Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 101: 1025-1035, 2006. First published May 4, 2006; doi:10.1152/japplphysiol.01470.2005
8750-7587/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
101/4/1025    most recent
01470.2005v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by O’Donnell, D. E.
Right arrow Articles by Webb, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by O’Donnell, D. E.
Right arrow Articles by Webb, K. A.

Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD

Denis E. O’Donnell,1 Alan L. Hamilton,2 and Katherine A. Webb1

1Respiratory Investigation Unit, Departments of Medicine and Physiology, Queen’s University, Kingston; and 2Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario, Canada

Submitted 22 November 2005 ; accepted in final form 27 April 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
During constant-work-rate exercise in chronic obstructive pulmonary disease, dyspnea increases steeply once inspiratory reserve volume (IRV) falls to a critical level that prevents further expansion of tidal volume (VT). We studied the effects of this mechanical restriction on the quality and intensity of exertional dyspnea and examined the impact of an anticholinergic bronchodilator. In a randomized, double-blind, crossover study, 18 patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 s = 40 ± 3%predicted; mean ± SE) inhaled tiotropium 18 µg or placebo once daily for 7–10 days each. Pulmonary function tests and symptom-limited cycle exercise at 75% of each patient’s maximal work capacity were performed 2 h after dosing. Dyspnea intensity (Borg scale), operating lung volumes, breathing pattern, and esophageal pressure (n = 11) were measured during exercise. Dynamic hyperinflation reached its maximal value early in exercise and was associated with only mild increases in dyspnea intensity and the effort-displacement ratio, which is defined as the ratio between tidal swings of esophageal pressure (expressed relative to maximum inspiratory pressure) and VT (expressed relative to predicted vital capacity). After a minimal IRV of 0.5 ± 0.1 liter was reached, both dyspnea and the effort-displacement ratio rose steeply until an intolerable level was reached. Tiotropium did not alter dyspnea-IRV relationships, but the increase in resting and exercise inspiratory capacity was associated with an improved effort-displacement ratio throughout exercise. Once a critically low IRV was reached during exercise, dyspnea rose with the disparity between respiratory effort and the VT response. Changes in dyspnea intensity after tiotropium were positively correlated with changes in this index of neuromechanical coupling.

chronic obstructive pulmonary disease; respiratory mechanics; tiotropium

DYSPNEA AND ACTIVITY LIMITATION are the dominant symptoms of chronic obstructive pulmonary disease (COPD) and contribute importantly to perceived poor health status in this population (24). Consequently, relief of these symptoms is among the primary goals of management (44). Our understanding of the mechanisms of exertional dyspnea in COPD continues to increase. Earlier studies have shown that exertional dyspnea intensity in COPD increases as ventilation increases relative to capacity. Dyspnea intensity also increases with the magnitude of inspiratory effort (pleural pressure relative to maximum inspiratory pressure) and its duration (29). We have previously reported that the intensity of perceived inspiratory difficulty during exercise correlated well with the increased effort-displacement ratio, which is defined as the ratio between tidal swings of esophageal pressure (Pes) expressed relative to the maximum inspiratory pressure (effort) and the tidal volume (VT) response expressed relative to the predicted vital capacity (VC) (displacement) and is a crude index of neuromechanical uncoupling of the respiratory system (36). In some patients, gas-exchange abnormalities leading to critical arterial hypoxemia or hypercapnia may also contribute either directly or indirectly to perceived exertional dyspnea (38). All of these factors are clearly interdependent and likely contribute, in a complex integrative fashion, to respiratory discomfort in a manner that varies from patient to patient. Several recent mechanistic studies have provided evidence that mechanical factors, specifically acute dynamic lung hyperinflation, importantly influence respiratory discomfort during exercise (36, 37). Moreover, in recent clinical studies, dyspnea alleviation after a number of therapeutic interventions, which include bronchodilators (7, 37, 44, 45), lung volume reduction surgery (27, 32), and oxygen therapy (40, 52), has been associated with reduction of lung hyperinflation.

The mechanisms by which dynamic lung hyperinflation (DH) leads to dyspnea are unknown. In particular, it is difficult to reconcile the potential salutary effects of DH on respiratory sensation (through improvement of expiratory flow rates at the higher lung volumes) with the negative effects that arise from the attendant VT restriction and the excessive loading and functional weakening of the inspiratory muscles. Other potential dyspneogenic mechanisms in the setting of DH include heightened inspiratory effort, induction of inspiratory muscle fatigue (or failure), and chemoreceptor stimulation as a result of attendant CO2 retention and arterial O2 desaturation. However, we have previously argued that an increased sense of contractile muscle effort need not be perceived as "unsatisfied" or lead to respiratory distress (39). Moreover, it remains uncertain whether overt ventilatory muscle fatigue actually occurs during symptom-limited exercise in COPD (31). Furthermore, the occurrence of exercise hypercapnia is highly variable in COPD and its contribution to exertional dyspnea in this setting remains unknown (42).

Several previous studies have shown that during constant-work-rate cycle exercise testing the slope of the relationship between dyspnea intensity (measured by the Borg scale) and exercise time is essentially linear (37, 40, 44, 45). In contrast, we have recently reported that the relationship between dyspnea and dynamic inspiratory reserve volume (IRV) during constant-load cycle exercise is distinctly alinear in patients with moderate-to-severe COPD (45, 48). Thus there is a discernible inflection point beyond which dyspnea rises steeply to intolerable levels at a given IRV. This inflection point generally occurs when IRV has declined to a critical, minimal value of 0.3 to 0.5 liters below total lung capacity (TLC) and marks the point at which further VT expansion is impossible (45, 48). In this study, we sought to extend previous investigations to better understand the relationship between critical mechanical constraints during exercise and the quality and intensity of dyspnea. On the basis of the results of previous studies in healthy individuals during chest wall strapping (39) and in patients with interstitial lung diseases (38), we postulated that a limited ability to expand VT in the face of increasing respiratory drive (and effort) during exercise would contribute to dyspnea intensity, and its dominant qualitative dimension of unsatisfied inspiration. In COPD, the finding of a close association between improved dyspnea ratings and an increased ability to expand VT as result of pharmacological lung volume deflation supports the idea that mechanical VT restriction is an important and potentially reversible dyspneogenic factor (45).

