Current perspectives on the obesity hypoventilation syndrome

PURPOSE OF REVIEW: Identifying and treating obesity hypoventilation syndrome is an important therapeutic goal, especially given the high morbidity and mortality associated with untreated disease. Significant weight loss or effective treatment of upper airway obstruction will reverse daytime hypoventilation, suggesting that these two mechanisms play key roles in the development and progression of this disorder. Only a subset of morbidly obese patients will develop awake hypercapnia, however, even in the presence of sleep disordered breathing. This implies that complex interplay between a number of known and unknown mechanisms is needed to produce daytime respiratory failure in this patient population. RECENT FINDINGS: Work in the mouse model of obesity has been central in advancing our understanding of the role leptin plays in stimulating ventilation. Leptin deficiency or development of leptin resistance in obesity leads to alterations in central respiratory drive and reduced ventilatory responsiveness, permitting development of carbon dioxide retention. Changes in neuromodulators resulting from the effects of hypoxia may further exacerbate the problem by depressing arousal from sleep in the face of abnormal breathing. SUMMARY: Understanding the various mechanisms contributing to development of obesity hypoventilation is important in order to identify new approaches to effective long-term management of this disorder.     

Assessment and management of patients with obesity hypoventilation syndrome

Obesity hypoventilation syndrome (OHS) is characterized by obesity, daytime hypercapnia, and sleep-disordered breathing in the absence of significant lung or respiratory muscle disease. Compared with eucapnic morbidly obese patients and eucapnic patients with sleep-disordered breathing, patients with OHS have increased health care expenses and are at higher risk of developing serious cardiovascular disease leading to early mortality. Despite the significant morbidity and mortality associated with this syndrome, diagnosis and institution of effective treatment occur late in the course of the syndrome. Given that the prevalence of extreme obesity has increased considerably, it is likely that clinicians will encounter patients with OHS in their clinical practice. Therefore maintaining a high index of suspicion can lead to early recognition and treatment reducing the high burden of morbidity and mortality and related health care expenditure associated with undiagnosed and untreated OHS. In this review we define the clinical characteristics of the syndrome and review the pathophysiology, morbidity, and mortality associated with it. Last, we discuss currently available treatment modalities.     

Recent advances in obesity hypoventilation syndrome

Obesity hypoventilation syndrome (OHS) consists of a combination of obesity and chronic hypercapnia accompanied by sleep-disordered breathing. During the last 3 decades, the prevalence of extreme obesity has markedly increased in the United States and other countries. With a global epidemic of obesity, the prevalence of OHS is bound to increase. Patients with OHS have a lower quality of life with increased health-care expenses and are at a higher risk for the development of pulmonary hypertension and early mortality compared to eucapnic patients with sleep-disordered breathing. Despite the significant morbidity and mortality associated with this syndrome, it is often unrecognized and treatment is frequently delayed. Clinicians must maintain a high index of suspicion since early recognition and treatment reduces the high burden of morbidity and mortality associated with this syndrome. In this review, we will discuss the definition and clinical presentation of OHS, provide a summary of its prevalence, review the current understanding of the pathophysiology, and discuss the recent advances in the therapeutic options.     

Sleep and breathing in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder, with hypotonia being the predominant feature in infancy, and developmental delay, obesity, and behavioral problems becoming more prominent in childhood and adolescence. Children with this disorder frequently suffer from excessive daytime sleepiness and have a primary abnormality of the circadian rhythm of rapid eye movement sleep. They also have primary abnormal ventilatory responses to hypoxia and hypercapnia, and these abnormalities may be exacerbated by obesity. Children with PWS are at risk of a variety of abnormalities of breathing during sleep, including obstructive sleep apnea and sleep-related alveolar hypoventilation. Clinical evaluation should include a careful history of sleep-related symptoms and assessment of the upper airway and lung function. Polysomnography should be considered for those with symptoms suggestive of sleep-disordered breathing. Treatment options depend on the underlying problem, but may include behavioral interventions, weight control, adenotonsillectomy, and nocturnal ventilation.     

