Abstract
Patients with severe chronic obstructive pulmonary disease (COPD) develop dynamic lung hyperinflation (DH) during symptom-limited incremental and constant work exercise with cycle ergometer and treadmill. The increase in end-expiratory lung volume seems to be the best predictor of dyspnea. Quantification of DH is based on the relatively complex use of on-line measurement of inspiratory capacity (IC) from flow volume loops. We reasoned that DH could occur during daily activities such as walking, and that it could be simply measured using the spirometrically determined IC. We studied 72 men with COPD (FEV1 = 45 ± 13.3% predicted). IC was measured at rest and after a 6-min walk test. Exertional dyspnea was evaluated using the Borg scale and dyspnea during daily activities with the modified Medical Research Council (MRC) scale. IC decreased significantly from 28.9 ± 6.7% TLC at rest to 24.1 ± 6.8% TLC after exercise (p < 0.001). Exertional dyspnea correlated with Δ IC (r = − 0.49, p < 0.00001) and baseline MRC (r = 0.59, p < 0.00001). In many patients with COPD, walking leads to DH that can be easily determined with simple spirometric testing. DH helps explain exercise capacity limitation and breathlessness during simple daily activities.
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality throughout the world. Exertional dyspnea is the cardinal symptom of patients with COPD. However, the perception of breathlessness varies considerably between patients with similar degrees of airflow limitation (1, 2). Increased central output and ineffective inspiratory muscle response (3-6) and development of dynamic lung hyperinflation (DH) (7, 8) are thought to contribute to the development of exertional dyspnea. That patients with COPD increase their end-expiratory lung volume with exercise has long been known (9, 10). However, the relationship between that increase and the perception of dyspnea during exercise has been documented using exercise testing under controlled laboratory conditions and relatively complex physiologic measurements that are difficult to duplicate (1-6). Therefore, the reported results may not necessarily represent the exercise performed during daily activities. In addition, the methodology that has been utilized to determine DH is not readily available to all.
Most clinicians evaluate their patients with questions that relate breathlessness to activity of daily living such as walking. This may be one of the reasons why the 6-min walk test (6MWD) has become a popular alternative tool to the more formal cardiopulmonary exercise test. The 6MWD is a reliable and safe tool to assess the functional status of patients suffering from chronic cardiac and pulmonary diseases. It is also useful in detecting the effectiveness of different forms of treatment for patients with COPD (11). The two physiological factors known to influence the 6MWD are: the degree of airflow limitation (FEV1) and the single-breath carbon monoxide diffusion capacity assessed at rest (12, 13). However, the mechanisms responsible for the development of exertional dyspnea during 6MWD have not been adequately evaluated.
In this study we tested the hypothesis that dyspnea during 6MWD could be associated with the development of lung hyperinflation. In addition, we sought to prove that the use of spirometrically determined inspiratory capacity (IC) would simplify the measurement and provide a valid field alternative to more complex determinations of dynamic hyperinflation.
All the patients were white men recruited from the outpatient clinic. They all had COPD according to the ATS criteria (14). The protocol was approved by the Human Studies Board of the Hospital Miguel Servet in Zaragoza, Spain. All patients signed the informed consent form.
The patients were clinically stable and had been receiving optimal medical therapy for at least 8 wk. Patients were included if they had a postbronchodilator FEV1 of < 80% predicted with a FEV1/FVC ratio < 0.7, and a history of smoking > 20 pack-years. Patients were excluded if they had: a history suggesting asthma, a 12% or higher increase in FEV1 after bronchodilator, active heart disease, musculoeskeletal disorders, peripheral vascular diseases or other disabling conditions that would interfer with the tests. The baseline characteristics of the patients are shown in Table 1.
