Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) primarily describe their exertional dyspnea using descriptors alluding to increased effort or work of breathing and unsatisfied inspiration or inspiratory difficulty.
Objectives: The purpose of this study was to examine the impact of changes in dynamic respiratory mechanics during incremental (INCR) and high-intensity constant work-rate (CWR) cycle exercise on the evolution of dyspnea intensity and its major qualitative dimensions in patients with moderate-to-severe COPD.
Methods: Sixteen subjects with COPD performed symptom-limited INCR and CWR cycle exercise tests. Measurements included dyspnea intensity and qualitative descriptors, breathing pattern, operating lung volumes, and esophageal pressure (Pes).
Measurements and Main Results: During both exercise tests, there was an inflection in the relation between tidal volume (Vt) and ventilation. This inflection occurred significantly earlier in time during CWR versus INCR exercise but at a similar ventilation, Vt, and tidal Pes swing. Beyond this inflection, there was no further change in Vt despite a continued increase in ventilation and tidal Pes. During both tests, “work and effort” was the dominant dyspnea descriptor selected up to the inflection point, whereas after this point dyspnea intensity and the selection frequency of “unsatisfied inspiration” rose sharply.
Conclusions: Regardless of the exercise test protocol, the inflection (or plateau) in the Vt response marked the point where dyspnea intensity rose abruptly and there was a transition in the dominant qualitative descriptor choice from “work and effort” to “unsatisfied inspiration.” Intensity and quality of dyspnea evolve separately and are strongly influenced by mechanical constraints on Vt expansion during exercise in COPD.
Previous studies on mechanisms of exertional dyspnea in chronic obstructive pulmonary disease (COPD) have largely focused on sensory intensity of respiratory discomfort and its correlation with increased contractile respiratory muscle effort. Little is known about the evolution and physiologic basis for perceived unsatisfied inspiration, which has been shown to be a dominant qualitative dimension of dyspnea in chronic obstructive pulmonary disease at the limits of tolerance.
This study charts the evolution of both the intensity and qualitative domains of dyspnea during cycle exercise in COPD. The results show that, regardless of the exercise testing protocol (incremental or constant work rate), the attainment of critical constraints on tidal volume expansion marked the point where both dyspnea intensity and selection of perceived unsatisfied inspiration sharply escalated.
According to the last American Thoracic Society statement, dyspnea is “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (1). Intolerable dyspnea is the most common exercise-limiting symptom in patients with advanced chronic obstructive pulmonary disease (COPD) (2). The nature and mechanisms of dyspnea are complex and multifactorial but respiratory mechanical factors undoubtedly contribute (1, 3–5). Previous studies have shown that the experience of respiratory discomfort at the termination of exercise is distinctly different in health and in patients with COPD. Thus, healthy individuals select qualitative descriptors that allude to increased effort or work of breathing, whereas patients with COPD additionally select descriptors that depict the distressing sensation of unsatisfied inspiration or inspiratory difficulty (i.e., “I cannot get enough air in,” “breathing in requires more effort,” “I feel a need for more air”) (4–6). The current study is the first to chart the evolution of these qualitative dimensions of dyspnea throughout exercise and to examine their relation with dynamic respiratory mechanical events.
Previous studies using high-intensity constant work rate (CWR) cycle tests have shown that the relation between increase in dyspnea intensity and increase in the constraints on tidal volume (Vt) expansion (i.e., decrease in inspiratory reserve volume [IRV]) during exercise seems biphasic (5–9). In early exercise, dyspnea intensity rises linearly up to the moderate range at the Vt inflection point where IRV becomes critically reduced (phase I), and thereafter rises steeply to very severe levels (phase II). It is not known if this biphasic sensory response pattern is different during incremental (INCR) and CWR cycle testing where the time course of change in ventilation, operating lung volumes, breathing pattern, and esophageal pressure (Pes) generation may be distinctly different. It is also unknown whether mechanical events at the Vt inflection point are associated with a change in the quality of dyspnea or whether the “ventilatory history” of the exercise test affects the ability of the patient to identify change in the mechanical properties of the respiratory system. We postulated that, regardless of the exercise testing protocol, critical constraints on Vt displacement in the face of increasing contractile respiratory muscle effort (and increased central neural drive) would lead to an increased frequency of selection of unsatisfied inspiration relative to increased effort in phase II (5).
