European Respiratory Society
Obstructive Sleep Apnoea

Obstructive sleep apnoea (OSA) is a common and progressive chronic disease. It is responsible for a high number of comorbidities and is linked with increased mortality, including a rise in the rate of sudden cardiac death. It is widely acknowledged that OSA now affects millions of people worldwide. This Monograph considers this high-impact condition from four different perspectives: pathogenesis; at-risk populations; clinical scenarios; and treatment and management. Comprehensive and up-to-date chapters provide the reader with a concise overview of OSA, making this book a useful reference for pulmonologists concerned with the management of this disease.

  • ERS Monograph
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    1. Page 1
      Renaud Tamisier, Laboratoire EFCR, CHU de Grenoble, CS 10217, 38043 Grenoble Cedex 09, France. E-mail:

      OSA syndrome causes nocturnal chronic IH, sleep fragmentation, intrathoracic pressure swings and carbon dioxide surges. Clinical studies demonstrate a close relationship between IH and excess cardiovascular morbidity. To explore the consequences of IH per se, we and others have used different settings of IH in animals, cells and healthy humans to characterise the different pathways driven by IH that alter cardiovascular physiology, from vascular inflammation to atherosclerosis and excessive sympathetic tone to high BP. These different settings are clearly bringing different and complementary insights, independently of cofactors such as age, obesity and associated metabolic disease and CVD. Moreover, they allow us to trigger exposure in specific target cells or organs using different exposure durations, or using transgenic animals or a specific diet. In this chapter, we briefly review the different settings allowing IH exposure and summarise the mechanisms that have been proposed to reflect those underlying the cardiovascular morbidity associated with OSA syndrome.

    2. Page 9
      Danny J. Eckert, Neuroscience Research Australia (NeuRA), PO Box 1165, Randwick, Sydney, New South Wales 2031, Australia. E-mail:

      OSA is a multifactorial disorder with several physiological phenotypes. Pharyngeal anatomy/collapsibility is the primary abnormality in most OSA patients. However, the extent of UA anatomical compromise varies widely between OSA patients. Many have only a modest degree of anatomical impairment. Accordingly, a number of other non-anatomical contributors also play a role. These include an oversensitive ventilatory control system, a low respiratory arousal threshold, and poor pharyngeal muscle responsiveness or effectiveness during sleep. The contribution of these non-anatomical factors has only recently been recognised. This chapter reviews the data establishing the importance of these variables and describes a graphic, physiological model integrating them to illustrate their relative contribution. Ultimately, such a model could be useful for guiding therapy and advancing the field of OSA management beyond the “one size fits all” approach of CPAP.

    3. Page 24
      Isaac Almendros, Section of Sleep Medicine, Dept of Pediatrics, Biological Sciences Division, The University of Chicago, KCBD, Room 4115D, 900 E. 57th Street, Chicago, IL 60637-1470, USA. E-mail:

      Recently, an increasing number of epidemiological studies has focused on potential associations between cancer and OSA, and are generating intense interest in the field. IH and sleep fragmentation, the two hallmark features of OSA, have been shown to increase tumour growth, invasion and metastasis in mice. However, the potential mechanisms underlying the intersection between cancer and OSA are only now being explored and are, therefore, far from being well understood. This is due, in part, to the multiplicity of sleep disorder phenotypes and also to the myriad of cancers, which will require comprehensive and systematic translational investigations to elucidate specific biological mechanisms that account for the clinical correlates being currently uncovered. In this chapter, the state-of-the-art in vivo and in vitro published data on the effects of IH and sleep fragmentation in tumour malignancy are presented, and potential mechanistic pathways that may be involved (e.g. oxidative stress, inflammation and immunomodulation) are discussed.

    4. Page 37
      Ferran Barbé, Respiratory Dept, Hospital Univ Arnau de Vilanova, Rovira Roure 80, 25198 Lleida, Spain. E-mail:

      OSA is a common disease that affects approximately 10% of the middle-aged population and becomes more prevalent with age. It is caused by intermittent and repetitive collapse of the UA during sleep. The main acute physiological consequences of OSA are oxygen desaturation, intrathoracic pressure changes and arousals. OSA is associated with significant cardiovascular morbidity and mortality and is an independent risk factor for CVD. The pathogenesis of CVD in OSA is not completely understood but is likely to be multifactorial, involving a diverse range of closely interrelated and detrimental intermediate mechanisms that predispose patients to atherosclerosis, including oxidative stress, sympathetic activation, inflammation, hypercoagulability, endothelial dysfunction and metabolic dysregulation. IH is considered to lead to increased oxidative stress, systemic inflammation and sympathetic stimulation. Despite the existence of these detrimental mechanisms, there are epidemiological studies that suggest that some protective mechanisms could also be activated in OSA patients. This chapter describes the underlying mechanisms linking OSA with CVD.

