American Journal of Respiratory and Critical Care Medicine

Rationale: Smokers with a relatively preserved FEV1 may experience dyspnea and activity limitation but little is known about underlying mechanisms.

Objectives: To examine ventilatory constraints during exercise in symptomatic smokers with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I chronic obstructive lung disease (COPD) so as to uncover potential mechanisms of dyspnea and exercise curtailment.

Methods: We compared resting pulmonary function and ventilatory responses (breathing pattern, operating lung volumes, pulmonary gas exchange) with incremental cycle exercise as well as Borg scale ratings of dyspnea intensity in 21 patients (post-bronchodilator FEV1, 91 ± 7% predicted, and FEV1/FVC, 60 ± 6%; mean ± SD) with significant breathlessness and 21 healthy age- and sex-matched control subjects with normal spirometry.

Measurements and Main Results: In patients with COPD compared with control subjects, peak oxygen consumption and power output were significantly reduced by more than 20% and dyspnea ratings were higher for a given work rate and ventilation (P < 0.05). Compared with the control group, the COPD group had evidence of extensive small airway dysfunction with increased ventilatory requirements during exercise, likely on the basis of greater ventilation/perfusion abnormalities. Changes in end-expiratory lung volume during exercise were greater in COPD than in health (0.54 ± 0.34 vs. 0.06 ± 0.32 L, respectively; P < 0.05) and breathing pattern was correspondingly more shallow and rapid. Across groups, dyspnea intensity increased as ventilation expressed as a percentage of capacity increased (P < 0.0005) and as inspiratory reserve volume decreased (P < 0.0005).

Conclusions: Exertional dyspnea in symptomatic patients with mild COPD is associated with the combined deleterious effects of higher ventilatory demand and abnormal dynamic ventilatory mechanics, both of which are potentially amenable to treatment.

Scientific Knowledge on the Subject

Patients with mild chronic obstructive pulmonary disease (COPD) and a relatively preserved FEV1 may report poor perceived health status. The link between ventilatory impairment, symptom development, and activity limitation has never been systematically explored in mild GOLD stage I COPD.

What This Study Adds to the Field

Symptomatic patients with GOLD I COPD can have significant pathophysiologic abnormalities that lead to clinically important dyspnea and exercise intolerance. Dyspnea correlated with increased ventilation and dynamic lung hyperinflation during exercise.

Recent studies have confirmed that patients with mild airflow obstruction as defined by traditional spirometric criteria have evidence of airway inflammation (1). Moreover, patients with relatively preserved FEV1 may have extensive small airway dysfunction as measured by closing volume and tests of abnormal distribution of ventilation (24). In such patients, significant ventilation/perfusion (/) inequalities may exist as a result of inflammation of the lung parenchyma and its vasculature (5). This, in turn, may contribute to a higher ventilatory requirement than normal during exercise. It is known that patients with apparently mild airflow obstruction may report poor perceived health status, chronic activity-related dyspnea (6), and reduced activity levels. Such patients may seek medical attention for relief of dyspnea but the underlying mechanisms and the impact of therapeutic interventions other than successful smoking cessation remains unknown (7, 8).

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of mild chronic obstructive pulmonary disease (COPD) based on a fixed FEV1/FVC ratio (<0.7) has recently been criticized because of the risk of false-positive diagnosis, particularly in the elderly. The added concern is that overdiagnosis could lead to inappropriate treatment with expensive inhaled bronchodilator and corticosteroid treatment. This view is further justified by the absence of proof of the long-term safety and efficacy of these medications in patients with milder disease (FEV1 > 60% predicted). However, this must be balanced by the clinical experience that some symptomatic smokers who fit the mild GOLD criteria may indeed have extensive physiologic impairment that is obscured by a relatively preserved FEV1. It is reasonable to assume that, in older smokers, widespread small airway bronchiolitis, in conjunction with the natural pulmonary impairment associated with aging, will give rise to perceived greater breathing difficulty during exercise than in healthy nonsmoking control subjects. The main purpose of this study was, therefore, to increase our understanding of the mechanisms of exertional dyspnea and activity limitation in this population.

Previous studies have demonstrated that exercise capacity is abnormally diminished in subjects with a mildly reduced post-bronchodilator FEV1 (<80% predicted) (9, 10). In this study, we extend these observations by examining ventilatory constraints during exercise in symptomatic patients with GOLD stage I COPD (post-bronchodilator FEV1 ⩾ 80% predicted and FEV1/FVC < 0.7) so as to uncover potential mechanisms of dyspnea and exercise curtailment. We reasoned that, in mild COPD, a higher intensity of exertional dyspnea compared with age-matched healthy participants would be associated with the following: (1) greater ventilatory demand, (2) increased mechanical loading of the ventilatory muscles during exercise, or (3) a combination of both. We therefore compared ventilatory responses (breathing pattern, operating lung volumes, and gas exchange parameters) to incremental cycle exercise in 21 patients and 21 healthy age- and sex-matched control subjects. We then conducted a correlative analysis to examine possible contributors to exertional dyspnea intensity.

Some of the results of this study have been previously reported in the form of an abstract (11).

