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Six-Minute Walk Distance in Chronic Obstructive Pulmonary Disease

Reproducibility and Effect of Walking Course Layout and Length

Frank Sciurba, Gerard J. Criner, Shing M. Lee, Zab Mohsenifar, David Shade, William Slivka, and Robert A. Wise for the National Emphysema Treatment Trial Research Group

Johns Hopkins University, Baltimore, Maryland; Cedars Sinai-University of California, Los Angeles, California; Temple University School of Medicine, Philadelphia; and University of Pittsburgh, Pittsburgh, Pennsylvania

The 6-minute walk test is used in clinical practice and clinical trials of lung diseases; however, it is not clear whether replicate tests need to be performed to assess performance. Furthermore, little is known about the impact of walking course layout on test perfor- mance. We conducted 6-minute walks on 761 patients with severe emphysema (mean SD FEV 1 % predicted 26.3 7.2) who were participants in the National Emphysema Treatment Trial. Four hun-

dred seventy participants had repeated walks on a separate

day.

The second test was improved by an average of 7.0 15.2% (66.1 146 feet, p 0.0001, by paired t test), with an intraclass correlation coefficient of 0.88 between days. The course layout had an effect on the distance walked. Participants tested on continuous (circular

or oval) courses had a 92.2-foot longer walking distance than those

tested on straight (out and back) courses. Course length had

significant effect on walking distance. The training effect found in

no

these patients with severe emphysema is less than in previous re- ports of patients with chronic obstructive pulmonary disease. Fur- thermore, the layout of the track may influence the 6-minute walk performance.

Keywords: emphysema; exercise tests; reproducibility of results; diag- nostic techniques; clinical trials

The 6-minute walk test is used as an outcome measure in clinical trials of lung disease. Although the test has been somewhat standardized, there are differences in the testing

technique in different clinical centers and laboratories (1).

In particular, there is not agreement on the length of the

test

course, the shape of the test course (straight versus continu- ous circle or oval), whether a practice walk should be done

before the final test, and whether the better of two walks or the second of two walks should be the reported value. These

questions are of particular importance in

longitudinal

multicenter clinical trials in which test results may vary be-

multicenter trial of lung volume reduction surgery compared with medical treatment for advanced emphysema. The study investigators conduct 6-minute walk tests in participants at entry into the study and periodically thereafter. In this report, we analyze results of 6-minute walks for the first 761 random- ized participants. Of these, 470 participants undertook two 6-minute walks on successive days. This afforded us the op- portunity to examine the reproducibility of repeated 6-min- ute walks in this patient population. Because the length of the walking course differed among the 17 clinical centers, we were also able to examine what effects this would have on 6-minute walking distance. Furthermore, because some walk- ing courses were continuous (circular or oval) and others were straight, requiring turns, we were able to evaluate the effect of walking course layout on performance.

METHODS

Additional details on the methods of this research are available in the online supplement.

NETT

The NETT is a multicenter clinical trial comparing lung volume reduc-

tion surgery with medical treatment in patients with emphysema. The

details of the trial design have been published (2, 3).

Major enrollment criteria include bilateral emphysema judged suit-

able for lung volume reduction surgery documented by computed chest

tomography, FEV 1 less than or equal to 45% predicted (4), total lung capacity of at least 100% predicted (5), residual volume of at least

150% predicted (5), and Pa CO 2 less than 60 mm Hg (or less than 55

mm Hg in Denver). Enrollees had to be validated nonsmokers for 4 months and had to be free of important comorbid conditions.

Data Collection Schedule

tween centers and over time. Participants had a baseline evaluation before enrollment, including a

medical history and examination, lung function testing, blood testing, chest computed tomography, dobutamine cardiac stress testing, and

echocardiography. If necessary, additional studies such as cardiac con- sultation and cardiac catherization were performed to exclude people

with coronary artery disease or moderate to severe pulmonary hyper-

tension. The data that are presented here are taken from the baseline evaluation in participants ultimately enrolled in the trial, representing those with severe emphysema who are free of important comorbid conditions. We analyzed data from 761 randomized participants who had 6-minute walk tests at the 17 clinical centers. In 470 of the initial enrollees, the 6-minute walk test was repeated on the day after the first test to account for the effect of repeated testing.