The aims of the current study were to determine if these restrictive constraints on volume expansion at and beyond the Vt inflection have implications for the evolution of the qualitative dimensions of dyspnea during exercise, and whether these sensory-mechanical relations are influenced by the exercise protocol selected. Operating lung volumes, breathing pattern, and Pes-derived indices of respiratory mechanics were compared in patients with COPD during INCR and high-intensity CWR cycle exercise, in random order on separate days. To better understand the relation between dynamic respiratory mechanics and dyspnea, the selection frequency of its main qualitative descriptors before and after the Vt inflection during both exercise protocols was examined. Some of the results of this study have previously been reported in abstract form (10).
Subjects included 16 clinically stable patients with COPD (FEV1/FVC <0.7) (11) and a FEV1 less than or equal to 80% predicted. Exclusion criteria were (1) a disease other than COPD that could contribute to dyspnea or exercise limitation, (2) important contraindications to clinical exercise testing, or (3) use of supplemental oxygen or desaturation less than 85% during exercise.
This randomized, controlled, cross-sectional study received ethical approval from Queen's University and Affiliated Hospitals Health Sciences Human Research Ethics Board (DMED-906–05). After obtaining informed consent, subjects completed three visits conducted 7–10 days apart. Visit 1 included medical screening, evaluation of chronic activity-related dyspnea (12, 13), familiarization with all testing procedures including all aspects of dyspnea evaluation, pulmonary function testing, and INCR cardiopulmonary cycle exercise testing. Visits 2 and 3 included pulmonary function tests and either a CWR or INCR exercise test (randomized visit order) with detailed dynamic respiratory mechanical measurements. Before each visit, subjects withdrew short-acting inhaled bronchodilators for greater than or equal to 6 hours and avoided smoking greater than or equal to 60 minutes; caffeine, alcohol, and heavy meals greater than or equal to 4 hours; and strenuous physical exertion greater than or equal to 12 hours. Visits were conducted at the same time of day for each subject.
Pulmonary function tests were performed using automated equipment (Vmax 229d with Autobox 6,200 DL; SensorMedics, Yorba Linda, CA) according to recommended standards (14–17). Measurements were expressed as percentages of predicted normal values (18–23); predicted inspiratory capacity (IC) was calculated as predicted total lung capacity minus predicted functional residual capacity.
Symptom-limited exercise tests were conducted on an electrically braked cycle ergometer (Ergometrics 800S; SensorMedics) with a cardiopulmonary exercise testing system (Vmax229d; SensorMedics) as previously described (5, 24, 25). INCR tests consisted of a 1-minute warm-up of unloaded pedaling followed by 1-minute increments of 10 W each. CWR tests consisted of a 1-minute warm-up followed by an increase in work rate to 75% of the maximal incremental work rate; endurance time was defined as the duration of loaded pedaling. Operating lung volumes derived from IC maneuvers were measured at rest, every second minute during exercise, and at end-exercise (24). Pes-derived respiratory mechanical measurements were collected continuously with an integrated data-acquisition setup (5, 25); sniff maneuvers were performed at rest and immediately at end-exercise to obtain maximum values for Pes (PImax) (17).
Intensity of dyspnea (“How strong/intense is your breathing discomfort”?) and leg discomfort were rated using the modified 10-point Borg scale (26) at rest, every minute during exercise, and at peak exercise. The endpoints of this scale were anchored such that zero represented “no breathing or leg discomfort” and 10 was “the most severe breathing or leg discomfort that they could imagine experiencing.” Three dyspnea descriptor phrases were chosen for evaluation during exercise: (1) “my breathing requires more work and effort” (work and effort); (2) “I cannot get enough air in” (unsatisfied inspiration); and (3) “I cannot get enough air out” (unsatisfied expiration). The former two common descriptors were collected for primary analyses, whereas the latter was used as a control symptom that was not expected to be selected very often. Every minute during exercise just before intensity ratings, subjects were asked to select the phrases from this list that described their sensation of breathing discomfort: none to all of the three phrases could be chosen at any one time. At end-exercise, subjects were also asked to select applicable descriptor phrases from a more comprehensive questionnaire (27).
