The Proceedings of the American Thoracic Society 4:145-168 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200611-159CC
Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease
A Roundtable
Denis E. O'Donnell1,
Robert B. Banzett2,
Virginia Carrieri-Kohlman3,
Richard Casaburi4,
Paul W. Davenport5,
Simon C. Gandevia6,
Arthur F. Gelb7,
Donald A. Mahler8 and
Katherine A. Webb1
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
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{at}post.queensu.ca
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ABSTRACT
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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 bronchopulmonary afferents, and (2) centrally generated signals related to inspiratory motor command output or effort. Respiratory disruption that causes a mismatch between medullary respiratory motor discharge 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 escalating central neural drive and restricted thoracic volume displacement. 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 mechanics, reducing central neural drive, or both—thereby partially restoring neuromechanical coupling of the respiratory system. Self-management strategies address the affective aspect of dyspnea and are essential to successful treatment.
Key Words: dyspnea • mechanisms • respiratory mechanics • exercise • dynamic lung hyperinflation
| Introduction |
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| Denis E. O'Donnell |
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| The Clinical Problem |
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| • Dyspnea: The Clinical Problem |
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| Donald A. Mahler |
146 |
| Neurophysiology of Dyspnea |
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| • Chemical and Mechanical Loads: What Have We Learned? |
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| Paul W. Davenport |
147 |
| • Multiple Mechanisms Contributing to Dyspnea |
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| Simon C. Gandevia |
149 |
| • The Peripheral Mechanisms of Dyspnea |
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| Robert B. Banzett |
150 |
| Dyspnea in COPD: Current Concepts |
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| • Exertional Dyspnea in COPD: Mechanics and Neurophysiology |
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| Denis E. O'Donnell |
151 |
| Management of Dyspnea in COPD |
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| • Mechanisms of Dyspnea Relief after Bronchodilator Therapy |
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| Denis E. O'Donnell and Katherine A. Webb |
156 |
| • The Impact of Oxygen and Heliox |
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| Richard Casaburi |
158 |
| • The Impact of Education and Symptom Management |
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| Virginia Carrieri-Kohlman |
160 |
| Summary |
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| • Denis E. O'Donnell |
162 |
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Introduction
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Denis E. O'Donnell
This roundtable represented a unique opportunity to bring together 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 management 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 pathophysiologic 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 of modern treatment options such as bronchodilator therapy, oxygen, and heliox will be considered. Finally, the last section summarizes the impact of education and self-management strategies on symptom alleviation.
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Dyspnea: The Clinical Problem
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Donald A. Mahler
Dyspnea is common in patients with cardiac or respiratory disease as well as in healthy individuals who are obese and/or deconditioned. Certainly, the problems of obesity and sedentary life style are quite prevalent among elderly people who live in developed countries. Moreover, the aging process causes a gradual deterioration in lung function due to a decrease in lung elasticity, an increase in stiffness of the chest wall, and a decrease in respiratory muscle strength. Thus, there are several reasons why healthy older individuals may experience breathlessness.
In those less than 65 years of age, the prevalence of dyspnea in healthy adults ranges from 10 to 18% (1–6). More than 30% of elderly individuals (i.e., 
65 years of age) report breathlessness with activities of daily living, including walking on a level surface or up an incline (7–11). The finding is similar for people from different countries, including France, the United Kingdom, and the United States (9–11). Women appear to experience breathlessness more frequently than men (5, 6, 9, 12, 13).
Various techniques have been used to study the perception of dyspnea. These include breathing through added resistive loads, breathing hypoxic or hypercapnic gas mixtures, and performing an exercise test. Healthy older individuals and patients with obstructive airway disease who have advanced age exhibit a diminished estimation of the intensity of breathlessness when breathing through external resistive loads (14). Cross-sectional studies have also shown a decrease in the ventilatory response to both hypoxia and hypercapnia with advancing age (15, 16). During cardiopulmonary exercise testing, older subjects (mean age 66 years) report higher dyspnea ratings as measured by the slope of dyspnea/power (watts) compared with younger subjects (mean age 19 years) (17). This higher slope in older subjects was evident in both women and in men (17). Moreover, Johnson and colleagues (18) found that healthy older subjects rated breathlessness greater than general fatigue during exertion, whereas healthy young people indicated that fatigue was greater than breathlessness. These overall findings are likely due to the higher level of ventilation observed in older individuals during exercise. However, it is unclear whether the higher ventilation is a direct result of the aging process or more a consequence of sedentary lifestyle, deconditioning, and/or weight gain that typically occur with advancing age. Regardless, the increased ventilatory response observed in older individuals during exertion and the diminished ventilatory capacity (i.e., reduced respiratory muscle strength that occurs with advancing age) contribute to the high prevalence of dyspnea reported by elderly individuals (17).
How common is breathlessness with activity? A telephone survey of patients with COPD living in North America and in Europe documented the frequency of breathlessness with daily activities (19). According to this questionnaire, one-fifth of the patients reported that they were breathless even when just sitting or lying still and 24% when talking. One-third said they were breathless when doing light housework or while getting washed or dressed, and nearly 70% were short of breath when walking up a flight of stairs. It is clear from these data that COPD is associated with a considerable burden of disease, affecting many things that are fundamental to everyday life such as the ability to breathe, talk, sleep, have sex, work, and socialize. Furthermore, the severity of dyspnea generally progresses over time in patients with COPD (Figure 1) (20).
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Figure 1. Changes in dyspnea in 76 patients with chronic obstructive pulmonary disease (COPD) who were recruited in an observational study when in a stable clinical state and received standard medical care throughout the two-year period (data from Reference 20).
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The experience of dyspnea encompasses different qualities based on the specific diagnosis. For example, Elliott and colleagues (21) reported that patients with COPD living in the United Kingdom describe "distress" associated with breathlessness. In the United States, Mahler and colleagues (22) found that patients with COPD chose the following three statements from a list of 15 possibilities to describe their experience: "my breathing requires effort" (51%), "I feel out of breath" (49%), and "I cannot get enough air in" (38%). Seventy-five percent of patients studied by O'Donnell and colleagues (23) in Canada selected "increased inspiratory difficulty" and "unsatisfactory inspiratory effort" to describe their perception of breathlessness immediately after cycle ergometry. These descriptors of breathlessness selected by patients with COPD from different countries are quite similar and appear to represent the work and effort of the respiratory muscles associated with breathing.