The National Emphysema Treatment Trial (NETT) is a

(Received in original form March 3, 2002; accepted in final form February 18, 2003)

Supported by contracts with the National Heart, Lung, and Blood Institute

(N01HR76101, N01HR76102, N01HR76103, N01HR76104,

N01HR76105,

N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR761010,

N01HR761011, N01HR761012, N01HR761013, N01HR761014,

N01HR761015,

N01HR761016, N01HR76118, and N01HR761019), the Center for Medicare and

Medicaid Services (formerly the Health Care Agency for Healthcare Research and Quality.

Correspondence and requests for reprints should be addressed to Robert A. Wise, M.D., Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: rwise@ jhmi.edu

which is accessible from this issues table

of contents online at www.atsjournals.org

This article has an online supplement,

Financing Administration), and the

Am J Respir Crit Care Med

Originally Published in Press as DOI: 10.1164/rccm.200203-166OC on February 20, 2003

Vol 167. pp 1522–1527, 2003

Six-minute Walk Test Procedure

On a day before the first 6-minute walk, participants underwent cardio- pulmonary exercise testing with a cycle ergometer to exclude important cardiac rhythm disturbances or ischemic electrocardiographic changes. Before the first 6-minute walk, participants also undertook a 1- to 2-mile- per-hour treadmill test to determine whether they needed oxygen dur- ing the 6-minute walk test.

Internet address: www.atsjournals.org Each clinical site used the same walking course for all participants,

Sciurba, Criner, Lee, et al.: Six-minute Walk in Emphysema

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TABLE 1. PARTICIPANT CHARACTERISTICS (MEAN SD)

 

Participants with at Least One Test

Participants with

Characteristics*

Two Tests

n

761

470

Age, yr Female, % Height, cm Weight, kg BMI, kg/m 2 FEV 1 , L BTPS FEV 1 % predicted FVC, L BTPS FVC % predicted FEV 1 /FVC % MVV, L/min TLC, L BTPS TLC % predicted RV % predicted RV/TLC % D CO % predicted Required oxygen at rest, % Required oxygen during test, % SGRQ, total score 6MW distance % predicted Dyspnea score Muscle fatigue score

67.2 5.9

67.2 5.8

39

39

168.9 9.61 70.3 13.8 24.6 3.85 0.76 0.24 26.3 7.2 2.45 0.77 65.7 15.3 31.6 6.6 30.4 10.2 7.75 1.52 129.2 13.9 227.6 48.0 65.7 8.0 27.5 9.6

168.5 9.5 70.1 13.7

24.6 3.78 0.75 0.24 26.3 7.4 2.45 0.77 66.0 15.4 31.4 6.4 30.4 10.4 7.78 1.49 130.4 13.4 230.0 45.9 66.0 7.7 27.8 9.7

9.9

10.6

76.8

78.1

56.1 12.8 70.1 19.2 5.1 2.0 3.5 2.3

56.2

13.3

67.4 18.1

5.0

2.0

3.4 2.2

. 3 67.4 18.1 5.0 2 . 0 3.4 2.2 Figure 1. Scatter plot of first-day

Figure 1. Scatter plot of first-day and second-day 6-minute walk dis- tance. The bold line shows the line of identity. The dashed line is the regression of the second test to the first. The intraclass correlation between the two tests is 0.88, with the majority of points above the line of identity.

Definition of abbreviations: 6MW 6-minute walk; D CO diffusing capacity for carbon monoxide; L BTPS liters, body temperature and pressure saturated with water vapor; RV residual volume; SGRQ St. George’s Respiratory Question- naire; TLC total lung capacity. * Dyspnea Score and Muscle Fatigue Score are based on the Borg CR-10 scale.