Subjects

We studied 21 symptomatic patients with GOLD stage I COPD (post-bronchodilator FEV1 ⩾ 80% predicted and FEV1/FVC < 0.7) (12) who were referred to the COPD Centre at our institution. Patients were excluded if they had (1) other unstable medical conditions that could cause or contribute to breathlessness (i.e., metabolic, cardiovascular, or other respiratory diseases) or (2) other disorders that could interfere with exercise testing, such as neuromuscular diseases or musculoskeletal problems. In addition, 21 healthy age-and sex-matched subjects were included with normal baseline spirometry (FEV1 ⩾ 80% predicted, FEV1/FVC ⩾ 0.7) and absence of any health problems, including cardiovascular, neuromuscular, musculoskeletal, or respiratory diseases that could contribute to breathlessness or exercise limitation. Healthy subjects were recruited from the local community using word-of-mouth, notices posted in community health care facilities, and newspaper advertisements.

Study Design

This was a controlled, cross-sectional study in which informed consent was obtained from all subjects, and ethical approval was received from the Queen's University and Hospital Health Sciences Human Research Ethics Board. Subjects were tested on two occasions. On the first visit, after informed consent and appropriate screening of medical history, all subjects completed pulmonary function testing pre- and post-bronchodilator (400 μg salbutamol) and a variety of questionnaires: chronic activity-related dyspnea questionnaires included the Baseline Dyspnea Index (13) and the Medical Research Council scale (14), and a self-reported habitual physical activity questionnaire (Community Healthy Activities Model Program for Seniors [CHAMPS]), which was used to evaluate each subject's weekly caloric expenditure in physical activities (15). On the second visit, subjects completed pulmonary function testing and cardiopulmonary exercise testing.

Subjects with COPD were asked to withdraw from any respiratory-related medications for between 8 and 72 hours, based on the medication used (short- or long-acting), before any of the visits to eliminate any effect on exercise or pulmonary function. All subjects were required to eat a normal mixed diet before laboratory visits to provide valid experimental/metabolic results during exercise. Subjects were also asked to avoid the ingestion of alcohol, caffeine-containing products, and heavy meals for at least 4 hours, and to refrain from strenuous activity (e.g., cycling, running) for at least 12 hours before testing. Experimental visits were conducted at the same time of day for each subject.

Procedures

Routine spirometry, constant-volume body plethysmography, single-breath diffusing capacity (DlCO), and maximum inspiratory and expiratory mouth pressures (Pimax and Pemax, measured at FRC and TLC, respectively) were performed in accordance with recommended techniques (1620) using an automated pulmonary function testing system (6200 Autobox DL and Vmax229d; SensorMedics, Yorba Linda, CA). Closing volumes were measured using the single-breath nitrogen test as modified by Anthonisen and colleagues (21). Measurements were repeated 30 minutes post-bronchodilator (400 μg salbutamol) in all patients with mild COPD and in 10 healthy subjects. Measurements were standardized as percentages of predicted normal values (2228); predicted normal values for inspiratory capacity (IC) were calculated as predicted TLC minus predicted FRC.

Symptom-limited incremental exercise testing was conducted on an electronically braked cycle ergometer (Ergometrics 800S; SensorMedics) using the Vmax229d Cardiopulmonary Exercise Testing System (SensorMedics) according to recommended guidelines (29) as previously described (30). Exercise tests consisted of a steady-state resting period and a 1-minute warm-up of unloaded pedalling followed by a stepwise protocol in which the work rate was increased in 2-minute intervals by increments of 20 W. All exercise tests were terminated at the point of symptom limitation (peak exercise). Upon exercise cessation, subjects were asked to verbalize their main reason for stopping exercise: for example, breathing discomfort, leg discomfort, both breathing and leg discomfort, or some other reason to be documented.

Subjects rated the magnitude of their perceived breathing and leg discomfort at rest, every minute during exercise, and at peak exercise by pointing to the 10-point Borg scale. Oxygen saturation (SpO2) by pulse oximetry, electrocardiographic monitoring of heart rate (HR), rhythm and ST-segment changes, and blood pressure by indirect sphygmomanometry were performed at rest and throughout exercise testing. Breath-by-breath data were collected at baseline and throughout exercise while subjects breathed through a mouthpiece with nasal passages occluded by a nose-clip: computer software calculated minute ventilation (), oxygen uptake (), carbon dioxide production (), end-tidal carbon dioxide partial pressure (PetCO2), Vt, breathing frequency (f), inspiratory and expiratory time (Ti and Te, respectively), duty cycle (Ti/Ttot), and mean inspiratory and expiratory flow (Vt/Ti and Vt/Te, respectively). Exercise variables were measured and averaged over the last 30 seconds of each minute and at peak exercise. Exercise parameters were compared with the predicted normal values of Blackie and colleagues (31) and Jones and coworkers (32). Changes in end-expiratory lung volume (EELV) were estimated from IC measurements at rest, at the end of each 2-minute increment of exercise, and at peak exercise (33). Ventilation was also compared with the maximal ventilatory capacity (MVC), which was estimated by multiplying the measured FEV1 by 35 (34). The ventilatory threshold (VTh) was detected individually using the V-slope method (35). Breathing pattern was evaluated by examining individual Hey plots (36).

Additional detail on the methods for performing pulmonary function and exercise test measurements is provided in the online supplement.

Statistical Analysis

A sample size of 16 was used to provide the power (80%) to detect a significant difference in dyspnea intensity (Borg scale) measured at a standardized work rate during incremental cycle exercise based on a relevant difference in Borg ratings of ±1, an SD of 1 for Borg ratings changes found at our laboratory, α = 0.05. Results were expressed as means ± SD. A P < 0.05 level of statistical significance was used for all analyses.