The purpose of this study was first to examine mechanical events before and after this critical dyspnea-IRV inflection point during constant-work-rate exercise, so as to better understand the mechanisms of exertional dyspnea. We hypothesized that, early in exercise, dynamic hyperinflation would have net beneficial effects on respiratory sensation by attenuating expiratory flow limitation. However, after a critical IRV is reached, dyspnea intensity would rise with the increasing disparity between respiratory effort (tidal swings of Pes relative to the maximum attainable pressure) and the VT response (relative to the predicted VC), which becomes essentially fixed. To test the hypothesis that critical mechanical restriction is a key contributor to exertional dyspnea in hyperinflated COPD patients, we examined the time course of change in dyspnea intensity, ventilation, breathing pattern, operating lung volumes and Pes-derived measurements of dynamic ventilatory mechanics, with specific reference to the dyspnea-IRV inflection point. Our second objective was to assess the impact of changes in resting ventilatory mechanics (i.e., pharmacological lung volume reduction) on dyspnea-IRV relationships and effort-displacement ratios during exercise, to better understand the mechanisms of dyspnea alleviation. We postulated that bronchodilators would delay the attainment of this mechanical threshold (where VT becomes fixed) during exercise, thus improving the effort-displacement ratio and postponing the onset of intolerable dyspnea. We therefore evaluated the impact of the bronchodilator tiotropium on the time course of change in dyspnea intensity, IRV, and related mechanical events during constant-work-rate exercise using a placebo-controlled study design.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects

Subjects included stable patients with COPD (43) who had a cigarette smoking history ≥20 pack-years, forced expiratory volume in 1 s (FEV1) ≤65% predicted, plethysmographic functional residual capacity (FRC) ≥120% predicted, and a modified Baseline Dyspnea Index score ≤6 (53). Patients were excluded in the presence of significant diseases other than COPD that could contribute to dyspnea and exercise limitation, important contraindications to clinical exercise testing (16), use of daytime oxygen, or participation in a pulmonary rehabilitation program within 6 wk before the study.

Study Design

This randomized, double-blind, placebo-controlled, crossover study had local university/hospital research ethics approval. After giving written, informed consent, patients completed 1) an initial screening visit to determine eligibility for the study; 2) a second visit during the baseline period designed to familiarize patients with all tests that would be performed during subsequent treatment visits and to avoid possible learning effects; 3) two 7- to 10-day treatment periods, in randomized order, with a visit at the beginning and end of each (visits 3 through 6) and a 35-day washout period between treatments; and 4) a follow-up visit conducted 1 wk after completion of the second treatment period. Visit 1 included medical history, clinical assessment, chronic dyspnea evaluation, pulmonary function tests, and a symptom-limited incremental cycle exercise test. Visit 2 included pulmonary function tests and a constant-load exercise test. Pulmonary function tests and a constant-load cycle exercise test were performed pretreatment (visits 3 and 5). On the last day of each treatment period (visits 4 and 6), subjects completed pulmonary function tests with measurements of static lung recoil pressure 80 min postdose followed by a constant-load exercise test with measurements of respiratory mechanics 120 min postdose. The follow-up visit included a brief physical examination and pulmonary function tests. All constant-load exercise tests were conducted at a work rate equal to 75% of the maximal incremental work rate at visit 1.

During treatment periods, either inhaled tiotropium (18 µg once daily) or a matched placebo was added to the daily drug regimen. Permitted respiratory medication included regularly taken corticosteroids and theophyllines if stabilized for at least 6 wk before and throughout the study. Oral and long-acting beta2-agonists were not allowed for at least 1 wk before and throughout the study. Anticholinergics were withdrawn at least 1 day before the screening visit and not permitted throughout the study. Salbutamol (aerosol inhaler) was provided as rescue medication during the run-in and treatment periods. Before each visit, short-acting beta2-agonists, short-acting theophyllines, and long-acting theophyllines were withheld for at least 6, 24, and 48 h, respectively. Study medication was last taken ~24 h before treatment visits 4 and 6. Subjects avoided caffeine, heavy meals, alcohol, and major physical exertion before visits, which were all conducted in the morning.

Procedures

Pulmonary function measurements were collected according to recommended standards (2, 3, 4, 14) by use of automated equipment (Vmax 229d with Autobox 6200 DL; SensorMedics, Yorba Linda, CA) and expressed as percentages of predicted normal values (8, 10, 11, 15, 21, 25, 34); predicted inspiratory capacity (IC) was calculated as predicted TLC minus predicted FRC. Static lung recoil pressure (Pst) was measured via the SensorMedics Vmax229d system (19). Dynamic compliance (Cdyn) was measured during normal resting breathing and at timed rates of 10, 15, 20, 25 and 30 breaths/min.

Symptom-limited exercise tests were conducted on an electrically braked cycle ergometer (Ergometrics 800S; SensorMedics) by use of a cardiopulmonary exercise testing system (Vmax229d; SensorMedics) as previously described (37, 40, 44, 45). Incremental testing was performed at the first visit using 1-min increments of 10 W each. Constant-load tests at 75% of maximal incremental work rate were performed at all subsequent visits; endurance time was defined as the duration of loaded pedaling.

Measurements were collected while subjects breathed through a mouthpiece with nose clips and a low-resistance flow transducer. The following measurements were included: standard cardiopulmonary exercise test parameters (23) were collected in a breath-by-breath fashion; intensity of dyspnea (breathing discomfort) and leg discomfort using the 10-point Borg scale (9) was assessed at rest, during the last 30-s period of every 1-min interval during exercise, and at end exercise; operating lung volumes were derived from IC maneuvers (37, 41) performed at rest, within the last 30-s period of each 2-min interval during exercise, and at end exercise; Pes-derived mechanical measurements (1, 5, 17, 47) were collected in a breath-by-breath fashion with an integrated data-acquisition setup (see following paragraph); descriptors of dyspnea at end exercise were collected by questionnaire (39, 51); and reason for stopping exercise was collected.