cient of 0.88 (p 0.0001), but with a definite learning effect on

the second test (Figures 1 and 2). On average, the second 6- Values are taken from the initial test. minute walk distance was greater by 66.1 146 feet (p 0.0001,

by paired t test) (Figure 3). The mean improvement was 7.0 15.2% on the second test, with 70% of people improving on the second day. The mean absolute change between the two test days was 118 108 feet. On the second test day, 14.9% of the patients increased the walking distance more than the estimated clinically signicant threshold of 180 feet, and 4.7% of the pa- tients decreased more than this amount (11). People with greater distances on the first test had a tendency to improve more on the second test, suggesting that there was not simply regression to the mean. The Bland-Altman plot con- firms that the second-day test was consistently and significantly longer (Figure 2). The effect of using different strategies for test

although the length and shape of the walking course differed among centers. Participants took a short-acting bronchodilator within 2 hours before testing. Clinic staff gave identical scripted instructions to participants and explained the Borg category ratio scale (CR-10) (6, 7). A staff member walked behind the participant and carried the oxygen delivery system

if required. At each minute during the walk, the staff member told

the

participant how much time had elapsed and the remaining time and gave

scripted encouragement. At the end of the 6 minutes, the participant

was

told to stop, and the distance walked was recorded. Predicted values were calculated using the normative values of Enright and Sherrill (8).

Statistical Analysis

Results are presented as means and SDs. Changes in 6-minute walk distances were compared using a paired t test. Trends in differences between the first and second walk distances were evaluated using Bland- Altman analysis (9). Changes in the Borg scores were compared with zero using the Wilcoxon signed rank test. The effect of course layout and length was estimated using multiple linear regression adjusting for age, sex, height, and FEV 1 percentage predicted.

for age, sex, height, and FEV 1 percentage predicted. RESULTS The characteristics of the study population

RESULTS

The characteristics of the study population are presented in Table 1. The first 470 participants with replicated 6-minute walks were similar to those who performed only one walk in terms of age, sex, and lung function. As expected, the study population had evidence of severe obstructive lung disease with diminished single-breath carbon monoxide diffusing capacity, hyperinfla- tion, and air trapping. Disease impact on quality of life, measured by the St. George’s Respiratory Questionnaire, was considerable with a score of 56 12.8 on a scale of 100, with 100 representing

Figure 2. Scatter plot of the difference between the two walks plotted

the worst quality of life (10). against the mean value (Bland-Altman plot). The dashed line is the re-

gression of change in walking distance against mean value, indicating that those with higher values tended to improve more on the second day.

In general, we found that the 6-minute walk test was repro- ducible on subsequent days, with an intraclass correlation coeffi-

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OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 167 2003 Figure 3. The distribution of differences between

Figure 3. The distribution of differences between the second-day walk distance and the first-day walk distance. The mean SD improvement was 66.1 146 feet, which is significantly larger than zero (p 0.0001).

selection is shown in Table 2. The better of the two tests was, on average, 92.1 feet longer than the first test (Table 2). Linear regression models adjusting for baseline measures and including demographic, anthropometric, physiologic, previous rehabilitation, and quality-of-life measures showed that partici-

pants with higher maximum inspiratory pressure had more im- provement on the second walk (0.99 0.34 feet/cm H 2 O, p 0.005). There were no other clinical features that predicted which participants increased walking distance. Borg scores for breathlessness and leg fatigue were also repro- ducible on subsequent tests on average (Figure 4). The Borg score for breathlessness increased 0.33 1.74 U (median change

0, interquartile range 0 to 1) on the second test (p 0.0001,

Wilcoxon signed rank test). There was no significant change in the Borg score for leg fatigue on the second test with a mean change of 0.002 1.70 U (median change 0, interquartile range 1 to 1) (Figure 5). Regression models did not reveal any clinical, demographic, or physiologic features that predicted changes in the dyspnea or leg fatigue scores. Among the 14 clinics with straight walking courses, the mean length of the course ranged from 50 to 164 feet (mean 99.9 34.1 feet). Three clinics had continuous layout courses (either oval or square) that ranged in length from 185 to 397 feet in circumference (mean 298 75.4 feet). The 6-minute walk dis- tance was greater in those individuals who completed the test on a continuous track (1,156 302 feet for straight courses and 1,266 360 feet for continuous courses, p 0.003, t test). The effect of course layout persisted when adjusted for FEV 1 percent-

age predicted, age, sex, and height (adjusted difference 92.2 feet,

p 0.001). Among the 14 clinics with straight course layout,

there was no statistically significant effect of track length on 6-minute walk distance in bivariate as well as multivariate anal-

yses.

distance in bivariate as well as multivariate anal- yses. Figure 4. Scatter plots are shown for

Figure 4. Scatter plots are shown for Borg scores for breathlessness (A ) and for muscle fatigue (B ) at the end of the 6-minute walk (6MW) comparing the first and second test days. Data points are offset to allow better display of the individual data points. The bold diagonal line is the line of identity.