Group responses at different time points and/or intensities during exercise were compared using t tests with appropriate Bonferroni adjustments for multiple comparisons. Dyspnea descriptors were analyzed as frequency statistics and compared using the Fisher's exact test. Physiologic contributors to exertional dyspnea intensity in subjects with COPD were determined by multiple regression analysis. In this analysis, Borg dyspnea ratings at a standardized exercise work rate (dependent variable) were analyzed against concurrent relevant independent variables (i.e., exercise measurements of ventilation, breathing pattern, operating lung volumes, cardiovascular and metabolic parameters, and baseline pulmonary function measurements).

Subject characteristics are summarized in Table 1. Compared with the healthy control group, the COPD group showed significant expiratory airflow limitation and lung hyperinflation, a reduced DlCO, a greater closing capacity and N2 slope, and significantly greater chronic activity-related dyspnea. The healthy control subjects had normal spirometry and were well matched for age, sex, body mass index, and habitual physical activities, when compared with the subjects with COPD.

TABLE 1. SUBJECT CHARACTERISTICS AND PULMONARY FUNCTION IN PATIENTS WITH GOLD STAGE I CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND IN HEALTHY CONTROL SUBJECTS




Control

COPD

P Value
Male, %5764NS
Age, yr63 ± 964 ± 7NS
Body mass index, kg/m226.2 ± 3.427.7 ± 4.1NS
BDI focal score (0–12)11.5 ± 0.78.3 ± 2.0<0.0005
MRC dyspnea scale (1–5)1.1 ± 0.11.9 ± 0.1<0.0005
CHAMPS, kcal/wk consumed at moderate activities*1744 ± 8802820 ± 2103NS
FEV1, L2.77 ± 0.482.28 ± 0.56<0.05
(% predicted)(117 ± 9)(85 ± 11)<0.0005
FEV1 post–β2-agonist, L2.88 ± 0.522.47 ± 0.54NS
(% predicted)(124 ± 12)(91 ± 7)<0.0005
FEV1/FVC post–β2-agonist, %82 ± 460 ± 6<0.0005
FVC, L3.79 ± 0.673.93 ± 0.98NS
(% predicted)(106 ± 13)(102 ± 11)NS
PEFR, % predicted120 ± 1589 ± 16<0.0005
FEF25–75%, % predicted99 ± 2734 ± 12<0.0005
IC, % predicted109 ± 13105 ± 19NS
FRC, % predicted102 ± 21121 ± 20<0.005
TLC, % predicted105 ± 13114 ± 90.01
RV, % predicted97 ± 20129 ± 21<0.0005
RV/TLC, %33 ± 441 ± 6<0.0005
sRaw, % predicted132 ± 42290 ± 97<0.0005
Pimax at FRC, % predicted132 ± 46109 ± 35NS
Pimax at TLC, % predicted94 ± 2581 ± 23NS
DlCO, % predicted118 ± 2098 ± 21<0.005
CV/VC, % predicted*103 ± 21128 ± 47NS
CC/TLC, % predicted*97 ± 12118 ± 18<0.005
Estimated MVC, L/min
102.0 ± 16.4
79.6 ± 19.3
<0.0005

Definition of abbreviations: BDI = modified Baseline Dyspnea Index; CHAMPS = Community Healthy Activities Model Program for Seniors; CC = closing capacity; COPD = chronic obstructive pulmonary disease; CV = closing volume; DlCO = diffusing capacity of the lung for carbon monoxide; FEF25–75% = force expiratory flow between 25 and 75% of FVC; IC = inspiratory capacity; MRC = Medical Research Council; MVC = maximal ventilatory capacity estimated as 35 × FEV1; NS = not significant; PEFR = peak expiratory flow rate; Pemax = maximal expiratory pressure; Pimax = maximal inspiratory pressure; RV = residual volume; sRaw = specific airways resistance; TLC = total lung capacity.

Values are means ± SD.

*Data only collected in 10 of the 21 healthy control subjects.

All subjects with COPD were symptomatic and had a diagnosis of COPD; the majority (15 of 21) had a diagnosis made within the previous 5 years. Eleven subjects with COPD were prescribed respiratory medication: nine subjects used their inhalers on a regular basis (n = 9 long- and/or short-acting β2-agonist bronchodilators, n = 5 long- and/or short-acting anticholinergic bronchodilators, n = 7 inhaled corticosteroid/long-acting β2-agonist combination) and two subjects used a short-acting β2-agonist bronchodilator on an “as needed” basis only. Comorbidities in the COPD group included the following: stable coronary artery disease (n = 2), diabetes mellitus type 2 (n = 1), well-controlled hypertension (n = 2), and varying degrees of osteoarthritis (n = 4). Comorbidities in the control group included mild osteoarthritis (n = 4) and diabetes mellitus type 2 (n = 1). See the online supplement for more details on subjects.

All of the patients with COPD had a significant (⩾15 pack-years) smoking history (46.4 ± 19.8 pack-years; range, 15–100 pack-years). Five patients were current smokers and 16 were ex-smokers who had stopped smoking at least 2 years before the study. In the control group, there were no current smokers and all four ex-smokers had less than a 10 pack-year smoking history and had stopped smoking for more than 10 years.

