Mechanisms of activity-related dyspnea in pulmonary diseases
Introduction
Perceived respiratory difficulty or dyspnea is a major symptom of patients with chronic respiratory diseases (Leblanc et al., 1986, Mahler et al., 1995, Hamilton et al., 1996). In many, this symptom progresses relentlessly with time to reach incapacitating levels. Dyspnea leads to activity limitation, and is often associated with major psychological comorbidity, social isolation and poor perceived quality of life. The effective management of dyspnea remains a major challenge for caregivers, and modern treatment strategies that are based on attempts to reverse the underlying chronic condition are only partially successful. Activity-related dyspnea is usually the earliest and most troublesome symptom of patients presenting with chronic pulmonary disorders and is the main focus of this review. Recent studies that have explored the relationship between measured physiological stress during physical exertion (the dyspneogenic stimulus) and the attendant sensory response (intensity and quality of dyspnea) have provided new insights in the nature and mechanisms of perceived respiratory discomfort (Leblanc et al., 1986, Hamilton et al., 1996, O’Donnell et al., 1997b). In this review we will first, enumerate the psychophysical methods that are increasingly employed in the evaluation of dyspnea during cardiopulmonary exercise testing (CPET). Second, we will review the recent studies of the physiological mechanisms of dyspnea during CPET in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Third, we will compare the perceptual and ventilatory responses to exercise in these conditions so as to identify common mechanisms of dyspnea. Fourth, we will review the lessons learned from studies designed to uncover the mechanisms of dyspnea relief following therapeutic interventions. Finally, we will present a hypothetical neurophysiological construct for exertional dyspnea in pulmonary disease.
Section snippets
Evaluation of dyspnea during exercise
Classical psychophysical experiments employing external mechanical loading of the respiratory system have taught us that humans can reliably recognize even minor respiratory disruption, quantify sensory intensity and discriminate between different qualitative dimensions of breathing discomfort (Campbell et al., 1961, Bennett et al., 1962, Bakers and Tenney, 1970, Zechman and Davenport, 1978, Killian et al., 1980, Davenport et al., 1981, Zechman et al., 1981, Burdon et al., 1982). Conscious
Chronic obstructive pulmonary disease
Intolerable dyspnea is a major exercise-limiting symptom in patients with COPD. Dyspnea intensity is increased at any given exercise VO2, work rate or VE compared with age-matched healthy controls (Fig. 2). Qualitative descriptor choices by patients at the peak of exercise predominantly allude to perceptions of increased “work/effort” [i.e., “my breathing needs more effort (work)”] and “unsatisfied inspiration” (i.e., “I cannot get enough air in,” “I have difficulty breathing in,” “I cannot
Putative mechanisms of exertional dyspnea in pulmonary diseases
Reductionist experimental approaches which are designed to identify specific sources of exertional dyspnea located in specialized central and peripheral sensory systems are fraught with difficulty when applied to CPET. A major limitation is our inability to precisely quantify central respiratory neural drive or afferent sensory inputs from peripheral afferents in the lung, airways, respiratory muscles and chemoreceptors. This, coupled with the remarkable redundancy inherent in sensory systems,
Lessons learned from dyspnea-relieving treatments
Most of the studies that have examined potential mechanisms of dyspnea alleviation following the administration of different treatments were undertaken in COPD. Randomized placebo-controlled, crossover CPET studies of therapeutic interventions have been undertaken in an attempt to uncover physiological mechanisms of dyspnea causation and amelioration. Therapeutic interventions that reduce central neural drive during exercise (e.g., supplemental oxygen, opiates, reduced or delayed metabolic
The neurophysiology of exertional dyspnea: a synthesis
It is clear that the neurological mechanisms of activity-induced dyspnea are highly complex and multifactorial. To the extent that different qualitative aspects of dyspnea reflect different neurophysiological underpinnings, further scrutiny of the two dominant descriptors (“increased respiratory effort” and “unsatisfied inspiration”) identified by patients with COPD and ILD is justified.
Summary
Activity-related dyspnea is a dominant symptom of patients with chronic lung conditions and contributes to significant long-term morbidity. Application of established psychophysical methods to the setting of clinical laboratory exercise testing has increased our understanding of the mechanisms of exertional dyspnea in these patients. We have seen that, although the pathological abnormalities in obstructive and restrictive lung diseases are distinctly different, perceptual and ventilatory
Acknowledgement
Dennis Jensen, Ph.D. was supported by a John Alexander Stuart Fellowship (Department of Medicine, Queen's University and Kingston General Hospital).
References (220)
- et al.
Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease
Chest
(1990) - et al.
Sustained improvements in dyspnea and pulmonary function 3 to 5 years after lung volume reduction surgery
Chest
(2003) - et al.
The perception of some sensations associated with breathing
Respir. Physiol.
(1970) - et al.
‘Air hunger’ from increased PCO2 persists after complete neuromuscular block in humans
Respir. Physiol.
(1990) - et al.
Respiratory muscle strength, lung function and dyspnea in patients with sarcoidosis
Chest
(2001) Respiratory control at exercise onset: an integrated systems perspective
Respir. Physiol. Neurobiol.
(2006)- et al.
Mechanical chest-wall vibration does not relieve air hunger
Respir. Physiol. Neurobiol.
(2003) - et al.
Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes
Chest
(2003) - et al.
Respiratory-associated thalamic activity is related to level of respiratory drive
Respir. Physiol.
(1992) - et al.
Impulse activity in afferent vagal C-fibres with endings in the intrapulmonary airways of dogs
Respir. Physiol.
