Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease A Roundtable Denis E. O’Donnell 1 , Robert B. Banzett 2 , Virginia Carrieri-Kohlman 3 , Richard Casaburi 4 , Paul W. Davenport 5 , Simon C. Gandevia 6 , Arthur F. Gelb 7 , Donald A. Mahler 8 , and Katherine A. Webb 1 1 Queen’s University, Kingston, Ontario, Canada; 2 Harvard Medical School, Boston, Massachusetts; 3 University of California at San Francisco School of Nursing, San Francisco, California; 4 Los Angeles Biomedical Research Institute at Harbor–University of California at Los Angeles Medical Center, Torrance, California; 5 University of Florida, Gainesville, Florida; 6 Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia; 7 University of California at Los Angeles School of Medicine, Los Angeles, California; and 8 Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Introduction Denis E. O’Donnell The Clinical Problem • Dyspnea: The Clinical Problem Donald A. Mahler 146 Neurophysiology of Dyspnea • Chemical and Mechanical Loads: What Have We Learned? Paul W. Davenport 147 • Multiple Mechanisms Contributing to Dyspnea Simon C. Gandevia 149 • The Peripheral Mechanisms of Dyspnea Robert B. Banzett 150 Dyspnea in COPD: Current Concepts • Exertional Dyspnea in COPD: Mechanics and Neurophysiology Denis E. O’Donnell 151 Management of Dyspnea in COPD • Mechanisms of Dyspnea Relief after Bronchodilator Therapy Denis E. O’Donnell and Katherine A. Webb 156 • The Impact of Oxygen and Heliox Richard Casaburi 158 • The Impact of Education and Symptom Management Virginia Carrieri-Kohlman 160 Summary • Denis E. O’Donnell 162 Effective management of dyspnea in chronic obstructive pulmonary disease (COPD) requires a clearer understanding of its underlying mechanisms. This roundtable reviews what is currently known about the neurophysiology of dyspnea with the aim of applying this knowledge to the clinical setting. Dyspnea is not a single sensation, having multiple qualitative descriptors. Primary sources of dyspnea include: (1 ) inputs from multiple somatic proprioceptive and broncho- pulmonary afferents, and (2 ) centrally generated signals related to (Received in original form November 2, 2006; accepted in final form January 30, 2007 ) Supported by Boehringer Ingelheim Correspondence and requests for reprints should be addressed to Denis E. O’Donnell, M.D., F.R.C.P.I., F.R.C.P.C., Professor of Medicine & Physiology, Head, Division of Respiratory & Critical Care Medicine, Department of Medicine, Queen’s University, 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail: odonnell@ post.queensu.ca Proc Am Thorac Soc Vol 4. pp 145–168, 2007 DOI: 10.1513/pats.200611-159CC Internet address: www.atsjournals.org inspiratory motor command output or effort. Respiratory disruption that causes a mismatch between medullary respiratory motor dis- charge and peripheral mechanosensor afferent feedback gives rise to a distressing urge to breathe which is independent of muscular effort. Recent brain imaging studies have shown increased limbic system activation in response to various dyspneogenic stimuli and emphasize the affective dimension of this symptom. All of these mechanisms are likely instrumental in exertional dyspnea causation in COPD. Increased central motor drive (and effort) is required to increase ventilation during activity because the inspiratory muscles become acutely overloaded and functionally weakened. Abnormal dynamic ventilatory mechanics and excessive chemostimulation during exercise also result in a widening disparity between escalat- ing central neural drive and restricted thoracic volume displace- ment. This neuromechanical uncoupling may form the basis for the distressing sensation of unsatisfied inspiration. Interventions that alleviate dyspnea in COPD do so by improving ventilatory mechan- ics, reducing central neural drive, or both—thereby partially restor- ing neuromechanical coupling of the respiratory system. Self- management strategies address the affective aspect of dyspnea and are essential to successful treatment. Keywords: dyspnea; mechanisms; respiratory mechanics; exercise; dynamic lung hyperinflation Introduction Denis E. O’Donnell This roundtable represented a unique opportunity to bring to- gether clinicians and scientists from around the world to discuss dyspnea and the numerous contributing mechanisms along with current research, measurement tools, and treatment options. Clinical trials of new therapeutic agents now commonly include assessments of dyspnea, and physicians are beginning to use tools to measure dyspnea during office visits. Thus, in recent years, there is greater awareness of the important patient- centered outcomes and more interest in learning how to manage the symptoms of chronic obstructive pulmonary disease (COPD). This round table was created with a goal of generating interest in the topic, which may lead to further research and ultimately to the utilization of effective therapeutic options for the manage- ment of dyspnea. The article that follows summarizes the main content of the presentations but does not capture all of the discussions that ensued. The presentations cover a diverse range of topics, beginning with an overview of dyspnea as a common clinical problem. Current concepts of the neurophysiologic mechanisms of dyspnea will then be discussed. The pathophysiol- ogic and neurophysiologic underpinnings of exertional dyspnea in COPD will be reviewed to provide a rationale for effective therapeutic interventions. The impact and mechanisms of benefit