Symptom-limited Incremental Cycle Exercise

The majority of patients with COPD (60%) stopped exercise due to severe breathing discomfort, either alone or in combination with leg discomfort (Figure 1). In contrast, the majority of healthy control subjects (81%) stopped exercise primarily because of leg discomfort. Dyspnea intensity was higher in the COPD group during exercise at a given work rate (Figure 2): group mean differences were greater than 1 Borg unit at 60 W and thereafter during exercise (P < 0.05). Dyspnea/ and dyspnea/ slopes were also greater in COPD than control groups by 49 and 51%, respectively (P < 0.05). At the end of exercise, dyspnea intensity was rated 1.5 Borg units higher in subjects with COPD compared with control subjects (P = 0.08), and a significantly greater number of patients with COPD described their breathing as rapid compared with control subjects (45 vs. 5%, respectively; P < 0.05).

Measurements at the VTh and at peak exercise are shown in Table 2. Patients with COPD stopped exercise at a lower peak work rate, and HR than healthy control subjects: /work rate (Figure 3) and HR/work rate relationships were not different between the two groups throughout the exercise. Compared with the control group, in the COPD group was significantly higher at any submaximal exercise intensity: mean differences in ranged from approximately 5 L/minute at 20 W (P < 0.0005) and became greater with increasing work rate (Figure 3). At the VTh, was similar in both groups; however, patients with COPD reached their VTh at a lower as well as a lower work rate. More subjects with COPD (n = 10) than control subjects (n = 5) had a VTh below 50% of the predicted maximum work rate, whereas more subjects with COPD also had a VTh in the lower range (n = 5 between 40 and 49%, n = 8 between 50 and 59% of predicted peak ) than control subjects (n = 3 between 40 and 49%, n = 3 between 50 and 59% of predicted peak ). PetCO2 was lower in the COPD group compared with the control group at rest (36.0 ± 4.3 vs. 39.5 ± 4.5 mm Hg, respectively), at any given work rate during exercise (see Figure E1 of the online supplement) and at VTh (Table 2).

TABLE 2. MEASUREMENTS AT THE VENTILATORY THRESHOLD AND AT THE PEAK OF SYMPTOM-LIMITED INCREMENTAL CYCLE EXERCISE



Ventilatory Threshold

Peak Exercise

Control
COPD
Control
COPD
Dyspnea, Borg scale1.8 ± 1.53.0 ± 1.95.4 ± 2.86.9 ± 2.8
Leg discomfort, Borg scale2.4 ± 1.53.6 ± 1.96.8 ± 2.57.2 ± 2.2
Work rate, W91 ± 3279 ± 13144 ± 43116 ± 38*
(%predicted maximum)(62 ± 18)(49 ± 13*)(97 ± 23)(72 ± 14*)
, L/min1.34 ± 0.291.25 ± 0.332.11 ± 0.591.75 ± 0.55*
(%predicted maximum)(65 ± 12)(56 ± 9*)(101 ± 16)(78 ± 12*)
ml/kg/min18.7 ± 4.915.6 ± 3.8*29.1 ± 7.121.7 ± 5.7*
HR, beats/min121 ± 17118 ± 19156 ± 15142 ± 21*
(%predicted maximum)(72 ± 9)(70 ± 11)(93 ± 9)(85 ± 12*)
O2 pulse, ml O2/beat11.2 ± 2.910.8 ± 2.913.5 ± 3.312.4 ± 3.4
SpO2, %97 ± 196 ± 296 ± 296 ± 2
, L/min36.2 ± 7.839.8 ± 10.678.0 ± 23.967.7 ± 23.6
(% estimated MVC)(36 ± 6)(51 ± 13*)(75 ± 19)(85 ± 20)
/28.9 ± 4.234.3 ± 6.0*34.2 ± 6.736.8 ± 6.3
VE/27.7 ± 3.632.0 ± 5.2*37.7 ± 8.138.7 ± 6.3
PetCO2, mm Hg45.6 ± 4.241.0 ± 5.7*37.4 ± 5.637.3 ± 5.6
f, breaths/min24 ± 425 ± 538.5 ± 9.136.6 ± 8.1
Vt, L1.55 ± 0.351.64 ± 0.482.06 ± 0.471.87 ± 0.55
(%predicted VC)(44 ± 7)(42 ± 8)(54 ± 9)(45 ± 9*)
IC, L2.84 ± 0.512.82 ± 0.722.76 ± 0.532.56 ± 0.68
(%predicted)(105 ± 9)(95 ± 16*)(96 ± 14)(82 ± 15*)
ΔIC from rest, L0.02 ± 0.28−0.28 ± 0.27*−0.06 ± 0.32−0.54 ± 0.34*
(%predicted)(1 ± 11)(−10 ± 9*)(−2 ± 12)(−18 ± 11*)
IRV, L1.29 ± 0.481.18 ± 0.470.70 ± 0.370.69 ± 0.31
(%predicted TLC)(22 ± 8)(19 ± 7)(12 ± 6)(11 ± 4)
EFL, % of Vt overlapping maximal flow–volume curve
25 ± 27
63 ± 25*
40 ± 23
80 ± 19*

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; EFL = expiratory flow-limitation; FEF25–75% = force expiratory flow between 25 and 75% of FVC; HR = heart rate; IC = inspiratory capacity; IRV = inspiratory reserve volume; MVC = maximal ventilatory capacity estimated as 35 × FEV1; PetCO2 = partial pressure of end-tidal CO2; TLC = total lung capacity.

