The Role of Cardiopulmonary Exercise Testing (CPET) in Pulmonary Rehabilitation (PR) of Chronic Obstructive Pulmonary Disease (COPD) Patients

Abstract

Chronic obstructive pulmonary disease (COPD) is a common multisystem inflammatory disease with ramifications involving essentially all organ systems. Pulmonary rehabilitation is a comprehensive program designed to prevent and mitigate these disparate systemic effects and improve patient quality of life, functional status, and social functioning. Although initial patient assessment is a prominent component of any pulmonary rehabilitation (PR) program, cardiopulmonary exercise testing (CPET) is not regularly performed as a screening physiologic test prior to PR in COPD patients. Further, CPET is not often used to assess or document the improvement in exercise capacity related to completion of PR. In this review we will describe the classic physiologic abnormalities related to COPD on CPET parameters, the role of CPET in Risk Stratification/Safety prior to PR, the physiologic changes that occur in CPET parameters with PR, and the literature regarding the use of CPET to assess PR results. Finally, we will compare CPET to 6MW in COPD PR, the common minimal clinically important difference (MCID) is associated with CPET, and the potential future roles of CPET in PR and Research.

Keywords:

• Chronic obstructive pulmonary disease
• cardiopulmonary exercise testing
• pulmonary rehabilitation

COPD is a multisystem inflammatory disease

According to the Center for Disease Control (CDC), COPD is now the third leading cause of death in the United States with 15.7 million individuals that have been diagnosed with COPD. Cigarette smoking causes inflammatory changes in all systems of the body, resulting in a spectrum of cardiovascular and lung diseases, metabolic diseases such as diabetes and metabolic syndrome, osteoporosis, depression, reduced physical activity, and skeletal muscle weakness/cachexia. Figure 1 displays the pleotropic effects of cigarette smoke, as well as the longer-term manifestations in COPD.

Figure 1 Patients with COPD have lung inflammation that affects all organs of the body. Reproduced with permission from Boschetto et al. (38) (License Number: 4467500227437, License date Nov 14, 2018. Licensed Content Publisher: John Wiley and Sons. Licensed Content Publication: Respirology)

The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have adopted the following definition of Pulmonary Rehabilitation (PR):

“Pulmonary Rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviors” (1).

PR is one of many interventions targeted to improve the lives of patients with COPD, including education, self-management, smoking cessation, and integrated care (Figure 2).

Figure 2 The spectrum of support available for patients with COPD. Reproduced with permission from Spruit et al. (1). Reprinted with permission of the American Thoracic Society. Copyright© 2018 American Thoracic Society (1). The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

What does the physiology of COPD exercise limitation look like in CPET?

What pathophysiologic mechanisms limit exercise in patients with COPD as assessed by CPET? A normal sized adult walking at a moderate pace on a flat surface requires approximately 1 L/min of oxygen uptake. At this walking rate there is very little lactate generation, dyspnea, or muscle fatigue (2), and an individual is able to sustain this activity nearly without limitation. However, in a patient with COPD (Figure 3) there are three important pathophysiologic processes

Figure 3 Pathophysiology of exercise impairment in COPD. The three most important mechanisms of exercise limitation in COPD are (1) Gas Exchange Inefficiency, (2) Muscle Deconditioning and (3) Dynamic Hyperinflation. Adapted from Wasserman et al. (54)

1. gas exchange inefficiency of the lung,

2. deconditioning of the muscle, and

3. dynamic hyperinflation.