The inflection point of the Vt and ventilation (e) relationship was determined by two different observers (K.A.W. and P.L.) for each subject during each exercise protocol by examining individual Hey plots (28): if more than one inflection point was evident during exercise, the first was chosen. Exercise parameters were compared with the predicted normal values of Jones (29). Analysis time-points were defined as follows: (1) preexercise rest was the steady-state period after at least 3 minutes of breathing on the mouthpiece before exercise began; (2) isotime 1 and 2 were standardized exercise times of 2 minutes and 4 minutes for both INCR (i.e., 20 W and 40 W) and CWR tests; (3) Vt/e inflection point; and (4) peak was the average of the last 30 seconds of loaded exercise.
The sample size estimation of 16 was based on dyspnea intensity ratings measured previously in our laboratory (5, 6) and the assumptions: a SD of approximately 1.5 units, a difference of approximately 1.5 units found between the Vt/e inflection point and peak exercise, a two-sided test, 80% power, and α = 0.05. Results are expressed as means ± SD unless otherwise specified. A P value less than 0.05 level of statistical significance was used for all analyses. Statistical procedures were performed using either SPSS 18.0 for Windows (IBM, Chicago, IL) or Systat 8.0 for Windows (Systat Software, Inc., Chicago, IL).
Between-protocol (INCR vs. CWR) comparisons at rest were made using paired t tests. Comparisons during exercise were made using paired t tests with a Bonferroni adjustment for repeated measurements: four main evaluation time-points (i.e., isotime 1, isotime 2, Vt/e inflection, and peak) meant that an uncorrected P value of less than 0.0125 was considered significant. McNemar exact test was used for within- and between-protocol analyses of dyspnea descriptors.
Subject characteristics and resting pulmonary function measurements are summarized in Table 1. There were eight subjects with Global Initiative for Chronic Obstructive Lung Disease stage II COPD and eight with Global Initiative for Chronic Obstructive Lung Disease stage III COPD.
| Male: Female, n | 9: 7 |
| Age, yr | 65 ± 11 |
| Height, cm | 169 ± 10 |
| Body mass index, kg/m2 | 29 ± 4 |
| Smoking history, pack-years | 52 ± 43 |
| Baseline Dyspnea Index, focal score (0–12) | 6.8 ± 1.3 |
| MRC dyspnea scale (1–5) | 2.5 ± 0.7 |
| Resting pulmonary function (% predicted) | |
| FEV1, L | 1.22 ± 0.29 (48 ± 9) |
| FEV1/FVC, % | 45 ± 8 |
| IC, L | 2.30 ± 0.61 (83 ± 11) |
| SVC, L | 3.27 ± 0.85 (89 ± 10) |
| TLC, L | 7.16 ± 1.32 (120 ± 14) |
| RV, L | 3.89 ± 0.76 (180 ± 34) |
| FRC, L | 4.86 ± 0.99 (151 ± 25) |
| sRaw, cm H2O • s | 22.4 ± 9.9 (531 ± 229) |
| DlCO, ml/min/mm Hg | 15 ± 4.8 (67 ± 17) |
| MIP, cm H2O | 73 ± 23 (91 ± 25) |
| MEP, cm H2O | 136 ± 39 (79 ± 15) |
Physiologic responses to INCR and CWR exercise tests are summarized in Table 2 and Figure E1 of the online supplement. All measurements obtained at rest were similar for the INCR and CWR tests. Sniff PImax was 69 ± 17 cm H2O at rest for both protocols and did not change significantly at end-exercise. In early exercise (i.e., at 2 and 4 min), the patterns of response were significantly different between tests: oxygen consumption (o2), e, Vt, Fb, and tidal Pes swings were significantly higher, whereas IC was significantly lower during CWR than INCR exercise (see online supplement). Despite these expected intensity and time-related differences, physiologic measurements at peak exercise were similar for both tests (Table 2).
