American Journal of Respiratory and Critical Care Medicine

Rationale: It is not known if abnormal dynamic respiratory mechanics actually limit exercise in patients with mild chronic obstructive pulmonary disease (COPD). We reasoned that failure to increase peak ventilation and Vt in response to dead space (DS) loading during exercise would indicate true ventilatory limitation to exercise in mild COPD.

Objectives: To compare the effects of DS loading during exercise on ventilation, breathing pattern, operating lung volumes, and dyspnea intensity in subjects with mild symptomatic COPD and age- and sex-matched healthy control subjects.

Methods: Twenty subjects with Global Initiative for Chronic Obstructive Lung Disease stage I COPD and 20 healthy subjects completed two symptom-limited incremental cycle exercise tests, in randomized order: unloaded control and added DS of 0.6 L.

Measurements and Main Results: Peak oxygen uptake and ventilation were significantly lower in COPD than in health by 36% and 41%, respectively. With added DS compared with control, both groups had small decreases in peak work rate and no significant increase in peak ventilation. In health, peak Vt and end-inspiratory lung volume increased significantly with DS. In contrast, the COPD group failed to increase peak end-inspiratory lung volume and had a significantly smaller increase in peak Vt during DS. At 60 W, a 50% smaller increase in Vt (P < 0.001) in response to added DS in COPD compared with health was associated with a greater increase in dyspnea intensity (P = 0.0005).

Conclusions: These results show that the respiratory system reached or approached its physiologic limit in mild COPD at a lower peak work rate and ventilation than in healthy participants.

Clinical trial registered with www.clinicaltrials.gov (NCT 00975403).

Scientific Knowledge on the Subject

Variable abnormalities of dynamic respiratory mechanics and ventilatory demand have been identified during exercise in symptomatic patients with mild chronic obstructive pulmonary disease (COPD). It is not known if these factors constitute a true physiologic limit to exercise in this population because traditional estimates of breathing reserve are usually in the normal range.

What This Study Adds to the Field

This study uses selective loading of the respiratory system to determine if ventilatory limitation to exercise exists in mild COPD. The results suggest that the respiratory system reaches its true physiologic limit at a lower peak ventilation and power output in patients with Global Initiative for Chronic Obstructive Lung Disease stage I COPD compared with healthy age-matched participants.

Compared with nonsmoking healthy populations, smokers with milder chronic obstructive pulmonary disease (COPD) show decreased health-related quality of life (13), increased activity-related dyspnea, and reduced physical activity levels (48). The mechanisms of dyspnea and activity restriction in milder COPD are not fully understood.

Increased peripheral airways resistance is the dominant physiologic abnormality of COPD. Cross-sectional population studies have confirmed that vast pathophysiologic heterogeneity can exist in milder COPD (9). It is clear that the presence of apparently minor airflow obstruction (as measured by spirometry) may obscure widespread inflammatory damage to the peripheral airways, lung parenchyma, and its vasculature (10, 11). Previous studies conducted at rest have successfully quantified the extent of small airway dysfunction and pulmonary gas exchange impairment in mild COPD (1214). Reported abnormalities include reduced static lung recoil pressure, maldistribution of ventilation, early airway closure, and increased pulmonary gas-trapping (1214). More recently, it has been shown that these physiologic perturbations are amplified during the stress of cycle exercise (1517). Thus, compared with age-matched healthy control subjects, peak V̇e and exercise capacity were diminished in symptomatic patients with mild COPD (15, 16).

We have proposed that increased ventilatory requirements at any given power output, increased dynamic gas-trapping, and mechanical constraints on Vt expansion may contribute to reduced peak V̇e and V̇o2 in mild COPD. However, it remains unclear whether such factors actually constitute a ventilatory limitation to exercise in this population. Thus, most patients with mild COPD seem to have adequate ventilatory reserve, as traditionally estimated by peak V̇e as a percentage of maximal ventilatory capacity, at the limits of tolerance (15, 16). However, this approach has well-established limitations and may not be useful in patients with mild COPD who have a largely preserved FEV1.

