Hypoventilation Syndromes

Lee K. Brown, M.D., Teofilo Lee-Chiong, M.D.

For breath is life, and if you breathe well you will live long on earth. Sanskrit proverb

The unifying theme for this issue of Seminars in Respiratory and Critical Care Medicine is that of hypoventilation in all of its aspects: in infants, children, and adults; during wakefulness and sleep; and resulting from disease intrinsic to the lungs, the chest wall, or the central nervous system. Our fundamental aim was to assemble an expert panel of authors from within the pulmonary, neurology, and sleep medicine communities who are known for their academic excellence and distinction in research, but who also possess extensive, practical clinical experience in disorders of hypoventilation. There are myriad ways that the human organism can fail in the fundamental goal of maintaining respiratory homeostasis, commonly separated into the categories of “can't breathe” (abnormalities in respiratory mechanics) versus “won't breathe” (derangements in ventilatory control). The pathophysiology of ventilatory failure in many conditions can easily be attributed to one or the other of these mechanisms, but disorders combining aspects of both are not uncommon. Rather than an exhaustive, arcane review of respiratory pathophysiology and control of breathing, our authors concentrated on providing a practical guide for the active clinician who must, on a daily basis, sort through these different mechanisms, identify the underlying disorder, and apply the best treatment current evidence can recommend.

The first manuscript reviews obesity-hypoventilation (“Pickwickian”) syndrome (OHS), which is representative of those disorders that most likely combine the pathogenetic elements of “can't breathe” and “won't breathe” that together result in chronic ventilatory failure. The authors, Drs. Berger, Goldring, and Rapoport, from New York University School of Medicine, have been responsible for more than 20 years of seminal research in the pathophysiology of OHS; our current management of this disorder is largely based on their findings.

The second paper focuses on the congenital hypoventilation syndrome, taking the reader into the realms of infancy rather than adulthood and disturbed control of breathing rather than abnormal mechanics. This disorder is emblematic of the advances attributable to the Genome Project and related research into the genetic origins of disease. The lead author is Dr. Madeleine Grigg-Damberger, Professor of Neurology at the University of New Mexico School of Medicine. In addition to maintaining an active practice treating pediatric and adult patients with ventilatory failure from neurological disease, Dr. Grigg-Damberger has made substantial contributions to the development of practice standards in both sleep medicine and clinical neurophysiology.

Our discussion of hypoventilation syndromes next turns to the category of restrictive chest wall disorders. With the passing (hopefully forever) of thoracoplasty and other disfiguring procedures for cavitary tuberculosis, it might seem that the only important conditions remaining in this class are obesity and neuromuscular diseases, both of which are covered separately in this issue. However, skeletal deformities such as kyphoscoliosis, the wide variety of restrictive pleural processes, and the chronic inflammatory disease ankylosing spondylitis are all deserving of our attention. In addition, although the number of post-thoracoplasty patients continues to decline they may still be found in the practice of the active pulmonologist. The senior author of this manuscript is extraordinarily well suited to this task: Dr. Albert Miller brings to bear more than 40 years of experience in the management and study of these disorders. His research has contributed much to our understanding of respiratory impairment in individuals with a variety of environmental exposures, including asbestos and other inorganic dusts, neuromuscular diseases affecting respiration, and congenital thoracic deformity. Dr. Miller is also the esteemed mentor of one of us (LKB) and of his coauthor, Dr. Joseph Donath.

In the past, cystic fibrosis (CF) has been a frequent culprit responsible for hypoventilation in most pediatric pulmonology practice. The disorder is now increasingly making an appearance in adult medicine; recent data indicate that more than half of CF patients born between 1974 and 1979 survive past 30 years of age, and ~95% of those born between 1990 and 1994 are still alive and entering their teenage years. Ventilatory failure is an important cause of morbidity and mortality in this population, and the pathogenesis is not necessarily as straightforward as one might expect. Dr. Jennifer Taylor-Cousar has been honored as a Career Development Scholar in the Clinical and Translational Science Center at the University of New Mexico. She directs the University of New Mexico Hospital Adult Cystic Fibrosis Center and in this next chapter reviews the basic science of CF pathogenesis and contemporary management of this all too prevalent disorder.

No journal issue on hypoventilation would be complete without discussing the evaluation and treatment of patients exhibiting ventilatory failure from diverse etiologies. Such evaluation demands an accurate and thorough history and physical examination, pulmonary function testing (that may include specialized assessment of ventilatory control and respiratory muscle strength), various imaging modalities, electrophysiological measurements, blood and body fluid analyses (including genetic testing), and polysomnography. Considerable clinical acumen is then necessary to synthesize these disparate sets of data, arriving at an accurate diagnosis and practical plan of treatment. Senior author Dr. Richard B. Berry has been a leader in the development of authoritative guidelines for the use of noninvasive positive pressure treatment modalities. He is a respected investigator with a body of work encompassing control of breathing as well as the clinical evaluation and management of sleep disordered breathing. Dr. Berry and his colleague Dr. Sriram contribute a wealth of experience in pulmonary and sleep medicine to their manuscript.