Sleep abnormalities associated with neuromuscular disease: pathophysiology and evaluation

The development of respiratory failure is common in patients with neuromuscular disorders that involve the respiratory muscles. However, the high incidence of sleep-related breathing problems in this population is less well known. In patients with neuromuscular disease, nocturnal breathing abnormalities frequently precede respiratory failure during wakefulness by months or even years. These nocturnal breathing problems are caused by multiple factors, including diaphragm and upper airway muscle weakness, scoliosis, obesity, and central respiratory control problems. Advances in the understanding of the links between sleep-disordered breathing and the development of daytime dysfunction and respiratory failure has revolutionized the management of these individuals. Mask positive pressure therapy is now available to improve both quality of life and longevity for these individuals. The lack of correlation between daytime testing and the severity of nocturnal breathing abnormalities makes it difficult to predict the presence of sleep-disordered breathing. Further, patients may not always be aware of symptoms associated with sleep-disordered breathing, even if specifically questioned. However, simple bedside measurements of vital capacity and inspiratory muscle strength can provide useful guides for when nocturnal respiratory monitoring is indicated.     

Obesity hypoventilation syndrome: from sleep-disordered breathing to systemic comorbidities and the need to offer combined treatment strategies

Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (body mass index ≥ 30 kg/m(2)), daytime hypercapnia (partial arterial carbon dioxide concentration ≥45 mm Hg) and sleep-disordered breathing after ruling out other disorders that may cause alveolar hypoventilation. Through the prism of the International Classification of Functioning, OHS is a chronic condition associated with respiratory, metabolic, hormonal and cardiovascular impairments, leading to a decrease in daily life activities, a lack of social participation and high risk of hospitalization and death. Despite its severity, OHS is largely underdiagnosed and the health-related costs are higher than those of apnoeic or obese eucapnic patients. The present review discusses the definition, epidemiology, physiopathology and treatment modalities of OHS. Although nocturnal positive airway pressure therapies represent first-line treatment and are effective in improving patient outcomes, there is a need to offer combined treatment strategies and to assess the effect of multimodal therapeutic strategies on morbidity and mortality.     

Sleep and long-term ventilation

The development of sleep-disordered breathing is common in patients with chronic respiratory insufficiency due to neuromuscular and restrictive disorders, as well as in those with COPD. Nocturnal hypoventilation and obstructive and central apneas result in daytime symptoms of hypersomnolence and fatigue, and contribute to abnormalities in awake gas exchange. Long-term mechanical ventilation, delivered invasively by tracheostomy or more recently by NPPV, has been shown to eliminate sleep-disordered breathing and correct abnormalities in nocturnal gas exchange, resulting in an improvement in sleep quality. Improved daytime symptoms and gas exchange, with the suggestion of a decrease in morbidity and mortality, support the use of long-term mechanical ventilation during sleep in selected patients with these disorders.     

Pulmonary complications of obesity

Obesity can profoundly alter pulmonary function and diminish exercise capacity by its adverse effects on respiratory mechanics, resistance within the respiratory system, respiratory muscle function, lung volumes, work and energy cost of breathing, control of breathing, and gas exchange. Weight loss can reverse many of the alterations of pulmonary function produced by obesity. Obesity places the patient at risk of aspiration pneumonia, pulmonary thromboembolism, and respiratory failure. It is the most common precipitating factor for obstructive sleep apnea and is a requirement for the obesity hypoventilation syndrome, both of which are associated with substantial morbidity and increased mortality. There are numerous medical and surgical therapies for obstructive sleep apnea and obesity hypoventilation. Weight reduction in the obese is among the most effective of these measures.     