In contrast to the situation in more advanced COPD, selective unloading of the respiratory system using inhaled bronchodilators (with or without inhaled corticosteroids) in mild COPD was not consistently associated with increased submaximal V̇e, decreased dyspnea, or improved exercise tolerance (17, 18). The studies were inconclusive and several possible explanations for the negative results could be considered: the respiratory system does not limit exercise performance in patients with mild COPD in whom leg discomfort is often the dominant exercise-limiting symptom, the level of unloading was insufficient, or exercise intolerance is multifactorial such that unloading the respiratory system stressed another system (e.g., peripheral muscles), which then replaced it as the locus of exercise limitation.

In the current study, we sought to determine if mechanical factors were the proximate limitation to exercise in mild COPD by selectively stressing the respiratory system by adding dead space (DS) to the breathing apparatus. This approach is in accordance with the definition of limitation proposed by Whipp and Pardy (19) as “those factors that actually prevent a particular function from increasing in the face of an increased requirement for ventilation.” Previous studies have shown that added DS during exercise results in significant increases in peak Vt and V̇e and preservation of exercise capacity, at least in younger healthy participants (2022). Brown and coworkers (23) used DS loading to demonstrate that impaired respiratory mechanics was the proximate limitation to exercise in advanced COPD. We reasoned that in mild COPD, the inability to further increase end-inspiratory lung volume (EILV), Vt, and V̇e at standardized work rates and at the peak of exercise in response to DS loading would indicate true respiratory limitation to exercise, particularly in the setting of adequate cardiac reserve. We also postulated that DS loading in the face of such mechanical constraints on Vt expansion would lead to an earlier onset of intolerable dyspnea in COPD but not in health. We therefore compared breathing pattern, operating lung volumes, and dyspnea intensity ratings during incremental cycle exercise with DS loading or unloaded control in patients with mild COPD and age- and sex-matched healthy individuals. Some preliminary results of this study are reported in the form of an abstract (24).

Subjects

Subjects included 20 patients with Global Initiative for Chronic Obstructive Lung Disease stage I COPD (25) and 20 healthy age- and sex-matched participants with no significant smoking history and normal spirometry. Subjects were excluded if they had other medical conditions that could contribute to dyspnea or exercise limitation, or if they had any contraindication to exercise testing.

Study Design

This randomized, controlled, cross-sectional study received ethical approval from the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (DMED-1243-09). After written informed consent, subjects completed three visits scheduled 2–10 days apart at the same time of day. Visit 1 included medical screening; anthropometric measurements; symptom and activity assessments; prebronchodilator and post-bronchodilator (400 μg salbutamol) pulmonary function tests; and a symptom-limited incremental cycle exercise test for familiarization purposes. At visits 2 and 3, pulmonary function tests were followed by an incremental exercise test performed under either control (CTRL) or added DS conditions, in randomized order. Subjects with COPD withdrew short- and long-acting bronchodilators for 6 and 24 hours before visits, respectively.

Subject Characterization

Chronic activity-related dyspnea was assessed with the Baseline Dyspnea Index (26). The Community Healthy Activities Model Program for Seniors questionnaire estimated weekly caloric expenditure (27). Computed tomography (CT) scans of the chest were assessed quantitatively for extent of emphysema by density mask analysis (28). Detailed pulmonary function tests were performed using automated equipment (Vmax229d, Vs62j, and Masterscreen IOS; SensorMedics, Yorba Linda, CA) (2934); measurements were expressed as percentages of predicted normal values (3540).

Cardiopulmonary Exercise Testing

Symptom-limited incremental exercise tests were performed on an electronically braked cycle ergometer (Ergometrics 800S; SensorMedics) using a cardiopulmonary exercise testing system (Vmax229d; SensorMedics) as previously described (15, 41). Tests consisted of a steady-state resting period, a 1-minute warm-up of unloaded pedaling, followed by 2-minute increments of 20 W each. Breath-by-breath measurements were evaluated as 30-second averages at rest; at each work rate; and at peak exercise (the last 30 s of loaded pedaling). Operating lung volumes were derived from inspiratory capacity (IC) measurements at rest, each stage of exercise, and peak exercise (42). Subjects rated their intensity of breathing and leg discomfort at rest, each stage of exercise, and peak exercise with the modified 10-point Borg scale (43); zero represented “no discomfort” and 10 represented “the most severe discomfort they could imagine experiencing.” At end-exercise, subjects verbalized their main reasons for stopping exercise.