| Vt/e Inflection Point* | Peak | |||
| INCR | CWR | INCR | CWR | |
| Exercise time, min | 5 ± 1.7 | 2.6 ± 0.9† | 7.9 ± 2.7 | 6 ± 2.4† |
| Work rate, W | 50 ± 17 | 61 ± 20 | 81 ± 27 | 60 ± 20† |
| Dyspnea, Borg | 2.9 ± 1.8 | 3.1 ± 2.1 | 7 ± 2.2 | 7 ± 2.4 |
| Leg discomfort, Borg | 3.5 ± 1.8 | 4.2 ± 2.2 | 7.1 ± 2.3 | 7.6 ± 2.2 |
| o2, L/min | 0.95 ± 0.27 | 1.09 ± 0.39 | 1.27 ± 0.41 | 1.24 ± 0.37 |
| o2, % predicted | 55 ± 16 | 60 ± 14 | 68 ± 18 | 66 ± 17 |
| Heart rate, beats/min | 127 ± 22 | 113 ± 25 | 142 ± 22 | 131 ± 18 |
| SpO2, % | 94 ± 3 | 94 ± 3 | 93 ± 5 | 93 ± 5 |
| e, L/min | 34.1 ± 10.5 | 38.3 ± 10.6 | 48.3 ± 14.9 | 46.2 ± 12.1 |
| e/co2 | 41 ± 8 | 41 ± 7 | 40 ± 8 | 40 ± 6 |
| Fb, breaths/min | 28 ± 7 | 30 ± 6 | 37 ± 9 | 36 ± 8 |
| Ti/Ttot | 0.41 ± 0.03 | 0.41 ± 0.03 | 0.41 ± 0.04 | 0.41 ± 0.04 |
| Vt, L | 1.22 ± 0.32 | 1.28 ± 0.32 | 1.30 ± 0.34 | 1.26 ± 0.30 |
| Vt/IC, % | 69 ± 13 | 73 ± 9 | 80 ± 12 | 79 ± 10 |
| IC, L | 1.83 ± 0.49 | 1.77 ± 0.47 | 1.64 ± 0.41 | 1.63 ± 0.41 |
| IRV, L | 0.60 ± 0.36 | 0.50 ± 0.23 | 0.33 ± 0.23 | 0.37 ± 0.21 |
| Rl, cm H2O/L/s | 7.6 ± 3.6 | 7.1 ± 4.8 | 8.5 ± 4.6 | 7.3 ± 2.6 |
| Tidal Pes, %PImax | 37 ± 15 | 37 ± 16 | 54 ± 20 | 46 ± 12 |
| Pes/PImax:Vt/prVC | 1.10 ± 0.46 | 1.07 ± 0.53 | 1.58 ± 0.65 | 1.39 ± 0.55 |
| Inspiratory Pes, %PImax | 20 ± 8 | 24 ± 8 | 29 ± 11 | 28 ± 7 |
| Expiratory Pes, %MEP | 10 ± 6 | 8 ± 5 | 14 ± 8 | 11 ± 4 |
When measurements of breathing pattern, operating lung volumes, and respiratory mechanics were plotted relative to e, response patterns were similar for both CWR and INCR exercise tests (Figure 1). A notable inflection in the Vt/e relationship occurred in most subjects during both INCR (15 of 16) and CWR (14 of 16) exercise: one subject did not have an inflection in either test so paired comparisons were made for n = 14 subjects with an inflection point in both tests (Table 2). The Vt/e inflection point coincided with an inflection in the IRV/e relationship. Although the Vt/e inflection point occurred earlier in time in the CWR test than the INCR test (2.6 vs. 5 min; P < 0.0005), the e and other physiologic measurements at this point were similar between protocols (Table 2). e at the inflection point of the INCR test correlated significantly with that of the CWR test (r = 0.631; P = 0.015). Beyond the inflection point during both protocols, there was no significant further rise in Vt despite a continued increase in e (by increasing Fb) and respiratory effort (Pes/PImax).
Figure 1. (A–F) When measurements were expressed relative to minute ventilation, responses to incremental (INCR) and constant work rate (CWR) cycle exercise were similar. Shaded areas show the tidal esophageal pressure (Pes) swing and the tidal volume (Vt) excursion during incremental exercise: near end-exercise where tidal Pes swings continue to increase, the Vt response levels off resulting in an increased effort-displacement ratio (i.e., neuromechanical dissociation). EELV = end-expiratory lung volume; EILV = end-inspiratory lung volume; Fb = breathing frequency; IC = inspiratory capacity; IRV = inspiratory reserve volume; min PesIC = the minimum Pes value measured during a maximal inspiratory effort to TLC as part of an IC maneuver during exercise; TLC = total lung capacity.
