea at baseline and incident diabetes in an observational cohort study including 1,233 consecutive patients without diabetes ( 105 ). Also in a long-term follow-up of a community-based sample of men there was an independent association between oxygen desaturation index >5 at baseline and incident diabetes mellitus at follow-up after 11 years (OR 4.4; 95% CI, 1.1-18.1), after adjusting for age, BMI, and hypertension at baseline and delta BMI and years with CPAP during follow-up ( 106 ).
Clinic-based studies suggest that patients with OSA syndrome have a higher mortality risk ( 107 ) and that treatment with tracheostomy or CPAP attenuates this risk ( 108 - 110 ). The lack of randomized, controlled interventional trials clearly limits the evidence, as non-treated patients have either been non-compliant with prescribed therapy or have for some reason not been selected for effective treatment. Clinical mortality studies might also be biased, as patients under treatment for some other serious morbidity might also be more likely to be referred for an evaluation of sleep apnea, leading to an overestimation of mortality.
The results diverge in studies investigating whether patients with OSA syndrome have a shorter survival or not. No increased mortality rate was found between apnea-hypopnea scores in two prospective studies investigating elderly populations ( 111 , 112 ), while a significant association was seen in another study, but in women only ( 113 ). Lavie et al. in a prospective study found that the apnea index was a predictor of excess mortality in the fourth and fifth decade but not in elderly men ( 107 ). This is in accordance with the results from of a population-based study from Uppsala in Sweden where men aged 30-69 years were investigated by postal questionnaire and followed over 10 years ( 114 ). Snoring men reporting excess daytime sleepiness had a significant increase in mortality, but the age-adjusted relative risk decreased with increasing age and was no longer significant after age 50 years. Snoring alone had no impact on mortality in any of the age groups ( Table 2 ).
The impact of OSA on mortality in population-based cohorts has recently been analyzed in the Wisconsin Study ( 23 ), and in the Sleep Heart Health Study ( 115 ), and both reported an increased mortality rate with increasing severity of sleep apnea ( Table 2 ). Subjects with an AHI ≥30 had an adjusted hazard ratio for all-cause mortality of 3.0 (95% CI, 1.4-6.3) and 1.46 (95% CI, 1.14-1.86) respectively, compared with those with an AHI of <5. Similar results were obtained for cardiovascular mortality in both studies and the exclusion of subjects treated for sleep apnea did not change the results. However, the adjusted hazard ratios for severe sleep apnea only remained significant in younger men <70 years in the Sleep Heart Health Study.
Conclusions
OSA is highly prevalent in the population. It is related to age and obesity. Only a part of subjects with OSA in the population have symptoms in the form of daytime sleepiness. The prevalence of OSA and OSA syndrome has increased in epidemiological studies over time. Differences and the increase in prevalence of sleep apnea are probably due to different diagnostic equipment, definitions, study design and characteristics of included subjects. Cardiovascular disease, especially stroke is related to OSA and subjects under the age of 70 run an increased risk of early death if they suffer from OSA.
Acknowledgements
Conflicts of Interest: The authors declare no conflict of interest.
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