Dead Space

An added DS (35-mm plastic tubing) with a volume of 600 ml was inserted between the mouthpiece and a two-way nonrebreathing Hans Rudolph valve. The low resistance breathing circuit was similar to that used in a previous study (22). Although the DS arrangement was not concealed, subjects were naive to the purpose of the DS and gave no indication of being aware of the added DS throughout the experiment. V̇o2 and V̇co2 measurements were not available under DS conditions because the testing system could not accurately correct for the large DS volume used in this study.

Statistical Analysis

A sample size of 20 per group provided 80% power to detect a 1 Borg unit difference between groups in dyspnea intensity at a standardized work rate during incremental cycle exercise, based on a SD of 1 unit, α = 0.05, and a two-tailed test of significance; this also provided at least 80% power for within-group comparisons. Between-group comparisons of subject characteristics were performed using unpaired t tests. A repeated-measures analysis of variance (ANOVA) was performed to evaluate differences between testing conditions (CTRL and DS) for measurements at rest, at standardized work rates, and at peak exercise; the group by condition interaction term in this analysis was used to test if DS-CTRL changes were different between the two groups. Paired t tests were applied to evaluate the DS-induced changes within groups, in particular for those variables with a significant group by condition interaction in the repeated-measures ANOVA. Reasons for stopping exercise were compared using Fisher exact test. Results are reported as means ± SD unless otherwise specified. A P less than 0.05 was used for statistical significance.

Subjects

Subject characteristics are summarized in Table 1. Groups were well matched for age, sex, height, and body mass index. Subjects with COPD were more symptomatic, had reduced physical activity levels and exercise capacity, and had significant pulmonary function abnormalities compared with healthy control subjects. Chest CT scans in 18 of the 20 subjects with COPD revealed 14 ± 8% of the lung as low-attenuation areas using a threshold of −950 Hounsfield units (HU), or 30 ± 10% using a threshold of −910 HU. More details about subjects can be found in the online supplement

TABLE 1. SUBJECT CHARACTERISTICS

 HealthyMild COPD
Male:female, n11:911:9
Age, yr65 ± 868 ± 6
Height, cm167 ± 9166 ± 9
Body mass index, kg/m226.9 ± 2.827.4 ± 6.3
Smoking history, pack-years0.2 ± 0.742.6 ± 21.6*
BDI focal score (0–12)11.4 ± 0.98.7 ± 2.0*
CHAMPS, kcal/wk for all activities5,966 ± 2,9752,535 ± 2,392*
Peak work rate, W (% predicted)162 ± 55 (121 ± 32)92 ± 26* (75 ± 22*)
Peak V̇o2, L/min (% predicted)2.45 ± 0.84 (142 ± 33)1.58 ± 0.45* (100 ± 20*)
o2 at AT, L/min1.29 ± 0.510.94 ± 0.21*
Post-bronchodilator FEV1, L3.12 ± 0.67 (122 ± 11)2.26 ± 0.50* (95 ± 11*)
Post-bronchodilator FEV1/FVC, %77 ± 561 ± 5*
Prebronchodilator pulmonary function (% predicted)  
 FEV1, L2.96 ± 0.72 (117 ± 13)2.08 ± 0.45* (87 ± 11*)
 FEV1/FVC, %74 ± 659 ± 5*
 PEFR, L/s8.61 ± 2.58 (125 ± 24)6.37 ± 1.69* (96 ± 18*)
 FEF25–75%, L/s2.35 ± 1.04 (89 ± 13)0.82 ± 0.29* (33 ± 10*)
 IC, L3.01 ± 0.82 (111 ± 18)2.59 ± 0.62 (99 ± 18*)
 SVC, L4.17 ± 0.92 (116 ± 12)3.70 ± 0.71 (108 ± 14)
 FRC, L2.92 ± 0.63 (93 ± 23)3.48 ± 0.76* (112 ± 20*)
 RV, L1.76 ± 0.44 (83 ± 21)2.38 ± 0.67* (108 ± 29*)
 TLC, L5.93 ± 0.97 (102 ± 13)6.07 ± 1.11 (106 ± 12)
 sRaw, cm H2O·s5.4 ± 2.2 (129 ± 57)10.3 ± 5.1* (243 ± 107*)
 DlCO, ml/min/mm Hg21.5 ± 5.5 (104 ± 17)16.2 ± 4.2* (82 ± 16*)
 MIP, cm H2O90 ± 26 (115 ± 24)76 ± 27 (98 ± 33)
 MVV, L/min127.9 ± 30.783.2 ± 24.9*
 Closing volume, L0.57 ± 0.710.55 ± 0.34
 N2 slope, %/L2.8 ± 1.1 (197 ± 71)5.9 ± 2.2* (406 ± 210*)
 R5, cm H2O/L/s4.1 ± 1.25.1 ± 1.8
 R5-20, cm H2O/L/s12.4 ± 7.225.3 ± 10.1*
 X5, cm H2O/L/s−1.1 ± 0.5−1.8 ± 1.2*
Fres, Hz11.4 ± 3.216.9 ± 4.5*