(1977)
The effect of the resistive loading of inspiration and expiration on pulmonary stretch receptor discharge
Respir. Physiol.
Respiratory-associated rhythmic firing of midbrain neurons is modulated by vagal input
Respir. Physiol.
The Fowler breathholding study revisited: continuous rating of respiratory sensation
Respir. Physiol.
Relief of ‘air hunger’ of breathholding: a role for pulmonary stretch receptors
Respir. Physiol.
Nebulized opioids use in COPD
Chest
Effect of chest wall vibration on dyspnea during exercise in chronic obstructive pulmonary disease
Respir. Physiol. Neurobiol.
Roles for perceived voluntary commands in motor control
Trends Neurosci.
Projection of low-threshold afferents from human intercostal muscles to the cerebral cortex
Respir. Physiol.
Exercise training improves exertional dyspnea in patients with COPD: evidence of the role of mechanical factors
Chest
Symptom intensity and subjective limitation to exercise in patients with cardiorespiratory disorders
Chest
Pathophysiology of activity limitation in patients with interstitial lung disease
Chest
Theories on the nature of the coupling between ventilation and gas exchange during exercise
Respir. Physiol. Neurobiol.
Venous pressure and dyspnea on exertiona in cardiac failure: was Tinsley Randolph Harrison right?
Respir. Physiol. Neurobiol.
Sensitivity of vagal afferent endings to chemical irritants in the rat lung
Respir. Physiol.
DLco/Q and diffusion limitation at rest and on exercise in patients with interstitial fibrosis
Respir. Physiol.
Effects of pregnancy, obesity and aging on the intensity of perceived breathlessness during exercise in healthy humans
Respir. Physiol. Neurobiol.
Effects of training with heliox and noninvasive positive pressure ventilation on exercise ability in patients with severe COPD
Chest
Mechanisms of gas-exchange impairment in idiopathic pulmonary fibrosis
Am. Rev. Respir. Dis.
Regional chest wall volumes during exercise in chronic obstructive pulmonary disease
Thorax
Last Word on Point: Counterpoint: the major limitation to exercise performance in COPD is (1) inadequate energy supply to the respiratory and locomotor muscles, (2) lower limb muscle dysfunction, (3) dynamic hyperinflation
J. Appl. Physiol.
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
Am. J. Respir. Crit. Care Med.
Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolar-capillary diffusion
Am. J. Med.
Effect of mild-to-moderate airflow limitation on exercise capacity
J. Appl. Phyiol.
High level quadriplegics perceive lung volume change
J. Appl. Physiol.
Breathlessness in humans activates insular cortex
NeuroReport
The affective dimension of laboratory dyspnea: air hunger is more unpleasant than work/effort
Am. J. Respir. Crit. Care Med.
Pulmonary hypertension in chronic obstructive pulmonary disease
Eur. Respir. J.
Gas exchange during exercise in mild chronic obstructive pulmonary disease: correlation with lung structure
Am. Rev. Respir. Dis.
Pulmonary hypertension in interstitial lung disease
Eur. Respir. J.
Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease
Am. J. Respir. Crit. Care Med.
The ability of man to detect non-elastic loads to breathing
Clin. Sci.
Peripheral muscle weakness in patients with chronic obstructive pulmonary disease
Am. J. Respir. Crit. Care Med.
“Tightness” sensation of asthma does not arise from the work of breathing
Am. J. Respir. Crit. Care Med.
Self-control and external control of mechanical ventilation give equal air hunger relief
Am. J. Respir. Crit. Care Med.
Psychophysical basis of perceived exertion
Med. Sci. Sports Exerc.
Low-density gas breathing during exercise in chronic obstructive lung disease
Respiration
Oxygen-assisted exercise in chronic obstructive lung disease: the effect on exercise capacity and arterial blood gas tensions
Am. Rev. Respir. Dis.
Quantitative analysis of the alveolar plateau in the diagnosis of early airway obstruction
Am. Rev. Respir. Dis.
Effect of ventilatory drive on the perceived magnitude of added loads to breathing
J. Appl. Physiol.
Cardiovascular function at rest and on exercise in patients with cryptogenic fibrosing alveolitis
Thorax
Cited by (185)
Effectiveness of Continuous Chest Wall Vibration With Concurrent Aerobic Training on Dyspnea and Functional Exercise Capacity in Patients With Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial
2021, Archives of Physical Medicine and RehabilitationThe role of cardiopulmonary exercise testing in evaluating children with exercise induced dyspnoea
2021, Paediatric Respiratory ReviewsMultidimensional breathlessness response to exercise: Impact of COPD and healthy ageing
2021, Respiratory Physiology and NeurobiologyCitation Excerpt :The breathlessness sensory qualities of unsatisfied inspiration and breathing too shallow were also rated higher by people with COPD compared to their age-matched healthy counterparts at any given percent predicted peak V’E or absolute V’E, and at end exercise (e.g., 0−10 Borg rating of unsatisfied inspiration at end exercise: people with COPD = 4.8 ± 2.3 vs healthy older adults = 2.8 ± 2.3). Intensity ratings were inversely related to the pathological exercise-induced reductions in IRV, which is in line with our current understandings of the neurophysiology of exertional breathlessness (O’Donnell et al., 2009, Parshall et al., 2012). That is, as inspiratory constraints on VT expansion became progressively more severe (with attendant progressive neuromechanical uncoupling of the respiratory system), intensity ratings of inspiratory difficulty increased progressively.
Therapeutic Approaches for the Treatment of Interstitial Lung Disease: An Exploratory Review on Molecular Mechanisms
2024, Mini-Reviews in Medicinal Chemistry