Role of chemoreceptors in mediating dyspnea

Abstract

Dyspnea, or the uncomfortable awareness of respiratory distress, is a common symptom experienced by most people at some point during their lifetime. It is commonly encountered in individuals with pulmonary disease, such as chronic obstructive pulmonary disease (COPD), but can also be seen in healthy individuals after strenuous exercise, at altitude or in response to psychological stress. Dyspnea is a multifactorial sensation involving the brainstem, cortex, and limbic system, as well as mechanoreceptors, irritant receptors and chemoreceptors. Chemoreceptors appear to contribute to the sensation of dyspnea in two ways. They stimulate the respiratory control system in response to hypoxia and/or hypercapnia, and the resultant increase respiratory motor output can be consciously perceived as unpleasant. They also can induce the sensation of dyspnea through an as yet undetermined mechanism—potentially via direct ascending connections to the limbic system and cortex. The goal of this article is to briefly review how changes in blood gases reach conscious awareness and how chemoreceptors are involved in dyspnea.

Introduction

Dyspnea is the uncomfortable awareness of breathing, the sensation of breathlessness or the experience of air hunger (American Thoracic Society, 1999). It is an important clinical symptom used to assess functional status of chronically ill patients with cardiorespiratory or neuromuscular disease, and has thus been the subject of extensive recent reviews (Manning and Mahler, 2001, McConnell and Romer, 2004, O’Donnell et al., 2007). Healthy subjects can experience dyspnea during strenuous exercise, at high altitude, after breath-holding, or during stressful situations that cause anxiety or panic. Dyspnea occurs more frequently in the aged, the obese and the deconditioned. Certain medications can induce dyspnea as a side effect, and it is often the reason cited for cessation of a new medication or for medication non-compliance. It has been a difficult symptom to study, because it is a subjective and uniquely human experience so animal models have limited use in understanding its mechanisms, and it relies on often vague descriptions by patients (American Thoracic Society, 1999).

Dyspnea is a normal phenomenon that is protective against abnormalities in gas exchange. It can be caused by any number of derangements of normal cardiorespiratory function including primary pulmonary, cardiac or neuromuscular diseases. Pulmonary diseases include COPD, asthma, emphysema, interstitial lung disease, pulmonary edema, pulmonary embolism and pulmonary infections. Cardiac diseases include congestive heart failure and acute myocardial infarction (American Thoracic Society, 1999). Neurological diseases commonly leading to dyspnea include, but are not limited to, amyotrophic lateral sclerosis, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis and Parkinson's disease.

Awareness of respiratory sensation can occur in normal situations or during dyspnea. During dyspnea there is a heightened level of awareness of respiratory sensation and a strong emotional component. The neural basis of dyspnea is therefore likely to involve activation of both the cortex and the limbic system. As will be discussed below there is emerging evidence for cortical and limbic activation associated with dyspnea.

Dyspnea can be induced by an increase in CO₂ or decrease in O₂. There are several possibilities for how this occurs including direct effects from chemoreceptor activation or indirect effects either through interactions with other respiratory afferents or through activation of corollary discharges. There is evidence in the literature for each of these possibilities; however the specific mechanisms of the chemoreceptor contribution have not yet been elucidated. In order to understand how changes in blood gases cause dyspnea we need to understand how changes in O₂ and CO₂ are detected, how they influence breathing, and how these changes are transmitted to the forebrain.

Our goal with this review will be fourfold. First we will describe peripheral and central chemoreception and their contribution to the control of breathing. Second, we will describe the evidence that there can be conscious awareness of chemoreceptor input and that this input can induce the sensation of dyspnea. Third, we will speculate as to the mechanisms by which changes in blood gases reach consciousness and how they induce the sensation of dyspnea. Finally, we will discuss chemoreceptor contributions to dyspnea in certain human disease states.