Definition of abbreviations: AT = anaerobic threshold; BDI = modified Baseline Dyspnea Index; CHAMPS = Community Healthy Activities Model Program for Seniors questionnaire; COPD = chronic obstructive pulmonary disease; DlCO = diffusing capacity of the lung for carbon monoxide; FEF25–75% = forced expiratory flow between 25 and 75% of FVC; FEF50% = forced expiratory flow at 50% of vital capacity; Fres = resonant frequency during impulse oscillometry; IC = inspiratory capacity; MIP = maximal inspiratory pressure; MVV = maximal voluntary ventilation; PEFR = peak expiratory flow rate; R5 = resistance at 5 Hz; R5-20 = difference in resistance between 5 Hz and 20 Hz; RV = residual volume; sRaw = specific airway resistance; SVC = slow vital capacity; X5 = distal capacitive reactance at 5 Hz.

Values are means ± SD. Percentage of predicted normal values are in parentheses.

*P < 0.05 COPD versus healthy group.

P = 0.05 COPD versus healthy group.

Baseline abnormalities in exercise performance in mild COPD were evaluated during the CTRL test. Measurements at peak exercise are shown in Table 2. Compared with healthy control subjects, subjects with COPD showed reduced peak work rate and V̇o2; reduced peak V̇e and Vt; greater ventilatory demands (V̇e-work rate slopes) and ventilatory inefficiency (V̇e/V̇co2); earlier anaerobic threshold; elevated end-expiratory lung volume (EELV) and EILV (in conjunction with reduced IC and inspiratory reserve volume [IRV]) at rest and throughout exercise; and increased exertional dyspnea intensity (see online supplement). Although the distribution of reasons for stopping exercise was not significantly different across groups, 50% of subjects with COPD stopped because of breathing discomfort, either alone or in combination with leg discomfort, whereas leg discomfort was the dominant reason for stopping in 65% of healthy subjects.