Adult balloon-tipped esophageal catheters (Ackrad Laboratories, Cranford, NJ) were placed according to an accepted technique (5). Pes was sampled continuously at a rate of 100 Hz by using a differential pressure transducer (MP45; Validyne Engineering, Northridge, CA), a signal conditioner (Carrier amplifier; Gould Electronics, Chandler, AZ), and computer data-acquisition software (Advanced CODAS; Dataq Instruments, Akron, OH). The continuous flow signal from the Vmax229d system was simultaneously input into this system for further analysis. Maximum inspiratory sniff maneuvers were performed preexercise at rest and immediately at end exercise to obtain maximum values for Pes (PImax); this corrects for changes in operating volumes but not for other possible confounding variables such as changes in velocity of shortening. The inspiratory threshold load was calculated as the difference between Pes at the onset of inspiratory flow and Pes at isovolume on the predicted chest-wall compliance curve (1). Campbell’s diagrams were constructed to calculate expiratory flow resistive work (WEres) and inspiratory work of breathing, which was divided into its elastic (WIel) and flow resistive (WIres) components (17). The tension-time index of the inspiratory muscles (TTI) was calculated as the product of mean inspiratory Pes/PImax and the inspiratory duty cycle (TI/Ttot) (5). An index of neuromechanical coupling was calculated as the ratio of respiratory effort (tidal Pes/PImax) to thoracic displacement (VT/predicted VC) (36).

Analysis of Exercise Endpoints

All breath-by-breath measurements were averaged in 30-s intervals throughout each test stage, i.e., rest, exercise, and recovery. Raw volume (integrated flow) and Pes signals were also averaged in 30-s intervals for reconstruction of Pes-volume loops. Cardiopulmonary and Pes-derived measurements collected over the first 30-s period of every second minute during exercise were linked with symptom ratings and IC measurements collected in the latter 30 s of the respective minute (to avoid contamination of averaged breath-by-breath data by irregular breaths surrounding IC maneuvers).

Preexercise rest was defined as the steady-state period after at least 3 min of breathing on the mouthpiece while seated at rest before exercise was started: cardiopulmonary parameters were averaged over the last 30 s of this period and IC measurements for this period were collected during breathing on the same circuit immediately after completion of the quiet breathing period. A standardized time near end exercise (isotime) was defined as the highest common exercise time achieved during all constant-load tests performed by a given subject, rounded down to the nearest whole minute. Peak exercise was defined as the last 30 s of loaded pedaling: cardiopulmonary parameters were averaged over this time period, and IC measurements and Borg ratings were collected immediately at the end of this period. By plotting individual dyspnea (Borg rating)-IRV curves throughout exercise, a point of inflection was determined for each subject, i.e., the point of intersection of two linear relationships.

Statistical Analysis

The sample size of 18 provides the power (80%) to detect a difference in IC measured at a standardized exercise time based on a relevant difference of 0.3 liter, a SD of 0.3 liter for IC changes found at our laboratory, {alpha} = 0.05, and a two-tailed test of significance. Results are reported as means ± SE. A P < 0.05 significance level was used for all analysis, with appropriate Bonferroni correction for multiple comparisons. Treatment responses were compared by paired t-tests. Comparisons were made for linear exercise response slopes and for measurements at rest, isotime, and peak exercise. Dyspnea descriptors and reasons for stopping exercise were analyzed using Fisher’s exact test. Pearson correlations were used to establish associations between standardized dyspnea ratings and relevant independent variables; forward stepwise multiple regression analysis was carried out with significant variables and relevant covariates.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Eighteen subjects completed the study (Table 1); no subjects experienced oxygen desaturation below 88% or significant elevation of end-tidal CO2 tension (PETCO2) during incremental cycle exercise. Eleven subjects had Pes-derived mechanical measurements at both treatment visits (Table 1). Of the seven subjects with incomplete mechanical data, three completed testing at visit 4 but did not wish to undergo insertion of the esophageal balloon-catheter a second time at visit 6; one subject experienced intolerable coughing after catheter placement, resulting in its removal at both treatment visits; one subject had previously broken his nose and the catheter would not pass through his nasal passages; and two subjects refused to undergo this procedure at the time of their treatment visits.


View this table:
[in this window]
[in a new window]
  		Table 1. Subject characteristics

 
No significant sequence or carryover effects were found with respect to pulmonary function, physiological measurements during exercise, or exertional dyspnea. Pretreatment responses to constant-work-rate (50 ± 5 W) exercise were highly reproducible, i.e., oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), VT, breathing frequency (F), inspiratory time (TI), expiratory time (TE), oxygen saturation, PETCO2, and heart rate were not different when plotted against exercise time.

Dyspnea "Threshold" During Exercise

Although dyspnea increased linearly with exercise time, there was a clear inflection point noted in the dyspnea-IRV relationship during constant-load exercise after placebo, i.e., dyspnea increased steeply once IRV fell to a critical level (Fig. 1). This inflection point occurred early in exercise at a mean time of 2.7 ± 0.3 min: one severely hyperinflated patient with a resting IC of 1.0 liter and an IRV of only 0.4 liter had no obvious inflection because she was already on the steep portion of the curve even at rest, 10 patients had an inflection within 2 min of the beginning of loaded exercise, and the inflection occurred by minute 4 of exercise in the remaining subjects. Measurements at the inflection point were as follows: VO2 of 13.6 ± 1.1 ml·kg–1·min–1, VE of 31.3 ± 2.5 l/min, F of 27 ± 1 breaths/min, VT of 1.17 ± 0.08 liters or 72 ± 3%IC, Pes/PImax of 39 ± 4%, and a TTI for the respiratory muscles of 0.16 ± 0.01. Beyond the inflection during exercise there was no further change in VT, IC, IRV, PETCO2, TE, or VT/TE; a continued increase in VE, F, TI, VT/TI, Pes/PImax, inspiratory and expiratory Pes, Pes/VT ratios, and TTI; a continued decrease in Cdyn; and an increase in dyspnea intensity. The dyspnea-IRV relationship was highly reproducible within subjects across tests and remained unchanged by tiotropium: mean plots were superimposable and, for all tests, the inflection point occurred at a similar exercise time, VO2, VE, breathing pattern, and Pes/PImax.


Figure 1
View larger version (31K):
[in this window]
[in a new window]
  		Fig. 1. Mechanical threshold of dyspnea is indicated by the abrupt rise in dyspnea after a critical "minimal" inspiratory reserve volume (IRV) is reached that prevents further expansion of tidal volume (VT) during exercise. Beyond this dyspnea-IRV inflection point during exercise, dyspnea intensity, breathing frequency (F), respiratory effort (Pes/PImax, where Pes is esophageal pressure and PImax is maximum values for Pes), and the effort-displacement ratio all continue to rise. Dashed lines indicate the threshold where mechanical limitation to VT expansion is reached. Arrows indicate the dyspnea-IRV inflection point. Values are plotted after placebo and expressed as means ± SE. TLC, total lung capacity; VC, vital capacity.