| Parameter | Mean ± SD | Range | ||
|---|---|---|---|---|
| Age, yr | 65.3 ± 7.3 | 52–75 | ||
| BMI, kg/m2 | 24.7 ± 4.1 | 20.5–30.2 | ||
| FEV1, L | 1.3 ± 0.6 | 0.6–2.3 | ||
| FEV1, % pred | 45.1 ± 13.3 | 24–70 | ||
| FVC, L | 45.1 ± 13.3 | 1.5–4.1 | ||
| FVC, % pred | 79.6 ± 14.1 | 68–115 | ||
| RV, % pred | 203.1 ± 43.5 | 139–290 | ||
| TLC, % pred | 124.6 ± 14.1 | 92–155 | ||
| Dl CO, % pred | 64.6 ± 29.9 | 26–121 | ||
| PaO2 , mm Hg | 64.1 ± 8.6 | 45–83 | ||
| PaCO2 , mm Hg | 43.6 ± 4.9 | 36–59 | ||
| MRC scale | 1.9 ± 1 | 0–4 | ||
| 6MW, m | 439 ± 93 | 212–771 | ||
| IC at rest, L | 2.16 ± 0.5 | 1.3–3.83 | ||
| ICdyn, L | 1.89 ± 0.5 | 1.1–3.06 | ||
| IC at rest, % TLC | 28.9 ± 6.7 | 17.5–50.2 | ||
| ICdyn, % TLC | 24.1 ± 6.8 | 13.2–40.1 |
Pulmonary function test. All measurements were made following the recommendations of the ATS (15). Forced spirometry (FVC and FEV1) and diffusion capacity for carbon monoxide (Dl CO) using the single-breath method were determined using a conventional system (Sensormedics, Yorba Linda, CA). Static lung volumes were determined in a constant-volume whole-body plethysmograph. Arterial blood gas (PaO2 and PaCO2 ) and pH were measured at rest while breathing room air using a blood gas analyzer (ABL 330; Radiometer; Copenhagen, Denmark). The predictive values for lung function parameters were derived from those published by the European Community for Coal and Steel (16).
Six-minute walk test. The 6-min walk test was carried out in a corrider 50 m long, following a modification of the protocol described by Guyatt and colleagues (17). One well-trained researcher supervised the test. Patients were instructed to walk from end to end of the corridor and to cover as much distance as possible in the allotted period of 6 min. The patients were encouraged every 30 s using two phrases: “You are doing well” or “Keep up the good work,” and were allowed to stop and rest during the test, but were instructed to resume walking as soon as they felt able to do so. At the beginning, at 2-min increments, and at the end of the test, breathlessness was measured using a modified Borg scale. Oxygen saturation was monitored with a pulse oxymeter set at the fastest response (Biox 3740; Ohmeda, Boulder, CO). Supplemental O2 was provided to five patients by nasal prongs to maintain SaO2 > 90%. During the test, the technician accompanied the patient carrying a trolley with the oximeter, the panel with the Borg scale, and the oxygen tank.
The first 11 consecutive patients underwent four tests on four different days. The 6MWD increased in the second test compared with the first, with no further increases in the third and fourth walk. This is in agreement with previous results indicating no improvement in 6MWD after two tests (18). All subsequent patients underwent two tests separated by 1 h, and the best result was taken to represent the 6MWD.
Breathlessness. Functional dyspnea was assessed using the modified Medical Research Council (MRC) scale (19). This includes five grades of physical activities that provoke dyspnea. Dyspnea during the 6MWD was determined using the modified Borg scale (20).
Inspiratory capacity. All patients were instructed on the performance of the IC maneuver. The IC was determined using calibrated pneumotachography by having the patients inhale while seating. After four to six consistent end-expiratory levels, the patient was instructed to inspire to TLC and then to return to normal breathing. From at least three acceptable trials, the two largest IC measurements had to agree within 5% or 60 ml. Before and after the 6MWD the better of two reproducible maneuvers were recorded for analysis.
To test the adequacy and reproducibility of the IC maneuver and to train the research assistant in the procedure, an initial group of 10 patients was studied at rest and after 6MWD under special conditions. Rib-cage and abdominal displacement were measured by inductance plethysmography (IP) (21) (Respitrace; Ambulatory Monitoring, Ardsley, NY). Pleural pressure (Ppl) was recorded using an esophageal balloon. Airflow was determined using a pneumotachometer. The sum signal from the IP, the Ppl, and the flow signals were simultaneously displayed. This allowed the technician to determine the precise moment of end-expiration during tidal breathing (EELV) and the minimum Ppl during the IC maneuver (TLC). The patient was instructed to perform an IC maneuver from EELV to TLC (“take a breath all the way in”). During this maneuver, the technician encouraged the subject until a maximal negative plateau was reached, so that TLC was really achieved. After training, the technician was able to obtain accurate and reproducible IC maneuvers with or without the simultaneous display of Ppl, flow and IP signals.
In patients with COPD, TLC does not change with exercise (10) and the IC can be reliably determined (22). To test whether TLC change with walking, we measured end expiratory thoracic gas volume (EELV) and TLC by plethysmography and simultaneous spirometric IC in five patients before and after 6MWD. The mean changes in EELV and IC were 0.22 and −0.32 L (p < 0.05), whereas TLC did not change (7.5 ± 0.67 L versus 7.46 ± 0.71 L, p = 0.45). (See A.)