[More] [Minimize]The selection frequency of the three descriptors evaluated serially during INCR and CWR exercise is shown in Figure 2A. As expected, the sense of unsatisfied expiration was seldom chosen during exercise. The sense of work and effort was greater than unsatisfied inspiration up until the Vt/e inflection point (at inflection: all tests, P = 0.015; CWR, P = 0.035; INCR, P = 0.236); between this inflection point and peak exercise in both tests, the selection frequency of work and effort did not rise any further, whereas selection of unsatisfied inspiration increased steeply (all tests, P = 0.001; CWR, P = 0.031; INCR, P = 0.063) to reach comparable or greater levels. At end-exercise, the selection frequency of the three main descriptor phrases (Figure 2A) and the selection frequency from the more comprehensive descriptor questionnaire (Figure 2B) were similar across protocols.
Figure 2. (A) Selection frequency of the three descriptor phrases evaluated during incremental (INCR) and constant work rate (CWR) exercise: increased work and effort (Effort), unsatisfied inspiration (IN), and unsatisfied expiration (OUT). Arrows indicate the point corresponding to the inflection point of the tidal volume-ventilation relation during exercise. (B) Selection frequency of the dyspnea descriptors collected by questionnaire at end-exercise. Descriptor choices were similar in both tests with dyspnea described predominantly as a sense of “inspiratory difficulty,” “unsatisfied inspiration,” and increased “work” of breathing.
[More] [Minimize]Similar to the physiologic variables, dyspnea intensity ratings were significantly greater earlier in time during CWR than INCR exercise but reached a similar peak value (see Figure E2). Dyspnea intensity ratings were similar for both protocols when expressed relative to e (not shown); Vt (Figure 3A); and IRV (Figure 3B). The relation between dyspnea intensity and IRV was two-phased: dyspnea rose gradually to reach an inflection point (corresponding to the Vt/e inflection point), then rose almost vertically to reach the symptom-limited endpoint of exercise. As shown in a previous study (5), the relation between the Pes/PImax:Vt/predicted VC ratio and IRV was also biphasic (Figure 3C): the sharp increase in dyspnea after the inflection point correlated significantly with the corresponding increase in the effort/displacement ratio (partial r = 0.125; P = 0.002), with no difference in this relationship across protocols (interaction term P = 0.548). A biphasic relation was also found between the selection frequency of unsatisfied inspiration and IRV (Figure 3D). The selection frequency of work and effort increased with dyspnea ratings up to the inflection point, after which they no longer changed together (Figure 3E). The relationship between dyspnea ratings and selection of unsatisfied inspiration was relatively linear throughout exercise for both tests (Figure 3F).
Figure 3. (A) Exertional dyspnea intensity is shown relative to tidal volume (VT) and (B) inspiratory reserve volume (IRV). (C) The ratio between respiratory effort (Pes/PImax) and tidal volume displacement (VT/predicted VC) is shown relative to IRV. (D) The selection frequency of the descriptor “unsatisfied inspiration” (IN) during exercise showed an inflection when expressed relative to IRV. (E) The selection frequency of effort did not increase in direct proportion with increasing dyspnea intensity throughout exercise, whereas (F) the selection frequency of “unsatisfied inspiration” (IN) showed a more linear relationship with increasing exertional dyspnea intensity in both exercise tests. Arrows indicate the point corresponding to the inflection point of the tidal volume-ventilation relation during exercise. CWR = constant work rate exercise; INCR = incremental exercise; Pes/PImax = tidal esophageal pressure swing relative to maximum inspiratory sniff pressure; VT/predicted VC = tidal volume relative to predicted vital capacity.
[More] [Minimize]The main findings of this study are as follows: (1) despite time-related differences in metabolic and ventilatory requirements during INCR and high-intensity CWR tests, dyspnea intensity, breathing pattern, operating lung volumes, and respiratory mechanical measurements were similar when expressed as a function of increasing ventilation; (2) dyspnea intensity rose steeply during each test protocol after the Vt/e inflection point where IRV had decreased to a critical level of approximately 0.5–0.6 L; and (3) regardless of the test protocol, work and effort was the dominant qualitative descriptor of dyspnea before the Vt/e inflection point, whereas the selection frequency of unsatisfied inspiration increased steeply relative to work and effort after this inflection.
The study subjects had moderate-to-severe chronic airflow limitation and lung hyperinflation and reported clinically important chronic activity-related dyspnea despite optimal pharmacotherapy. Exercise performance was diminished mainly because of impaired dynamic ventilatory mechanics and the attendant severe dyspnea. At the symptom-limited termination of exercise during INCR and CWR tests, peak metabolic and cardiopulmonary parameters, dynamic respiratory mechanics, and dyspnea intensity ratings were similar.