 
Correlates of dyspnea intensity were examined before and after the dyspnea-IRV inflection point, first taking into account repeated measurements within each patient. In early exercise before reaching this threshold, dyspnea intensity correlated best with the TTI (partial multiple r = 0.84, P < 0.0005), tidal Pes/PImax (partial multiple r = 0.81, P < 0.0005), VE (partial multiple r = 0.79, P < 0.0005), and VT/predicted VC (partial multiple r = 0.73, P < 0.0005). Before the inflection, dyspnea also correlated with inspiratory Pes/ PImax (partial multiple r = 0.78, P < 0.0005) and expiratory Pes standardized as a percentage of maximal expiratory pressure (partial multiple r = 0.79, P < 0.0005); inspiratory and expiratory "effort" contributed equally to dyspnea and increased together in early exercise (r = 0.92, P < 0.005). After the dyspnea-IRV inflection, the continued increase in dyspnea intensity correlated best with the ratio of tidal Pes/PImax to VT/predicted VC (partial multiple r = 0.61, P < 0.0005) and with the ratio of inspiratory Pes/PImax to VT/predicted VC (partial multiple r = 0.60, P < 0.0005). There was no drug effect on any of these relationships.

Resting Pulmonary Function and Lung Mechanics

Improvements in spirometry and body plethysmography after treatment with tiotropium compared with placebo are shown in Table 2: FEV1 and FVC increased with no associated change in the FEV1/FVC ratio, lung hyperinflation (residual volume, FRC) decreased, airway resistance decreased and conductance increased for a given lung volume. There were no significant differences in resting breathing pattern parameters after tiotropium compared with placebo, other than an increase in TI/Ttot (P = 0.003). There was no difference between Cdyn during normal resting breathing or the frequency dependence of Cdyn after tiotropium compared with placebo, i.e., the decrease in Cdyn that occurred as F increased was similar after tiotropium and placebo. Pst was not different after placebo and tiotropium (31 and 30 cmH2O, respectively), and the coefficient of retraction (Pst/TLC) was unchanged.


View this table:
[in this window]
[in a new window]
  		Table 2. Postdose pulmonary function and steady-state resting breathing pattern at the end of each treatment period

 
Responses to Constant-Load Exercise

Posttreatment endurance time was greater by 0.9 ± 0.8 min or 30 ± 18% after tiotropium compared with placebo but not significantly (Table 3, Fig. 2). The distribution of reasons for stopping exercise was different after tiotropium compared with placebo (P < 0.01): after tiotropium, fewer subjects stopped owing primarily to breathing discomfort and more subjects stopped because of leg discomfort or other reasons.


View this table:
[in this window]
[in a new window]
  		Table 3. Postdose "peak" of symptom-limited constant-load exercise at a mean work rate of 50 W or 31% predicted maximum

 

Figure 2
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Ventilatory responses to constant-load exercise are shown against exercise time after tiotropium compared with placebo (n = 18). Dashed lines indicate the threshold where mechanical limitation to VT expansion is reached. *P < 0.05 tiotropium vs. placebo at isotime during exercise (dotted line in top left graph represents the exercise time point for isotime comparisons). Values are means ± SE. TI, inspiratory time.

 
Exertional dyspnea.   Dyspnea at isotime during exercise decreased after tiotropium by 0.7 ± 0.4 Borg units (P = 0.06) (Table 4). Posttreatment differences in dyspnea at isotime correlated with concurrent differences in F (r = 0.624, P = 0.006), VT/predicted VC (r = –0.579, P = 0.012), and TE (r = –0.544, P = 0.020). The selection frequency of dyspnea descriptor phrases at end exercise was similar after tiotropium compared with placebo, except for the phrase "I cannot take a deep breath in," which was chosen by seven patients (39%) after placebo and only one patient (6%) after tiotropium (P < 0.05). In addition, 72% of patients chose descriptors within the cluster for "unsatisfied inspiration" with placebo, whereas only 44% selected within this cluster after tiotropium (P = 0.09).


View this table:
[in this window]
[in a new window]
  		Table 4. Postdose values at isotime (5.1 ± 0.7 min) during constant-load exercise

 
Ventilatory responses.   Ventilatory responses to constant-load exercise after tiotropium and placebo are shown in Fig. 2. After tiotropium compared with placebo there was no change in ventilation; breathing pattern was slower and deeper; and lung hyperinflation was reduced, as reflected by an increase in IC (Fig. 2). There were no significant differences in peak VO2 or VE, although breathing pattern was significantly slower and deeper at end exercise (Table 3). Breathing pattern changes correlated with IC changes at isotime exercise. At isotime during exercise after tiotropium, midtidal expiratory flows increased significantly and the extent of encroachment on the maximal expiratory flow-volume curve at the same volume decreased (Table 4). However, the percentage of VT overlapping the maximal expiratory flow-volume loop (i.e., extent of expiratory flow limitation) was not significantly different after tiotropium compared with placebo at rest, isotime, or end exercise.

Respiratory mechanics.   Table 5 summarizes Pes-derived measurements at isotime during exercise and at end exercise. At isotime (and isoventilation) during exercise after tiotropium compared with placebo (Table 5), tidal Pes decreased because of decreases in both peak inspiratory and expiratory pressures; Pes/PImax decreased; Pes/VT and the ratio of Pes/PImax to VT/predicted VC decreased; Cdyn increased because of a decrease in F; the TTI of the respiratory muscles decreased; and inspiratory and expiratory resistive work of breathing (WIres, WEres) decreased. These isotime differences continued through to end exercise (Fig. 3). Changes in Pes-derived mechanical measurements (i.e., Pes/PImax, Pes/VT, TTI, Cdyn, WIel, WIres, WEres) did not correlate with any volume [i.e., IC, IRV, VC, end-expiratory (EELV) and end-inspiratory lung volume (EILV), residual volume] changes during exercise, although decreases in EELV at isotime correlated with decreases in the inspiratory threshold load (r = 0.78, P < 0.005) in a relationship of 10 cmH2O/l.