DISCUSSION

The 6-minute walk test is widely used for the evaluation of

functional status in patients with lung disease in both clinical

RESULTS FOR PARTICIPANTS practice as well as clinical trials (12–16). The test is widely used

because it involves a familiar daily activity and involves the use of minimal technical resources (17). Because verbal encouragement can improve test perfor- mance, most protocols use standardized verbal prompts that are similar to those that we have used (18). Less well documented, however, is the short-term variability of the test in patients with advanced chronic obstructive pulmonary disease (COPD). Be-

TABLE 2. SIX-MINUTE WALK

WITH TWO SESSIONS (N 470)*

 

First Test

Second Test

Best Test

Distance walked, feet Distance, % predicted Borg score dyspnea Borg score leg fatigue

1,124.0 298.6 67.4 18.1 5.01 2.02 3.45 2.20

1,190.1 312.8 71.4 19.1 5.34 2.05 3.45 2.28

1,216.1 307.5

72.9

18.6

5.26 2.04 3.51 2.30

* Results are expressed as mean SD.

Sciurba, Criner, Lee, et al.: Six-minute Walk in Emphysema

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Criner, Lee, et al. : Six-minute Walk in Emphysema 1525 There have been several studies of

There have been several studies of repeated walking tests in COPD patients. Leach and colleagues found in 30 patients with hypoxemia from COPD and restrictive lung diseases that the learning effect of subsequent 6-minute walks was 14.9% (22). This is a greater learning effect than we found in our more impaired patients who were given supplemental oxygen to pre- vent hypoxemia. McGavin and colleagues found that a second 12-minute walking test was associated with a 7% improvement, closer to what we found in this study (23). Swinburn and col- leagues found a 16% improvement on four successive 12-minute walks in 17 COPD patients over the course of 1 week (24). Knox and colleagues performed 12 5-minute walks over 3 consecutive days in 36 COPD patients. He found that there was a 33% im- provement in walking distance, with half of the improvement occurring in the first three walks on Day 1. If the 12 walks were repeated over a 4-week interval, however, the total learning effect was only approximately one-fourth as large (25). Stevens and colleagues performed three 6-minute walk tests in 21 COPD patients on separate days and found a mean increase of 10% on the second test and an additional 3% on the third test (26). We are not certain why we found a smaller learning effect than other series, but it may relate to the severity of disease, the scripted encouragements, the instructions to perform a maximal test, the prior treadmill and cycle exercise testing, or the familiar- ity of the patients with the testing staff and environment. A possible explanation of our findings is that some of the NETT patients had previous experience with pulmonary rehabilitation and therefore were not truly “naive” to the test procedures. We could not, however, find any difference in learning effect based on prior pulmonary rehabilitation exposure. The obvious implication of our results and the results of others is that clinical trials that rely on 6-minute walks before and after an intervention should include appropriate control groups, or repeated tests, to account for this learning effect. If a single 6-minute walk test is used, there should be a contempora- neous control group and the tests should be spaced several weeks apart to minimize the learning effect. The selection of reference equations also depends on the testing method. Normative values for 6-minute walk tests have been derived from single test ses- sions (8). Reference equations from healthy volunteers who per- formed multiple tests on a single day predict significantly longer distances if the best of multiple tests is chosen as the study value (21, 27). There can be statistically and potentially clinically

Figure 5. The distribution of differences between the second-day walk Borg scores for breathlessness (A ) and for leg fatigue (B ). The distribu- tions are skewed in opposite directions. The mean change in the Borg dyspnea score is 0.33 1.74 U, which is significantly greater than zero (p 0.0001). The mean change for the leg fatigue score on the second

test is 0.002 1.70 U, which is not statistically different from zero. important differences depending on whether the rst, second,