TABLE 2. MEASUREMENTS AT PEAK INCREMENTAL CYCLE EXERCISE DURING CONTROL AND ADDED DEAD SPACE CONDITIONS

 HealthyCOPD
 CTRLDSCTRLDS
Exercise duration, min15.9 ± 5.715.2 ± 5.7*8.7 ± 2.67.6 ± 2.7*
Work rate, W162 ± 58158 ± 57*92 ± 2683 ± 28*
Dyspnea, Borg scale6.1 ± 3.25.9 ± 3.35.3 ± 2.16.0 ± 2.4*
Leg discomfort, Borg scale6.8 ± 3.26.4 ± 3.26.1 ± 2.15.8 ± 2.3
Reason for stopping exercise, %    
 Dyspnea1025540*
 Leg discomfort65504010
 Dyspnea + legs20254545
 Other50105
e, L/min (% MVV)95.0 ± 30.9 (73 ± 3)95.8 ± 29.7 (74 ± 10)55.6 ± 16.0 (69 ± 17)58.6 ± 16.1 (73 ± 19)
Heart rate, beats/min (%predicted max)157 ± 15 (90 ± 20)157 ± 13 (90 ± 16)136 ± 19 (82 ± 11)133 ± 20 (81 ± 12)
PetCO2, mm Hg32.2 ± 4.840.5 ± 6.3*33.6 ± 4.541.3 ± 5.2*
SpO2, %94.5 ± 2.993.5 ± 3.494.5 ± 2.193.6 ± 2.6
Fb, breaths/min42 ± 939 ± 7*35 ± 935 ± 7
Vt, L2.26 ± 0.652.47 ± 0.76*1.62 ± 0.411.73 ± 0.51*
Vt/IC, %76 ± 1183 ± 8*68 ± 1172 ± 13
IC, L3.02 ± 0.852.96 ± 0.792.42 ± 0.502.42 ± 0.56
ΔIC peak − rest, L0.10 ± 0.510.18 ± 0.52−0.30 ± 0.43−0.21 ± 0.35
IRV, L0.76 ± 0.420.50 ± 0.24*0.78 ± 0.320.69 ± 0.39
EILV, L (% predicted TLC)5.12 ± 0.89 (88 ± 6)5.35 ± 0.93* (92 ± 4*)5.16 ± 0.84 (90 ± 7)5.26 ± 0.90 (91 ± 8)
EELV, L (% predicted TLC)2.85 ± 0.59 (50 ± 12)2.88 ± 0.55 (50 ± 12)3.54 ± 0.64 (62 ± 8)3.53 ± 0.63 (62 ± 8)
TI, s0.72 ± 0.140.75 ± 0.140.84 ± 0.200.83 ± 0.17
TE, s0.77 ± 0.170.82 ± 0.170.98 ± 0.220.98 ± 0.23
TI/TTOT0.49 ± 0.020.48 ± 0.030.46 ± 0.040.46 ± 0.05
Vt/TI, L/s3.23 ± 1.043.31 ± 0.992.00 ± 0.542.12 ± 0.54
Vt/TE, L/s3.07 ± 1.013.09 ± 1.021.70 ± 0.481.82 ± 0.54

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; CTRL = control; DS = dead space; EELV = end-expiratory lung volume; EILV = end-inspiratory lung volume; Fb = breathing frequency; IC = inspiratory capacity; IRV = inspiratory reserve volume; MVV = maximal voluntary ventilation; PetCO2 = end-tidal carbon dioxide tension; SpO2 = oxygen saturation; TI = inspiratory duration; TE = expiratory duration; TI/TTOT = inspiratory duty cycle; VT/TI = mean inspiratory flow rate; VT/TE = mean expiratory flow rate.

Values are means ± SD.

*P < 0.05 DS vs. CTRL within-group.

P < 0.05 COPD vs. healthy for CTRL test.

P < 0.05 between-group difference in DS-CTRL change by repeated-measures analysis of variance.

Physiologic Effects of Added DS on Exercise

Sequence order was balanced with 10 subjects with COPD and 13 healthy subjects undergoing CTRL testing first. There were no significant sequence effects for any of the main endpoints.

Measurements at peak exercise are summarized in Table 2. With DS compared with CTRL, exercise duration decreased significantly by 0.8 ± 0.7 and 1.0 ± 0.8 minutes, and the attained peak work rate decreased by 9 ± 10 and 10 ± 12 W in the healthy and the COPD groups, respectively (all P < 0.0005). These differences corresponded to a decrease in total cumulative work of 10 ± 8% in the healthy group and 21 ± 14% in the COPD group. By repeated-measures ANOVA, there were no between-group differences in the physiologic responses to DS at peak exercise.

The magnitude of increase in V̇e with added DS was not different between groups at rest or at a given work rate: V̇e increased by 7.6 and 7.4 L/min at rest in the healthy and COPD groups, respectively; and by 9.7–11.3 L/min at work rates up to 60 W (Figure 1). Mean peak V̇e did not increase significantly in either group; however, intersubject variability in the peak V̇e response was large in both groups as indicated by the wide SD (Table 2). Compared with CTRL, breathing with added DS resulted in similar increases in end-tidal carbon dioxide tension (PetCO2) in both groups at rest and throughout exercise (Figure 1). When the ventilatory response to added DS was examined at progressive work rates (44), V̇e/PetCO2 slopes were found to be similar within and between groups at the 20-, 40-, and 60-W loads (Figure 2). The slope of this response at peak exercise was significantly reduced compared with lower work rates within both groups (20–60 W in COPD, 20–100 W in health; P < 0.05) and was not statistically different between groups despite the higher peak V̇e and work rate in the healthy group compared with the COPD group.

