Detecting Improvements in Dyspnea in COPD Using a Three-Minute Constant Rate Shuttle Walking Protocol

Abstract

Rationale: We examined the responsiveness of a 3-minute constant rate shuttle walking protocol to detect improvements in exertional dyspnea following acute bronchodilation in COPD. Our hypothesis was that the 3-minute constant rate shuttle walking protocol would be able to adequately put forth improvements in exertional dyspnea following acute bronchodilation in this population. Methods: Using a placebo controlled, double-blind cross-over design, 39 patients with moderate to severe COPD performed a 3-min constant rate shuttle walking test during which they were asked to walk on a flat corridor at a speed that was externally imposed by an audio signal. During the test, dyspnea was graded using the 10-point modified Borg scale. The test was performed twice, following the administration of saline placebo or of 500 μg nebulized ipratropium bromide. Results: Improvements of respiratory pattern (respiratory rate and tidal volume) and statistically and clinically significant reductions in Borg dyspnea scores (∆ dyspnea score = 1.0 ± 0.2, p < 0.01) were seen during the 3-min shuttle walking protocol with ipratropium bromide compared to placebo. Conclusion: This 3-minute shuttle walking protocol adequately detected dyspnea and breathing pattern improvements following acute bronchodilation in COPD.

Keywords: :

• COPD
• exercise
• shuttle walking test
• bronchodilation
• dyspnea

Introduction

Exertional dyspnea is a prominent symptom in chronic obstructive pulmonary disease (COPD) and an important contributor to exercise limitation and decreased quality of life. Bronchodilators appear to alleviate the subjective sensation of dyspnea through different mechanisms (1). The current exercise tests that are used to measure changes in exercise tolerance and in exertional dyspnea (2–4) are relatively demanding from a methodological point of view in such a way that they cannot be easily implemented outside specialized respiratory investigation units.

We recently developed and validated a 3-minute constant rate shuttle walking exercise protocol specifically designed to quantify dyspnea (5). During this test, which is a modification of the endurance shuttle walking test, patients are asked to walk around two cones set up in a flat corridor and separated by 10 m. An audio signal is used to impose the walking speed and the test ends at a fixed duration of 3 minutes or until symptoms become intolerable. At a prespecified time point during the test, and at the end of the test (3 min), patients are asked to score their perception of dyspnea on a Borg scale. The feasibility and reproducibility of this test in providing a standardized physical stimulus and a measurable level of dyspnea in patients with moderate to severe COPD has been reported (5). The objective of the present study is to examine whether the 3-minute constant rate shuttle walking exercise test can be used to detect improvements in exertional dyspnea following acute bronchodilation in COPD. The overall objective of this research program is to develop a simple exercise test to assess the efficacy of different interventions to alleviate dyspnea in patients with COPD.

Our hypothesis was that the 3-minute constant rate shuttle walking exercise test will be able to detect improvements in exertional dyspnea and respiratory pattern (respiratory rate and tidal volume) during exercise following acute bronchodilation in patients with COPD.

Methods

Patient population

Patients with COPD were recruited from the Montreal Chest Institute and the Institut Universitaire de cardiologie et de pneumologie de Québec. Inclusion criteria were: age >50 years, smoking >10 packs/year, post-bronchodilator forced expiratory volume in 1 second (FEV₁) between 30 and 80% predicted and FEV₁/forced vital capacity (FVC) < 70% (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II and III). Exclusion criteria were: respiratory exacerbation within the 2-month period preceding the study, history of asthma, significant O₂ desaturation (oxygen pulse saturation [SpO₂] < 85%) at rest or during exercise, presence of another pathology that could influence exercise tolerance. The study protocol was approved by our respective institutional research ethics boards and written informed consent was obtained in all patients (approval # HL-08–011). The study was registered at Clinicaltrials.gov, registration number: NCT00807534.

Study design

The study required 3 visits at the research facility. Each visit was separated by 24 hours to 4 days. The first visit included a baseline assessment of pulmonary function and patients received medical clearance to participate in the study. Patients were then asked to perform 1 incremental shuttle walking test (ISWT) (6) to asses peak exercise capacity. After 30 minutes of rest, patients were familiarised to the 3-min constant speed shuttle walking test. The goal of familiarisation was to reduce the learning effect that typically occurs when an individual complete the same endurance test several times.