With regards to gas exchange inefficiency, COPD patients display various combinations of hypoxia, hypercapnia, acidosis, and mismatching the ventilation to perfusion (VA/Q) with increased dead space to tidal volume ratio (V_D/V_T), all resulting in increased ventilatory requirements. The COPD patient is also prone to muscle fatigue, has diminished blood flow, reduced aerobic ATP generation, excess lactic acidosis, and additional CO₂ load from bicarbonate buffering of the excess lactate. Finally, the process of dynamic hyperinflation causes increased work of breathing, high airway resistances, airflow obstruction, increased dead space ventilation, and decreased elastic recoil all reducing the ability of the COPD patient to deliver and meet the required ventilatory capacity for the work rate. Therefore, the combination of inefficient gas exchange, muscle deconditioning, and progressive failure of the ventilatory pump attributable to dynamic hyperinflation produces marked exercise limitation and progressive dyspnea during exercise (3).

Bearing these important pathophysiological processes in mind, let’s examine a typical individual CPET response to exercise in a COPD patient (age 57, height 174 cm, weight 73.6 km, BMI 24.4) with severe obstruction in resting spirometry (Figure 4).

Figure 4 Pre- and Post-Bronchodilator spirometry of a patient with severe COPD. Pre/Post Bronchodilator responses indicating severe (0.94 L, 30% of predicted) reduction in FEV₁ and a very low FEV₁/FVC (35%). There is a bronchodilator response that meets ATS/ERS criteria (>12% and 200 mL in either FEV₁ or FVC). Further lung function results were: The total lung capacity (TLC) is normal (6.57 L or 96% predicted) and the diffusing capacity for carbon monoxide (DLco) is 107 mL/min/mmHg or 37% of predicted (not shown). Reference values for spirometry were according to Hankinson (55), for the lung volumes were according to the ECSC (56) and for the diffusion capacity by Miller et al. (57). Reprinted with permission of the American Thoracic Society. Copyright© 2018 American Thoracic Society (57). American Review of Respiratory Disease is an official journal of the American Thoracic Society.

The CPET results for this patient are graphically shown in Figure 5. The patient performed a 5 W/min ramp pattern exercise on a cycle ergometer to the limit of tolerance. The patient has a reduced peak oxygen uptake (∼1.1 L/min) and severely reduced exercise capacity (60 w of work on a cycle ergometer). His peak ventilation is 38.5 L/min and his predicted MVV from PFTs is ∼42 L/min. Therefore, he reaches a very high percentage (>90%) of his predicted peak ventilation during exercise and his breathing reserve is well less than 14 L/min, all suggesting ventilatory limitation. Further, the inspiratory capacity falls during exercise consistent with dynamic hyperinflation. There is significant oxygen desaturation, the ventilatory equivalents for oxygen and carbon dioxide are elevated (∼32) and the patient has baseline hypercapnia that worsens with exercise, again suggesting severe ventilatory limitation. Using transcutaneously determined arterialized capillary pCO₂ to estimate V_D/V_T, it is well above 0.3 throughout exercise (∼0.42). The lactic acidosis threshold, O₂ pulse, and heart rate response suggest that the exercise is not cardiovascular limited. The blood pressure response to exercise is slightly exuberate at peak exercise (200/100 mmHg).