Clinical complications of obesity

The development of important respiratory disorders and significant hypertension in association with increasing body weight is not widely recognized. Altered respiratory function results from a combination of mechanical impedance to breathing exerted by thoracic and abdominal fat and a ventilation-perfusion mismatch. Sleep-disordered breathing with periods of hypoventilation, with or without apnoeic episodes, may commonly occur in patients with extreme obesity. Nocturnal hypercapnia and hypoxia in such patients may lead to a decrease in ventilatory drive, abnormal central respiratory control and possibly, in time, the development of the obese-hypoventilation syndrome. Respiratory abnormalities should be suspected in obese patients with a history of restlessness at night, loud snoring and daytime somnolence. Treatment is substantial weight reduction, but short-term measures include the use of compressed air via nasal cannulae for obstructive apnoea, and drugs which alter sleep pattern or stimulate respiration. The alterations in endocrine function, which accompany weight gain, may contribute to an increase in blood pressure and there appears to be a relationship between plasma insulin and catecholamine concentrations, fat cell size and the development of hypertension. The confirmation of a raised blood pressure requires that readings be taken with an adequately sized arm-cuff. In many instances endocrine function becomes normal with weight loss, and there is a corresponding decrease in blood pressure. The ideal management for an obese hypertensive patient is the combination of a suitable calorie-restricted diet with a programme of physical exercise.     

Misinterpretation of Sleep-Breathing Disorder by Periodic Limb Movement Disorder

We report a case of misinterpretation of sleep-disordered breathing due to periodic limb movement disorder. A 67-year-old man was diagnosed with sleep-disordered breathing and subsequently placed on treatment with nasal continuous positive airway pressure (CPAP). The initial diagnostic evaluation did not include measurement of anterior tibialis electromyogram. The respiratory disturbance index of the initial evaluation was 23. After a brief period of nasal CPAP use, the patient discontinued the treatment because no significant change in daytime alertness was noted and signs of CPAP-related insomnia appeared.The patient was restudied polysomnographically with monitoring of anterior tibialis electromyograms. This study identified 392 leg movements of which 65% were associated with brief EEG arousal from sleep.Double-blind analysis of respiratory disturbance and leg movements yielded a total number of 360 arousals in the overnight recording. Eighty-five percent of all respiratory events could be associated with central hypoventilation following periodic limb movement-associated EEG arousal. No significant hypoxia was recorded with these events.We hypothesize that chemoreceptor stimulation secondary to EEG arousal during sleep is responsible for this central hypoventilation.This case report highlights that recording and scoring of leg movements must be an integral part of polysomnographic evaluations.     

Sleep in restrictive and neuromuscular respiratory disorders

Thoracic restrictive disorders (i.e., chest wall deformities or neuromuscular diseases), may predispose to sleep-disordered breathing, poor sleep quality, and nocturnal hypoventilation. These disorders intensify the effects of reductions in both respiratory center output and central chemosensitivity and increases in upper airway resistance that occur with the onset of sleep. Normally, rapid eye movement (REM) sleep suppresses the activity of nondiaphragmatic breathing muscles, further reducing ventilation. Diaphragmatic or upper airway muscle weakness and reduced chest wall compliance in patients with thoracic restrictive disorders enhance the severity of sleep-disordered breathing during REM sleep, worsening gas exchange abnormalities and sleep fragmentation and impairing daytime functioning. Although daytime respiratory function and nocturnal oxygen saturation are not well correlated, some markers may be useful for identifying patients with thoracic restriction at risk for sleep-disordered breathing. Although some patients may respond to continuous positive airway pressure (CPAP) alone, noninvasive positive pressure ventilation (NPPV) is a more important part of disease management for patients with restrictive thoracic disorders. This technique improves nocturnal ventilation and sleep quality but may also contribute to sleep fragmentation in some patients. If the patient is an unsuitable candidate for or fails NPPV, tracheostomy mechanical ventilation should be considered.     

Apneas,hypopneas, and respiratory effort-related arousals: moving closer to a standard

The spectrum of sleep disordered breathing ranges from intermittent snoring to the obesity hypoventilation syndrome with the obstructive sleep apnea/hypopnea syndrome fitting somewhere in between. Recently, improved definitions and monitoring techniques are allowing for clearer differentiation of the syndromes within this spectrum. These new standards have also produced better understanding of the prognosis and treatment options for patients fitting into different points within this spectrum. Furthermore, effective communication of current definitions and techniques has resulted in improved reimbursement for the treatments of patients with sleep disordered breathing.     