At each of the following two visits, patients completed a total of 2 exercise tests consisting in 3 minutes of constant rate shuttle walking. Each exercise was conducted at 2 different walking speeds (see below for further details). A 30-minute rest period was given between each walking bout to allow physiological parameters to return to baseline. Saline placebo or 500 μg of ipratropium bromide (Atrovent®, Boehringer Ingelheim) was nebulised in a randomised double blind fashion 1 hour before the first exercise test of each testing day. Both placebo and the active medication had an identical appearance. Ipratropium was chosen because of its consistent effects on exercise tolerance and dyspnea (7,8). The study followed a crossover design with each patient being his/her own control. The exercise tests were supervised by a research professional who was unaware of the medication that was administered.

Concomitant therapeutic interventions

Patients were maintained on their usual medication although the following medications were stopped before visits 2–5: short-acting β2-agonists and short acting anticholinergics, 6 hours before, long acting β2 agonists, 24 hours before, and theophyllines, 48 hours before. Due to long washout period, tiotropium was switched to ipratropium 4 times a day, 2 weeks before the study. If any rescue medication was taken within 6 hours of the study procedure, the visit was rescheduled.

Pulmonary function testing

Standard pulmonary function tests, including spirometry, lung volumes, and diffusion capacity (DLCO) were obtained (9–11). The predicted value for inspiratory capacity (IC) was obtained by subtracting the FRC predicted value from TLC predicted value. Maximum voluntary ventilation (MVV) was estimated by multiplying FEV₁ by 35 (12).

Incremental shuttle walking test

Peak walking capacity was determined with the ISWT (6), which was performed in an enclosed corridor on a flat 10 m-long course. Encouragement was provided during the test and patients received standardised instructions to walk for as long as possible.

The 3-minute constant rate shuttle walking test

This test consisted of 1 bout of 3 minutes of walking at the initial walking speed of 4.0 km/h. Thirty minutes after this first bout of walking, a second test was performed at a walking speed of either 6.0 or 2.5 km/h. The second walking speed was determined by the ability to carry through the test at 4.0 km/h. If a patient could not complete the first test, then the second speed was stepped down to 2.5 km/h. If a patient was able to carry though the first test, then the second walking speed was raised to 6.0 km/h.

Patients were asked to perform 2 tests at 2 different speeds in order to determine, amongst the 3 different walking speeds, the highest speed that could be sustained for the entire 3 minutes. In doing so, our objective was to induce a level of dyspnea that was sufficiently high to be amenable to therapy. The walking speeds were selected based on our previous work⁵ showing that these were sufficiently demanding to induce measurable levels of dyspnea and that most moderate to severe patients with COPD were able to complete the test for the desired duration (5). Patients were directed to follow the audio signal for the entire 3 minutes of the test or until they became symptom limited. They were instructed to walk between the two cones set up in the hospital hallway pacing their walk in a way not to wait at the cones for the following audio signal.

Physiological measures

During each exercise test, cardiorespiratory parameters (V.O₂, V.CO₂, V._E, respiratory rate, tidal volume, were monitored breath-by-breath with a portable telemetric system (Jaeger Oxycon Mobile®). Heart rate and SpO₂ were also monitored continuously during exercise. Because of the limited availability of the portable metabolic system in one centre, these measurements were available in 31/39 patients.

Dyspnea and leg fatigue measurement

Patients were asked to rate their level of breathlessness and of leg fatigue on a modified 10-point Borg scale (13) at rest, and at 1, 2 2.5 and 3 minutes during exercise. The Borg scores were obtained by a technician standing along the walking course and asking patients to point on the Borg scale at the pre-determined times. Walking was not interrupted by this procedure. The questions asked were: “What is your level of shortness of breath?” and “what is your level of leg fatigue?”

Outcomes

The primary outcome variable was the changes in Borg scores at the end (3 minutes) of walking at the highest speed that was carried through for the whole 3 minutes under both experimental conditions (ipratropium bromide and placebo) by each individual patient (2.5 km/hr = 3 patients; 4.0 km = 30 patients; 6.0 km/ = 5 patients, one patient was unable to complete any of the walking speed). Secondary outcome variables included the changes in Borg scores at rest and at 1, 2 and 2.5 minutes during the highest walking speed that was completed by each patient under both experimental conditions. We also compared the physiological responses at the end of the walking tests between the two experimental conditions again using data obtained at the highest speed that was carried through for the whole 3 minutes under both experimental conditions.

