Review Article Chronic hypoventilation syndromes and sleep-related hypoventilation Sebastian Böing1*, Winfried J. Randerath1,2* 1Institute of Pneumology, Clinic for Pneumology and Allergology, Centre of Sleep Medicine and Respiratory Care, Bethanien Hospital, Solingen, Germany; 2University of Cologne, Solingen, Germany *These authors contributed equally to this work. Contributions: (I) Conception and design: All authors; (II) Administrative support: C Miltz; (III) Provision of study materials or patients: None; (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. Correspondence to: Winfried J. Randerath, MD, FCCP, Professor of Medicine. Institute of Pneumology, Clinic for Pneumology and Allergology, Centre of Sleep Medicine and Respiratory Care, Bethanien Hospital, University of Cologne, Aufderhöherstraße 169-175, 42699 Solingen, Germany. Email: [email protected]. Abstract: 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. Keywords: Chronic hypoventilation syndromes; sleep related hypoventilation; hypercapnic respiratory failure; pathophysiology; obesity hypoventilation syndrome (OHS) Submitted Jan 02, 2015. Accepted for publication Jun 05, 2015. doi: 10.3978/j.issn.2072-1439.2015.06.10 View this article at: http://dx.doi.org/10.3978/j.issn.2072-1439.2015.06.10 Introduction respectively, and destabilize the acid-base balance. However, consecutive increases of the pH value (respiratory alkalosis) Under physiological conditions, alveolar ventilation is closely or decreases (respiratory acidosis) are only measured adapted to metabolism. The minute ventilation is regulated during acute changes of ventilation. In contrast, if hyper- according to the prevailing carbon dioxide production so that or hypoventilation continues for hours, the pH level is the arterial carbon dioxide partial pressure (PaCO ) is adjusted − 2 stabilized by variations of the renal bicarbonate (HCO3 ) to values between 35-45 mmHg. Increases (hyperventilation) excretion (1). Therefore, chronic hypoventilation or decreases (hypoventilation) of the minute ventilation lead syndromes are characterized by: to excess elimination or accumulation of carbon dioxide, • Diminishment of the minute ventilation, i.e., © Journal of Thoracic Disease. All rights reserved. www.jthoracdis.com J Thorac Dis 2015;7(8):1273-1285 1274 Böing and Randerath. Chronic hypoventilation syndromes reductions of the tidal volume or breathing frequency; failure after general anesthesia, severe respiratory illness • Elevation of the PaCO2 >45 mmHg; or respiratory depressants (6). However, in most cases − • pH level in a normal range and an increase of HCO3 hypoventilation begins during childhood and is more (metabolic compensation). pronounced during sleep. The failure of central respiratory Chronic hypoventilation is also called hypercapnic drive may be associated with respiratory rest during sleep. respiratory failure or type II respiratory failure. The CCHS may be accompanied with other phenomena like diminution of minute ventilation can generate from all levels Hirschsprung’s disease, cardiac arrhythmia, and tumors (6,7). of the respiratory system including insufficient respiratory Idiopathic central alveolar hypoventilation is diagnosed drive (brain stem), impaired transmission of the breathing if diseases of lung parenchyma, airways, pulmonary impulses (spinal cord, peripheral nerve), and morphological vessels, chest volume or neuromuscular diseases (NMD), or functional abnormalities of the musculo-skeletal system drug treatment, obesity or congenital hypoventilation of the thorax. Failure of the respiratory regulation on the can be excluded (3,5). Several questions on idiopathic one hand or execution of the impulses on the other hand central alveolar hypoventilation are unresolved. The represent different facets of the pathophysiology which can pathophysiology is unclear although an impairment of be described as “won’t breathe” and “can’t breathe” (2). the hypercapnic and hypoxic chemoresponsiveness and Congenital central alveolar hypoventilation and opioid respiratory drive has been discussed. use represent examples of central disturbances, while Late-onset central hypoventilation with hypothalamic amyotrophic lateral sclerosis (ALS), phrenic nerve palsy, dysfunction is a disorder of the central control of ventilation (3). muscle dystrophies, idiopathic sclerosis are examples of It can be diagnosed if sleep related hypoventilation develops insufficient execution of ventilation. However, the obesity after the first years of life. The patients present with obesity, hypoventilation syndrome (OHS) combines components endocrine abnormalities of hypothalamic origin, severe of both pathomechanisms. Chronic hypoventilation with emotional or behavioral disturbances or a tumor of neural daytime hypercapnia and sleep-related hypoventilation origin (two of these four findings are required). Moreover, (SRH) do not differ substantially. Actually, SRH seems mutations of the PHOX2B-gene and other disorders to represent an early stage of chronic hypoventilation. explaining hypoventilation have to be excluded. Although Nevertheless, this hypothesis has to be confirmed and the disease is associated with hyperphagia, hypoventilation the number of patients with advancing severity has to be persists even if patients lose weight. Diabetes insipidus, evaluated in future research. inappropriate antidiuretic hormone hypersecretion, The most recent edition of the International precocious puberty, hypogonadism, hyperprolactinemia, Classification of Sleep Disorders (3) describes six subtypes hyperthyroidism and decreased growth hormone secretion of hypoventilation disorders in the chapter of sleep related are associated endocrine dysfunctions (3,5). breathing disorders: In contrast to these rare disorders, the OHS and chronic • OHS; hypoventilation due to medical disorders or pharmaceutical • Congenital central alveolar hypoventilation syndrome influences represent the huge majority of chronic and SRH. (CCHS); OHS patients are characterized by obesity (BMI >30 kg/m2) • Late-onset central hypoventilation with hypothalamic and wakefulness hypercapnia. Hypoventilation in OHS dysfunction; cannot primarily be explained by other thoraco-pulmonary, • Idiopathic central alveolar hypoventilation; neuromuscular or idiopathic diseases or pharmaceutical • Sleep related hypoventilation due to a medication or influences (3,5,8,9) (Table 1). substance; Sleep related hypoventilation due to a medical disorder • Sleep related hypoventilation due to a medical disorder. is diagnosed in patients with underlying diseases of the The term CCHS replaces the name “Ondine’s curse”. lung parenchyma or the airways, the pulmonary vessels or CCHS requires evidence of a mutation of the PHOX2B- neurological or musculo-skeletal disorders. In addition, gene leading to a diffuse imbalance of the autonomic system. SRH can be induced by drugs which depress ventilatory Differences in the mutation discriminate congenital from drive or impair muscle function. Long-acting narcotics, de novo development (4). Despite its congenital character, anesthetics, sedatives and muscle relaxants and also alcohol the disease may manifest in adulthood in some cases (3,5). have been discussed (3,5). Chronic opioid intake may be Late-onset phenotypes may present with respiratory associated with central apnoeas, atactic respiration but also © Journal of Thoracic Disease. All rights reserved. www.jthoracdis.com J Thorac Dis 2015;7(8):1273-1285 Journal of Thoracic Disease, Vol 7, No 8 August 2015 1275 Table 1 Characteristics of the obesity hypoventilation syndrome (OHS) Definition criteria Description Chronic hypoventilation Hypercapnia in wakefulness and sleep (PaCO2 ≥45 mmHg or 6 kPa) Obesity Body mass index (BMI) ≥30 kg/m² Absence of other causes of hypercapnia Diseases of the lung parenchyma, airways, pulmonary vessels Neurological, musculo-skeletal or other idiopathic disorders Congenital