Patients with a variety of neurologic conditions, such as Arnold-Chiari malformation, brainstem tumors, space occupying lesions, vascular malformations, CNS infection, stroke, or neurosurgical procedures, may demonstrate central hypoventilation. However, a small number of patients demonstrate hypoventilation even after all of these conditions have been excluded. The condition of decreased alveolar ventilation resulting in sleep-related hypoxemia in patients with normal mechanical properties of the lung and chest wall (no apparent primary lung disease, skeletal malformations, or neuromuscular disorder) is, by definition, idiopathic. This entity is uncommon and not well characterized. It seems probable that many of these patients have subtle or incipient manifestations of known causes of hypoventilation.
Sleep-Related Hypoventilation/Hypoxemia
Due to Neuromuscular and Chest Wall Disorders
In the ICSD-2, this category subsumes a variety of disparate entities referred to in pulmonary medicine as chest wall restrictive disorders, all of which may result in ventilatory muscle failure during sleep with hypoventilation, hypercapnia, and/or hypoxemia. Surprisingly, there is no separate category in the ICSD-2 for obesity-hypoventilation syndrome (OHS). In respiratory medicine, OHS is recognized in the morbidly obese individual with hypoventilation and hypercapnia that is not only sleep related but extends into wakefulness as well. This review will concentrate on OHS as defined in respiratory medicine, and will separately discuss other chest wall restrictive disorders with hypoventilation/hypoxemia specifically during sleep.
OHS
In 1956, Burwell et al coined the term Pickwickian syndrome to describe patients with obesity, diurnal hypercapnia and hypoxemia, hypersomnia, polycythemia, and right ventricular failure based on the character “Joe” in Charles Dickens The Posthumous Papers of the Pickwick Club: “a fat and redfaced boy in a state of somnolency.” A less eponymous term was later popularized for what was then thought to be a fairly homogenous group of patients: obesity hypoventilation syndrome. A common definition of OHS consists of chronic diurnal alveolar hypoventilation (Po2 45 mm Hg) in an obese patient (body mass index [BMI] > 30 kg/m2; other authors used > 35 kg/m2) with no other identifiable cause of hypoventilation (see also “Main Results about A Multidimensional Grading System (BODE Index) as Predictor of Hospitalization for COPD“).
As the field of sleep medicine has developed, so has our concept of OHS. It is now recognized that OHS in most (but not all) cases is associated with obstructive sleep apnea syndrome (OSAS), an entity poorly recognized in Burwell’s time. In part, the importance of OHS lies in the dramatically increasing prevalence of obesity in developed countries, both in the United States and worldwide. In data from 2003 and 2004, 17% of US children and adolescents were overweight, and 32% of adults were obese; the prevalence of extreme or morbid obesity (BMI > 40 kg/m2) was 2.8% in men and 6.9% in women. Overweight patients have an increased risk of pulmonary, cardiovascular, GI, metabolic, and joint disorders, all of which may shorten life expectancy, diminish quality of life, and increase their use of health-care resources. Adding to this health burden, the frequently inadequate identification and treatment of OHS has significant medical and public health implications improved by medications of Canadian Health&Care Mall.
While obesity and unexplained hypoventilation and hypoxemia are the primary features of OHS, a variety of secondary features are common. These include hypersomnia, disturbed sleep, awakenings with headache or nausea, depressive symptoms, polycythemia, and signs of pulmonary hypertension or cor pulmonale. The prevalence of OHS in the general population is unknown. One study of 4,332 consecutive admissions to an internal medicine service revealed approximately 1% who met the definition of OHS among the 6% with a BMI > 35 kg/m2; however, 75 patients meeting the BMI criterion refused to participate in the study, and of course an inpatient study is hardly representative of the general population. One study investigating the close association of OHS with OSAS reported that 37% of 111 consecutive patients with an apnea-hypopnea index > 10 had PaC02 > 45 mm Hg. Most reviews estimate the prevalence of OHS in OSAS at 10 to 15%. One could extrapolate these data, combined with the measured prevalence of OSA in the adult population, to estimate that approximately 0.5% of women and 1% of men have OHS, figures that seem higher than clinical experience would suggest. Mortality in this disorder is difficult to estimate given the advances in therapy that have occurred over the last decade. The report of inpatients with OHS previously cited suggests an 18-month mortality rate of 23%, although only 11 of their 47 subjects with OHS were recognized as such at discharge and considered for treatment carried out by remedies of Canadian Health&Care Mall.