As expected, the time course of change in metabolic and ventilatory requirements was different between the two protocols. Thus, o2 and e were significantly higher during CWR compared with INCR exercise in the first 4 minutes of exercise. During both tests, the Vt/e inflection occurred when Vt expanded to reach approximately 70% of the IC, a point where e had reached an average of approximately 34–38 L/min. The greater metabolic and ventilatory demand earlier during high-intensity CWR meant that the Vt inflection occurred significantly earlier in time than with the INCR protocol. However, when all of the physiologic and sensory responses to cycle exercise were expressed as a function of increasing e, there were no significant differences between protocols. These data indicate that, irrespective of the ventilatory history (i.e., the time course of change in ventilation or the intensity of the preinflection ventilatory load), it is the ventilatory requirement of a specific physical task that dictates the evolution of change in operating lung volumes, breathing pattern, esophageal pressure generation, and dyspnea intensity ratings.
This study showed that, regardless of the test protocol, there was a biphasic relationship between increasing dyspnea and decreasing IRV (or increasing Vt/IC ratio). Before the inflection (phase I), dyspnea intensity rose linearly into the moderate range (Borg rating ∼ 3) with decreasing IRV. After the inflection point, dyspnea intensity rose more steeply to intolerable levels. The greater metabolic and ventilatory demand in phase I during CWR meant that dyspnea intensity as a function of time was uniformly higher compared with INCR exercise (see online supplement). By contrast, after the Vt inflection (phase II) during both CWR and INCR tests, the difference in dyspnea intensity began to disappear as ventilatory and mechanical abnormalities became more similar near the symptom-limited peak of exercise.
In keeping with previous studies (4–6), the major qualitative descriptors at the termination of exercise in COPD were clustered in work and effort and unsatisfied inspiration categories. This study extends the previous work by showing that, regardless of the exercise test protocol, these major qualitative descriptors evolve separately throughout exercise and are strongly influenced by mechanical events, such as the Vt inflection point. In phase I, before this inflection, subjects were more likely to select work and effort and less likely to select the unsatisfied inspiration descriptor. At the Vt inflection point, patients selected work and effort approximately twice as often as the unsatisfied inspiration descriptor. However, after this point during INCR and CWR exercise, unsatisfied inspiration was increasingly selected as the dominant qualitative descriptor despite patients having the option of selecting any, none, or all of the three descriptors. Clearly, differences between the two exercise tests in the time course of change in ventilation and dynamic respiratory mechanics in phase I did not influence the ability to perceive critical mechanical constraints on Vt expansion. Interestingly, selection of unsatisfied inspiration and dyspnea intensity ratings increased linearly together throughout exercise (Figure 4F), whereas similar concordance was not seen with work and effort and dyspnea intensity. In phase II the selection of the work and effort descriptor reached a plateau despite continued increases in Pes/PImax and e. It is noteworthy that patients seldom selected expiratory difficulty as a representative descriptor. This may reflect the fact that tidal expiratory pressures at peak exercise represented only 11–14% of maximal expiratory pressure.
Both the intensity of dyspnea and the selection frequency of work and effort increased in parallel with the concomitant increases in tidal respiratory effort swings and ventilatory output throughout exercise. Neurophysiologically, increased perceived breathing effort is believed to reflect the awareness of increased motor command output to the respiratory muscles and increased central corollary discharge from the respiratory motor centers to the somatosensory cortex (3, 30, 31).