Values are means ± SD.

*P < 0.05, COPD versus control within the given stage of exercise.

During exercise in COPD, IC decreased significantly by 0.54 ± 0.34 L (P < 0.0001), with changes in IC ranging between +0.26 L (9% predicted) and −1.11 L (−41% predicted). In contrast to COPD, there was no significant change in IC from rest to peak exercise in the normal group (0.06 ± 0.32 L or 1 ± 9% predicted). Although 19 of 21 (90%) patients with COPD decreased their IC during exercise by more than 0.2 L, only 24% of the control subjects decreased IC, 29% increased IC, and 47% did not change IC.

Upon evaluation of individual Hey plots (36), the average at the Vt inflection point was similar at 44 and 45 L/minute in the control and COPD group, respectively (Figure 4); however, this inflection occurred at a significantly (P < 0.05) lower and work rate in COPD. Between-group differences in breathing pattern were found beyond this : in COPD, there was a plateau in Vt at this point so that further increases in were achieved by increasing f alone; in the control group, further increases in were achieved by increasing both Vt and f. In COPD, Vt after the inflection point was constrained by further reductions in IC of 0.23 L (P < 0.0005). Interestingly, the inspiratory reserve volume (IRV) at the Vt/ inflection point was similar across groups.

Mechanisms of Exertional Dyspnea

The relationships between Borg ratings of dyspnea intensity and (% estimated MVC) or IRV (% predicted TLC) during exercise were both superimposed in COPD and control groups, indicating that dyspnea intensity increased as a function of each of these independent variables. This concept is supported by the strong correlation across groups between ratings of exertional dyspnea at the highest common work rate (80 W) and the concurrent expressed as % estimated MVC (r = 0.61, P < 0.0005) and IRV standardized as % predicted TLC (r = −0.62, P < 0.0005); the best physiologic correlate of dyspnea intensity at this work rate was the concurrent IC expressed as % predicted (r = −0.63, P < 0.0005). Although (% estimated MVC) and IRV (% predicted TLC) were moderately interrelated (r = −0.58, P < 0.005), each variable explained an additional 10% to the variance in dyspnea ratings after accounting first for the other. Dyspnea intensity and absolute values of at this work rate were not as strongly correlated (r = 0.39, P = 0.013); however, explained an additional 8% of the variance in dyspnea intensity after accounting for the concurrent IC %predicted. By stepwise multiple regression analysis, dyspnea intensity at 80 W was best described by the combination of concurrent measurements of IC % predicted and peak tidal expiratory flow (r2= 0.56, P < 0.0001). Within the COPD group, the strongest correlates of exertional dyspnea intensity at a given work rate (80 W) were the simultaneous measurements of IC % predicted (r = −0.57, P = 0.011), IRV expressed as % predicted TLC (r = −0.51, P = 0.025), and the Vt/IC ratio (r = 0.47, P = 0.042).

The main findings of this study are as follows: (1) exercise capacity was significantly reduced and exertional dyspnea ratings were higher at a given work rate in symptomatic patients with GOLD stage I COPD, compared with healthy control subjects; (2) resting pulmonary function tests confirmed that patients had significant small airway dysfunction; (3) ventilatory abnormalities during exercise in patients with mild COPD included higher ventilatory demand, significant dynamic lung hyperinflation (DH), and a relatively rapid and shallow breathing pattern.

Our patients with COPD with a relatively preserved FEV1 had mild to moderate chronic activity-related dyspnea as measured by validated questionnaires. In fact, 11 of 21 patients had previously sought medical attention for dyspnea and were receiving regular or as-needed inhaled bronchodilator therapy. Peak symptom-limited was reduced by 22% of the predicted normal value (Table 2), and patients were more likely to report dyspnea (and less likely to report leg discomfort) as an exercise-limiting symptom compared with age- and sex-matched healthy participants (Figure 1). We are satisfied that the reduced exercise performance in our patients with COPD was not the result of reduced motivational effort: patients reported intolerable exertional symptoms at the peak of exercise and generally demonstrated significant encroachment on their cardiopulmonary and metabolic reserves. Although exercise limitation was multifactorial and the proximate cause likely varied among individuals, significant ventilatory constraints and attendant respiratory difficulty were evident in the majority of patients.

During exercise, dyspnea intensity ratings were higher at a given power output (e.g., by 2 Borg units at 80 W) (Figure 2), whereas both dyspnea/ and dyspnea/ slopes were approximately 50% steeper in the COPD than in the healthy control group. We considered the following potential contributors to exertional dyspnea in patients with mild COPD: (1) higher ventilatory demand as a result of pulmonary gas exchange or metabolic abnormalities, (2) greater abnormalities of dynamic ventilatory mechanics and muscle function that would cause dyspnea to increase for any given ventilation compared with health, or (3) a combination of both of these.