Data are presented as mean ± SD. IC is expressed as absolute volumes and as percentages of TLC. Eleven patients performed all the tests in 4 separate days to validate the reproducibility of the changes in Borg score and IC with the 6MWD. The statistical significance of differences in mean values of objective and subjective measurements was determined using repeated-measures analysis of variance. Because there were no differences between variables across study days, two tests were completed on the same day in all the patients. Values at rest and at the end of the 6MWD and the absolute decrease in IC (in liters or as percent measured TLC) were compared using Student's paired t test. Linear regression was used to relate the changes in Borg score from rest to the end of the 6MWD (ΔBorg) with the walked distance and the change in IC (ΔIC). The association between breathlessness or 6MWD (dependent variables) and resting lung function or dynamic lung volumes (independent variables) were determined using Pearson's correlation coefficient analysis. Those significant contributors were then introduced in a stepwise multiple linear regression analysis to determine the best predictor of exertional dyspnea and exercise capacity. A p < 0.05 was considered significant. (See B.)
The values for age, body mass index (BMI), pulmonary function test, dyspnea rating and 6MWD are shown in Table 1. The FEV1 ranged from 24 to 70% predicted. Most patients had some degree of lung hyperinflation as reflected by a high RV (203.1 ± 43.5% predicted) and TLC (124.6 ± 16.1% predicted). The patients also had a wide range of Dl CO. The group included hypoxemic and mild hypercapnic patients. The ratings of MRC dyspnea ranged from 0 (nonexertional dyspnea at all) to 4 (breathless on dressing or undressing).
The mean 6MWD for all patients was 439 meters (range, 212 to 771 m) and correlated positively with FVC and FEV1 and negatively with parameters reflecting airway trapping (RV, RV/TLC). The Dl CO showed the best correlation among the resting pulmonary function tests (Table 2). The MRC dyspnea score correlated with the 6MWD. Neither PaO2 nor PaCO2 correlated with 6MWD. This is not surprising, because oxygen saturation was kept above 90% using supplemental O2. There was no difference in 6MWD between patients with and those without oxygen. Inspiratory capacity decreased from 28.9 ± 6.7% TLC at rest to 24.1 ± 6.8% TLC at the end of the 6MWD (p < 0.001). Both values (IC at rest and ICdyn) had a positive correlation with 6MWD (r = 0.41 and r = 0.52, respectively, p < 0.001).
| Walking distance (m) | ΔBorg | |||
|---|---|---|---|---|
| Age, yr | 0.03 | 0.09 | ||
| BMI, kg/m2 | 0.06 | 0.18 | ||
| FEV1, % pred | 0.42‡ | −0.22 | ||
| FVC, % pred | 0.29* | −0.21 | ||
| RV, % pred | −0.32* | 0.19 | ||
| TLC, % pred | −0.12 | 0.06 | ||
| RV / TLC, % | −0.38† | 0.11 | ||
| PaO2 , mmHg | 0.21 | −0.16 | ||
| PaCO2 , mm Hg | −0.27 | 0.12 | ||
| Dl CO, % pred | 0.58§ | −0.18 | ||
| IC at rest, % TLC | 0.41† | 0.09 | ||
| ICdyn, % TLC | 0.52§ | 0.04 | ||
| ΔIC, % TLC | 0.26 | −0.49§ | ||
| MRC scale | −0.58§ | 0.59§ |
A stepwise linear regression analysis showed that the MRC and the Dl CO were the best predictors of 6MWD. Together with ICdyn they explained 51% of the variance (Figure 1). With the addition of FEV1 the r2 increased to only 0.57. No other variables improved the model.
Fig. 1. (Upper panel ) Scatterplot showing the correlation between walked distance and carbon monoxide diffusion capacity (r = 0.58, p < 0.00001). (Lower panel ) Scatterplot showing the correlation between walked distance and inspiratory capacity measured at the end of the 6MWD test expressed as % TLC (r = 0.52, p < 0.00001).
[More] [Minimize]After the 6MWD, all but four patients (who scored 0 on the Borg scale) reported some degree of breathlessness. The values ranged from 0.5 (almost nothing) to 9 (very severe). The exertional dyspnea expressed as the change in Borg rating from resting (time 0) to the end of the 6 MWD (ΔBorg) correlated with MRC (Table 2). Age, BMI, FEV1, and FVC did not correlate with ΔBorg. In contrast, ΔBorg had a small but significant correlation with ΔIC (r = −0.49, p < 0.00001), that is, with the change in IC from rest to the end of the 6MWD (Figure 2). ΔIC also correlated with MRC dyspnea (r = −0.56, p < 0.00001).