    5. Page 51
      T. Douglas Bradley, University Health Network, Toronto General Hospital, 9N-943, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada. E-mail:

      OSA is highly prevalent in patients with HF. The relationship between OSA and HF is likely to be bi-directional. The presence of OSA leads to exaggerated swings in negative intrathoracic pressure, surges in sympathetic nervous system activity, IH and frequent awakenings, all of which may have adverse cardiovascular consequences and contribute to the progression of HF. Fluid overload, secondary to HF, may lead to increased fluid shift from the legs during sleep. Resulting fluid redistribution to the neck may lead to UA narrowing and increased UA collapsibility that could contribute to the pathogenesis of OSA. In patients with OSA, therapies that reduce leg fluid volume while awake, such as compression stockings and diuretics, or therapies that reduce total body fluid volume at night, such as diuretics and nocturnal dialysis, can attenuate OSA severity. In HF patients with OSA, diuretic therapy leads to increased UA size and attenuation of OSA severity.

    1. Page 66
      Francisco Campos-Rodríguez, Sleep-Disordered Breathing Unit, Respiratory Dept, Hospital Universitario de Valme, 41014, Seville, Spain. E-mail:

      OSA is a common disorder with sex differences with respect to prevalence, clinical complaints and pathophysiology. Despite these differences, most of the research on OSA has been conducted in studies with a large predominance of men, so the consequences and appropriate treatment of this sleep disorder in women have rarely been addressed.

      Recent data suggest that women with OSA may have greater quality of life impairment than their counterparts. The association between OSA and cardiovascular consequences is controversial, but recent observational studies have shown an increased incidence of severe cardiovascular outcomes and mortality in women with OSA. Treatment with CPAP may play a role in reversing this excess cardiovascular risk in women.

      The physiological changes of pregnancy may predispose females to develop OSA. OSA during pregnancy has been associated with increased risk of adverse maternal and fetal outcomes. CPAP may play a role in protecting against these consequences, but more research in this field is still needed.

    2. Page 90
      Frédéric Roche, Dept of Clinical Physiology, EFCR, CHU Nord, Level 6, F-42055 Saint-Étienne Cedex 2, France. E-mail:

      Ageing substantially increases the incidence of OSA. However, the disease remains underdiagnosed despite the rising costs of healthcare that the lack of support can cause. In middle-aged adults, EDS, CVD, depression, accelerated cognitive decline and traffic accidents should prompt screening and an evaluation of the severity of OSA. Although OSA in the elderly seems to have a lower impact on mortality than it does in middle-aged adults, the risk of stroke and new-onset hypertension appears to increase in elderly patients. In addition, the presence of CSA must prompt a thorough heart disease assessment, even in the elderly. Both elderly and middle-aged symptomatic OSA patients derive equivalent benefits from CPAP treatment. In the future, epidemiological as well as interventional studies should be carried out in elderly patients, whose number will increase hugely in the coming years.

    3. Page 103
      Sheila Sivam, Sleep & Circadian Research Group, Woolcock Institute of Medical Research, PO Box M77, Missenden Road, NSW 2050, Australia. E-mail:

      OSA is more prevalent in the obese. Bariatric surgery is an effective method to reduce and maintain longer-term weight loss. The additional benefits of weight loss on comorbidities associated with obesity, such as cardiovascular risk factors and cancer, as well as relative reduction in death has resulted in the increased popularity of bariatric surgery in the obese population. Many trials demonstrate a greater beneficial effect of bariatric surgery over lifestyle modification for weight loss, as well as for OSA severity and metabolic outcomes. However, this is not a universal finding. Despite significant reductions in OSA severity, very few patients are cured of OSA following bariatric surgery hence post-operative polysomnography may be necessary prior to cessation of CPAP. Furthermore, ongoing diet and behavioural modification is necessary to maintain the significant weight loss achieved with bariatric surgery.