In the past, several multicenter randomized trials have examined lung function, particularly FEV1, as the primary outcome measure to assess specific therapy. However, neither inhaled ipratropium bromide nor inhaled corticosteroids have been shown to affect the decline in FEV1 over time (24, 25). These negative results require the pulmonary community to reconsider the goals of treatment. Accordingly, the severity of dyspnea has become an important outcome measure in clinical trials of patients with COPD. Moreover, the ATS/ERS Task Force has stated that "all patients who are symptomatic merit a trial of drug treatment" (26).
New approaches to the study of dyspnea need to be considered. Whereas many earlier laboratory studies have examined the mechanisms contributing to dyspnea in healthy subjects, it is important to investigate the pathophysiologic mechanisms in patients with respiratory disease. Presently, established instruments or scales are available to measure the intensity of breathlessness (27). However, future efforts should be directed to the development of more responsive instruments for patients to report the severity of dyspnea in clinical trials. Finally, based on our current knowledge, dyspnea should be included as a primary or secondary outcome in multicenter randomized controlled trials investigating the efficacy and effectiveness of various treatments for patients with COPD.
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Chemical and Mechanical Loads: What Have We Learned?
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Paul W. Davenport
Dyspnea is not a single sensory modality but rather a combination of modalities: central neural, chemical, and mechanical. Respiratory disruption results in a cognitive awareness of breathing, which is mediated by neural processes. Sufficient disruption leads to distressing emotions, and this dysfunction motivates and elicits behavioral adaptations such as escape behavior. Respiratory sensations of sufficient magnitude can dominate cognitive awareness; hence, there has to be a cognitive neural basis for respiratory somatosensation. It follows that appropriate manipulation of these neural processes will provide insight into the mechanisms mediating dyspnea. The goal of research surrounding dyspnea is to use physiological changes to understand psychological processes and to use psychological changes to understand physiological processes. To investigate dyspnea, the modality mediating the sensation, the threshold, the magnitude of stimulation, the neural mechanisms, and the outcomes/compensations need to be considered.
Animal Studies
To date, many lessons have been learned from external mechanical loading experiments in animal (28–32) and human studies (33–40). Animal studies have been performed mainly in rats (41–45), cats (30, 46–51), and dogs (31, 52–55). Conditioned fear induced by hypercapnia in rats is known to cause changes in the breathing pattern (28, 29). These stimuli elicit neural activation, and the activated neurons can be found using c-Fos expression in several nuclei in the central nervous system (41). Mechanical loads also stimulate these central neural fear centers. Nsegbe and coworkers (28) performed a controlled experiment in which a 1-minute tone (the conditioned stimulus, CS) was paired with a hypercapnic stimulus (8.5% CO2, the unconditioned stimulus, US). After the CS alone, breath duration was significantly longer in the experimental than in the control group and mean ventilation was significantly lower, thus showing inhibitory conditioning. This conditioning may have resulted from the association between the CS and the inhibitory and aversive effects of CO2 (28). In another study, the association of an odor and hypoxia elicited a biphasic ventilatory conditioned response, of which the first component is integrated into conditioned arousal (29). These and other studies indicate that chemical and mechanical respiratory stimuli that produce a sensation of dyspnea in humans, can elicit detection, fear, escape behavior and anxiety in animals, thus indicating an animal analog of dyspnea (28, 29, 31).
Human Studies
Human studies have shown similar findings. Hypercapnic conditioning linked to odor resulted in a conditioned ventilatory response with word descriptors related to breathing effort, suffocation, and rapid breath (56, 57). These hypercapnic sensations are modulated by lung volume and breathing effort. Mechanical loads in human studies elicit respiratory perceptions that exhibit a threshold, quantification of magnitude, discrimination of quality, and regulation of breathing pattern (33–36, 39, 40, 58, 59). This perception is modulated by physiological state changes such as respiratory muscle "strength" changes (60), respiratory drive (61, 62), background load on the respiratory muscles (36, 63), hypercapnia (64), and hypoxia (65–67). Intrinsic resistive and elastic loading of the respiratory muscles (68) and hyperinflation (69–72) also elicit respiratory sensations. Functional magnetic resonance imaging (MRI) (69, 73–76) and respiratory-related evoked potentials (RREP) (77) have shown that respiratory chemostimulation, mechanostimulation, and motor drive change brain neural activity (61, 64, 77–80). Brain-evoked activity is also elicited by respiratory muscle stimulation (50, 51, 81, 82), inspiratory occlusion (64, 77, 78), inspiratory loads (79, 80), and mouth stimulation (83, 84). Brain activity is attention dependent (85–89), load threshold dependent (85), and modulated by background load as well.
Respiratory-related Evoked Potentials
Observations from RREP studies have also provided more information regarding human response and the neural gating process. Modality-specific activation of cortical neural processing centers depends on a change in neural activity that gates-in modality-specific information to the brain information processing centers (90–94). This activation leads to cognitive awareness of the modality. The significance of gating-in and gating-out sensory modalities is the need to attend to essential physiological functions. Scalp electroencephalographic measures have been shown to reflect neural markers of increased stimulus redundancy. It has been demonstrated (90, 95, 96) that an auditory mid-latency evoked potential positive peak at about 50 milliseconds (P50) and a negative peak at about l00 milliseconds (N100) after stimulus onset can be used as neural measures of stimulus filtering (i.e., gating). It has been reported (95, 97) that in application of stimulus pairs, with the individual stimuli separated by 500 milliseconds, the second stimulus (S2) normally has a reduced amplitude when compared with the first stimulus (S1). The S2/S1 ratio is normally approximately 0.5, demonstrating the reduction of neural activation of the redundant stimulus; this is defined as gating for these modalities. The N100 has reduced S2 amplitude, especially in somatosensory modalities. The N100 amplitude and S2/S1 ratio can be modulated by attention and background brain state. Respiratory sensation activates the somatosensory cortex (77, 78, 98) and is closely related to the limb somatosensory system (77).