Statistical analysis

Results are reported as mean ± SD, except in Figure 1 where SEM are shown for clarity purposes. A p-value <0.05 was considered as statistically significant. For the primary outcome analysis of Borg scores as well as physiologic data, comparisons of the values observed with ipratropium and placebo were made using a 2 · 2 cross-over design in which the period, sequence and treatment effects were considered.

Figure 1.  Dyspnea (panel A) and leg fatigue (panel B) Borg scores (mean ± SEM) during the 3-minute constant rate shuttle walking test under both experimental conditions (ipratropium bromide [triangles] and placebo [circles]). *p < 0.01. Symptom scores were obtained at the highest speed that was carried through for the whole 3 minutes under both experimental conditions by each individual patient (2.5 km/hr = 3 patients; 4.0 km/hr = 30 patients; 6.0 km/hr = 5 patients, one patient was unable to complete any of the walking speeds).

Results

Table 1 shows baseline data of our study population. On average, patients had moderate or severe COPD, hyperinflation and gas retention as well as moderately reduced diffusion capacity. After randomization, we realized that one patient with GOLD I COPD was included in the study. It was decided to retain this patient into the study.

Table 1.  Baseline characteristics of the study population

	Value	SD
Number of subjects	39	-
Males/females, n	27/12	-
Age (years)	64	5
Body mass index (kg/m^2)	28	5
Current smokers (n)	17	-
GOLD (I/II/III)	1/23/15	-
Pulmonary Function
FEV1 (L)	1.37	0.52
FEV1 (% predicted)	51	14
FVC (% predicted)	94	17
FEV1/FVC (%)	43	11
FRC (% predicted)	141	36
TLC (% predicted)	115	20
RV (% predicted)	152	47
DLCO (% predicted)	53	13

Values are mean ± SD.

Definition of abbreviations: GOLD: Global Initiative for Chronic Obstructive Lung Disease; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; FRC: functional residual capacity; TLC: total lung capacity; RV: residual volume; DLco: single-breath diffusing capacity for carbon monoxide.

Table 2 shows peak data obtained during the ISWT. Peak V.O₂ averaged 17.5 ± 4.1 mL/kg/min. Physiologic data at peak ISWT showed no ventilatory reserve and that the locus of symptom limitation was dyspnea in a majority of patients.

Table 2.  Physiological responses to the incremental shuttle walking test

	Value	SD
V. O2 peak (L/min)	1.4	0.4
V. O2 peak (mL/kg/min)	17.5	4.1
V. E peak (L/min)	52	19
V. E /MVV (%)	99	20
Peak heart rate	119	20
Distance walked (m)	420	152
Locus of symptom limitation (dyspnea/fatigue)	31/8	-
Peak dyspnea Borg score	5.8	2.4
Peak leg fatigue Borg score	4.7	2.2

Values are mean ± SD.

Definition of abbreviations: V. O2 : oxygen uptake; V. E: minute ventilation; MVV: maximum voluntary ventilation.

Ipratropium bromide induced significant bronchodilation (post –pre-bronchodilator FEV₁ = 180 (160) mL and post –pre-bronchodilator FVC = 130 (231) mL, mean (SD), both p < 0.01). Among the 39 patients, 38 were able to complete at least one walking speed. The maximal walking speed that was reached was: 2.5 km/hr (n = 3), 4.0 km/hr (n = 30) and 6 km/hr (n = 5). Borg dyspnea scores were reduced at all time points during walking with ipratropium bromide in comparison to placebo (Figure 1). At minute 3, the mean reduction in dyspnea amounted to 1.0 ± 0.2, p < 0.01 (from 4.5 ± 2.3 with saline to 3.4 ± 2.4 with ipratropium bromide). The majority of patients (27/39) experience a reduction in dyspnea Borg score of at least 1 point lower with ipratropium bromide compared to placebo. There was no change in leg fatigue scores with bronchodilation. Women reported higher dyspnea scores than men under placebo (Borg dyspnea scores of 5.2 ± 2.4 and 4.3 ± 2.3, for women and men, respectively). However, ipratropium bromide reduced dyspnea in both genders (Borg dyspnea scores of 4.2 ± 2.2 and 3.1 ± 2.4 for women and men, respectively).