View this table:
[in this window]
[in a new window]
  		Table 5. Mechanical measurements during exercise testing after treatment with tiotropium and placebo

 

Figure 3
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3. Respiratory mechanics during exercise after tiotropium compared with placebo (n = 11). Pes/PImax, the tension-time index of the respiratory muscles, and the effort-to-displacement ratio are all decreased during exercise after tiotropium. VT response is increased for a given effort after tiotropium compared with placebo. Dashed lines indicate the threshold where mechanical limitation to VT expansion is reached. *P < 0.05 tiotropium vs. placebo at isotime during exercise. Values are means ± SE. pred VC, predicted vital capacity.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The main findings of this study are as follows: 1) dyspnea intensity increased sharply during exercise after a minimal IRV value was reached during constant-work-rate exercise; this dyspnea-IRV inflection point marked the onset of a widening disparity between respiratory effort and VT displacement. 2) Before this inflection point, the effort-displacement ratio remained relatively constant and only mild dyspnea was reported despite acute DH. 3) Bronchodilator therapy was associated with a consistent reduction in operating lung volumes with improved effort-displacement ratios and reduced dyspnea intensity.

Dyspnea-IRV Inflection

Several studies have shown a correlation between increasing dyspnea intensity during exercise and reduction in dynamic IC, suggesting that acute DH is an important contributing factor (36, 41). This hypothesis has been bolstered by the results of studies that have found that dyspnea reduction after pharmacological (7, 37, 44) or surgical volume reduction (27, 32) correlated well with improvements in IC (or EELV) and IRV (or EILV), reflecting reduced DH. However, the relationship between exertional dyspnea and DH is complex and poorly understood. The present study confirmed the findings of two previous studies by demonstrating that the dyspnea-IRV relationship was distinctly alinear during constant-work-rate cycle exercise in patients with moderate to severe COPD (45, 48). Dyspnea intensity rose steeply to intolerable levels at a mean minimal IRV of ~0.5 liter below TLC. The inflection point, which was highly reproducible within patients, occurred early in exercise when ventilation had reached 31 l/min and VT had reached its peak value of 72% of the actual IC. At this minimal IRV, the IC had also declined to its minimal value and respiratory effort had increased to 40% of PImax. An increased TTI for the respiratory muscles at this time point represented 80% of its peak value and reflects a substantial increase in the oxygen cost of breathing (33). In this study, arterial blood gases were not available but there was no significant arterial oxygen desaturation or increase in end-tidal CO2 throughout exercise. It is noteworthy that in this group of severely compromised patients with COPD, these acute derangements in dynamic ventilatory mechanics that took place before the dyspnea-IRV inflection point were associated with only mild increases in dyspnea (mean Borg rating 2.4 "slight") and that the effort-displacement ratio was held relatively constant until the minimal IRV was reached.

The operating position of the VT on the respiratory system’s sigmoidal pressure-volume (P-V) relation determines the efficacy with which neural drive is converted to mechanical output and essentially dictates the relationship between tidal inspiratory muscle effort and VT displacement (56). We have previously shown that in healthy elderly individuals the effort-displacement ratio remains relatively constant at 0.7 ± 0.1 throughout symptom-limited incremental exercise (Fig. 4), reflecting the favorable operating position of VT on the compliant portion of the respiratory system’s P-V curve (36). In COPD patients at rest, the effort-displacement ratio was increased compared with health, reflecting the increase in airway resistance and the negative effects of expiratory flow limitation and lung hyperinflation that characterize this disease. Although the ratio rose further in the first minute of exercise in our study patients, it reached a plateau over the ensuing 2 min despite acute increases in EELV and EILV by an average of 0.4 and 1.04 liter, respectively, and a steep rise in VE. We therefore postulate that the negative effects of acute DH, which include increased elastic and threshold loading of the inspiratory muscles together with functional inspiratory muscle weakness, may have been counterbalanced by the reduced resistive work associated with breathing at a higher lung volume. Thus preservation of the effort-displacement ratio in this manner may help to minimize the rise in respiratory discomfort in early exercise.


Figure 4
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4. Ratio between Pes/PImax and VT displacement (VT standardized as a fraction of predicted VC), an index of neuromechanical dissociation, is shown during exercise after tiotropium and placebo in chronic obstructive pulmonary disease (COPD; n = 11) compared with a previously studied group of age-matched normal subjects (n = 12) (36). The effort-displacement ratio is increased in COPD compared with normal throughout exercise, with an upward trend after a ventilation of ~30 l/min that did not occur in the normal subjects. Compared with placebo, tiotropium reduced this ratio throughout exercise in COPD.

 
Some of the potential mechanical and sensory advantages of early DH are quickly overridden, however, once the IRV and IC reach their minimal values. For the remainder of the exercise test, VT is therefore fixed at the upper alinear extreme of the respiratory system’s P-V relation. Over these last minutes of exercise in this study, the rise in ventilation was achieved exclusively by increasing breathing frequency. Respiratory effort rose linearly with increasing ventilation to reach ~50% of PImax. In this setting, the fixed VT response contributed to the rise in the effort-displacement ratio. The almost vertical rise in dyspnea intensity after reaching the minimal IRV correlated strongly with the increased effort-displacement ratio.

Mechanisms of Dyspnea

At the end of exercise when dyspnea was reported as severe, the majority of patients selected qualitative descriptors from two dominant clusters that alluded to a sense of "heightened work/effort of breathing" and "unsatisfied inspiration." We and others have argued that these discrete respiratory sensations may have different neurophysiological underpinnings (36, 51). Before reaching the minimal IRV, the change in dyspnea intensity with exercise correlated well with increasing effort (Pes/PImax), with the increasing TTI and with increasing ventilation. Previous studies have shown similar correlations and collectively support the idea that the sense of increased contractile respiratory muscle effort is pervasive during exercise and contributes to the experience of exertional breathlessness both in health and disease (29). In COPD, acute mechanical loading and functional weakness of the inspiratory muscles during exercise result in a relatively higher inspiratory effort than normal for a given force generation by the muscles. Increased central motor command output, with corollary discharge to the sensory cortex, remains a plausible mechanistic explanation for the perception of the heightened effort or work of breathing during exercise (13).

The majority of our patients selected descriptors in the "unsatisfied inspiration" cluster. The steep rise in dyspnea at the minimal IRV correlated better with the increased effort-displacement ratio than with increased effort per se. The fact that inspiration is perceived as unsatisfied implies that sensory feedback from respiratory mechanoreceptors may have an important role. It is possible, therefore, that sensory feedback from a multitude of mechanoreceptors throughout the respiratory system (in the muscles, chest wall, airways, and lung parenchyma) collectively conveys the information to consciousness that the mechanical output achieved is inadequate for the prevailing respiratory drive. In the final phase of exercise, central drive had likely reached near-maximal levels yet the VT response was essentially fixed at only 30% of the predicted VC. At a comparable VO2 in health, the VT expands to ~60% of the predicted VC. Respiratory mechanoreceptors are ideally placed to detect any disparity between the volume displacement achieved and that which is expected (12).