Respiratory Sensory Gating System Model
The results of the above studies of respiratory mechanosensation, particularly the RREP N1 response, lead to the respiratory sensory gating system model (Figure 2). This model is based on several assumptions: (1) cognitive sensory events reflect neural processes, (2) sensory afferents transduce respiratory-related mechanical parameters, (3) threshold gating of cognitive awareness, (4) perceptual quantification of magnitude, (5) respiratory perception modality specificity, (6) modulation by initial conditions or state, (7) multimodal respiratory afferent activation, (8) activation of affective mechanisms, and (9) elicited compensatory responses. This model is an oversimplification of the cognitive and neural processes that are hypothesized to mediate cognitive awareness of ventilation. While the model does not provide a full explanation of the mechanisms of respiratory somatosensation, it does predict investigative strategies that will lead to refinement of the model and a new understanding of the neural mechanisms mediating respiratory cognition.
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Figure 2. The respiratory sensory gating system model is a helpful way to organize the hypothesized connections, although it does not fully explain the mechanisms.
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Respiratory mechanosensation is state dependent, where state refers to both the existing background physiological state and the cognitive/behavioral/affective state. Further, it is proposed that respiratory mechanosensory state dependency is a gated neural process. There are two gating stages, a threshold gate and frequency-dependent sensory information processing gate (or filter). Threshold gating is the change in respiratory status to a point of activation of the postulated neural gate allows respiratory information to be transmitted to the somatosensory regions of the cerebral cortex. Sensory information filtering reflects whether or not attention is directed to primary somatosensory information resulting in further cognitive processing, and possible affective or behavioral responses. This also has a threshold gating element, where activation of primary somatosensory cortex can reach a criterion threshold above which further affective processing is obligatory.
Threshold gating simplified.
Threshold gating of respiratory mechanosensation can be demonstrated with a simple experiment. Subjects are unaware of their breathing motion until they are asked to focus their attention on the movement of their thorax. With a change in their attention, they can now feel their chest expand during inspiration and decrease in volume during expiration. As predicted by the model, this experiment tells us the respiratory mechanoreceptors were active during breathing that was undetected, before attending to their breathing. This afferent information did not change when subjects attended to their breathing: subjects only changed the central neural cognitive state by changing attention, that is, attentional modulation of gating. This also means that an unknown central neural mechanism blocked this mechanosensory information from activating neural cognitive centers when subjects did not attend to their breathing. What changed? It is hypothesized that the mechanosensory information that subjects feel with attention to their breathing was gated-out (threshold gate) of their cognitive centers. Neural processes mediating attention (Figure 2) acted on the gate and gated-in respiratory mechanical information. If subjects were then asked to sense if their breathing was comfortable, they made this judgment and moved into the second stage of respiratory perception, affective awareness. They initially gated-in sensory information when they felt their chest move; they then decided if their breathing had a comfortable or uncomfortable qualitative sense. The second stage is the stimulus frequency dependent gating well documented in auditory, visual, and somatosensory modalities.
Cognitive Respiratory Sensation: A Neural Construct
Respiratory motor drive is generated in the brainstem respiratory neural network. This respiratory drive produces the motor breathing pattern, thus resulting in ventilation. Ventilation is monitored by multiple sensory systems, of which we present only four major categories: muscle afferents, lung receptors, airway receptors, and chemoreceptors. (There are, of course, additional respiratory afferents, but we have limited the number of afferent populations in this model for the sake of simplicity.) These afferent systems provide sensory input to the brainstem respiratory network, yet it is also known that these afferents also project to higher brain centers (49, 50). Respiratory sensations are produced by respiratory changes that preferentially activate one or more of these groups of afferents. However, these sensations do not occur with normal respiratory mechanics, ventilation, and eupneic breathing patterns. This implies that a change of sufficient magnitude (threshold) in these respiratory sensory systems changes central neural information processing (gating), resulting in a cognitive awareness of breathing. Changes in breathing effort also can be perceived. Higher brain centers are activated when ventilatory drive is increased and some neurons show a respiratory rhythm during eupneic breathing (99–101). This suggests that respiratory motor drive is integrated with sensory input by gated comparator mechanisms that are connected into the cognitive centers that mediate the sense of breathing. The background status of ventilation also modulates respiratory sensation. Respiratory sensation and perception is further modulated by attention, experience/learning, and affective state. As noted above, attending to breathing results in cognitive awareness of ventilation.
Experience and learning also are important components of respiratory sensation. Respiratory perception studies for most respiratory modalities begin with a familiarization or training session to train the subject to the sensation elicited by the specific ventilatory perturbation. This means the subject must experience the respiratory change and learn to associate that change with the sensation it produces. The association cortex is the brain region that mediates attention, experience, and learning. Hence, we propose that respiratory sensation is modulated by the association cortex.
Respiratory sensation also is dependent on affective state of the subject. Anxiety and distress elicit profound changes in ventilation and strong respiratory sensations (102). Thus, respiratory sensations are modulated by the affective neural control system. Other sensory modalities can interact to change the sensory threshold. In physical therapy, the distraction of changing a sensory system modifies the ability of the patient to perform the rehabilitation task (103).
These observations suggest that eliciting a cognitive respiratory sensation depends on the integration of respiratory afferent activity, respiratory motor drive, affective state, attention, experience, and learning. These neural parameters input to a hypothesized gating center that has an output that elicits a cognitive neural response if the combined input exceeds the threshold for gating the respiratory sensation, a gated comparator. Future research is needed to investigate systematically the gating of respiratory sensory cognition, modulation of respiratory sensation by physiological state, the role of affective systems on respiratory sensations, and the role of specific neural systems in regulating respiratory cognition.