best, or mean value is reported. Because of the small difference and the burden of a second day of exhaustive exercise testing in patients with advanced obstructive lung disease and the little additional information that such testing provides, we have elimi- nated the second 6-minute walk from the NETT protocol. The recent American Thoracic Society guidelines for 6-minute walk tests do not require a practice walk. They do recommend, how- ever, that if a practice walk is done, the repeat test should be done on the same day at least 1 hour later and that the larger of the two values should be reported (28). The data presented here may be useful in interpreting changes in walking distance after an intervention in individual patients. If the study is repeated within a short period such that a learning effect may be involved, an individual patient would need to improve by more than 352 feet (66 feet 1.96 146 feet) to be 95% confident that there had been improvement. If the short- term learning effect is discounted, for example in tests done 4 weeks apart, then an improvement of 286 feet (1.96 146) is necessary to be 95% confident that the change was not random variation. This threshold is similar to the upper 95% confidence interval of clinically important changes in 6-minute walk distance

a learning effect (19, 20). Gibbons and colleagues performed four 6-minute walks on the same day in 79 healthy adults. They found that the longest distance occurred on the first walk 14% of the time and that the longest of the four walks averaged 6.6% longer than the initial test, similar to the magnitude of

improvement in our COPD patients (21). of 280 feet reported by Redelmeier and colleagues (11).

6-minute walking distance and treadmill exercise testing has been reported in cardiac patients, which has been attributed to

at 1 to 2 miles per hour. Similar short-term improvement

to familiarity with the walking course, better pacing, or motiva- tional factors. It is also possible that the patients were less fa- tigued on the second test day because the test had not been preceded by an oxygen titration test requiring treadmill walking

cant improvement of approximately 66 feet. This was likely

others do not. There is also little known about the effects of the walking course on test results. This analysis was performed on enrollees in the NETT to address these questions. On the second day of testing, we found a statistically signifi-

laboratories require a practice walk before the test walk,

cause the test requires some degree of strategy and pacing, some

whereas

due

in

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The impairment of 6-minute walk distance (70.1% predicted) on average was not as severe as one might predict from the

walking courses, which does not support this hypothesis. It is possible that the range of course lengths was insufficient to test

severity of impairment of FEV 1 (26.3% predicted) or quality of life (St. George’s Respiratory Questionnaire, 56.2 out of 100).

this adequately or that our hypothesized mechanism for the effect of track layout in incorrect. Whichever explanation is

It

is possible that this reflects the selected population enrolling

correct, we note that literature reference values derived from a

in

NETT or may reflect the benefit of oxygen supplementation,

20-m course are similar to those derived from a 50-m course

which was used by 78% of the patients. For clinical purposes,

(21, 27). Thus, it seems less important to standardize the length

it

is important to consider other factors than walking distance.

of the course as long as it exceeds the minimum of 50 feet, which

Van Stel and colleagues found that half of 53 COPD patients experienced declines in 6-minute walk distance after rehabilita- tion, whereas 83% reported improved exercise capacity that could be attributed to cardiovascular conditioning, less oxygen

was the shortest distance among the 14 centers with straight courses. The American Thoracic Society guidelines suggest that the minimum course length be at least 100 feet and suggests a straight rather than a continuous course (28).

desaturation, and less dyspnea with everyday activities (29). In summary, we have found that the 6-minute walking test

Thus, the 6-minute walking distance is only one dimension of

functional assessment of COPD treatments. implemented in a large multicenter trial. There is a statistically

significant improvement, averaging 7% when the test is repeated on a second day. The shape of the walking course (continuous versus straight) appears to be a determinant of distance walked but not the length of a straight course.

was slightly higher on the second walk, perhaps corresponding

in patients with advanced emphysema is a measure that can be

The Borg score for dyspnea at the end of the 6-minute walk

to

greater effort expenditure to achieve the longer distance. This

is

different from the findings of Belman and colleagues who

found lower dyspnea scores on four successive treadmill tests in nine patients with COPD despite comparable maximal exercise

achievement (30). The Borg score for leg fatigue was not

on the second test day. The range of Borg scores was quite large.

There was a weak negative correlation between distance walked and the dyspnea score (r 0.22) but none for the leg fatigue

score. The average degree of dyspnea on study Day 1 was 5.01

2.01, corresponding to a descriptor of “severe.” This is

lower than the value of 5.2 reported by Hamilton and colleagues during symptom-limited ergometer exercise testing in untrained patients with pulmonary disease (31). We found a lower mean Borg score for leg fatigue than dyspnea in our study population

slightly

greater

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