Sleep breathing disorders and nocturnal respiratory pattern in patients with Glycogenosis type II

Patients affected by glycogenosis type II frequently present sleepdisordered breathing. The presence of symptoms suggestive of sleep breathing disorders was investigated, by a questionnaire, in 10 patients, affected by adult or juvenile forms of glycogenosis type II. Diurnal respiratory function, diaphragm weakness and nocturnal respiratory pattern were evaluated at the enrolment. In patients presenting sleep disordered breathing, the same parameters were re-evaluated after treatment with assisted non invasive ventilation. Out of 10 patients, 5 presented symptoms suggestive of sleep-disordered breathing at the baseline, 2 a pattern of sleep apnea syndrome and 3 nocturnal hypoventilation. All patients presented diaphragmatic weakness. No correlation was found between forced vital capacity values (FVC) in sit position and nocturnal respiratory disorders. Five patients with respiratory disorders were treated with non invasive ventilation. All patients – after one month of treatment - showed an improvement in symptoms with reduced diurnal hypersomnia (ESS < 10), absence of morning headaches and nocturnal awakenings, and reduced nicturia regardless the modality of ventilation. We recommend that all patients with glycogenosis type II, once diagnosed, are carefully monitored for the development of respiratory involvement, even in the absence of reduced FVC values and in the early stages of the disease, to receive appropriate therapy.Key words: glycogenosis, apnoea, hypopnea, hypoventilation, non invasive ventilation     

Sleep disorders in neuromuscular diseases

PURPOSE OF REVIEW: Patients with neuromuscular disorders (NMD) are especially vulnerable to sleep-related dysfunction. Sleep-disordered breathing often precedes diurnal respiratory failure in NMD patients, requiring timely recognition and management with noninvasive ventilation (NIV). This paper reviews the mechanisms, diagnostic evaluation, and management of sleep disorders in various neuromuscular diseases. RECENT FINDINGS: The severity, duration, and type of NMD influence the pattern of sleep disturbance. Several investigators have addressed other clinical aspects including rating scales for sleep complaints, hypocretin-1 deficiency, excessive daytime somnolence, and relation of sleep disorder with length of CTG trinucleotide repeats in myotonic dystrophy. Benefits of NIV on quality of life and survival in adults and children with chronic NMD are well established, and recently have been documented even in patients with nocturnal hypoventilation and daytime normocapnia. In contrast, the timing for investigation with polysomnography and for initiation of NIV is debated. SUMMARY: Patients with chronic NMD should be routinely assessed for sleep-disordered breathing and sleep complaints, because these are treatable complications in an otherwise progressive disease process. Further research is needed to establish the indications for polysomnography and to determine the optimal timing for initiating NIV to treat sleep-disordered breathing in patients with neuromuscular diseases.     

Pickwickian syndrome and hypersomnia with periodic respiration]

A classical definition of Pickwickian syndrome associates alveolar hypoventilation, obesity and hypersomnia with periodic breathing. Obesity in itself is enough to explain the alveolar hypoventilation and some of the sleep disorders, but in fact all three elements of this syndrome are intricated. Obesity, whether associated with a Pickwickian syndrome or not, affects ventilatory mechanics similarly. With the cause of sleep disorders are associated central ventilatory pauses, appearing periodically followed by phases of apnoea secondary to buccopharyngial hypotony. The alveolar hypoventilation is therefore the consequence of obesity and periodic apnoea. It also results from a low respiratory frequency considering that the tidal volume is also decreased. These different elements suggest some disorder of the centers controling ventilation. One can describe different nosological forms, all having as a common factor hypersomnia with periodic respiration, the latter being a determining factor in the diagnosis. Therapy, including weight reduction and symptomatic treatment of alveolar hypoventilation, is now augmented by new drugs acting on the central nervous system.     