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Multiple Mechanisms Contributing to Dyspnea
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Simon C. Gandevia
Evolution has built in mechanisms at many levels, from the subcellular level to the level of tissues and organs and ultimately to the whole-body level, to optimize acquisition, transport, and delivery of oxygen. A similar, but not identical, set of adaptations allows the removal of carbon dioxide. Presumably this must reflect the critical importance for survival of oxygen usage and carbon dioxide elimination. If dyspnea is taken to mean a perceived difficulty with breathing (a view accepted by most participants at the Roundtable), then it is not surprising that it can be signaled by a range of proprioceptive and visceral ("deep") afferents. Indeed, many different subjective components of dyspnea can be distinguished by patients and normal subjects (104). Furthermore, it would be expected that dyspnea would be associated with the activation of cerebral structures concerned not only with the processing of the afferent input but also with the assessment of the emotional and threat-related consequences of the stimulus that produces it. Indeed, some definitions of dyspnea specifically refer to an unpleasantness in the sensation (in which dyspnea is an "unpleasant" urge to breathe) (105).
When considering the central mechanisms underlying or contributing to the sensation, it remains useful to compare the generation of difficulty in breathing with the difficulty which may occur with the disruption of any voluntary movement and then to add in the effects that are specific to pulmonary ventilation, such as the afferent inputs from chemoreceptors, the upper and lower airway. Hence the list of classes of peripheral receptors that respond to stimuli that are potentially able to generate dyspnea is long: it includes receptors in the upper airway, lower airway, lung parenchyma, and respiratory muscles, as well as peripheral and central chemoreceptors. One lesson that has been learned over several decades from development of ideas about proprioceptive sensations associated with joints in the limbs is that inputs from all classes of mechanoreceptors that can signal any aspect of joint movement and position will be capable of contributing to, and under particular conditions dominating, proprioceptive sensation. Hence, the relevant inputs may arise in specialized mechanoreceptors in the skin, joint, or muscles. Interestingly, at different times, receptors at each of these three locations have been considered quite unimportant for this role; and, with hindsight, their exclusion has been based on somewhat flimsy logic (106). There are also multiple proprioceptive elements (force, position, effort, etc.) that can be separated for a particular circumstance (e.g., lifting a heavy suitcase). Hence, for a sensation as critical as dyspnea, it would be perilous to exclude any particular receptor class with an afferent modulation by respiration from a direct sensory role, and it is essential to recognize that there is more than one type of dyspnea (see the contribution to the roundtable by Banzett).
Those proprioceptive mechanisms involved with the detection and grading of loads to limb muscles are also involved in the detection and grading of loads to breathing. There is sufficient evidence from animal and human studies that the relevant afferent classes project to the primary sensorimotor cortex (see the contribution to the Roundtable by Davenport). Here, there is the likelihood that it is the relationship between more than one proprioceptive input or "channel" that is critical. For example, if chest wall expansion is less than expected for the delivery of a particular voluntary motor command or "effort," then it can be determined that the respiratory system is loaded, the inspiratory muscles weakened, or that these muscles are operating at a less effective part of their length–tension curve. The degree of such a mismatch will provide an index of the size of the disturbance (107–109). Despite initial studies by Campbell and colleagues (110), there is now overwhelming evidence that signals directly related to hypercapnia generate dyspnea, presumably via the activation of central chemoreceptors. Some of these studies have required complete neuromuscular paralysis to deliver a pure chemoreceptor stimulus decoupled from the usual accompanying hyperventilation (111, 112).
Another basic, nociceptive-like signaling system involves unmyelinated C fibers, which were first studied in detail by Paintal, and by the Coleridges (113, 114). They have receptive fields within the lung (pulmonary C fibers) or bronchi (bronchial C fibers), depending on their accessibility to chemicals injected via the right or left atrium. They are activated by a range of local factors including capsaicin, phenyl diguanide, mechanical distortion, and even cigarette smoke (115). Activation of these fibers in conscious humans generates potent respiratory sensations. It is possible that this occurs not only during pathologic conditions (such as left ventricular failure or pulmonary embolism), but also during the terminal phase of strenuous exercise (116). Other classes of pulmonary afferents probably also contribute to specific sensations relating to cough and chest tightness (117). Recent studies examined the capacity of the pulmonary C fibers to reflexly limit locomotion and voluntary movement. This is the J reflex proposed by Paintal to limit exercise when left ventricular failure was incipient. Unlike the paralysis of locomotor movements and motoneuronal inhibition induced by activation of these afferents in many experimental animals, conscious humans do not develop inhibition of limb motoneurons during activation of these afferents (by intravenous lobeline), but the noxious sensations remain (118). Hence, the potent viscero-somatic component of this reflex response to pulmonary insults has probably been brought under forebrain control in humans, particularly when they are awake, but the sensory and autonomic aspects of the overall response remain intact in humans.
One influential hypothesis about dyspnea was the "length–tension" hypothesis of Campbell (107). It remains conceptually tenable as a way of looking at dyspnea, in which a disparity between achieved and required ventilation is perceived. Alternatives, in the same style, focus on the disparity between achieved and "commanded" ventilation, or on the disparity between commanded ventilation and the size of the inspiratory capacity (see the contribution to the Roundtable by O'Donnell). At a central neural level, these types of comparisons are likely to be difficult to distinguish and "part and parcel" of the conscious and unconscious monitoring of respiration, but it is clear that signals from specialized receptors in muscle, joints, and so on, as well as from the lung and upper airways, can all contribute. Signals of central motor command or effort may also bias judgments, particularly when they are pathologically high, such as when inspiratory muscles are weak. However, recent studies have revealed more than one use for signals of motor command (119), so that their role is not simply to contribute to respiratory "effort" sensation.
Finally, the application of new methods of neuroimaging (positron emission tomography and functional magnetic resonance imaging) (120) and neurostimulation (transcranial stimulation) has provided insight into how the central nervous system is organized when performing respiratory acts and when it receives respiratory stimulation. Apart from the expected somatic inputs to the sensorimotor cortex from thoracic structures (including the diaphragm) and outputs from the primary motor cortical to respiratory muscles, stimuli that generate dyspnea activate many central structures. These were first shown to involve the anterior insula (121), but other areas show activity in different studies including regions of cingulate cortex, the cerebellum (particularly the vermis), and other limbic areas including the amygdala (107, 122–124).