Several previous 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 (i.e., VT expansion), dyspnea quickly escalates to intolerable levels (18, 22, 50, 55). Moreover, resumption of spontaneous breathing was associated with immediate improvement in respiratory comfort, despite persistent (or even increased) chemical loading. During exercise in health, mechanical restriction of VT (by chest strapping) induced severe dyspnea (described as unsatisfied inspiration) in the setting of added chemical loading (39). We postulate that in COPD a similar mismatch between central drive and mechanical response (i.e., neuromechanical dissociation), as crudely reflected by the increased effort-displacement ratio, is fundamental to the origin of dyspnea or its dominant qualitative dimension.

The precise neurophysiological mechanisms of perceived unsatisfied inspiration could not be determined in this study. It is certainly possible that acute DH could result in fatigued or excessively shortened inspiratory muscle fibers that fail to respond appropriately to increased electrical activation. Accordingly, as originally proposed by Campbell and Howell (12), spindles in the ventilatory muscles (which accurately sense the disparity between length and tension development) are ideally suited to serve as the proximate peripheral source of this sensory information. However, on the basis of the existing literature, it is not clear whether overt inspiratory muscle fatigue consistently occurs in the setting of symptom-limited exercise, even in severe COPD (26, 31). In this regard, it is noteworthy that even at the peak of exhaustive exercise, our dyspneic study patients with advanced disease were capable of generating maximal inspiratory pressures (despite higher operating lung volumes) equivalent to preexercise resting values. This notwithstanding, we cannot rule out the possibility of ventilatory muscle fatigue occurring in this setting of sustained high-intensity, constant-work-rate exercise in our patients, particularly given the prevailing length-tension abnormalities and the increased velocity of shortening of the inspiratory muscles. In the presence of contractile fatigue, greater central motor command output and greater perceived effort would be required for a given exercise ventilation.

It is known that the sense of unsatisfied inspiration can be experienced in the setting of mechanical restriction of VT both in healthy participants during chest wall restriction (39) and in patients with restrictive lung disease (38), even when the inspiratory muscles are not excessively shortened, as is the case in COPD patients. Thus it is entirely plausible that reduced thoracic displacement (for a given neural drive) may be sensed by a multitude of additional chest wall and intrapulmonary mechanosensors that are designed to convey precise, simultaneous, proprioceptive sensory feedback information (54, 57). The absence of significant arterial oxygen desaturation or exercise hypercapnia during exercise suggests that chemoreceptor stimulation was less likely to contribute to perceived unsatisfied inspiration in our study patients.

The relative importance of the various peripheral mechanosensory inputs in conveying this sense of unsatisfied inspiration could not be determined in this study. An additional study, demonstrating that the quality of exertional dyspnea changes from predominant heightened "effort" early in exercise to predominant "unsatisfied inspiration" after the point where VT expansion reaches its maximal limit, would lend support to the idea that critical mechanical restriction is a key underlying mechanism. Additional studies demonstrating the preservation of the dyspnea-IRV relationship in the face of experimentally induced changes in arterial blood gases, breathing pattern, ventilation, and the level of inspiratory effort would also help to confirm the central importance of mechanical restriction in dyspnea causation.

Interestingly, few patients selected descriptors of expiratory difficulty at the peak of constant-load exercise. Peak expiratory Pes during exercise averaged only 11 cmH2O or 12% of maximal static expiratory pressure measured from TLC. This is not dissimilar to the value shown previously in age-matched control subjects at a similar VO2 during exercise (36). The critical maximum pressure associated with expiratory flow limitation, as measured by isovolume pressure-flow plots, has been reported to be in this range at a similar operating volume (1.0 liter below TLC) in patients with COPD of similar severity (20, 28). In keeping with the study of Leaver and Pride (28), it seems that patients with moderate to severe COPD reach, but do not exceed, this critical pressure during constant-work-rate exercise. Thus they utilize the maximal expiratory flows available to them at that volume, while avoiding dynamic airway compression and its negative sensory consequences.

Effects of a Bronchodilator

Release of cholinergic tone after tiotropium was associated with improved airway conductance at all lung volumes, enhanced lung emptying, and reduced hyperinflation. Because static lung recoil pressure and TE were similar during placebo and tiotropium, decreased airway resistance is the most likely explanation for the improved expiratory flows and lung emptying at rest and during exercise. Reduced hyperinflation permitted patients to achieve the same ventilation throughout exercise but with a reduced total work and oxygen cost of breathing (by 11 and 12%, respectively, at a standardized time during exercise). Consistent with previous studies, the breathing pattern after bronchodilator was slower and deeper during exercise, because of the increased TI. Reduced breathing frequency likely explained the increased Cdyn associated with tiotropium therapy. Significant TI prolongation (by an average of 12%) may reflect the effects of reduced EELV and inspiratory threshold loading on the inspiratory muscles: after tiotropium, the measured "mechanical TI" may more closely approximate the actual "neural TI" that marks the true beginning of electrical activation of the inspiratory muscles with each breath. Alternatively, the increased TI prolongation associated with tiotropium may reflect attenuation of dynamic airway compression (35). In a previous study, dynamic airway compression induced by the application of negative expiratory pressure in flow-limited COPD patients at rest resulted in consistent TI shortening (by an average of 17%) and was thought to be mediated via afferent feedback from airway mechanoreceptors in response to dynamic collapse (57). The corollary of this is that more sustained airway patency and reduced peak tidal expiratory Pes with tiotropium compared with placebo may reduce dynamic compression with associated prolongation of TI. To the extent that acute dynamic compression causes unpleasant respiratory sensation in COPD, its avoidance would be expected to have a beneficial effect on dyspnea.