    4. Page 115
      Leila Kheirandish-Gozal, Section of Pediatric Sleep Medicine, Dept of Pediatrics, Pritzker School of Medicine, The University of Chicago, 5841 S. Maryland Avenue/MC2117, Chicago, IL 60637-1470, USA. E-mail:

      In this chapter, we highlight salient differences in both the aetiology and pathophysiology of OSA in children compared with adults, and will document their clinical management implications. The aetiology of paediatric OSA is usually the confluence of multifactorial elements including anatomical factors (e.g. enlarged adenoids and tonsils) that promote intrinsic UA narrowing and factors that contribute to UA collapsibility (e.g. UA inflammation and altered neurological reflexes). Adenotonsillectomy remains the mainstay of treatment but medical anti-inflammatory therapies such as nasal steroids and leukotriene antagonists are gaining wider acceptance in the treatment of mild OSA. OSA morbidities primarily involve the neurocognitive, cardiovascular and metabolic systems. However, the phenotypic variance of paediatric OSA is only partially explained by its severity, such that a combination of genetic and environmental factors is likely to be an important contributor, opening the door for implementation of genomic and proteomic approaches to enable future personalised diagnosis and management.

    5. Page 131
      Jean-Louis Pépin, Laboratoire EFCR, CHU de Grenoble, BP217X, 38043 Grenoble cedex 09, France. E-mail:

      Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (BMI ≥30 kg·m−2), daytime hypercapnia (arterial carbon dioxide tension ≥45 mmHg) and sleep disordered breathing after ruling out other disorders that may cause alveolar hypoventilation. OHS is a chronic condition associated with impairments of body structures or functions, leading to a decrease in daily life activities, a lack of social participation, and high risk of hospitalisation and death. Despite its severity, OHS is largely underdiagnosed. This chapter discusses the definition, epidemiology, physiopathology and treatment modalities. Clinicians should adapt treatment modalities, aiming to improve the specific impairments, dysfunctions and handicaps of each OHS patient. From this perspective, the three main strategies available are nocturnal PAP therapies (NIV/CPAP), body weight loss strategies and rehabilitation.

    6. Page 147
      Eusebi Chiner Vives, Secció de Pneumologia, Hospital Universitari Sant Joan d'Alacant, Ctra. Alacant-València s/n, CP: 03550, Sant Joan d'Alacant, Spain. E-mail:

      OSA is a highly prevalent disorder with limited diagnostic resources. Alternatives to “gold standard” in-laboratory PSG include clinical prediction models, single-channel devices, home respiratory polygraphy and home PSG. In addition, ambulatory strategies or integrated models (with ambulatory and hospital elements) can be used in the diagnostic approach. Patients with the following have a high risk of developing OSA: obesity, HF, atrial fibrillation, hypertension, type 2 diabetes mellitus, stroke, pulmonary hypertension and a history of bariatric surgery evaluation. Specific diagnostic considerations in these patients are reviewed in this chapter, including commentaries regarding the selection of the diagnostic devices or clinical pathways in these groups of patients.

    7. Page 161
      José M. Marin, Respiratory Dept, Hospital Miguel Servet, 1–3, Avda Isabel la Católica, 50006-Zaragoza, Spain. E-mail:

      Increased prevalence of OSA is not seen amongst those with chronic pulmonary diseases such as COPD, asthma, pulmonary fibrosis or pulmonary hypertension. However, prognosis does worsen when OSA and chronic pulmonary diseases overlap. Obesity is a key risk factor for OSA development, not only in the general population but also in patients with chronic respiratory diseases. Sleep in pulmonary patients with OSA overlap is characterised by higher sleep fragmentation and more severe hypoxaemia than in those with COPD or OSA alone. Untreated OSA is associated with increased mortality in the classic “overlap syndrome” (OSA plus COPD); noninvasive ventilation reduces such excessive risk. OSA is an independent risk factor for asthma exacerbations and worsened respiratory symptoms in patients with asthma and pulmonary fibrosis. CPAP is a very effective treatment for OSA. All patients with chronic pulmonary diseases should be carefully evaluated to rule out the coexistence of OSA.

    8. Page 179
      Mark Elliott, Dept of Respiratory Medicine, St James' University Hospital, Beckett Street, Leeds, LS9 7TF, UK. E-mail:

      There is a strong association between OSA syndrome (OSAS) and road traffic accidents (RTAs). The reason for the high risk of RTAs in OSAS is probably related to excessive sleepiness and impaired cognitive function. The most important and effective method to reduce RTAs in OSAS is treatment with CPAP. The evidence for other treatments reducing RTAs is weak.

      The assessment of driving risk in an individual patient with OSAS is challenging. The use of subjective and objective tests has limitations. Driving simulators are potentially an important tool for the assessment of driving risk, but at this stage can only be used for research and cannot yet be recommended for routine clinical practise. It is unlikely that a single test with a clear cut-off, pass or fail, will ever be able to accurately predict who is safe and not safe to drive. The clinician will continue to have a major role, weighing up a number of different factors that are likely to impact upon safe driving.