By analogy with the range of areas activated by painful stimuli (125, 126), it is tempting to refer to the areas activated by stimuli generating dyspnea as a dyspnea "neuromatrix." Many of the areas are phylogenetically old and probably reflect the need to evaluate and respond to life-threatening stimuli. However, much remains to be done to understand this system. For example, just as there are differences between the sexes with respect to pain perception (127), such differences are likely to be important in some aspects of the experience of cardiorespiratory sensations (128). Even with the newer methods to assess human brain function, it is not trivial to determine the roles for the various areas which have shown altered activity, as it is difficult to control all the respiratory, emotional, autonomic, and attentional variables.
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The Peripheral Mechanisms of Dyspnea
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Robert B. Banzett
Dyspnea is not a single sensation—there are at least three distinct sensations of respiratory discomfort including air hunger, work/effort, and tightness. They are described as individual entities because patients and study subjects use different descriptors for each, because they can be evoked separately, and because they have different afferent neural pathways.
In the 1970s and 1980s, all dyspnea was thought to arise from afferent information from the respiratory muscles when they are driven to work harder by chemoreflex or while attempting to overcome a load. This hypothesis suggests that blocking the muscle contraction will block the sensation of dyspnea. Initial studies (110) demonstrated this effect, as the subjects were able to hold their breath longer with less sense of urgency to breathe after total neuromuscular block with tubocurarine. Following criticism of the methodology (129), a repeat study on a single subject (130) confirmed the initial results. In the 1990s, new experiments showed that dyspnea was unchanged by paralysis using both steady-state hypercapnia and breath-hold protocols (111, 112, 131). These experiments refuted the earlier results, and a new schema began to gain acceptance.
Air Hunger
The term "air hunger" was coined in the 1950s (132) to describe the sense of an uncomfortable urge to breathe, as felt at the end of a long breath hold. Subjects and patients volunteer descriptions such as "I'm starved for air," "I'm not getting enough air." The sense of air hunger in both laboratory subjects and patients is also accompanied by more emotional descriptors like "frightening" or "like I was going to die" (111, 133). Experiments with paralyzed subjects have shown that respiratory muscle contraction is not necessary to induce air hunger. Two groups (111, 112) have shown that the air hunger stimulus–response curve for CO2 is not altered by complete paralysis via neuromuscular block, thus disproving the theory from the 1980s. The most likely afferent stimulus for air hunger is corollary discharge conveying a copy of the medullary respiratory center discharge to the sensory areas of the forebrain (134–136), although a role for direct projection of chemoreceptors to the forebrain (137) has not been disproved.
The intensity of air hunger is set not only by the excitatory stimulus, but also by ongoing inhibition from mechanoreceptors that signal the current level of pulmonary ventilation. Hill and Flack reported a century ago that tidal breathing relieves air hunger at the end of a breath hold even if improvement of blood gasses is prevented (138). We have shown that increased tidal volume (delivered by a ventilator) can relieve air hunger in C1-C2 quadriplegics, suggesting that the pathway must be vagal (139, 140) (Figure 3). We conclude that pulmonary stretch receptor information is capable of relieving air hunger; chest wall afferent information probably has a weaker effect (141). There is some information from animal experiments that suggests this inhibition takes place at a level above the medullary respiratory centers, but below the cortex (142) (Figure 3).
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Figure 3. Neural pathways underlying air hunger. Proposed pathways for relief of air hunger by tidal inflation are shown by right hand arrows. Supporting data comes from References 100, 101, and 140.
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Sense of Effort
The work/effort sensation of dyspnea is often described as "breathing is difficult," "breathing takes a lot of work," or "breathing takes effort" (104, 143). Normal subjects do not perceive work/effort as threatening or frightening as long as the blood gases remain normal (143). Several types of stimuli can evoke the sense of work/effort. When PCO2 is held at normal levels, voluntary hyperpnea (143) and partial paralysis (144) in normal subjects elicit reports of work/effort, but not air hunger. Other stimuli include external loads, elevated end-expiratory volume, and respiratory muscle fatigue. The neural pathways proposed for these sensations include corollary discharge from motor cortical centers that drive voluntary breathing (108, 145, 146). Muscle mechanoreceptors and metaboreceptors are probably also involved, while corollary discharge from the brainstem is probably not (Figure 4).
Chest Tightness
The sensation of tightness seems to be unique to asthma, evoking descriptors such as the "chest is constricted" and the "chest feels tight." If tightness results from the added work, then it should be abolished when the work of breathing is supported by mechanical ventilation. This theory was refuted by a study demonstrating that work/effort sensation, but not tightness, was reduced when individuals with asthma with bronchoconstriction were mechanically ventilated (117). In another single-patient study, involving a mechanically ventilated C1-C2 quadriplegic, tightness was evoked by bronchoconstriction (R. Brown and R. M. Schwartzstein, personal communication). Further studies are needed to confirm that the pathway for tightness is vagal in origin (Figure 5).
Unsatisfied Inspiration
A challenge before us is to understand how these neural mechanisms operate alone or in combination to produce the dyspnea experienced by patients. For instance, O'Donnell and coworkers have shown that decline in inspiratory capacity is closely related to the magnitude of dyspnea, as patients with obstructive disease become dynamically hyperinflated (23, 147). What neural mechanisms underlie this relationship between a mechanical event and perceived sensation? The mechanisms described for work/effort sensation undoubtedly play a role in sensing the increased work expended against a stiffer respiratory system by disadvantaged inspiratory muscles—indeed, the patients report work and effort. The mechanisms described for air hunger may also play a role as respiratory drive begins to call for more tidal volume than available within the remaining inspiratory capacity. At this stage patients report that they cannot get enough air, that inspiration isn't satisfying—this is similar to subjects' descriptions of air hunger in other circumstances.
It is probable that additional sensations and pathways will be described—for example, the pathways described here do not adequately explain dyspnea associated with pulmonary vascular congestion. Although the concept that dyspnea has at least three distinct sensations is supported by the research to date, more investigation is needed to clarify the neural mechanisms underlying individual dyspnea sensations, to discover additional pathways, and to provide critical tests of the role of each of these individual pathways in the more complex phenomenon of clinical dyspnea.