Figure 5 Progressive ramp-incremental test on the cycle ergometer on a patient with severe COPD and dynamic hyperinflation. Panel 1 (top left), is oxygen uptake (VO₂), carbon dioxide output (VCO₂), and work rate as a function of time (3 min of rest, 3 min of unloaded cycling, and 12 min of exercise with 5 W/min increments, followed by 2 min of recovery). Panel 2 (top middle), is heart rate and oxygen pulse (O₂P) as a function of time. Panel 3 (top right), is heart rate and VCO₂ as a function of VO₂. This panel is used to identify the lactic acidosis threshold using the V-slope method (58) (in this example, approximately 0.85 L/min). Panel 4 (middle left), ventilatory equivalents for oxygen (V_E/VO₂) and carbon dioxide (V_E/VCO₂) as well as the V_D/V_T (calculated using the transcutaneously determined PaCO₂) are displayed. The left y axis is the ventilatory equivalents and the right y axis is the transcutaneous V_D/V_T (VDVTc, green filled circles). V_D/V_T is markedly elevated throughout exercise with a nadir of 0.44. In panel 5 (center graph), the ventilation and blood pressures are displayed. The patient had an end-exercise blood pressure of 200/100 mmHg. In panel 6 (middle, right), ventilation as a function of VCO₂ is displayed. The VE/VCO₂ slope is approximately 26 L/min. Panel 7 (bottom left) displays the end tidal oxygen (PETO₂), carbon dioxide (PETCO₂), the oxygen saturation (Sat), and the transcutaneous pCO₂ (TcPCO₂). End tidal and transcutaneous CO₂ are markedly elevated in this graph (56 and 48 mmHg, respectively). Oxygen saturation was progressively decreasing during exercise to a nadir of ∼85%. Panel 8 (bottom center), is the respiratory exchange ratio (RER) as a function of time. Panel 9 (bottom right), displays inspiratory capacity (golden stars) falling as a function of increasing ventilation. As such respiratory rate increases to almost 40 at end exercise with a tidal volume that does not exceed 1 liter. Finally, the exercise ventilation is essentially the MVV from 40 X FEV₁.

Comparing the flow volume loops during exercise (Figure 6) in the same COPD patient as Figure 5 during progressive exercise, we see that at rest severe airflow obstruction is present (blue outline showing the resting flow volume loop). However, the superimposed tidal breathing (red lines) early in exercise are at a slightly increased Functional Reserve Capacity (FRC). As exercise progresses, the tidal breathing loops move progressively towards Total Lung Capacity (TLC) and end-expiratory lung volume (EELV) increases resulting in progressive loss of inspiratory capacity. These changes all suggest dynamic hyperinflation as a significant contributor to exercise limitation in this patient. Interventions that reduce dynamic hyperinflation, reduce ventilatory requirements, improve gas exchange, and/or reduce muscle fatigue/deconditioning should improve the functional status of this patient. All of these physiologic goals are addressed in pulmonary rehabilitation (PR) (4). It has been shown that a substantial increase in exercise endurance is associated with a decrease in dynamic hyperinflation as a response to dynamic exercise training (5).

Figure 6 Dynamic hyperinflation during progressive exercise in a patient with COPD. This patient is the same patient as Figures 4 and 5. Panel 1 (early exercise) The flow volume loop (red line) compared to the resting flow volume loop (blue line). Total lung capacity (TLC) is on the left, residual volume (RV) is on the right. Panel 2 (mid exercise) The flow volume loops have moved to the left (towards TLC) consistent with dynamic hyperinflation. Panel 3 (peak exercise) The entire flow volume loop is shifted leftward with a marked reduction in expiratory flow compared to inspiratory flow. Of note, both the peak spontaneous expiratory and inspiratory flow rates at peak exercise approach that were obtained pre-exercise during the resting spirometry. All of these changes begin to resolve in early recovery (panel 4).

Analysis of morphological changes of the flow volume loops during exercise in COPD

Porszasz et al. have invented an ingenious method for analyzing the flow volume wave forms during cardio-pulmonary exercise testing (6, 7). This method involves assessing the rectangular area ratio (RAR) of each breath during a CPET. For a rectangular box, a line from the top left to the bottom right would yield an area ratio of 0.5 on each side of the line. A person without flow limitation has an RAR of about 0.6 at rest and during exercise this value approximates 0.8, whereas those with progressive airflow limitation, this ratio falls very often below 0.5, indicating that the expiratory flow-volume curve became concave. The phenomenon has been shown to be associated with dynamic hyperinflation (7) and that this improves with bronchodilation therapy; at the same time, exercise endurance improves (8). In Figure 7 (same patient as Figures 4, 5, and 6) the RAR is below 0.5 even during rest, suggesting that the expiratory flow/volume curve is concave. More importantly, during exercise RAR falls further below 0.4 and stays very low even during recovery. RAR values have been shown to be responsive to pharmacologic bronchodilator therapy by improving RAR during constant work rate exercise, presumably by reducing dynamic hyperinflation (8).