We postulated that tiotropium treatment would reduce lung volumes throughout exercise, thereby delaying the attainment of the minimal IRV at which the effort-displacement ratio (and dyspnea) rises abruptly. However, the results show that the time course of change in IRV during placebo and tiotropium was virtually identical, even though the actual minimal IRV achieved with the active drug was significantly higher (by 0.17 liter) than with placebo. Despite a reduction in absolute lung volumes and airway resistance with bronchodilator, the rate and magnitude of DH was identical to that of the placebo arm, again suggesting that the net effect of this adaptation is to preserve effort-displacement ratios in early exercise. Clearly, improved IC throughout exercise allowed sufficient VT expansion to meet the prevailing metabolic demands without the necessity to encroach further into the newly expanded IRV. The increased IRV and IC after tiotropium means that VT occupied a slightly more favorable position on the respiratory system’s P-V curve. The improvement in the effort-displacement ratio throughout exercise reflects this reduced elastic loading, as well as reduced resistive work and, possibly, improved inspiratory muscle function. Dyspnea relief after tiotropium treatment correlated with both increased VT and reduced breathing frequency, indirectly reflecting the reduced elastic load. The slope of the relationship between dyspnea and the effort-displacement ratio was similar with tiotropium and placebo, suggesting that improvement in dyspnea is linked to improvement in this ratio of effort to mechanical response. It is interesting to note that fewer patients selected descriptors of unsatisfied inspiration (especially the descriptor "I cannot take a deep breath in") after tiotropium compared with placebo. Collectively, these data are consistent with the notion that enhanced neuromechanical coupling explains, at least in part, relief of dyspnea after bronchodilator therapy (46).

In summary, our results support the hypothesis that mechanical restriction and the subsequent neuromechanical uncoupling of the respiratory system may contribute to dyspnea and perceived unsatisfied inspiration during constant-work-rate exercise in COPD. After reaching a minimal IRV, further VT expansion was impossible despite progressively increased effort and dyspnea soon became intolerable. Before reaching the minimal IRV, the effort-displacement ratio was stable despite DH, suggesting that the associated reduced resistive work counterbalanced the negative effects of the increased elastic work.