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Exertional Dyspnea in COPD: Mechanics and Neurophysiology
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Denis E. O'Donnell
Dyspnea and limitation of physical activity are the main symptoms of COPD and contribute importantly to perceived poor health status in this population. Our understanding of the source and mechanisms of exertional dyspnea continues to grow, and our ability to alleviate this symptom has recently improved. The mechanisms of dyspnea and exercise intolerance in COPD are complex and multifactorial (see Reference 147 for review). This review focuses primarily on ventilatory mechanical factors that can potentially be manipulated for the patients' benefit.
Ventilatory Mechanics in COPD
Expiratory flow limitation (EFL) is the pathophysiologic hallmark of COPD and arises because of the dual effects of permanent parenchymal destruction (emphysema) and airway dysfunction, which in turn reflects the effects of small airway inflammation (mucosal edema, airway remodeling/fibrosis, and mucous impaction) (148). Emphysema results in a reduced lung elastic recoil pressure, which leads to a reduced driving pressure for expiratory flow through narrowed and poorly tethered airways in which airflow resistance is significantly increased. EFL is said to be present when the expiratory flows generated during spontaneous tidal breathing represent the maximal possible flow rates that can be generated at that operating lung volume (149) (Figure 6).
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Figure 6. In a healthy subject (left panel) and a typical patient with COPD (right panel), tidal flow–volume loops at rest and during exercise are shown in relation to their respective maximal flow–volume loops. Peak exercise in COPD is compared with exercise at a comparable metabolic load in the age-matched person. Note expiratory flow limitation (tidal expiratory flow overlapping the maximal curve) at rest and during exercise and an increase in dynamic end-expiratory lung volume (EELV) during exercise in COPD. IC = inspirational capacity; IRV = inspiratory reserve volume; TLC = total lung capacity.
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In health, the relaxation volume of the respiratory system is dictated by the balance of forces between the inward elastic recoil pressure of the lung and the outward recoil pressure of chest wall (148) (Figure 7). In COPD, the increased compliance of the lung, as a result of emphysema, leads to a resetting of the relaxation voume of the respiratory system to a higher level than in health. This has been termed "static" lung hyperinflation (149). In patients with EFL during spontaneous resting breathing, end-expiratory lung volume (EELV) is also "dynamically" determined and is maintained at a level above the statically determined relaxation volume of the respiratory system. In flow-limited patients, the time-constant for lung emptying (i.e., the product of compliance and resistance) is increased in many alveolar units, but the expiratory time available (as dictated by the respiratory control centers) is often insufficient to allow EELV to decline to its normal relaxation volume, thereby resulting in air retention (or trapping) with further lung hyperinflation. EELV in COPD is, therefore, a continuous dynamic variable that varies with the extent of EFL, the prevailing ventilatory demand, and breathing pattern.
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Figure 7. Pressure–volume (P–V) relationships of the total respiratory system in health and in COPD. Tidal pressure–volume curves during rest (filled area) and exercise (open area) are shown. In COPD, because of resting and dynamic hyperinflation (a further increased end-expiratory lung volume [EELV]), exercise tidal volume ( V) encroaches on the upper, alinear extreme of the respiratory system's P–V curve where there is increased elastic loading. In COPD, the ability to further expand tidal volume is reduced (i.e., inspiratory reserve volume [IRV] is diminished). In contrast to health, the combined recoil pressure of the lungs and chest wall in hyperinflated patients with COPD is inwardly directed during both rest and exercise; this results in an inspiratory threshold load on the inspiratory muscles. RV = residual volume; TLC = total lung capacity. Reprinted by permission from Reference 241.
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The rate and magnitude of dynamic lung hyperinflation (DH) during exercise is generally measured in the laboratory setting by serial inspiratory capacity (IC) measurements (150–152). The IC is the maximal volume of air than can be inhaled after a spontaneous expiration to EELV. Since total lung capacity (TLC) does not change during activity, the change (decrease) in IC reflects the change (increase) in dynamic EELV, or the extent of DH (150–152) (Figure 5). This simple method has been shown to be reliable (reproducible and responsive) in recent multicenter clinical trials (70, 153). In two studies conducted in approximately 500 patients with moderate-to-severe COPD, the change in EELV during cycle ergometry averaged 0.4 L, with wide variation in the range (70, 153). Eighty-six percent of this population sample showed increases in EELV from rest to peak exercise, confirming the presence of significant DH. Those remaining patients (14%) demonstrated the most severe resting lung hyperinflation and therefore showed little further DH during exercise. The rate of rise of DH was more abrupt in patients with the highest ventilatory demand (reflecting greater ventilation/perfusion abnormalities) and generally reached a maximal value early in exercise.
The negative effects of acute DH during exercise are now well established (see Reference 154 for review): (1) DH leads to increases in the elastic and threshold loads on the inspiratory muscles, thus increasing the work and oxygen cost of breathing; (2) DH results in functional inspiratory muscle weakness by maximally shortening the muscle fibers in the diaphragm and other inspiratory muscles; (3) DH reduces the ability of tidal volume to expand appropriately during exercise, and this leads to early mechanical limitation of ventilation (Figure 8); (4) in some patients, this mechanical constraint on tidal volume expansion in the setting of severe pulmonary V/Q abnormalities (i.e., high fixed physiological dead space) leads to CO2 retention and arterial oxygen desaturation during exercise; and (5) DH adversely affects dynamic cardiac function. All of the above factors are clearly interdependent and contribute in a complex integrated manner to dyspnea and exercise limitation in COPD.
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Figure 8. Behavior of operating lung volumes (left) and respiratory effort (Pes/PImax) (right) as ventilation increases during exercise in COPD and in age-matched healthy subjects. In COPD, tidal volume takes up a larger proportion of the reduced inspiratory capacity (IC) at any given ventilation—mechanical constraints on tidal volume expansion are further compounded because of dynamic hyperinflation during exercise. As a result of functionally weakened inspiratory muscles and increased mechanical loading, tidal inspiratory pressures represent a much higher fraction of their maximal force-generating capacity in COPD than in health. Data from Reference 23. TLC = total lung capacity.