Figure 7 Breath-by-breath representation of the dynamic changes in the rectangular area ratio (RAR) during exercise. At the start of ramp pattern exercise in the same patient as in Figures 4, 5, and 6, the RAR value is consistently <0.5 even at rest. However, as exercise progresses it falls below 0.4, indicating severe airflow obstruction that is associated with dynamic hyperinflation (decreased inspiratory capacity and increasing end expiratory lung volumes, EELV) (compare with Figures 5 and 6).

What is the role of CPET in COPD pulmonary rehabilitation?

Detailed physiologic assessment

Moving from an individual CPET response in COPD to the role of CPET in PR, clinicians must identify where CPET adds important clinical information to the patient assessment at the start and end of PR. PR should be considered in a COPD patient experiencing marked symptoms of dyspnea, exercise limitation, reduction in activities of daily living/inactivity, reduced quality of life, recent COPD exacerbation, deconditioning, increased healthcare utilization, or loss of lean body mass/cachexia (1, 9–20). PR assessment is a comprehensive examination of a broad range of domains, including physical functioning, psychological, pharmaceutical, pulmonary function, dietary, psychosocial, smoking status, and current social functioning.

This review will focus on the physiologic assessment of the patient using exercise testing (CPET) pre/post PR. Traditionally, most PR programs have used the six-minute walk (6MW) as the physiologic assessment of choice (21, 22). In fact, 6MW distance at the start of PR does predict subsequent mortality (23), however, the average change in 6MW distance pre/post PR is only 43.9 m according to a recent Cochrane review (24).

Although 6MW gives a very limited assessment of the exercise performance pre/post exercise testing, CPET is much more comprehensive with respect to interrogating the cardiac (heart rate, peak oxygen uptake, lactic acidosis threshold, oxygen pulse, 12 lead ECG), pulmonary (ventilation as compared to MVV, inspiratory capacity, pulmonary gas exchange, saturation, dynamic hyperinflation, flow volume loops), muscle (power, lactic acidosis), perception of dyspnea (BORG Scores for shortness of breath and leg discomfort), and overall motivational function during exercise. CPET also allows for the objective evaluation of the integration of these important functions.

When CPET has been carefully studied in research settings pre/post rehabilitation (25) the authors found that high intensity interval cycle ergometer training for 6 weeks resulted in marked reductions in lactate values (31%), minute ventilation (15%), ventilatory equivalent for oxygen (12%), heart rate (8%), oxygen uptake (6%), and carbon dioxide output (11%) at the same exercise intensity. In addition, these variable changes were even more marked when high intensity exercise was compared to lower intensity PR training (Figure 8).

Figure 8 Changes in physiologic responses to identical exercise tasks induced by two different intensity training strategies in patients with COPD (high and low work rate training). Original Legend to Figure: Changes in physiologic responses to an identical exercise task (high constant work rate test0 produced by two exercise training strategies in patients with COPD. Left panel. High work rate training group (n = 11) Right panel. Low work rate training group (n = 8). Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society (25). American Review of Respiratory Disease is an official journal of the American Thoracic Society.

The changes observed in oxygen uptake, work rate, ventilation, ventilatory equivalents, heart rate, and V_D/V_T are displayed in Table 1. In general, using ramp pattern exercise to assess physiological changes pre/post PR, the oxygen uptake, work rate, and ventilation increase by about 10 to 36% with a slightly less increase in heart rate (6%). Comparing isotime values on ramp exercise pre/post PR (all at 40 W), there is indistinguishable change in oxygen uptake, however ventilation, ventilatory equivalents, heart rate and V_D/V_T all decrease after PR. During constant work rate testing (all at 32 W, ∼80% of peak exercise) pre/post PR identical oxygen uptakes are observed, however ventilation, ventilatory equivalents, heart rate and V_D/V_T all decrease post PR.