Increased Ventilatory Demand

Ventilation was increased significantly by approximately 30% or more for any given power output throughout exercise in patients with mild COPD compared with control subjects (Figure 3). /work rate slopes were similar and well within the normal range in both groups as has previously been described (37) (Figure 3). The DlCO in the COPD group was slightly but significantly diminished compared with the healthy group but remained within the predicted normal range. Five patients had a DlCO value that was lower than 80% predicted, indicating some reduction in the surface area for gas exchange in these heavy smokers. The ventilatory equivalents for CO2 and O2 were significantly elevated throughout exercise compared with in health, suggesting greater abnormalities. Thus, the higher / and / in our COPD group likely reflect an impaired ability to reduce a higher physiologic dead space during exercise. The contention that inequality contributed to the accelerated ventilatory response in patients with COPD is supported by the findings that was increased early in exercise before the onset of metabolic acidosis and that / ratios were also significantly (P < 0.05) elevated early in exercise (by 10 and 15% at 40 and 60 W, respectively) as well as at the VTh (by 19%) in patients with COPD compared with those in health. Indeed, Barbera and colleagues (5) originally described significant inequalities during exercise in a group of patients with mild COPD (mean FEV1/FVC = 59%) but found that gas exchange in these individuals was largely preserved through increased alveolar ventilation. Similarly, ventilatory efficiency was not critically compromised in COPD, and pulmonary gas exchange abnormalities were not sufficiently pronounced to cause greater arterial oxygen desaturation during the activity. It is noteworthy that PetCO2 was decreased at rest and remained similarly decreased throughout all exercise work rates (by ∼4 mm Hg) in patients with COPD compared with those in health, suggesting alveolar hyperventilation and possible alteration in the ventilatory control system.

Earlier metabolic acidosis secondary to the effects of skeletal muscle deconditioning was considered as a potential explanation for the earlier rise in and dyspnea in patients with COPD. Ventilatory thresholds did occur at a significantly lower in COPD (by 16%) than in health but nevertheless occurred within the expected normal range (Table 2). However, there was considerable overlap in the range and more subjects with COPD than control subjects had a VTh below 50% of the predicted maximum work rate or in the lower range of . Perceived exertional leg discomfort was relatively increased in patients with COPD. However, other indications of the effects of deconditioning, such as increased HR/ slopes, were not discernible in our patients with COPD. Moreover, our estimates of habitual physical activity using the CHAMPS questionnaire (15) were similar in both groups (Table 1). Significant cardiac impairment was also unlikely to contribute to the relatively reduced VTh in COPD because patients with active cardiac comorbidity were carefully excluded from this group and HR responses and reserve at peak exercise were normal, as were O2 pulse and blood pressure measurements. We can conclude, therefore, that pulmonary abnormalities stimulated ventilation during exercise in COPD and that this was likely compounded later in exercise by the effects of metabolic acidosis.

Regardless of the mechanism, the increased ventilatory demand likely contributed to the greater dyspnea intensity and exercise curtailment in patients with COPD. Thirteen of 21 patients with COPD reached a /MVC greater than 85% at a lower peak exercise capacity than in health, suggesting clinically significant ventilatory constraints to exercise in these individuals (38). A high ventilatory index (/MVC) has traditionally been linked to higher levels of exertional dyspnea during exercise (39). In this study, a correlative analysis confirmed an association between dyspnea intensity ratings and the /MVC ratio (r = 0.61, P < 0.05). The higher ventilatory demand in patients with COPD ultimately reflects a relatively increased central neural drive and contractile muscular effort (relative to the maximal possible value) for the ventilatory muscles. Neurophysiologically, the perception of increased effort is believed to be conveyed via central corollary discharge from the motor centers to the somatosensory cortex, where it is consciously appreciated as unpleasant (3941).

Abnormal Dynamic Ventilatory Mechanics

Dyspnea/ slopes were consistently elevated during exercise in COPD, suggesting increased intrinsic mechanical loading and/or functional weakness of the ventilatory muscles. Resting pulmonary function tests confirmed important mechanical abnormalities in the setting of a relatively preserved FEV1, VC, IC, and maximal static respiratory muscle strength. The presence of clinically significant small airway dysfunction was suggested by the following: (1) maximal expiratory flow rates were uniformly diminished over the effort-independent portion of the maximal flow–volume curve, (2) closing capacity was increased, (3) maldistribution of ventilation was suggested by the nitrogen washout test, and (4) all plethysmographic lung volumes were elevated. The time course of change in the various lung volume and capacity components with disease progression is unknown. In our sample, TLC and FRC were increased in proportion (suggesting increased lung compliance) such that IC was preserved. Tantucci and colleagues (42) have previously shown that reduction of resting IC (<80% predicted) in patients with moderate to severe COPD indicated the presence of expiratory flow limitation at rest (measured by the negative expiratory pressure technique), with negative implications for exercise performance. It follows that our patients with COPD were unlikely to manifest expiratory flow limitation at rest but nevertheless encroached on their maximal expiratory flow reserve relatively early in exercise. During the accelerated ventilatory response to exercise in COPD, EELV increased by an average of 0.54 L from rest to peak exercise, whereas in healthy participants it increased by an average of 0.06 L. These findings are consistent with the previous report by Babb and colleagues (9) who demonstrated DH by 0.42 L in a group of patients with GOLD stage 2 COPD. Similar levels of DH have been reported in patients with moderate to severe COPD, but at much lower ventilations and work rates than in our patients with milder disease (33). The presence of this degree of DH suggests that the respiratory system's mechanical time constant for lung emptying was delayed even in mild COPD. Thus, in the setting of exercise tachypnea (and reduction of expiratory time), progressive air trapping is the inevitable consequence. Our older control group showed an inability to decrease EELV during higher exercise intensities, likely reflecting the well-documented effects of aging on lung compliance, which predisposes these individuals to expiratory flow limitation (43, 44). It follows that the superimposition of small airway bronchiolitis and possibly regional emphysema, as a result of smoking, on the already impaired physiology of the aging lung may amplify the negative clinical consequences. Whether the impact of similar smoking damage on the lungs and airways of younger individuals is less marked has not been studied but is a reasonable postulation.