The DS-induced increase in V̇e was accomplished by increasing Vt with no significant change in breathing frequency (Fb) (Figure 3). In both health and COPD, the increase in Vt was achieved by increasing EILV and encroaching further on the IRV without changing EELV or IC (Figure 3). In the healthy group, the mean increase in Vt was 0.43 L at rest, 0.56–0.60 L at standardized work rates during exercise, and 0.20 L at peak exercise. In COPD, the mean increase in Vt at rest was similar at 0.41 L, but the increase in Vt during exercise was significantly less than that in the healthy group at 20, 40, and 60 W (P < 0.01) and tapered off progressively with increasing work rate. The smaller Vt response in the COPD group was associated with a smaller IRV throughout exercise: at end-exercise, IRV reached a similarly reduced level in COPD and health but at a significantly lower peak V̇e in the former. During exercise with added DS compared with CTRL, there were no consistent changes in breath timing, whereas inspiratory and expiratory flows increased in direct proportion to increases in V̇e in both groups.

DS had no significant effect on oxygen saturation at rest or at submaximal work rates in either group; however, both groups decreased oxygen saturation at peak exercise by 1 ± 2% (P = 0.05). In health, breathing with added DS had no significant effect on heart rate at rest or at peak exercise, but heart rate increased by approximately three beats per minute at standardized work rates during exercise (only reaching statistical significance at 20 W). Similarly in COPD, added DS did not affect resting or peak heart rate and increased heart rate at submaximal work rates by between 3.8 and 5.2 beats per minute (P < 0.05).

Sensory Consequences of Added DS during Exercise

In the healthy group, the main reasons for stopping exercise were not significantly different between the CTRL and DS conditions. In the COPD group, the proportion of subjects who chose breathing discomfort as the primary reason for stopping exercise increased from 5% in the CTRL test to 40% in the DS test (P < 0.05); this was accompanied by a decrease in the proportion of subjects who chose leg discomfort as the main reasons for stopping exercise (P = 0.06).

There was a significant between-group difference in the magnitude of the dyspnea response to DS at 40 W, 60 W, and peak exercise (P < 0.05). In COPD, added DS did not change dyspnea intensity at rest or at 20 W, but significantly (P < 0.05) increased dyspnea ratings at 40 W, 60 W, and at peak exercise compared with CTRL (Figure 4). In contrast, DS in health had no significant effect on dyspnea intensity ratings at these lower work rates (20–60 W) or at peak exercise, but resulted in a small increase in dyspnea intensity at intermediate work rates. Dyspnea/V̇E plots did not change significantly in response to DS in either group (Figure 4).

The main findings of this study were as follows: (1) we confirmed that patients with mild COPD had greater respiratory impairment, lower peak V̇e, and greater dyspnea and exercise intolerance than age-matched healthy control subjects; (2) on average, selective stress on the respiratory system by adding DS was associated with small decreases in peak work rate and exercise duration with no significant increase in peak V̇e in both health and COPD; (3) critical mechanical constraints on Vt expansion were present at a relatively lower peak work in COPD in contrast to health, such that Vt increases during DS loading were significantly less in COPD; and (4) added DS was associated with greater increases in dyspnea intensity ratings at lower work rates in COPD compared with health.

Our patients met Global Initiative for Chronic Obstructive Lung Disease stage I spirometric criteria for COPD and reported greater chronic dyspnea and reduced daily activity levels compared with age- and sex-matched healthy control subjects. Thirteen subjects had a previous diagnosis of COPD and 60% of the sample was already receiving regular medications for perceived breathing difficulty. Despite the largely preserved FEV1, there was evidence of significant peripheral airway obstruction and CT scans confirmed minor structural emphysema in the majority.

Cardiopulmonary Exercise Test Responses in Mild COPD

Consistent with the results of recent studies, patients with COPD reported severe dyspnea and leg discomfort at a lower peak work rate than in health. Ventilatory requirements were increased, EELV and EILV were consistently elevated, and peak Vt and V̇e were significantly diminished. The cause of the increased ventilatory demand remains uncertain: V̇e/V̇co2 was slightly but consistently elevated compared with health at standardized work rates, suggesting reduced efficiency of CO2 elimination because of higher physiologic DS or alterations in the central respiratory controller. Gagnon and coworkers (45) recently showed that during cycle exercise in patients with advanced COPD, spinal anesthesia with an intrathecal infusion of fentanyl was associated with a reduction in V̇e/V̇co2, presumably by interrupting afferent inputs from Type III and IV receptors in the active locomotor muscles. The extent to which this mechanism contributed to the higher V̇e/V̇co2 in our patients with mild COPD could not be determined. Compared with the healthy group, our subjects with COPD had significantly lower anaerobic thresholds, and greater heart rates and perceived leg discomfort at submaximal work rates. Collectively, these results suggest that the less active patients with COPD were more likely to be deconditioned. However, formal assessment of cardiac function and systemic oxygen delivery is required to determine if associated acid-base disturbances stimulated ventilation in this group.

