Dyspnea frequently accompanies a variety of cardiopulmonary abnormalities. Although dyspnea is often considered a single sensation, alternatively it may encompass multiple sensations that are not well explained by a single physiologic mechanism. To investigate whether breathlessness experienced by patients represents more than one sensation, we studied 53 patients with one of the following seven conditions: pulmonary vascular disease, neuromuscular and chest wall disease, congestive heart failure, pregnancy, interstitial lung disease, asthma, and chronic obstructive pulmonary disease. Patients were asked to choose descriptions of their sensation(s) of breathlessness from a dyspnea questionnaire listing 19 descriptors. Cluster analysis was used to identify natural groupings among the chosen descriptors. We found that patients could distinguish different sensations of breathlessness. In addition, we found an association between certain groups of descriptors and specific conditions producing dyspnea. These findings concur with those in an earlier study in normal volunteers in whom dyspnea was induced by various stimuli. We conclude that different types of dyspnea exist in patients with a variety of cardiopulmonary abnormalities. Furthermore, different mechanisms may mediate these various sensations.

Various theories about the genesis of dyspnea have often assumed that the sensation is similar from patient to patient and is generated by a single underlying mechanism. To investigate whether breathlessness induced in normal volunteers by different stimuli represents one or more than one sensation, we studied 30 subjects in whom breathlessness was induced by each of 8 different stimuli: breath-holding, CO2 inhalation, inhalation of CO2, with ventilation voluntarily targeted below the level dictated by chemical drive, breathing with a resistive load, breathing with an elastic load, voluntary elevation of functional residual capacity, voluntary limitation of tidal volume, and exercise. For each stimulus, subjects were asked to choose description of their sensation(s) of breathlessness from a questionnaire listing 19 descriptors. The responses from this questionnaire were evaluated using cluster analysis to search for relationships among descriptors and to identify natural groupings. We found that distinct groups of descriptors emerged, i.e., subjects could distinguish different sensations of breathlessness. In addition, we found an association between certain descriptor groups and stimuli. We conclude that the term breathlessness may encompass multiple sensations, and, therefore, may not be explainable by a single physiologic mechanism.

Respiratory sinus arrhythmia (RSA) is used as a noninvasive measure of vagal cardiac input, but its causative mechanisms in humans remain undetermined. We compared the RSA of five lung-denervated double-lung transplant patients with intact hearts to six normal (N) control subjects, five heart-denervated patients, and two liver transplant patients at matched tidal volumes (VT's) and breathing frequencies. In N and liver transplant subjects, RSA was significant during eupnea and increased two- to threefold with increasing VT and inspiratory effort. In heart- and lung-denervated subjects, RSA at eupnea was significant but was only 53% of that in N subjects and was not respondent to changing VT, inspiratory effort, or breathing frequency. We also compared the RSA of N subjects during voluntary (active) and passive positive pressure ventilation at normocapnia. RSA was reduced from 11 +/- 2.2 beats/min during active ventilation to 5.4 +/- 0.8 beats/min during PPV. We conclude that vagal feedback from pulmonary stretch receptors is obligatory for the generation of a neurally mediated RSA in awake humans at normal and raised levels of VT and respiratory motor output. In intact humans, we also hypothesize an important effect for nonpulmonary central and/or peripheral modulation of RSA. It is likely that the key mechanisms for neurally mediated RSA in unanesthetized humans are mutually dependent.

Suppression of ventilation by tasks such as talking may produce breathlessness in normal individuals under conditions when a strong respiratory drive exists, e.g., during exercise, and in patients with severe lung disease. To investigate the nature of breathlessness produced by a dissociation between ventilation and chemical drive, we studied ten naive normal subjects who breathed at various levels of ventilation while end-tidal PCO2 (PETCO2) was held at 55 mm Hg. After a 10-min equilibration period of free breathing at PETCO2 = 55 mm Hg, subjects used a visual target to adjust ventilation to five different levels ranging from 50% below to 50% above the chemically driven ventilation (CDV). Ratings of breathlessness were made on a visual analogue scale relative to the intensity of breathlessness experience at CDV. As ventilation was targeted to levels below CDV, all subjects became increasingly breathless; the response was more variable when ventilation was targeted to levels above CDV. Overall, the relationship between ventilation and breathlessness was described by a hyperbolic function, for which the coefficient of determination (R2) was 0.92. Ventilation was suppressed below CDV without recruitment of antagonistic muscles during inspiration. The intensity of breathlessness was not correlated with measures of respiratory effort. We conclude that suppressed ventilation is a useful model for the study of breathlessness not fully explained by measures of respiratory effort and we speculate that the dissociation between chemical drive and afferent signals produced by motion of the lung and chest wall is important in modulating the sensation of breathlessness.

Passive lung inflation in humans causes reflex expiratory prolongation that is abolished by vagal blockade. We have studied two aspects of this classic Breuer-Hering reflex in humans: the effect of pulmonary denervation from bilateral lung transplantation, and the effect of alveolar hypocapnia. Lung inflations were performed in six normal subjects and four lung transplant patients during triazolam-induced sleep using a negative pressure body box. Lung inflation with isocapnic gas in normal subjects resulted in expiratory prolongation lasting up to 60 s and occurring at a volume threshold of 40 to 60% of inspiratory capacity (1.1 to 1.7 L). Expiratory prolongation increased in a graded fashion as volume of lung inflation increased. Inhibition of inspiration at any given inflation volume was prolonged by inflations with air as compared with inflations with isocapnic gas. In lung transplant patients lung inflations of up to 2 L caused no prolongation of expiration. We conclude that bilateral lung transplantation abolished expression of the reflex in humans, and that in normal intact humans the duration of expiratory prolongation with lung inflation is prolonged by alveolar hypocapnia.