Why did unsatisfied inspiration receive more attention and become increasingly dominant in phase II? Static lung hyperinflation with further dynamic increases in end-expiratory lung volume in phase I resulted in end-inspiratory lung volume reaching a near minimal IRV (i.e., the Vt inflection point) at a relatively low e. After the Vt inflection point, tidal Pes swings progressively increased to a peak of approximately 50% of their maximum value in the setting of little or no further Vt expansion. Thus, the effort/volume displacement ratio (Pes/PImax:Vt/predicted VC) increased to almost double its resting value at peak exercise. This is in sharp contrast to the situation in health where this ratio is largely preserved from rest to peak exercise, reflecting the operating position of the expanding Vt on the linear portion of the respiratory system's sigmoid pressure–volume relation (4). Previous mechanistic studies have shown that when the spontaneous increase in Vt is constrained (either volitionally or by external imposition) in the face of increased chemostimulation, respiratory discomfort (specifically, air hunger or unsatisfied inspiration) is the result (5, 27, 32–37). We have proposed that near the limits of tolerance in COPD this increasing dissociation between reflexly increased central neural drive (amplified by acid–base disturbances) and blunted Vt displacement forms, at least in part, the neurophysiologic basis of perceived unsatisfied inspiration (3, 5, 27). In support of this contention, bronchodilator therapy in COPD (which reduced lung hyperinflation, increased Vt expansion, and improved the effort/displacement ratio) was associated with a significant reduction in the selection frequency of unsatisfied inspiration at end-exercise (5, 6). Besides causing Vt restriction, a high end-expiratory lung volume in COPD forces Vt to the upper noncompliant reaches of the respiratory system's pressure–volume relation and negatively affects inspiratory muscle performance. Thus, it is also possible that altered afferent information from the overburdened (increased elastic and threshold loading) and functionally weakened (altered length-tension and force-velocity characteristics) respiratory muscles may contribute directly or indirectly to the intensity and quality of dyspnea in phase II.
The primary analysis of qualitative dimensions of dyspnea during exercise was confined to the two most common and representative descriptors based on our previous studies (work and effort, unsatisfied inspiration); other descriptors not included here may also be relevant to the complex experience of exertional dyspnea in COPD. In this study, we did not scale the sensory intensity of these major descriptors or evaluate their affective impact in each individual; during pilot testing, this more comprehensive analysis could not be successfully applied (32). Because a healthy control group is lacking in this study, we cannot comment on whether the described change in the quality of dyspnea with exercise is peculiar to COPD. However, unsatisfied inspiration, the descriptor of interest, was rarely selected as a representative descriptor in healthy individuals of similar age at peak exercise in a previous study (4). Finally, it remains to be seen whether our results can be extrapolated to other activities, such as walking, or to specific subpopulations with additional potential sources of dyspnea (e.g., those with significant arterial oxygen desaturation during exercise). The question arises whether the sensory responses described here in a small group of patients with moderate resting lung hyperinflation are representative of the broader COPD population with a range of mechanical impairment. A recent study confirmed that Vt/e inflection points with attendant biphasic dyspnea intensity responses were present across a broad range of FEV1 in a large COPD population (9). The ventilation at which the Vt inflection and rise in dyspnea occurred varied with the degree of resting lung hyperinflation (or IC).
During physical activity in COPD, the time course of change in dynamic respiratory mechanics and the concomitant change in the intensity and quality of dyspnea are dictated by the specific ventilatory requirements of the physical task. Regardless of the exercise test protocol, the occurrence of an inflection (or plateau) in the Vt response marks the point where dyspnea intensity rises more abruptly and inspiratory difficulty becomes more frequently selected as the most representative qualitative descriptor. The practical implication of our study is that the Vt inflection during exercise in COPD marks a reproducible mechanical event with important sensory consequences. This can easily be detected in most patients by examining the Vt/e and the dyspnea/Vt relations. Therapeutic interventions that reduce ventilatory requirements (e.g., oxygen, exercise training, or opiates) or reduce lung hyperinflation (pharmacologic or surgical volume reduction) should theoretically delay the appearance of the Vt inflection and the attendant dyspnea during physical activity.
The authors thank Emiliano Brunamonti, Ph.D. (Department of Physiology, Queen's University), for providing technical assistance; Giorgio Scano, M.D., and Roberto Duranti, M.D. (Department of Internal Medicine, University of Florence, Florence, Italy), for thoughtful criticism of the manuscript; and Yuk-Miu Lam, Ph.D. (Department of Community Health and Epidemiology, Queen's University), for statistical assistance.
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Supported by the William Spear/Richard Start Endowment Fund, Queen's University. Pierantonio Laveneziana received a John Alexander Stuart Fellowship, Department of Medicine, Queen's University.
Author contributions: All authors played a role in the content and writing of the manuscript. D.E.O. was the principal investigator and contributed the original idea for the study; D.E.O., P.L., and K.A.W. had input into the study design and conduct of study; P.L., J.O., and K.W. collected the data; and K.A.W. and P.L. performed data analysis and prepared it for presentation.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201106-1128OC on September 1, 2011
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