The reduced operating lung volumes and improved airway conductance after bronchodilator did not affect the extent or rate of DH in early exercise and did not delay the time to reach a minimal IRV. Ultimately, the improved dyspnea reflected more favorable operating lung volumes, reduced resistive loading, improved VT expansion, and improved effort-displacement ratios throughout exercise.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This research was supported by the Ontario Ministry of Health, Toronto, Ontario, Canada; Boehringer Ingelheim (Canada), Burlington, Ontario, Canada; and Pfizer Canada, Kirkland, Quebec, Canada.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Dr. Farzad Saberi for assistance with the study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. O’Donnell, 102 Stuart St., Kingston, Ontario, Canada K7L 2V6 (e-mail: odonnell{at}post.queensu.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Agostoni E and Mead J. Statics of the respiratory system. In: Handbook of Physiology: Respiration. Washington, DC: Am. Physiol. Soc., 1964, sect. 3, vol. I, chapt. 13, p. 387–409.
  2. American Thoracic Society. Standardization of spirometry 1994 update. Am J Respir Crit Care Med 152: 1107–1136, 1995.[ISI][Medline]
  3. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique - 1995 update. Am J Respir Crit Care Med 152: 2185–2198, 1995.[ISI][Medline]
  4. American Thoracic Society/European Respiratory Society. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 166: 518–624, 2002.[Free Full Text]
  5. Baydur A, Behrakis PK, Zin WA, Jaeger M, and Milic-Emili J. A simple method for assessing the validity of the esophageal balloon technique. Am Rev Respir Dis 126: 788–791, 1982.[ISI][Medline]
  6. Bellemare F and Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue. J Appl Physiol 53: 1190–1195, 1982.[Abstract/Free Full Text]
  7. Belman MJ, Botnick WC, and Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with COPD. Am J Respir Crit Care Med 153: 967–975, 1990.
  8. Black LF and Hyatt RE. Maximal respiratory pressure: normal values and relationship to age and sex. Am Rev Respir Dis 99: 696–702, 1969.[ISI][Medline]
  9. Borg GAV. Psychophysical basis of perceived exertion. Med Sci Sports Exerc 14: 377–381, 1982.[ISI][Medline]
  10. Briscoe WA and Dubois AG. The relationship between airway resistance, airway conductance, and lung volumes in subjects of different age and body size. J Clin Invest 37: 1279–1285, 1959.[ISI]
  11. Burrows B, Kasik JE, Niden AH, and Barclay WR. Clinical usefulness of the single-breath pulmonary diffusing capacity test. Am Rev Respir Dis 84: 789–806, 1961.[ISI][Medline]
  12. Campbell EJM and Howell JBL. The sensation of breathlessness. Br Med Bull 9: 36–40, 1963.
  13. Chen Z, Eldridge FL, and Wagner PG. Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol 90: 99–113, 1992.[CrossRef][ISI][Medline]
  14. Coates AL, Peslin R, Rodenstein D, and Stocks J. Measurement of lung volumes by plethysmography. Eur Respir J 10: 1415–1427, 1997.[CrossRef][ISI][Medline]
  15. Crapo RO, Morris AH, Clayton PD, and Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopath Respir 18: 419–425, 1982.[ISI][Medline]
  16. ERS Task Force. Clinical exercise testing with reference to lung diseases: indications, standardization and interpretation strategies. Eur Respir J 10: 2662–2689, 1997.[CrossRef][ISI][Medline]
  17. Fleury B, Murciano D, Talamo C, Aubier M, Pariente R, and Milic-Emili J. Work of breathing in patients with chronic obstructive pulmonary disease in acute respiratory failure. Am Rev Respir Dis 131: 822–827, 1985.[ISI][Medline]
  18. Fowler WS. Breaking point of breath-holding. J Appl Physiol 6: 539–545, 1954.[Free Full Text]
  19. Gibson GJ and Pride NB. Lung distensibility: the static pressure-volume curve of the lung and its use in clinical assessment. Br J Dis Chest 70: 143, 1976.[CrossRef][ISI][Medline]
  20. Grimby G, Bunn J, and Mean J. Relative contribution of rib cage and abdomen to ventilation during exercise. J Appl Physiol 24: 159–166, 1968.[Free Full Text]
  21. Hamilton AL, Killian KJ, Summers E, and Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 152: 2021–2031, 1995.[Abstract]
  22. Hill L and Flack M. The effect of excess of carbon dioxide and of want of oxygen upon the respiration and the circulation. J Physiol 37: 77–111, 1908.
  23. Jones NL. Clinical Exercise Testing (3rd ed.). Philadelphia, PA: Saunders, 1988.
  24. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 56: 880–887, 2001.[Abstract/Free Full Text]
  25. Knudson RJ, Lebowitz MD, Holberg CJ, and Burrows B. Changes in normal maximal expiratory flow-volume curves with growth and aging. Am Rev Respir Dis 127: 725–734, 1983.[ISI][Medline]
  26. Kyroussis D, Polkey MI, Keilty SE, Mills GH, Hamnegard CH, Moxham J, Green M. Exhaustive exercise slows inspiratory muscle relaxation rate in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 153: 787–793, 1996.[Abstract]
  27. Laghi F, Jurban A, Topeli A, Fahey PJ, Garrity E Jr, Archids JM, DePinto DJ, Edwards LC, and Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 157: 475–483, 1998.
  28. Leaver DG and Pride NB. Flow volume curves and expiratory pressures during exercise in patients with chronic airflow obstruction. Scand J Respir Dis 42, Suppl: 23–27, 1971.
  29. Leblanc P, Bowie DM, Summers E, Jones NL, and Killian KJ. Breathlessness and exercise in patients with cardiorespiratory disease. Am Rev Respir Dis 133: 21–25, 1986.[ISI][Medline]
  30. Mador MJ, Kufel TJ, Pineda LA, and Sharma GK. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161: 118–123, 2000.[Abstract/Free Full Text]
  31. Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, Kesten S, and O’Donnell D. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest 128: 1168–1178, 2005.[Abstract/Free Full Text]
  32. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, and Celli BR. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 155: 1984–1990, 1997.[Abstract]
  33. McGregor M and Becklake M. The relationship of oxygen cost of breathing to respiratory mechanical work and respiratory force. J Clin Invest 40: 971–80, 1961.[ISI][Medline]
  34. Morris JF, Koski A, Temple WP, Claremont A, and Thomas DR. Fifteen-year interval spirometric evaluation of the Oregon predictive equations. Chest 92: 123–127, 1988.
  35. O’Donnell DE, Sanii R, Anthonisen NR, and Younes M. The effect of airway dynamic compression on breathing pattern and respiratory sensation in severe COPD. Am Rev Respir Dis 135: 912–918, 1987.[ISI][Medline]
  36. O’Donnell DE, Bertley JC, Chau LL, and Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms. Am J Respir Crit Care Med 155: 109–115, 1997.[Abstract]
  37. O’Donnell DE, Lam M, and Webb KA. Measurement of symptoms, lung hyperinflation and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158: 1557–1565, 1998.[Abstract/Free Full Text]
  38. O’Donnell DE, Chau LKL, and Webb KA. Qualitative aspects of exertional breathlessness in patients with interstitial lung disease. J Appl Physiol 84: 2000–2009, 1998.[Abstract/Free Full Text]
  39. O’Donnell DE, Hong HH, and Webb KA. Respiratory sensation during chest wall restriction and dead space loading in exercising men. J Appl Physiol 88: 1859–1869, 2000.[Abstract/Free Full Text]
  40. O’Donnell DE, D’Arsigny C, and Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163: 892–898, 2001.[Abstract/Free Full Text]
  41. O’Donnell DE, Revill SM, and Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164: 770–777, 2001.[Abstract/Free Full Text]
  42. O’Donnell DE, D’Arsigny C, Fitzpatrick M, and Webb KA. Exercise hypercapnia in advanced chronic obstructive pulmonary disease: the role of lung hyperinflation. Am J Respir Crit Care Med 166: 663–668, 2002.[Abstract/Free Full Text]
  43. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, Ford G, Gervais A, Goldstein R, Hodder R, Maltais F, and Road J. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2003. Can Respir J 10: 11A–65A, 2003.
  44. O’Donnell D, Flüge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, and Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnea and exercise tolerance in COPD. Eur Respir J 23: 832–840, 2004.[Abstract/Free Full Text]
  45. O’Donnell DE, Voduc N, Fitzpatrick M, and Webb KA. Effect of salmeterol on the ventilatory response to exercise in COPD. Eur Respir J 24: 86–94, 2004.[Abstract/Free Full Text]
  46. O’Donnell DE and Webb KA. Mechanisms of dyspnea in COPD. In: Dyspnea: Mechanisms, Measurement, and Management (2nd ed.), edited by Mahler D and O’Donnell DE. Boca Raton, FL: Taylor & Francis, 2005, chapt. 3, p. 29–58. (Lung Biology in Health and Disease 208)
  47. Pepe PE and Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. The auto-PEEP effect. Am Rev Respir Dis 126: 166–170, 1982.[ISI][Medline]
  48. Peters MM, Webb KA, and O’Donnell DE. Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnea in normoxic COPD. Thorax 61: 559–567, 2006.[Abstract/Free Full Text]
  49. Pride NB and Macklem PT. Lung mechanics in disease. In: Handbook of Physiology: The Respiratory System. Mechanics of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. III, pt. 2, chapt. 37, p. 659–692.
  50. Schwartzstein RM, Simon PM, Weiss JW, Fencl V, and Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 39: 1231–1237, 1989.
  51. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, and Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 142: 1009–1014, 1990.[ISI][Medline]
  52. Somfay A, Porszasz J, Lee SM, and Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in non-hypoxemic COPD patients. Eur Respir J 18: 77–84, 2001.[Abstract/Free Full Text]
  53. Stoller JK, Ferranti R, and Feinstein AR. Further specification and evaluation of a new clinical index for dyspnea. Am Rev Respir Dis 135: 1129–1134, 1986.
  54. Undem BJ and Kollarik M. The role of vagal afferent nerves in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2: 355–360, 2005.[Abstract/Free Full Text]
  55. Whitelaw WA, McBride B, Amar J, and Corbet K. Respiratory neuromuscular output during breath holding. J Appl Physiol 50: 435–443, 1981.[Abstract/Free Full Text]
  56. Younes M. Determinants of thoracic excursions during exercise. In: Exercise, Pulmonary Physiology and Pathophysiology, edited by BJ Whipp and K Wasserman. New York: Dekker, 1991, p. 1–65. (Lung Biology in Health and Disease 42)
  57. Zechman FR Jr and Wiley RL. Afferent inputs to breathing: respiratory sensation: In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 1, chapt. 14, p. 449–474.



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
D. Ofir, P. Laveneziana, K. A. Webb, Y.-M. Lam, and D. E. O'Donnell
Mechanisms of Dyspnea during Cycle Exercise in Symptomatic Patients with GOLD Stage I Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 622 - 629.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. Travers, D. J. Dudgeon, K. Amjadi, I. McBride, K. Dillon, P. Laveneziana, D. Ofir, K. A. Webb, and D. E. O'Donnell
Mechanisms of exertional dyspnea in patients with cancer
J Appl Physiol, January 1, 2008; 104(1): 57 - 66.
[Abstract] [Full Text] [PDF]