    1. Page 191
      Miguel Ángel Martinez-García, Pneumology Service, Hospital Universitario y Politécnico La Fe, Avenida Fernando Abril Martorell, no. 106, 46026-Valencia, Spain. E-mail:

      Resistant hypertension (RH) is defined as BP that stays above the goal despite the concurrent use of three anti-hypertensive agents at optimal doses. The prevalence of RH could be higher than 20% in hypertensive individuals, representing an additional cardiovascular risk in these patients.

      OSA is present in more than 70–80% of RH patients. Several pathophysiological mechanisms have been invoked to explain this relationship including an increased sympathetic tone and hyperaldosteronism. Obesity is the major confounder since it is highly prevalent in both OSA and RH.

      Some clinical trials have found that CPAP treatment has a beneficial effect on BP in patients with RH, with effects greater than those seen in well-controlled hypertensive patients.

      Current scientific evidence indicates that every patient with chronic snoring and RH (especially those with obesity), independent of the presence or absence of daytime hypersomnolence, should undergo a sleep study. This is due to the high prevalence of OSA with this high-risk cardiovascular profile and the potential beneficial effect of CPAP treatment.

    2. Page 205
      F. Javier Nieto, Dept of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin, 610 Walnut Street, WARF Building 707C, Madison, WI 53726, USA. E-mail:

      Emerging epidemiological research linking OSA with cancer outcomes is based on strong evidence from laboratory and animal experiments, which show that intermittent hypoxaemia can enhance cancer growth and/or metastasis by promoting angiogenesis, changes on immune function, or inflammatory changes and oxidative stress. In this chapter the epidemiological evidence linking OSA and cancer incidence or cancer mortality is critically analysed.Using Hill's causality analysis framework, this review found moderately strong evidence that OSA might promote cancer growth and decrease cancer survival. Evidence in support of a role of OSA as a risk factor for cancer incidence is substantially weaker but this hypothesis cannot be ruled out at this time.In addition to mechanistic studies, future research should include studies in different population settings and further clarification as to whether OSA increases cancer incidence, mortality or both. An additional critical area for further research is whether cancer patients with OSA would benefit from OSA treatment.

    3. Page 221
      Maria R. Bonsignore, DiBiMIS, University of Palermo, Via Trabucco 180, 90146 Palermo, Italy. E-mail:

      OSA is a common disorder with major cardiovascular and metabolic consequences. OSA is often associated with metabolic syndrome, a cluster of cardiometabolic risk factors, and prevalence of metabolic syndrome is particularly high in OSA patients. The role of obesity as a risk factor for OSA has been shown in population and clinical studies, and increased adipose tissue volume and neck circumference are closely linked with OSA, even though major sex-related differences exist. Besides OSA treatment, cardiometabolic risk factors should be assessed and possibly corrected in all OSA patients in order to reduce adverse events. Occurrence of metabolic syndrome should be investigated, and modifiable risk factors aggressively treated especially in obese patients. Improvement of the metabolic state after OSA treatment with CPAP has been reported by some but not all studies, suggesting the need to treat additional cardiometabolic disorders and adopt strategies aimed at reducing body weight in OSA patients.

    1. Page 238
      Jan Hedner, Sleep Disorders Center, Department of Pulmonary Medicine and Allergology, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden. E-mail:

      Excess body weight and lack of exercise are associated with increased risk of OSA. RCTs have shown that weight loss and physical activity improve sleep-disordered breathing in OSA patients. Moreover, long-term follow-up studies on the effect of an intensive lifestyle weight-management programme have yielded promising results. The therapeutic effect of weight-reduction drugs on OSA has not been systematically explored. Few drugs have been approved for pharmacological management of overweight and obesity in Europe despite an increasing obesity epidemic. Currently, there is no effective drug for OSA treatment in clinical practice. The fact that multiple pathophysiological mechanisms contribute to this complex disease highlights the importance of better patient phenotyping for tailored therapy. Recent advances in the field certainly bring hope for such a development.

    2. Page 253
      Frédéric Gagnadoux, Dépt de Pneumologie, CHU Angers, 4 rue Larrey, 49033 Angers, France. E-mail:

      Nasal CPAP is the primary treatment of OSA, but many patients are unable or unwilling to comply with this treatment. MADs have emerged as the main non-CPAP therapeutic option for OSA. Despite its lower efficacy to reduce sleep disordered breathing, most trials comparing MADs and CPAP reported similar health outcomes. The greater efficacy of CPAP may be offset by a lower compliance relative to MADs. Individual titration of mandibular advancement is of primary importance to achieve successful MAD therapy. Younger, thinner patients with positional OSA and lower AHI appear to be most successful with MAD therapy. However, there is no reliable method to individually predict treatment response. The dentist plays a key role in determining whether the patient is a good dental candidate for MAD therapy, selecting the appropriate device and detecting side-effects during long-term MAD therapy.