Physiological data during the 3-minute constant rate shuttle walking test is reported in Table 3. On average, the 3-minute constant rate shuttle waking test was done at a relative intensity corresponding to 80% of the peak V.O₂ and V._E values reached during the incremental shuttle walking test. Minute ventilation reached significantly higher levels with IB compared to placebo [44 (13) L/min vs 41 (12) respectively, p < 0.01]. Respiratory pattern was also significantly modified under ipratropium bromide compared to placebo with lower respiratory rates and higher tidal volumes. Inspiratory capacity was not measured during the test. There was no difference in oxygen consumption or carbon dioxide production, nor was there difference in heart rate and saturation.

Table 3.  Effects of ipratropium bromide on physiologic data at 3 minutes during the 3-minute constant rate shuttle walking test

	Placebo		IB		p-value (placebo vs IB)
	Baseline	3 minutes	Baseline	3 minutes	Baseline	3 minutes
V. E (L/min)	13 ± 4	41 ± 13	13 ± 4	44 ± 12	0.17	<0.01
VT (L)	0.65 ± 0.21	1.15 ± 0.40	0.68 ± 0.18	1.30 ± 0.42	0.19	<0.01
Respiratory rate (min-1)	20 ± 5	32 ± 6	20 ± 5	30 ±6	0.50	0.02
V. O2 (L/min)	0.31 ± 0.12	1.13 ± 0.37	0.31 ± 0.11	1.14 ± 0.40	0.88	0.96
V. CO2 (L/min)	0.30 ± 0.18	1.03 ± 0.42	0.27 ± 0.08	1.19 ± 0.45	0.61	0.40
Heart rate (BPM)	79 ± 18	107 ± 16	81 ± 18	108 ± 16	0.69	0.53
SpO2 (%)	94 ± 2	91 ± 3	94 ± 2	91 ± 5	0.72	0.97

Values are mean ± SD.

Abbreviations: FEV1: forced expiratory volume in 1 second;V. E: minute ventilation; VT: tidal volume; V. O2: oxygen uptake; V. CO2: carbon dioxide excretion; SpO2: oxygen pulse saturation. Physiological values were obtained at the highest speed that was carried through for the whole 3 minutes under both experimental conditions by each individual patient (2.5 km/hr = 3 patients; 4.0 km/hr = 30 patients; 6.0 km/hr = 5 patients, 1 patient was unable to complete any of the walking speed).

Discussion

In a previous study (5), we showed that the 3-minute constant rate shuttle walking test induced levels of dyspnea amenable to therapy in patients with COPD. The present study now reports on the responsiveness of this test to detect improvements in exertional dyspnea following acute bronchodilation in moderate to severe COPD. The main findings of this study were that the 3-minute constant rate shuttle walking test was responsive to bronchodilation with significant reduction in dyspnea scores during exercise that were associated with improvements in breathing pattern.

The 3-minute constant rate shuttle walking test induced dyspnea levels and metabolic requirements that were comparable to those seen in our previous study (5). The bronchodilatory effects of ipratropium bromide were consistent with the reported efficacy of this medication (7). Peak minute ventilation and tidal volume were higher while respiratory rate was slower after the administration of ipratropium bromide. These changes in breathing pattern are in keeping with previous studies (7,14) and can be explained by the improvement in FEV₁, a key determinant of maximal voluntary capacity and by reductions in operating volumes during exercise allowing more expansion in tidal volume (7,14).

Although inspiratory capacity was not assessed during exercise, the slower and deeper breathing pattern that was seen with ipratropium bromide is consistent with patients breathing at lower lung volumes (2,7). Besides, reduction in dynamic hyperinflation is a consistent finding after acute bronchodilation (7,15). These physiological effects of bronchodilation are central to their exercise enhancing effects because breathing at lower lung volumes reduces work of breathing and improves neuromechanical coupling, which ultimately results in less dyspnea perception by the patients (16).