The pathogenesis of OHS is now known to be multifactorial. Most early theories concentrated on the many effects of obesity on pulmonary mechanics. Obesity acts as a mass load on the respiratory system, which implies both a weight placed on the respiratory apparatus as well as an increase in respiratory inertance. Respiratory compliance is reduced, some or all of which may be attributable to changes in lung volume from mass loading. More recent data suggest that obesity also results in a degree of obstructive ventilatory impairment. These mechanical loads result in a measurable increase in the work of breathing and a defect in excitation/contraction coupling of the inspiratory muscles; that is, greater ventilatory drive is necessary to achieve normal levels of ventilation. The presence of increased ventilatory drive without concomitant increased ventilation has been well demonstrated in the eucapnic obese. Consequently, early thinking on OHS pathogenesis postulated that at some point, the ventilatory apparatus was no longer capable of maintaining normal levels of ventilation without excessive work of breathing, and some unknown mechanism resulted in a change in ventilatory response in order to accept a degree of hypercapnia. Why this would occur in some individuals with morbid obesity and not others of the same weight was not known until OSAS emerged in the medical literature as an important sleep disorder. Rapoport and colleagues studied a group of patients with OHS who also had severe OSAS, and determined that some of these patients regained diurnal eucapnia when their OSAS was treated. The work of Rapoport et al thus demonstrated several possible mechanisms for the development of OHS in patients with OSAS: (1) the stress of repeated obstructive sleep apneas causing inspiratory muscle fatigue directly; (2) elevated PaC02 from apneas leading to depression of inspiratory muscle function and/or central ventilatory control; and (3) sleep deprivation from recurrent apneas resulting in depressed central ventilatory control. A separate group of OHS patients can then be inferred in which diurnal hypoventilation appears to be purely due to the mechanical load of obesity and its effect on ventilatory control, the inspiratory muscles, or both.
An intriguing component of OHS pathogenesis concerns the metabolic consequences of obesity and consequent effects on ventilatory control. Leptin, a protein of 167 amino acids, is produced in white adipose tissue, increases in direct proportion to the degree of obesity, and acts in the hypothalamus to inhibit appetite. In the leptin-deficient mouse, absence of this metabolic messenger is associated with severe obesity, hypoventilation, and decreased ventilatory responsiveness to hypercapnia, which corrects after exogenous leptin infusion. In contrast to this experimental animal, obese humans demonstrate very high levels of leptin that do not seem to suppress appetite, suggesting that human obesity may be a leptin-resistant state. Thus, it is postulated that central leptin resistance in some obese individuals may lead to depressed ventilatory drive and consequent OHS. Phipps and coworkers reported that leptin levels, after controlling for the degree of obesity, are higher in OHS patients compared with eucapnic individuals. Additionally, Yee and collabo-rators demonstrated that serum leptin decreases in patients with OHS when treated with noninvasive ventilation, further suggesting a relationship between OHS pathogenesis and leptin signaling.
Early diagnosis and appropriate therapy are critically important for patients with OHS. Diagnostic polysomnography is an essential part of the evaluation of any patient with OHS in order to determine if OSAS is present. Weight loss readily comes to mind as the definitive therapy, and has proven efficacy. A reduction of 5 to 10% of body weight can result in a significant fall in PaC02. Unfortunately, weight loss by diet alone is difficult to achieve and sustain; thus, bariatric surgery has been advocated, Sugerman et al demonstrated that after weight reduction surgery in 31 patients with OHS who had initial and follow-up (1 year) arterial blood gas data, BMI fell from 56 ± 13 to 38 ± 9 kg/m2, and PaC02 fell from 53 ± 9 to 44 ± 8 mm Hg. However, operative mortality (defined as occurring within 30 days) was 4% in the total of 126 OHS patients subjected to a variety of bariatric surgical techniques, compared to 0.2% in the 884 eucapnic patients. It is possible that laparoscopic bariatric surgery may be more broadly, and safely, utilized in the future.