In a follow up study by Casaburi, et al. regarding CPET and PR (47) designed to look at high intensity exercise training (6 weeks of PR) on progressively increasing cycle ergometry exercise and constant work rate cycle exercise in patients with severe airflow obstruction (FEV₁ ∼1 L or ∼35% predicted), identical work rates (40 W on the ramp, 32 W for the constant work rate), the V_D/V_T (using pCO₂ from arterialized capillary blood in calculation) decreased from 0.54 ± 0.007 pre PR to 0.47 ± 0.007 post PR on the incremental test and from 0.53 ± 0.007 to 0.46 ± 0.007 on the constant work rate testing, a 13% change. This change in V_D/V_T was likely related to a slower respiratory rate (33 ± 7 vs 27 ± 6) and a larger tidal volume pattern (0.99 ± 0.30 vs 1.10 ± 0.31) as well as improvements in pulmonary blood flow (less Zone I lung from dynamic hyperinflation) (26). All of these changes improve pulmonary gas exchange during exercise.

Table 1. CPET variables on cycle ergometry that change with careful study of pulmonary rehabilitation (PR) data from Casaburi (25, 47) and Emtner (27).

CPET variable	Ramp peak value (Absolute pre/post value & % change)	Ramp isotime change (%)	Constant work rate isotime change (%)
VO2 (L/min)	0.86 to 1.0 (16% ⇑)	0.86 to 0.85 (0%)	0.86 to 0.87 (0%)
Work rate (W)	40 to 54 (35% ⇑)	(Assessed at 40 W)	(Assessed at 32 W)
VE (L/min)	33 to 36 (10% ⇑)	33 to 30 (9% ⇓)	32 to 29 (9% ⇓)
VE/VCO2 Ratio	NA	38 to 35 (8% ⇓)	40 to 35 (13% ⇓)
VE/VO2 Ratio	NA	38 to 34 (11% ⇓)	39 to 35 (10% ⇓)
Heart rate (bpm)	131 to 139 (6% ⇓)	131 to 127 (5% ⇓)	132 to 124 (6% ⇓)
VD/VT	NA	0.54 to 0.47 (13% ⇓)	0.53 to 0.46 (13% ⇓)
Endurance (min)	(1) On room air PR, endurance time at a constant work rate (32 W) increased from 5.8 minutes to 10.2 min (175%) (47) (2) Air vs. oxygen training in PR changed increased endurance time by 10.9 min (5.8 to 16.7 min, air, 287%) and 14.8 min (6.6 to 21.4 min, oxygen, 324%) (27) (3) High intensity PR (60% of the delta between AT and peak VO2, 66 W) vs low intensity PR (90% of the AT, 34 W) when examined at the high intensity WR resulted in an increase of 4.8 min (6.6 to 11.4 min, 172%), vs. 0.6 min (6.9 to 7.5 min, 109%). When the same groups were examined at the lower constant work rate (90% of the AT), the high intensity PR increased their time from 12.8 to 14.9, vs the low intensity group 13.4 to 15 min (25)

Oxygen supplementation in general allowed a greater increase in training work rate, a better increase in maximal exercise tolerance and more pronounced changes in physiological variables with a more dramatic change in exercise endurance tested at the same work rate pre- and post-training (27). Interestingly, in the same study, there was a dramatic improvement in dynamic hyperinflation (5).

A recent review by Puente-Maestu et al. evaluating the interventional efficacy of various exercise tests, demonstrated that ramp type CPETs in COPD patients post PR demonstrated a modest increase in peak VO₂ of 0.1 to 0.5 L/min, or about 10–40% of baseline, with a mean improvement of ∼11%. The mean change in peak work rate in watts (W) was 6.8 W from PR, and that the MCID for peak work rate was 4 W (28).