Medical management of obstructive sleep apnea

The last 20 years have seen remarkable gains in our understanding of the pathophysiology of sleep-disordered breathing. The rapid growth in both scientific and clinical knowledge has been fueled by the development of nonsurgical therapies for obstructive sleep apnea (OSA). These medical therapies have provided the avenue for public acceptance of the diagnosis and treatment of this common medical condition. However, medical therapy requires active patient participation, to achieve the desired outcomes of improved sleep continuity, daytime functioning, and quality of life. Conservative therapies, such as weight loss and patient positioning; and pharmacological therapies, have been disappointing. Positive pressure therapy has become the treatment of choice for the vast majority of OSA patients. Oral appliances offer an acceptable treatment alternative for select patients. Present research indicates that these mechanical approaches can produce significant decreases in the frequency and severity of sleep-disordered breathing and nocturnal oxyhemoglobin desaturation. Preliminary data from ongoing studies suggest that these interventions will reduce long-term morbidity and possibly mortality.     

Non‐invasive ventilation for obese patients with chronic respiratory failure: Are two pressures always better than one?

Obesity‐related respiratory failure is increasingly common but remains under‐diagnosed and under‐treated. There are several clinical phenotypes reported, including severe obstructive sleep apnoea (OSA), isolated nocturnal hypoventilation with or without severe OSA and OSA complicating chronic obstructive pulmonary disease (COPD). The presence of hypercapnic respiratory failure is associated with poor clinical outcomes in each of these groups. While weight loss is a core aim of management, this is often unachievable, and treatment of sleep‐disordered breathing with positive airway pressure (PAP) therapy is the mainstay of clinical practice. Although there are few long‐term clinical efficacy trials, the lack of equipoise would prevent the utilization of an untreated control group. The current data support the use of PAP therapy to improve respiratory failure and is associated with improvements in health‐related quality of life, reduced healthcare utilization and reduced mortality. Both continuous PAP (CPAP) and non‐invasive ventilation (NIV) appear safe and effective in patients with obesity‐related respiratory failure and OSA, with or without COPD, and the current evidence would not support a single therapy choice in all patients. There are no studies of CPAP in patients with isolated nocturnal hypoventilation, and NIV would be the current recommendation in this patient group. Whichever starting therapy is used, titration should be performed to correct sleep‐disordered breathing and reverse chronic respiratory failure, with consideration of step‐down of the treatment based on a clinical re‐evaluation. In contrast, failure to reach physiological and clinical treatment targets should lead to the consideration of treatment escalation.     

Chronic hypoventilation syndromes and sleep-related hypoventilation

Chronic hypoventilation affects patients with disorders on any level of the respiratory system. The generation of respiratory impulses can be impaired in congenital disorders, such as central congenital alveolar hypoventilation, in alterations of the brain stem or complex diseases like obesity hypoventilation. The translation of the impulses via spinal cord and nerves to the respiratory muscles can be impaired in neurological diseases. Thoraco-skeletal or muscular diseases may inhibit the execution of the impulses. All hypoventilation disorders are characterized by a reduction of the minute ventilation with an increase of daytime hypercapnia. As sleep reduces minute ventilation substantially in healthy persons and much more pronounced in patients with underlying thoraco-pulmonary diseases, hypoventilation manifests firstly during sleep. Therefore, sleep related hypoventilation may be an early stage of chronic hypoventilation disorders. After treatment of any prevailing underlying disease, symptomatic therapy with non-invasive ventilation (NIV) is required. The adaptation of the treatment should be performed under close medical supervision. Pressure support algorithms have become most frequently used. The most recent devices automatically apply pressure support and vary inspiratory and expiratory pressures and breathing frequency in order to stabilize upper airways, normalize ventilation, achieve best synchronicity between patient and device and aim at optimizing patients’ adherence.     

Medical treatment of obstructive sleep apnea

A variety of treatment options are available for the treatment of obstructive sleep apnea in addition to positive pressure therapy and surgery. These modes of treatment might be employed in patients who cannot tolerate positive pressure therapy despite aggressive measures to improve compliance. These options include weight reduction, sleep hygiene, positional therapy, and oxygen therapy. Some of the options are still experimental and include pharyngeal muscle and hypoglossal nerve stimulators. A variety of pharmacological agents have also been used. The mechanisms by which these drugs improve sleep-disordered breathing include increasing ventilatory drive and upper airway muscle tone, reducing the amount of rapid eye movement (REM) sleep, and enhancing daytime wakefulness.