The question arises whether the combination of increased ventilatory demand and dynamic mechanical abnormalities outlined previously resulted in actual ventilatory limitation to exercise in our patients. A peak V̇e of 69% of maximum voluntary ventilation (MVV) suggests a normal breathing reserve but is not a measure of ventilatory limitation per se (46). The finding that the Vt/IC ratio reached 68% and that EILV reached 90% predicted TLC at a peak V̇e of only 56 L/min (in the presence of adequate cardiac reserve) suggests that mechanical factors or the associated severe respiratory discomfort could have limited (or opposed) further increases in V̇e to support a higher peak work rate.

Effect of DS Loading

Most studies that have examined the effects of DS loading were conducted in young, untrained, healthy individuals and have concluded that ventilatory limitation does not normally contribute to exercise limitation: peak V̇e (and Vt) increased and peak work rate was similar to unloaded control (2022). In contrast, ventilatory constraints are more likely to contribute to exercise limitation in athletic young or older individuals who are able to achieve high peak work rates (44, 47, 48). In our healthy older participants at end-exercise, peak V̇o2 and power output was normal or greater than normal; cardiovascular limits were reached or approached (peak heart rate was 90% predicted, on average); and estimated breathing reserve averaged 27% (V̇e/MVV was 73%). Important respiratory mechanical constraints at peak exercise in these subjects included an inability to decrease EELV and an EILV reaching 87% of TLC. Consistent with the results of a previous study in older healthy individuals (49), average peak V̇e was not significantly increased by added DS despite increases in Vt and EILV, and mean peak power output was modestly but significantly reduced. It is noteworthy that healthy individuals did not develop a compensatory tachypnea to maintain peak V̇e under DS loading for reasons that are not clear. Collectively, our results provide evidence that in healthy older individuals, the cardiac and respiratory systems had reached or approached their physiologic limits at end-exercise under control conditions.

The effect of DS loading in mild COPD was in the same direction as in health: average peak V̇e did not increase significantly and peak power output decreased significantly. However, ventilatory limitation occurred at a substantially lower power output and V̇e in this group. At the highest equivalent work rate completed by both groups (when peak V̇e was 56 L/min in COPD), the increases in Vt during DS loading were smaller in COPD and were significantly decreased compared with health (Figure 3). These results confirm that the respiratory system reached or approached its physiologic limit in COPD under unloaded conditions at a lower peak work rate and in the presence of adequate cardiac reserve.

When the ventilatory response to added DS was examined in the manner proposed by McClaran and coworkers (44), V̇e/PetCO2 slopes were found to be similar within and between groups at comparable submaximal work rates (Figure 2). However, V̇e/PetCO2 slopes were significantly reduced at peak exercise in both groups and were not different between groups despite the lower peak V̇e and work rate in the COPD group. These results indicate that the respiratory system and its central controller adequately fulfilled its primary task of CO2 elimination during exercise in mild COPD, albeit at the expense of greater mechanical constraints and dyspnea at relatively lower V̇e in the COPD group.

Sensory Effects of DS Loading during Exercise

Dyspnea intensity ratings were greater at any given work rate and V̇e in mild COPD than in health, likely as a result of the combination of heightened ventilatory requirements and the presence of greater respiratory mechanical abnormalities, both of which are associated with increased contractile respiratory muscle effort (50). Of interest, DS loading was associated with consistently higher dyspnea ratings at standardized work rates during exercise in the COPD group and this symptom became more likely to be selected as the dominant exercise-limiting symptom by this group. The greater increase in dyspnea at lower submaximal work rates in COPD than in health with added DS is explained by the steeper dyspnea-V̇e relation in the former. This steeper slope, in turn, reflects the greater mechanical derangements that exist in mild COPD.