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Correlates of Dyspnea
A number of recent studies have shown strong statistical correlations between the reduction in IC during exercise and ratings of exertional dyspnea intensity in COPD (23, 151). This association was tested by evaluating the impact of therapeutic interventions. Improvement in dyspnea after bronchodilators and lung volume reduction surgery correlated well with increased IC, a measure of reduced lung hyperinflation (70, 71, 150, 155). A recent mechanistic study in our laboratory determined that DH early in exercise allowed flow-limited patients to increase ventilation acutely while minimizing respiratory discomfort (156). Thus, as a result of DH early in exercise, the airways are maximally stretched at the higher lung volumes (close to TLC) and EFL is attenuated, allowing patients to maximize expiratory flow rates. Thus, in early exercise, the ratio of inspiratory effort (relative to maximum) to tidal volume displacement remains constant. However, this advantage is quickly negated when tidal volume expands to reach a critically low inspiratory reserve volume (IRV) of approximately 0.5 L below TLC. At this "threshold," tidal volume becomes fixed on the upper, less compliant extreme of the sigmoid-shaped pressure–volume relation of the respiratory system, where there is increased elastic loading of the inspiratory muscles. After reaching this minimal IRV, dyspnea (inspiratory difficulty) rises abruptly to intolerable levels and reflects the widening disparity between inspiratory effort (and central neural drive) and the simultaneous tidal volume response, which becomes essentially fixed (i.e., increased effort:displacement ratio) (156) (Figure 9). Dyspnea intensity correlates well with the increase in this effort:displacement ratio during exercise in COPD (156). The above studies indicate that, although dyspnea is multifactorial in COPD, mechanical factors contribute importantly and that lung hyperinflation is therefore a promising therapeutic target for the alleviation of this distressing symptom.
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Figure 9. The mechanical "threshold" of dyspnea is indicated by the abrupt rise in dyspnea intensity after a critical minimal inspiratory reserve volume (IRV) is reached, which prevents further expansion of tidal volume (VT) during constant-load cycle exercise at 75% of the peak incremental work rate in COPD. Beyond this dyspnea/IRV inflection point, dyspnea intensity, respiratory effort (Pes/PImax), and the effort:displacement ratio all continue to rise. Arrows indicate the dyspnea/IRV inflection point during exercise. Values are expressed as means ± SEM. Adapted by permission from Reference 156.
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Neurophysiology of Dyspnea during Exercise
In COPD, dyspnea intensity during exercise is higher at any given ventilation, work rate, or metabolic load than in health (Figure 10). The precise mechanisms of dyspnea remain obscure, and there are multiple potential sources of respiratory discomfort (147). Possible components include: perception of heightened inspiratory effort; awareness of unrewarded effort; and perceptions arising from dyspneogenic afferent inputs from chemoreceptors and a multitude of mechanosensors in the airway, lung, and chest wall. One approach to the study of dyspnea is to identify the major qualitative dimensions of the symptom in an attempt to uncover different underlying neurophysiologic mechanisms (23) (see the contribution to the roundtable by Banzett). Two dominant clusters of qualitative descriptors are commonly selected by patients with COPD to describe their experience of respiratory difficulty at the termination of exercise: (1) a sense of heightened effort, work, or heaviness of breathing; and (2) the sense of "unsatisfied" inspiration, that is, "I cannot get enough air in" (Figure 11).
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Figure 10. The effort:displacement ratio and dyspnea intensity are shown relative to ventilation during incremental exercise in COPD and in age-matched healthy normal subjects. Tidal swings of respiratory effort (Pes/PImax) relative to the tidal volume response (VT/predicted VC) and exertional dyspnea intensity are greater throughout exercise in COPD compared with health. Values are shown as means ± SE. Adapted by permission from Reference 23.
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Figure 11. Qualitative descriptors of exertional dyspnea at the end of symptom-limited cycle exercise in COPD (right) and in age-matched healthy subjects (left). In COPD compared with health, there was a greater (*P < 0.05) predominance of awareness of "unsatisfied inspiration," "inspiratory difficulty" and "shallow" breathing. Adapted by permission from Reference 23.
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Increased Inspiratory Effort
Perceived heightened inspiratory effort is pervasive in health and respiratory disease, but is more intense and occurs at lower levels of exercise in patients with COPD (157). In health, several physiological adaptations minimize respiratory discomfort as ventilation increases to high levels during exercise. These include: reduced intra- and extrathoracic airway resistance, precise control of operating lung volumes, improved pulmonary ventilation/perfusion relations, and alterations of breathing pattern. Collectively, these adjustments optimize dynamic ventilatory mechanics and allow the preservation of harmonious neuromechanical coupling of the respiratory system throughout exercise with avoidance of respiratory discomfort. As ventilation increases during exercise in health, increased efferent inputs from cortical motor centers and the brainstem respiratory center, together with gated afferent inputs from multiple respiratory mechanosensors, are processed and integrated in the sensory cortex/association cortex. In health, if this sensory information is attended to, a conscious determination will generally be made that breathing is comfortable and appropriate for the specific physical task (see the contribution to the roundtable by Davenport). At the highest levels of ventilation, the sense of heightened inspiratory effort increases and reflects the increased central (voluntary) motor command output to the ventilatory muscles and may be consciously perceived through corollary discharge (or efferent copy) to the sensory cortex (100, 158) (see the contribution to the roundtable by Banzett). Increased respiratory muscular effort in health is always appropriately rewarded by increased mechanical output (and ventilation), even at high exercise intensities. Thus, this perception of increased effort or work of breathing need not be unpleasant and therefore need not elicit an emotive "distress" response (limbic system activation) with corresponding behavioral compensation.
In COPD, all of the physiologic adaptations in health (described above) that optimize neuromechanical coupling and minimize discomfort are seriously disrupted (see the section by O'Donnell on pathophysiology of COPD). In COPD, muscular effort is therefore substantially increased at any given ventilation compared with health, reflecting the increased loading and functional weakening of inspiratory muscles. Several studies in COPD have shown that during exercise, there is a close correlation between increased inspiratory effort (measured by tidal esophageal pressure relative to maximum) and the intensity of dyspnea measured by the Borg scale (23, 159). Increased corollary discharge remains a plausible mechanism for perceived increased inspiratory effort, and this idea is consistent with concepts of sensory physiology that have previously been applied to other working skeletal muscle groups. It is conceivable that, in the exercising patient with COPD, increased corollary discharge to the sensory cortex/association cortex (beyond a certain threshold) may be sensed as abnormal and consequently evoke negative threat-related affective responses.