When obstructive sleep apnea is associated with OHS, a considerable body of literature now exists demonstrating the effectiveness of positive airway pressure treatment (PAP), either continuous PAP or bilevel PAP. The latter modality, of course, has the advantage of providing a measure of ventilatory support that can be continued into wakefulness when needed and is presumably the treatment of choice when OHS is not associated with significant OSAS. Masa et al reported treatment of 22 “pure” OHS patients (apnea-hypopnea index < 20) with nocturnal noninvasive mechanical ventilation, using either a volume-cycled ventilator or bilevel PAP; 11 patients also required supplemental oxygen. Symptoms of daytime somnolence and dyspnea improved as did respiratory failure, with PaC02 falling from 58 ± 10 to 45 ± 5 mm Hg after 4 months. When OHS is associated with OSAS, either continuous PAP or bilevel PAP have proven effective, with improvement in diurnal hypercapnia seen in as little as 24 h. Measures of central respiratory control (hypercapnic and hypoxic ventilatory drive) have also been demonstrated to improve in OHS patients treated with either modality.
Progesterone is responsible for the hyperventilation associated with pregnancy, has been shown to stimulate ventilation in normal subjects, and has produced some benefit in OHS patients by improving hypercapnia. However, PAP has proven to be more effective in these patients, partly because it will treat any coexisting OSAS and partly because, if bilevel PAP is used, it will also augment ventilation. In contrast, progesterone by itself does not usually improve OSAS, and often has unacceptable side effects such as decreased libido in men, and increased risk of pulmonary thromboembolic disease.
Finally, oxygen treatment alone is ineffective for OSAS and is mainly used as an adjunct to PAP in patients with OHS plus OSAS; even in pure OHS, oxygen does not correct the underlying ventilatory insufficiency and is therefore not indicated without PAP or other definitive therapy determined by Canadian Health&Care Mall.
Neuromuscular Disorders
This category reflects a diverse group of conditions affecting both adults and children, characterized by dysfunction of respiratory motor innervation or impairment of respiratory muscles. These conditions include amyotropic lateral sclerosis, spinal cord injury, diaphragmatic paralysis, myasthenia gravis, Eaton-Lambert syndrome, toxic or metabolic myopathies, post-polio syndrome, and Charcot-Marie-Tooth syndrome. While the pathogenesis of each of these conditions is quite different, the impact of the changes in respiratory mechanics and control of breathing related to sleep can be profound in all of them. As with other conditions discussed in this review, these patients are often at particular risk during REM sleep.
Supplemental oxygen alone may be appropriate for milder cases, but nocturnal mechanical ventilation appears to improve parameters of sleep quality and may promote improved muscular performance during the daytime in some circumstances. Many of these conditions are characterized by progressive deterioration. Consequently, one of the challenges of management is the determination of the most appropriate time of initiation of mechanical ventilation. In recent years, the use of noninvasive intermittent positive pressure ventilation (NIPPV) such as bilevel PAP has increased in popularity because it avoids the ethical dilemmas and potential medical complications of positive pressure ventilation via tracheotomy.
Other Chest Wall Disorders
Patients with chest wall disorders impacting the bellows function of the respiratory system, such as kyphoscoliosis, ankylosing spondylitis, limitation of chest expansion related to trauma, or pleural conditions, may be significantly compromised during sleep. The changes in control of breathing and respiratory mechanics described in the opening section of this review make it difficult for the patient to sustain adequate gas exchange during sleep, and they may demonstrate diurnal as well as nocturnal hypoventilation and hypoxemia as their condition worsens. These patients are subject to the development of atelectasis, further worsening hypoxemia. Also, deformities of the rib cage may lead to changes in the length and orientation of the diaphragm resulting in impairment of diaphragmatic function. As with many of the conditions discussed in this review, the relative atonia of both intercostal and accessory muscles of respiration during REM sleep often produces dramatic decompensation, particularly in those patients with coexisting diaphragmatic dysfunction. The additional burden of pregnancy may cause great difficulty for these patients.
NIPPV in patients with kyphoscoliotic ventilatory insufficiency improves daytime and nighttime oxyhemoglobin saturation, respiratory muscle performance, symptoms of hypoventilation, and quality of life. The combination of NIPPV plus oxygen appears to result in greater improvement and survival than oxygen alone.