In both groups, participants stopped exercising when Vt expanded to reach a critically reduced IRV of approximately 10% TLC during CTRL and DS conditions. However, with the increased chemical stimulation, this mechanical limit was reached at a lower work rate, particularly in COPD where it was linked to an earlier rise in dyspnea to severe levels. These data support our previous contention that critical limits of Vt expansion at the minimal IRV are more important in determining the rise of dyspnea during exercise than increases in EELV (decreases in IC) per se (51).

Several experimental studies in health have shown that perceived dyspnea (or “air hunger”) rises sharply if the normal Vt response is restricted, either voluntarily or by external imposition, in the setting of an increased ventilatory drive to breathe (22, 52, 53). For example, when the normal Vt increase was restricted by chest wall strapping during exercise in healthy participants, imposition of the DS resulted in earlier exercise termination, compared with the unrestricted condition, because of a steeper rise in dyspnea to intolerable levels (22). We believe that similar mechanisms are at play in our patients with mild COPD at higher exercise levels. Thus, the widening disparity between increased central neural drive (sensed by increased central corollary discharge), likely amplified by metabolic acidosis, and the limited volume displacement of the respiratory system (sensed by multiple mechanoreceptors) may also form the basis for the increased respiratory discomfort during DS loading in COPD (50).

Limitations

Groups could not be matched for fitness levels at study entry and our healthy control subjects were generally more active than patients with COPD. Thus, we cannot exclude the possibility that deconditioning could have contributed to ventilatory limitation in some COPD volunteers. We used a standardized DS of 0.6 L in all participants knowing that individual ventilatory responses vary with lung size. However, average V̇e increased during submaximal exercise to a similar extent in both groups, indicating a comparable physiologic stress with DS loading. Moreover, the main outcome of interest was within-subject effects of DS loading on physiologic and sensory parameters in groups that were carefully matched for age and sex. Participants were not masked to the DS intervention but were naive to the specific purpose of the experiments. Breathing pattern responses during DS were remarkably consistent throughout exercise in all participants, making the possibility of nonphysiologic alterations in breathing pattern because of awareness of additional tubing in the circuit less likely. The lack of measurements of V̇co2 and arterial Pco2 during the DS condition meant that we were unable to assess ventilatory efficiency.

Conclusions

Although older healthy individuals reached a peak V̇o2 that was at or above the predicted level, evidence of ventilatory and cardiac limitation was present at the limits of tolerance. By contrast, at a significantly lower peak power output and V̇e in the COPD group, the respiratory system had reached or approached its physiologic limit, in the setting of adequate cardiac reserve. Although responses to DS loading were qualitatively similar in both groups, critical mechanical constraints or limitation and greater breathing discomfort occurred at a much lower V̇e in the COPD group.

We propose that the troublesome chronic dyspnea and reduced daily activity levels reported by our mild COPD group is related, in part, to the abnormal respiratory mechanics and higher ventilatory demand associated with physical work in this group. Thus, the largely preserved FEV1 and normal breathing reserve (MVV-peak V̇e) as conventionally derived underestimated significant dynamic mechanical constraints to increasing ventilation during exercise. Our results set the stage for further studies designed to evaluate the impact of combined interventions that improve respiratory mechanics (e.g., bronchodilators) and reduce ventilatory demand (e.g., exercise training) in patients with mild COPD who report persistent activity-related dyspnea.

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Correspondence and requests for reprints should be addressed to Denis E. O’Donnell, M.D., 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail:

Supported by the William Spear/Richard Start Endowment Fund, Queen’s University, and the Ontario Thoracic Society. R.C.C. was supported by the Queen’s Graduate Award and the Queen Elizabeth II Graduate Scholarship in Science and Technology. J.A.G. was supported by postdoctoral fellowships from the Natural Sciences and Engineering Research Council of Canada, the Canadian Thoracic Society, and the Canadian Lung Association.

Author Contributions: All authors played a role in the content and writing of the manuscript. D.E.O.’D. was the principal investigator and contributed the original idea for the study. D.E.O.’D. and K.A.W. had input into the study design and conduct of study. R.C.C., J.A.G., S.C., N.R., N.A., and A.C.-T. collected the data. R.C.C., J.A.G., and K.A.W. performed data analysis and prepared it for presentation.

Originally Published in Press as DOI: 10.1164/rccm.201211-1970OC on April 12, 2013

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