In the same review, when constant work rate exercise testing (CWRET) based upon the initial ramp pattern CPET was evaluated pre/post rehabilitation at intensities of 75–80% of incremental peak work rate (WR_peak), the improvements in the limit of tolerance (t_lim, 10 studies of PR) ranges from 100 to 700 s, with a mean increase of ∼350 s or ∼100% increase from the pre PR baseline. Obviously, this change on the constant work rate cycle test is much more dramatic than peak VO₂ or peak WR from a ramp pattern test. Puente-Maestu also demonstrates that PR is a more beneficial nonpharmacological intervention in COPD patients than Heliox, Oxygen, or Non-Invasive Ventilation during exercise, and that the mean MCID thresholds for CWRET is an improvement of 105 s or 33% from baseline pre-PR (28).

Cardiopulmonary exercise testing and pulmonary rehabilitation: safety, risk stratification, and exercise intensity

In their clinical therapeutics article, Casaburi and ZuWallack (4) stated the following regarding evaluation of the potential patient for PR prior to enrollment: “stress test for cardiovascular evaluation, perhaps in the form of a cardiopulmonary exercise test, should be performed.” (4) CPET is preferred compared to PFTs and 6MWT as the degree of organ dysfunction assessment across multiple domains is superior. Current guidelines recommend (29) CPET as it “provides valuable information before exercise training to determine safety and to optimize training intensity.” (18, 30) Guidelines and thought leaders in COPD PR strongly recommend a complete physiologic assessment of the patient pre/post PR using CPET for safety reasons alone, separate from the substantial and important physiologic information.

What is the physiologic effect of exercise training on exercise capacity as assessed by CPET?

Limb muscle dysfunction is an important systemic consequence of COPD and PR can have an important positive effect on muscle biology (Figure 9). Exercise rehabilitation in a COPD Pulmonary Rehabilitation program improves muscle function in the exercising limb as well as the morphology of the muscle (11, 31–33).

Figure 9 Morphological and structural alterations reported in limb muscles in patient with COPD. Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society. Maltais et al. (11).

Specifically, with regards to the effect of PR on the exercising limbs with aerobic exercise training, muscle fibers can be divided into slow (S or Type I) and fast (F or Type II) types. Fast twitch fibers can be low (FF, high glycolytic) or high fatigue resistant (FR, high oxidative potential). PR causes Type IIb fibers (fast twitch, glycolytic, low oxidative potential, FF) to undergo structural and biochemical changes to more closely mirror Type IIa fibers (fast twitch, glycolytic, higher capacity for oxidative metabolism, FR) (34). Positive effects in Type I fibers (slow twitch, oxidative muscle fibers) are also observed (11, 35). These changes combine to reduce the amount of lactic acid produced at any particular exercise intensity and allow more exercise to be performed prior to ventilatory limitation and dynamic hyperinflation.

The relative benefits and disadvantages of CPET (either cycle or treadmill) versus six minute walk (6MW) in PR are expressed in Table 2. Although 6MW is frequently used as the initial (and final) assessment of exercise tolerance in PR, it suffers from not having much physiologic data to isolate the specific organ system limiting exercise performance. In addition, the safety level of a patient exercising in a controlled laboratory (treadmill or cycle) is superior to a 6MW done in a corridor. Finally, CPET can provide additional data for customizing the PR program to the patient at hand. With regards to 6MW, it is advantageous in that it is easy to explain, does not require sophisticated equipment, and walking may be more real world than a cycle ergometer test. However, 6MW has no measurements beyond heart rate and pulse oximetry, just lately, the pulse oximetry is supported by devices that can record it, but unless these devices are being used, both heart rate measurement and pulse oximetry are done prior and after the test, or sporadically if the personnel reads off the display of the device. Unless the laboratory utilizes a portable gas exchange device (e.g., COSMED or OXYCON), there is no measurement of gas exchange, ventilation, EKG or inspiratory capacities to assess dynamic hyperinflation. Finally, provider supervision is optimal for CPET and is rarely provided for 6MW.