Fig. 2. Relationship between the change in Borg breathlessness rating and change in IC from rest to the end of the 6MWD (r = −0.49, p = 0.00001).
[More] [Minimize]There were two findings in this study of patients with COPD. First, simple walking results in dynamic hyperinflation that can be easily determined using the measured IC. Second, the increased perception of dyspnea during walking correlates with the degree of DH.
The first finding is that in a large group of patients with COPD, the 6MWD resulted in DH. The ventilatory response to exercise differs between normal persons and patients with COPD. During incremental exercise in normal subjects, minute ventilation increases primarily as a function of increases in tidal volume. Respiratory frequency increases only at higher levels of exercise (23). At peak exercise the end-expiratory lung volume decreases because of progressive recruitment of the muscles of expiration. In contrast, patients with COPD can only minimally increase the tidal volume during ergometry or treadmill exercise, because they are already breathing at high lung volume, and further increase in volume results in a disproportionate decrease in dynamic and static compliance, an increase in respiratory muscle load and in the work of breathing (8-10). Because TLC does not change with exercise (22) the only way to increase minute ventilation is to increase the breathing frequency (3-5). The premature termination of expiration caused by the faster respiratory rate further increases EELV and decreases IC (8-10, 25, 26).
The mechanisms responsible for dyspnea during exercise in COPD include: increased central output (6), ineffective respiratory muscle function (2-5), and dynamic hyperinflation (7, 8). The importance of DH in the genesis of exercise dyspnea is highlighted by the good correlation between the decrease in breathlessness after lung-volume reduction surgery (24) and inhaled bronchodilators (7, 25) and the reduction in exercise DH.
Many patients with COPD complain of dyspnea during activities such as walking, which may be partly responsible for their poor quality of life (27). We reasoned that dyspnea during walking could occur from changes similar to those described during incremental or steady-state exercise testing. To test this hypothesis we chose the 6MWD because it reflects the capacity to undertake day-to-day activities, induces dyspnea, and is used to assess the effectiveness of therapies such as lung-volume reduction surgery, lung transplantation, or pulmonary rehabilitation (11, 12, 17). In addition, the 6MWD has been validated clinically (11) and correlates with treadmill exercise (18). However, the 6MWD differs from treadmill exercise in that the patient paces the walk to cover the longest possible distance, whereas the load in the treadmill is constant. In addition, the presence of the side rail with the treadmill may allow the patient changes in position that affect the respiratory muscle recruitment and breathing pattern (28). Finally, the 6MWD is a test that does not require equipment and is easy to perform.
In agreement with previous studies (12, 13), we found that pulmonary function tests (e.g., FEV1 or Dl CO) only explain a small part of the variability of the 6MWD. The degree of increase in DH further improves our predictive capacity. As reported for incremental exercise, Dl CO and DH were better predictors of walking capacity than FEV1. The relationship between PFT and 6MWD is similar to that observed during incremental exercise (5, 26, 29). Further studies will help determine the importance of peripheral muscle function, comorbidity, cardiovascular response, or other factors on the walked distance.
Another useful observation is that a spirometrically obtained IC can be used to accurately determine the degree of DH, which with a few exceptions (9, 26) has relied on more complex measurements using the flow-volume loops obtained during laboratory exercise testing (5, 8, 24, 25). Questions could be raised as to the accuracy of our methodology. The validation of the technique using esophageal balloons and inductance plethysmography proves that with simple training, the end-expiratory volume can be adequately identified using a spirometer with a real-time display of tidal breathing. This is particularly easy in patients with the most severe obstruction who have the longest expiratory time. The degree of DH that we measured, is similar to that reported by O'Donnell and colleagues (8, 25) during a submaximal exercise test in patients with COPD and by our group before and after lung-volume reduction surgery (24). Actually, because there was certain time lag between the end of the 6MWD and the determination of the IC, the measured volume may have actually underestimated the degree of DH.