      We will review the evidence in favour of MAD therapy and discuss the main challenges to the success of MADs in treating OSA.

    3. Page 266
      Winfried J. Randerath, Institute of Pneumology at the University Witten/Herdecke, Clinic for Pneumology and Allergology, Centre of Sleep Medicine and Respiratory Care, Bethanien Hospital, Aufderhöherstraße 169–175, 42699 Solingen, Germany. E-mail:

      Sleep-related breathing disorders can present with several phenotypes of OSA and CSA, and also hypoventilation. These include disorders with increased (e.g. high altitude or periodic breathing in CVDs) or reduced respiratory drive (e.g. opioid-induced sleep apnoea), and reduced minute ventilation in neuromuscular, skeletal or chronic pulmonary diseases. A subgroup of patients present with combinations of various phenotypes, which can be called a coexisting or complicated breathing pattern. The term “complex sleep apnoea” should be reserved for patients with newly emerging and persisting CSA under application of PAP. Optimal treatment requires precise determination of the underlying pathophysiology in order to select the best available therapy. New devices and algorithms combine fixed or automatically adapted expiratory pressure to overcome UA obstruction, variable pressure support to address increased or decreased ventilatory drive, and mandatory breaths to counterbalance CSA. The spectrum of PAP algorithms allows for individualised treatment and should be carefully adapted under polysomnographic control by experienced sleep specialists.

    4. Page 280
      Valentina Isetta, Unit of Biophysics and Bioengineering, Faculty of Medicine, University of Barcelona, Casanova 143, Barcelona, 08036, Spain. E-mail:

      Adequate adherence to treatment with CPAP is important, particularly during the first weeks of therapy. Therefore, different educational and training approaches have been suggested as potential tools to improve adherence, based on integrative and multidisciplinary networking. However, due to the current social and economic situation, overloaded sleep centres frequently have difficulties providing these services. Strategic changes towards alternative and more cost-effective methods of diagnosis and treatment are urgently needed. The use of telemedicine, defined as the use of information and communication technology to deliver healthcare at a distance, has significant potential for the management of patients with OSA. Together with its potential impact on healthcare utilisation and subsequent cost reductions, telemedicine promotes equity of access to healthcare. Moreover, its delivery is efficacious, facilitating the decentralisation of services and improvement of networking among different healthcare professionals. Nevertheless, further definitive long-term studies with cost-effectiveness analyses are needed.

    5. Page 293
      Doug McEvoy, Adelaide Institute for Sleep Health, Repatriation General Hospital, Daws Road, Daw Park, SA, Australia, 5041. E-mail:

      OSA is a highly prevalent, chronic condition that is frequently associated with modifiable risk factors and multiple medical comorbidities. Effective management of OSA requires a comprehensive, multidisciplinary, patient-centred approach that addresses not only the sleep disordered breathing events but also includes evaluation for and treatment of related medical comorbidities and strategies to optimise treatment adherence. Integrated care for OSA involves collaboration between health professionals from a variety of disciplines. There is significant potential for specialist nurses, as well as primary care physicians, to take greater responsibility for the diagnosis and management of OSA. Strategies aimed at promoting patient self-management and improving communication between patients and healthcare providers, including structured chronic disease self-management programmes and use of e-health interventions and related technologies, may be of benefit for patients with OSA.

    6. Page 305
      Patrick Lévy, EFCR, Pôle Thorax et Vaisseaux, CHU de Grenoble, BP 217 X, 38043, Grenoble, France. E-mail:

      Treatment of OSA has been extensively studied in the past 15 years. There has been a large number of controlled studies evaluating CPAP effects on sleepiness and daytime functioning, BP, cardiovascular outcomes, and metabolic parameters. These studies may help to determine to what extent CPAP is able to reverse the chronic consequences of OSA. Although there is a clinically significant impact of CPAP on EDS and daytime functioning as well as a reduction in BP, EDS may persist in a significant proportion of patients and BP may fall only modestly under CPAP, i.e. 1 to 3 mmHg. In addition, other cardiovascular morbidities seem to be moderately improved by CPAP. Other treatments, such as weight loss, positional treatment, oral appliances (MADs), UA stimulation and UA surgery, should be considered, although the degree of evidence is much less strong than that regarding CPAP. Using these data, in this chapter, we describe treatment strategies according to OSA severity. Lastly, we suggest that comparison and combination of treatment modalities, e.g. CPAP for OSA alleviation and specific cardiovascular or metabolic treatments, may be critical as regards full reversion of the chronic consequences of sleep apnoea.