Table 2. CPET vs 6MW in COPD PR—pro/con table.

	CPET (cycle or treadmill)	6MW
Pro	Systematic and Integrated Assessment of All Organ Systems involved in Exercise Excellent Safety Test Prior to PR Allows a custom exercise program to be designed around the patient	Easy to explain and perform Minimal equipment required More “Real World” than Cycling
Con	Sophisticated equipment required. Substantial technician and supplies required Requires a physician to staff	No real time EKG monitoring for arrhythmias or ischemia unless portable telemetry equipment utilized. Most Likely Submaximal Evaluation No Gas Exchange unless a portable gas exchange system utilized.

Many studies have focused on the minimal clinically important difference (MCID), i.e., how large an effect is required to be perceptible and important to the patient (28, 36, 37). Some of the important values regarding physiologic testing, 6MW, and CPET are summarized in Table 3. These assessments/measurements/physiologic testing should be considered important patient centered outcomes in the design of any PR intervention.

Table 3. Minimal clinically important differences, MCID for CPET and PR

Measurement	MCID (Improvement)
Lung function—Trough FEV1	100 ml (48)
Dyspnea evaluation TDI UCSD SOBQ	1 unit (49) 5 units (50)
Health Status–SGRQ	4 units (51)
Exercise capacity 6MWD (Severe COPD) Ramp pattern exercise test Constant Work Rate Cycle	26 ± 2 m (52) 4 W (28) Tlim 105 s or 33% increase (53)
Dyspnea during exercise tests Borg VAS	1 unit (52) 10–20 units (50)

Minimal clinically important difference (MCIDs) values in various domains of PR evaluation. Adopted from Jones et al (2014) (36).

Future role of CPET in COPD PR and research

What does the future hold for PR and CPET? The authors envision more PR programs routinely adopting CPET since it is a more sophisticated, comprehensive, and definitive method to physiologically assess the patient prior to and after PR. 6MWT is not sensitive to the important physiologic changes that occur with PR, nor can it detect safety issues such as ischemia, arrhythmias, or desaturation, all common to smokers with heart and lung disease prior to an intensive PR program (38). It is important to acknowledge that to a certain extent, CPET and the 6MWT may complement each other and both can meaningfully inform PR programs for the benefit of patients. However, we must emphasize that the 6MWT is self-paced, therefore is not a maximal test and because of the very restricted instrumentation, it does not provide information about physiological changes usually characteristic for the effect of exercise training that is part of PR. Rather, other than being informative about the habitual walking intensity, it does not provide specific information about the physiological mechanisms limiting exercise.

With regards to research, the important questions regarding CPET and PR involve the mechanisms of improvement in functional capacity (lungs, muscles, motivation, etc.) when pulmonary function remains essentially unchanged pre/post PR. If these mechanisms of exercise improvement can be illuminated, they can potentially be augmented and specifically targeted for improvement, either through combining PR with pharmacologic therapy, or by intensifying the effect of PR during the program to achieve improved outcomes from the exercise performed (12, 39–42). Indeed, as regenerative medicine moves forward (43–46), CPET is the ideal assessment mechanism to document physiologic improvement (including the organ system(s) responsible) in COPD patients undergoing exercise therapy (PR) after regenerative interventions.

Conflict of interest

Dr. Stringer reports grants from AstraZeneca, Boehringer-Ingelheim, Astellas, other support from Allergan-Syneos, Wolters Kluwer - Lippincott Williams & Wilkins, all outside the submitted work.

Dr. Marciniuk reports grants from Boehringer-Ingelheim, GlaxoSmithKline, Lung Association of Saskatchewan, Novartis, AstraZeneca, Canada Health Infoway, Canadian Institutes of Health Research, Schering-Plough; personal fees and other from Canadian Foundation for Healthcare Improvement, other from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Saskatchewan Health Authority, Health Canada, University of Saskatchewan, all outside the submitted work.