The second finding is that DH helped explain the dyspnea reported by the patients during the 6MWD. The change in breathlessness (ΔBorg) was independent of age, BMI, pulmonary function, or arterial blood gas determinations. One previous study demonstrated a small but significant relationship between Dl CO and breathlessness during walking in COPD, suggesting that worsening of gas exchange could play a role in exertional dyspnea (12). The absence of any relationship between resting Dl CO and ΔBorg in our patients could be explained by the addition of supplemental oxygen given during the test to those patients who developed exercise oxygen desaturation. However, there were no differences in ΔBorg during the walking test between patients receiving oxygen and those who did not. This suggests that alternative factors such as DH must play a more important role in exercise breathlessness, as has been shown for the incremental exercise test (8, 9). In our patients with COPD and a wide range of mechanical impairments, DH also occurred during the 6MWD. There was a modest but significant correlation between a decrease in IC and an increase in Borg scores at the end of the test. The lack of a better correlation may be due to the fact that a low ΔIC could occur in patients with a very high resting EELV who were unable to hyperinflate as they had no room to do so, and to patients with lesser degree of COPD who do not dynamically trap air. In spite of this, the mean IC change in our patients was 271 ml, very close to the 300 ml that O'Donnell and coworkers (30) have shown to correlate with clinically significant changes in dyspnea.
In COPD, the mechanism of DH during incremental exercise, and its relation with exertional dyspnea have been explored. In one study, ΔEELV, ΔVt, and ΔRR accounted for 61% of variance in ΔBorg (8). Our results prove that similar changes also occur during walking, perhaps because the exercise intensity during the test may be near maximum in patients with severe COPD. This possibility is supported by several studies. Swinburn and colleagues (31) reported no difference in peak oxygen uptake and V˙emax during incremental exercise versus the 12MWD test. Also, Borg rating at 2-min intervals increased gradually and similarly in both tests. O'Donnell and Webb (8) reported an increase in EELVdyn at submaximal exercise standardized at a V˙e of 30 L/min. This small change in EELV predicted 31% of the variance in Borg rating. Our findings and those previously reported, indicate that DH occurs even at submaximal work load in severe COPD and that it is an important contributor to the dyspnea observed during daily activities.
Dyspnea evaluated with the modified MRC scale was also a good predictor of walked distance in our patients. This is in accordance with previous studies that have shown a consistent relationship between MRC, exercise capacity (2, 12, 13, 32– 34) and ΔBorg rating (12, 35). One new reported finding in our study, is the significant correlation observed between breathlessness, whether reported during daily activity (MRC) or scored during an exercise test (Borg at 6MWD), and DH measured during walking. This suggests that air trapping and DH occurs during day-to-day activities such as walking.
In summary, this study shows that in patients with COPD, dynamic hyperinflation can occur during activities such as walking. We have also shown that similar to the findings reported during laboratory-controlled exercise testing, dynamic hyperinflation is in part responsible for the dyspnea reported with walking. Further studies are needed to determine the relevance of DH not only as a factor limiting physical activity but also affecting the quality of life in patients with COPD.
Inspiratory Capacity, Dynamic Hyperinflation, Breathlessness, and Exercise Performance during the 6-Minute Walk Test in COPD.
| Patient No. | TLC pre, L | TLC post, L | IC pre, L | IC post, L | ||||
|---|---|---|---|---|---|---|---|---|
| 1 | 7.12 | 7.04 | 2.09 | 1.6 | ||||
| 2 | 6.77 | 6.60 | 1.51 | 1.24 | ||||
| 3 | 7.96 | 7.99 | 2.07 | 1.84 | ||||
| 4 | 7.23 | 7.33 | 1.56 | 1.43 | ||||
| 5 | 8.42 | 8.36 | 1.62 | 1.14 | ||||
| Mean ± SD | 7.5 ± 0.67 | 7.46 ± 0.71 | 1.77 ± 0.29 | 1.45 ± 0.28* | ||||
| APPENDIX B. SUMMARY OF THE REPEATABILITY OF THE 6MWD (METERS) IN 11 PATIENTS WITH SEVERE COPD (FEV1 = 41 ± 12% PREDICTED). EACH WALK COMPLETED IN A SEPARATE DAY. THERE WERE NO DIFFERENCES BY ANOVA. | ||||||||
| Patient No. | Walk 1 | Walk 2 | Walk 3 | Walk 4 | ||||
| 1 | 368 | 388 | 370 | 360 | ||||
| 2 | 457 | 467 | 459 | 455 | ||||
| 3 | 506 | 520 | 501 | 531 | ||||
| 4 | 431 | 413 | 422 | 436 | ||||
| 5 | 488 | 456 | 461 | 490 | ||||
| 6 | 450 | 468 | 481 | 455 | ||||
| 7 | 511 | 518 | 501 | 520 | ||||
| 8 | 230 | 209 | 239 | 228 | ||||
| 9 | 381 | 390 | 411 | 385 | ||||
| 10 | 210 | 198 | 218 | 211 | ||||
| 11 | 356 | 370 | 349 | 359 | ||||
| Mean ± SD | 398 ± 103 | 400 ± 109 | 401 ± 98 | 402 ± 107 | ||||
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