Unsatisfied Inspiration
The distressing sensation of "unsatisfied inspiration" seems to be characteristic of respiratory diseases and is rarely reported in health, even at symptom-limited peak oxygen uptake (VO2). The "unsatisfied inspiration" descriptor cluster (cannot get enough air in, my breath does not go in all the way, I feel the need for more air) selected by patients with COPD when dyspnea intensity is severe at the end of exercise has obvious semantic overlap with perceived "air hunger" (the uncomfortable urge to breathe) described in health during chemostimulation (with or without mechanostimulation). These discrete respiratory sensations, which are usually accompanied by distress, may very well share common neurosensory mechanisms (i.e., neuromechanical dissociation and limbic system activation). However, this hypothesis needs to be formally tested.
It is reasonable to assume that unsatisfied inspiration is modulated by peripheral sensory inputs that signal that the mechanical/muscular response of the respiratory system is inadequate for the prevailing central neural output. In COPD, restricted volume expansion and disrupted neuromuscular coupling as a result of the effects of dynamic hyperinflation are putative mechanisms of unsatisfied inspiration that have recently been considered.
Several studies in resting healthy humans have shown that when chemical drive is increased in the face of voluntary suppression or restriction of the spontaneous breathing response, dyspnea quickly escalates to intolerable levels (138, 160–162). Moreover, resumption of spontaneous breathing (restored tidal volume displacement) was associated with immediate improvement in respiratory comfort, despite persistent (or even increased) chemical loading (138, 160–162). In health, mechanical restriction of tidal volume by chest strapping during exercise-induced severe dyspnea (described predominantly as unsatisfied inspiration) in the setting of added chemical loading (163) (Figure 12). Chest strapping resulted in a blunted tidal volume response to exercise (compared with unloaded control) and caused a large increase in the ratio of respiratory effort (i.e., tidal esophageal pressure swings relative to maximum) to thoracic displacement (i.e., tidal volume expressed as percent of predicted vital capacity) (Figure 12). The relative importance of the various sensory systems that ultimately contribute to an awareness of unsatisfied breathing remain to be determined. However, alteration in afferent inputs from vagal pulmonary receptors and chest wall mechanosensors, which are gated to command obligatory attention in cortical cognitive centers, remain prime candidates for the purpose of sensing abnormal thoracic displacement.
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Figure 12. (A) Mechanical restriction by chest wall strapping (CWS) in the setting of added chemical loading (DS) induced very severe dyspnea during cycle exercise compared with an unloaded control test in 12 healthy young men. CWS+DS resulted in a blunted tidal volume response to exercise and caused a large increase in the ratio of respiratory effort (i.e., tidal esophageal pressure swings relative to maximum inspiratory pressure [Pes/PImax]) to thoracic displacement (i.e., tidal volume expressed as % predicted vital capacity [VC]). (B) Qualitative descriptors of exertional dyspnea at the end of symptom-limited cycle exercise in health during an unloaded control test and during mechanical restriction induced by chest wall strapping (CWS) combined with deadspace loading (DS). There was a greater (*P < 0.05) predominance of awareness of unsatisfied inspiration, inspiratory difficulty, and shallow breathing with CWS+DS compared with Control. Graphs constructed with data from Reference 163.
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Because of resting and further dynamic hyperinflation during exercise in COPD, the ability to expand tidal volume is constrained as it becomes positioned in the upper noncompliant extreme of the respiratory system's pressure–volume relationship. Tidal volume responses are therefore shallow and become relatively fixed early in exercise despite the escalating drive to breathe. Therefore, effort-displacement ratios rise precipitously when tidal volume expands to reach the minimal IRV, and this index correlates strongly with ratings of dyspnea intensity (Figure 13). Therefore we postulate that in COPD, a mismatch between central neural drive and the mechanical response (neuromechanical dissociation), as crudely reflected by the increased effort:displacement ratio, is fundamental to the origin of dyspnea or its dominant qualitative dimension (Figure 14).
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Figure 13. Significant inter-relationships were found between dyspnea intensity, the effort:displacement ratio (i.e., a crude index of neuromechanical dissociation) and the extent of dynamic hyperinflation (i.e., end-expiratory lung volume [EELV]) at a standardized level of exercise in patients with COPD. Pes = esophageal pressure; PImax = maximal inspiratory pressure; TLC = total lung capacity. Reproduced by permission from Reference 147.
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Figure 14. Model of neuromechanical dissociation in COPD. In health during exercise there is a harmonious matching of motor output (via corollary discharge) to the mechanical response of the respiratory system (via afferent peripheral feedback from multiple mechanoreceptors)—neuromechanical coupling. In COPD, there is a disparity between respiratory effort and the mechanical response of the system—neuromechanical dissociation. This disparity gives rise to sensations of respiratory discomfort such as "unsatisfied inspiratory effort."
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At the end of exercise in COPD when dyspnea intensity reaches intolerable levels, the muscle fibers in the inspiratory muscles are maximally shortened (and weakened or possibly fatigued) and thoracic displacement with each breath is greatly constrained in the face of near-maximal contractile muscle effort and chemical drive (i.e., metabolic acidosis and possibly critical hypoxemia or hypercapnia). In some individuals it is possible that carbon dioxide retention during exercise will directly or indirectly amplify dyspnea (or air hunger) through increased activation of central chemoreceptors. Applying current neurophysiologic constructs for the genesis of dyspnea, the conscious awareness of unsatisfied inspiration may arise from integrated sensory inputs which reach the sensory cortex/association cortex from: (1) cortical (motor) and brainstem centers; and (2) respiratory mechanosensors in the muscles, lung, and chest wall (see Neurophysiology section in this document). The muscle spindles and Golgi tendon organs in the foreshortened, weakened, and possibly fatigued inspiratory muscles are ideally placed to act as the proximate source of this peripheral feedback information of an inadequate volume or ventilatory response (107, 164). However, an
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ABSTRACT
Introduction