DH in our COPD group was associated with a more rapid, shallow breathing at ventilations beyond 45 L/minute (Figure 4). Consequently, the Vt inflection point on individual Hey plots happened at an earlier and work rate (but at a similar dynamic IRV) in COPD than in health. Thus, in patients with COPD, Vt did not increase further from the inflection point to peak (an increase of 23 L/min), and increases in near end-exercise were achieved mainly by increasing breathing frequency. In this regard, it is interesting that, at end-exercise, patients with COPD selected the qualitative dyspnea descriptor “rapid” more frequently than the healthy group. By contrast, Vt expansion in health continued after the Vt inflection point (by a further 0.23 L) and tachypnea was relatively delayed.

Mechanical abnormalities contributed to perceived exertional respiratory difficulty in COPD. On the basis of the result of a previous mechanical study in moderate to severe COPD (45), we speculate that DH was likely advantageous early in exercise by attenuating expiratory flow limitation at the relatively higher absolute lung volume. This may have permitted our patients with COPD to increase to approximately 40 L/minute over the first few minutes of exercise with only mild increases in perceived respiratory discomfort (i.e., Borg, ∼2 units). Thereafter, further lung hyperinflation would be expected to cause increased elastic loading and functional weakness of the inspiratory muscles (already burdened with increased resistive loading) and to constrain Vt expansion in the setting of a progressively increasing central neural drive (45). Over the final minutes of exercise, it is clear that, in our patients with COPD, central respiratory drive was relatively increased, whereas Vt expansion was more restricted compared with health. We have previously argued that this increasing disparity between respiratory effort (or neural drive) and simultaneous thoracic volume displacement (i.e., neuromechanical dissociation) may, in part, form the basis for the perception of greater respiratory difficulty in patients with COPD (45). In the current study, dyspnea/IRV relationships were superimposed in the COPD and control groups. However, it is noteworthy that, at a standardized power output of 80 W, dyspnea intensity was significantly higher and dynamic IRV was proportionately lower in the COPD group than in the control group, indicating deleterious mechanical effects on respiratory sensation. The notion that DH contributes to exertional dyspnea is bolstered by the finding that, within the COPD group, ratings of dyspnea intensity increased as dynamic IRV diminished during exercise (r = −0.51, P < 0.05). Moreover, consistent with a number of previous studies in patients with moderate to severe COPD, increased dyspnea intensity ratings at a standardized exercise stimulus correlated well with reduced dynamic IC expressed as %predicted (4648). Thus, mechanical factors contributed more to the variance of exertional dyspnea intensity than the increased ventilation, although ventilation explained an additional 8% of the variance in dyspnea ratings after accounting for IC in a stepwise regression analysis.

It is important to emphasize that even among this small group of patients with COPD, considerable pathophysiologic heterogeneity was evident. For example, three patients had disproportionate reduction of DlCO (<70% predicted) and were subsequently found to have radiographic evidence of localized emphysema. The extent to which our results can be generalized to the larger population of less symptomatic patients with GOLD stage I COPD (e.g., those identified by screening spirometry) remains to be determined. We can conclude, however, that in older symptomatic smokers with a largely preserved FEV1, clinically significant physiologic impairment and exertional symptoms may be present.

In summary, this is the first study to examine mechanisms of exertional dyspnea in patients with mild COPD as judged by traditional spirometric criteria. Our study demonstrates that extensive small airway dysfunction may exist in symptomatic patients with mild COPD with relatively preserved FEV1, FVC, and resting IC. When abnormal airway function and increased mismatching are superimposed on preexisting age-related pulmonary impairment, greater exercise curtailment and troublesome exertional symptoms are the result. Dyspnea causation is multifactorial, but our results indicate that the combination of increased ventilatory demand and abnormal dynamic ventilatory mechanics is likely important. For smokers who experience persistent and apparently disproportionate dyspnea (with reference to FEV1), cardiopulmonary exercise testing is useful in uncovering the severity and mechanisms of this symptom, on an individual basis.

1. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.
2. Buist AS, Ross BB. Quantitative analysis of the alveolar plateau in the diagnosis of early airway obstruction. Am Rev Respir Dis 1973;108:1078–1087.
3. Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W. Small airway function improvement after smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med 2006;174:853–857.
4. Stanescu D, Sanna A, Veriter C, Robert A. Identification of smokers susceptible to development of chronic airflow limitation: a 13-year follow-up. Chest 1998;114:416–425.
5. Barbera JA, Riverola A, Roca J, Ramirez J, Wagner PD, Ros D, Wiggs BR, Rodriguez-Roisin R. Pulmonary vascular abnormalities and ventilation-perfusion relationships in mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;149:423–429.
6. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001;56:880–887.
7. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166:675–679.
8. Buist AS, Sexton GJ, Nagy JM, Ross BB. The effect of smoking cessation and modification on lung function. Am Rev Respir Dis 1976;114:115–122.
9. Babb TG, Viggiano R, Hurley B, Staats B, Rodarte JR. Effect of mild-to-moderate airflow limitation on exercise capacity. J Appl Physiol 1991;70:223–230.
10. Carter R, Nicotra B, Blevins W, Holiday D. Altered exercise gas exchange and cardiac function in patients with mild chronic obstructive pulmonary disease. Chest 1993;103:745–750.
11. Ofir D, Laveneziana P, Webb KA, O'Donnell DE. Abnormal ventilatory responses to incremental cycle exercise in mild COPD [abstract]. Am J Respir Crit Care Med 2007;175:A768.
12. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C. Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555.
13. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984;85:751–758.
14. Fletcher CM, Elmes PC, Fairbrain AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. BMJ 1959;2:257–266.
15. Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. CHAMPS physical activity questionnaire for older adults: outcomes for interventions. Med Sci Sports Exerc 2001;33:1126–1141.
16. Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, et al. General considerations for lung function testing. Eur Respir J 2005;26:153–161.
17. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al. Standardisation of spirometry. Eur Respir J 2005;26:319–338.
18. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP, et al. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511–522.
19. MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720–735.
20. American Thoracic Society; European Respiratory Society. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518–624.
21. Anthonisen NR, Danson J, Robertson PC, Ross WR. Airway closure as a function of age. Respir Physiol 1969;8:58–65.
22. Morris JF, Koski A, Temple WP, Claremont A, Thomas DR. Fifteen-year interval spirometric evaluation of the Oregon predictive equations. Chest 1998;93:123–127.
23. Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir 1982;18:419–425.
24. Burrows B, Kasik JE, Niden AH, Barclay WR. Clinical usefulness of the single-breath pulmonary diffusing capacity test. Am Rev Respir Dis 1961;84:789–806.
25. Briscoe WA, Dubois AB. The relationship between airway resistance, airway conductance and lung volume in subjects of different age and body size. J Clin Invest 1958;37:1279–1285.
26. Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969;99:696–702.
27. Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995;152:2021–2031.
28. Buist AS, Ross BB. Predicted values for closing volumes using a modified single breath nitrogen test. Am Rev Respir Dis 1973;107:744–752.
29. American Thoracic Society; American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:211–277.
30. Ofir D, Laveneziana P, Webb KA, O'Donnell DE. Ventilatory and perceptual responses to cycle exercise in obese women. J Appl Physiol 2007;102:2217–2226.
31. Blackie SP, Fairbarn MS, McElvaney GN, Morrison NJ, Wilcox PG, Pardy RL. Prediction of maximal oxygen uptake and power during cycle ergometry in subjects older than 55 years of age. Am Rev Respir Dis 1989;139:1424–1429.
32. Jones NL, Makrides L, Hitchcock C, Chypchar T, McCartney N. Normal standards for an incremental progressive cycle ergometer test. Am Rev Respir Dis 1985;131:700–708.
33. O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:770–777.
34. Gandevia B, Hugh-Jones P. Terminology for measurements of ventilatory capacity; a report to the thoracic society. Thorax 1957;12:290–293.
35. Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ. Principles of exercise testing and interpretation. Baltimore, MD: Lippincott, Williams & Wilkins; 1999.
36. Hey EN, Lloyd BB, Cunningham DJ, Jukes MG, Bolton DP. Effects of various respiratory stimuli on the depth and frequency of breathing in man. Respir Physiol 1966;1:193–205.
37. Lewis MI, Belman MJ, Monn SA, Elashoff JD, Koerner SK. The relationship between oxygen consumption and work rate in patients with airflow obstruction. Chest 1994;106:366–372.
38. Palange P, Ward SA, Carlsen KH, Casaburi R, Gallagher CG, Gosselink R, O'Donnell DE, Puente-Maestu L, Schols AM, Singh S, et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007;29:185–209.
39. Gandevia SC, Macefield G. Projection of low-threshold afferents from human intercostal muscles to the cerebral cortex. Respir Physiol 1989;77:203–214.
40. Chen Z, Eldridge FL, Wagner PG. Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol 1992;90:99–113.
41. Davenport PW, Friedman WA, Thompson FJ, Franzen O. Respiratory-related cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 1986;60:1843–1848.
42. Tantucci C, Duguet A, Similowski T, Zelter M, Derenne JP, Milic-Emili J. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J 1998;12:799–804.
43. Delorey DS, Babb TG. Progressive mechanical ventilatory constraints with aging. Am J Respir Crit Care Med 1999;160:169–177.
44. Johnson BD, Reddan DF, Pegelow KC, Seow KC, Dempsey JA. Flow limitation and regulation of functional residual capacity during exercise in physically active aging population. Am Rev Respir Dis 1991;143:960–967.
45. O'Donnell DE, Hamilton AL, Webb KA. Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD. J Appl Physiol 2006;101:1025–1035.
46. Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR. Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1395–1399.
47. O'Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3:180–184.
48. Puente-Maestu L, de Garcia PJ, Martinez-Abad Y, Ruiz de Ona JM, Llorente D, Cubillo JM. Dyspnea, ventilatory pattern, and changes in dynamic hyperinflation related to the intensity of constant work rate exercise in COPD. Chest 2005;128:651–656.
Correspondence and requests for reprints should be addressed to Dr. Denis O'Donnell, M.D., F.R.C.P.C., 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail:

Related

No related items
American Journal of Respiratory and Critical Care Medicine
177
6

Click to see any corrections or updates and to confirm this is the authentic version of record