The next article in this series deals with diaphragm paralysis, both unilateral and bilateral, and was written by Asher Qureshi, MD, Medical Director of the Sleep Disorders Center at the Saint Francis Hospital and Medical Center in Hartford, Connecticut. Because of the generalized muscle hypotonia and atonia that accompany the sleeping process, diaphragm paralysis can lead to nocturnal hypoventilation and hypoxemia. Bilateral diaphragmatic paralysis is also associated with the development of sleep apnea in some patients. Unilateral diaphragmatic paralysis does not generally result in chronic respiratory failure or cor pulmonale unless accompanied by parenchymal lung diseases.

Hypoventilation can also develop in persons with advanced asthma or chronic obstructive pulmonary disease (COPD). In his article, Dr. David A. Beuther of National Jewish Health in Denver, Colorado, addresses the key features of hypoventilation in these chronic pulmonary disorders, including relevant clinical clues to its emergence as well as proper assessment and management. Asthma, a disorder characterized by episodic dyspnea and wheezing, and airway hyperreactivity to a variety of stimuli, may be associated with overnight bronchoconstriction and sleep-related hypoxemia; episodes of hypoventilation are less common. In contrast, COPD is defined by airflow limitation that is usually progressive and is not fully reversible as well as abnormal inflammatory response and lung injury. Oxygen desaturation can occur during sleep in persons with moderate to severe COPD secondary to periods of hypoventilation, which is worse during rapid eye movement (REM) sleep; in more advanced cases, hypoxemia and hypercapnia can occur during both wakefulness and sleep.

We had asked Dr. Richard J. Castriotta, Professor of Medicine and Director of the Division of Pulmonary, Critical Care & Sleep Medicine University of Texas Medical School at Houston to write the manuscript on hypoventilation after spinal cord injury and its management. Cowritten with Dr. Jayasimha N. Murthy, their article explores the mechanisms underlying respiratory compromise following traumatic injury to the spinal cord, their unique clinical presentations, and the often complex management issues that need to be addressed, often by a multidisciplinary team, when caring for these patients. The prevalence of traumatic spinal cord injury secondary to combat injuries or vehicular accidents is expected to rise, and as survival improves due to improved immediate medical care, more patients will require chronic ventilatory support for respiratory impairment.

An infant or child is not merely a small adult, and significant differences in central control of ventilation as well as respiratory mechanics from the latter are present. Many hypoventilation syndromes first become clinically apparent during infancy and early childhood, when they may present as failure to thrive, cyanosis, or apparent life-threatening events. The article on congenital hypoventilation syndromes was written by Dr. Thomas G. Keens and his associates, Drs. Daniel J. Lesser, Sally L. Davidson Ward, and Sheila S. Kun. Dr. Keens is a pediatric pulmonologist at the Children's Hospital Los Angeles and professor of pediatrics, physiology, and biophysics at the Keck School of Medicine of the University of Southern California. He has spent much of his 31-year career at the Children's Hospital Los Angeles conducting research on sudden infant death syndrome and other disorders of ventilatory control and respiratory physiology in children.

Ventilatory compromise may complicate the clinical course of many neuromuscular disorders, including Duchenne muscular dystrophy, myotonic dystrophy, postpolio syndrome, and amyotrophic lateral sclerosis. In these disorders, sleep-related respiratory alveolar hypoventilation can precede abnormalities during wakefulness by months to years, and its likelihood is greater in those with reduced maximal inspiratory pressures or forced vital capacity. In addition, individuals may also present with either central or obstructive apnea/hypopneas. Finally, the development of diaphragmatic dysfunction in persons with amyotrophic lateral sclerosis adversely affects survival. This topic is reviewed in detail by Dr. Shirley Jones, an assistant professor in the Department of Medicine at the Texas A & M Health Science Center College of Medicine at Temple, Texas, writing with Drs. Alfredo Vazquez-Sandoval and Eric Huang.

The final chapter in this issue of Seminars is perhaps the most important offering for the pulmonary or critical care clinician caring for patients with hypoventilation syndromes on a daily basis; if the reader has time to digest only one paper in this volume, this is the one to choose. For many years, management of these disorders involved a choice between tracheotomy and chronic home ventilation by way of negative pressure body ventilators that were bulky, inefficient, and often impractical, or oxygen therapy that was largely only palliative for individuals with ventilatory failure. The last few decades have witnessed the introduction of noninvasive positive pressure ventilation incorporating ventilator technology with increasingly sophisticated capabilities that has revolutionized the treatment of hypoventilation syndromes. Dr. Patrick J. Strollo Jr. directs the distinguished University of Pittsburgh Sleep Medicine Center and as of this writing is president-elect of the American Academy of Sleep Medicine. He and coauthor Dr. Salman R. Khan have written a thorough and practical guide to the use of these contemporary treatment modalities.

The pace at which medical knowledge accumulates continues to accelerate, particularly due to contributions from the burgeoning fields of molecular and cellular biology and computer technology. In no field of medicine has this been more evident than as applied to the evaluation and treatment of hypoventilation syndromes. During our lifetime, debilitating conditions leading to ventilatory failure are in the process of disappearing (poliomyelitis, thoracoplasty for tuberculosis); therapies for other disorders may soon be available that will relegate them to the dustbin of history (gene therapy for cystic fibrosis), and many such patients now benefit from noninvasive positive pressure ventilation in the comfort of their own home. We are pleased that the publishers of Seminars have recognized the need to review these advances, and hope that this issue not only encourages optimal evaluation and management of hypoventilation syndromes but also provides additional encouragement for those actively engaged in researching these important disorders.