As expected from the improvements in expiratory flows and in breathing pattern during exercise, statistically significant changes in Borg dyspnea scores were seen during the 3-minute constant rate shuttle walking test. In addition to reaching statistical significance, the one-point reduction in dyspnea on the Borg scale is also felt to be clinically relevant as such an improvement should be perceived by the patients (17). However, whether this one-point clinically relevant threshold will also apply to the specific situation of the 3-minute constant workrate shuttle walking test will need to be specifically tested. As shown in Figure 1, the reductions in dyspnea with bronchodilation became increasingly obvious during exercise, a finding that is congruent with a progressively larger impact of bronchodilation on respiratory mechanics and neuromechanical coupling during exercise as ventilatory requirements and operating volumes were increasing (16).

Exertional dyspnea is the most prominent symptom in COPD. Dyspnea can be quantified during the 6-minute walking test but pre- and post-intervention comparisons are made difficult since the walking speed and thus the exercise stimulus is not controlled during the test. One strategy to evaluate the effects of interventions on exertional dyspnea is to compare dyspnea at iso-time while controlling the walking or cycling speed during the endurance shuttle walking test (4) or the constant workrate cycling test (2,18).

One limitation of this approach is that pre- and post-intervention dyspnea measurements are not always obtained at the same time point since the duration of the test is variable. To overcome this problem, linear interpolation can be used to estimate of dyspnea. However, this approach is not as robust as when a “real” dyspnea score is directly obtained from the patients. Although the 3-minute constant rate shuttle walking test represents only a small modification of the existing endurance shuttle walking test, we believe that allowing to directly assess dyspnea at a given exercise stimulus is a significant advantage over the existing exercise testing modalities. Another practical advantage of this test is that it does not require performing an incremental shuttle test in order to determine the walking cadence in addition to being shorter than the full endurance shuttle walking test.

Methodological considerations

One practical challenge with the 3-minute shuttle walking protocol is to select the initial cadence for testing. An elegant way to do this would be to predict the appropriate walking cadence based on one or several baseline characteristics of the patients. However, considering the general inability to predict exercise tolerance in an individual subject from any resting measurements, this approach appears elusive. We therefore adopted a pragmatic approach to this problem based on our past experience in performing these tests in patients with COPD (5).

Thirty-five out of 39 (90%) patients succeeded with the initial walking pace (4 km/hr). Taking into account the 3 further patients who completed a lower walking speed (2.5 km/hr), (97%) of participants were able to carry out at least one 3-minute walking protocol. With such a high completion rate, it is unlikely that any predictive equation would perform better in order to identify the appropriate initial walking speed. Therefore, the proposed testing protocol, consisting of 1 or 2 of the 3-minute exercise tests and of a brief resting period interspersed between tests should be feasible in clinical practice. The current testing protocol for the 3-minute walking protocol seems ready to undergo scrutiny of a larger clinical research. However, its reliability in the context of a multicentre trial will have to be tested.

Physiological parameters were assessed during exercise using a wireless portable system V.O₂ system (Jaegger Oxycon® Mobile). This was done to quantify the effect of ipratropium bromide on respiratory pattern during exercise. Such monitoring would however not be necessary if the goal of the 3-minute shuttle walking test is to quantify dyspnea. Another important methodological consideration is the choice of the bronchodilator. Although ipratropium bromide is less widely used by clinicians nowadays, its effects on exertional dyspnea, dynamic hyperinflation and exercise tolerance are well characterized (7,8,14).

On average, patients reported a moderate to severe dyspnea rating at the end of the 3-minute test. To put the intensity of the 3-minute constant rate shuttle walking test into perspective, it is interesting to note that its intensity (80% peak value) was actually less that what is reported for the 6-minute walking test (near maximal) (3), which is considered to be safe and routinely used in clinical practice without detailed cardiopulmonary monitoring. The patients recruited for this study had moderate-to-severe COPD. As such, we do not know whether our results would also apply to a milder patient population.

Conclusion

We conclude that improvements in exertional dyspnea following bronchodilation can be reliably measured using the 3-minute externally paced constant rate shuttle walking test in moderate-to-severe COPD patients. This time-based, externally imposed cadence test appears as a promising tool to assess the impact of bronchodilation on dyspnea in future COPD clinical trials.

Declaration of interest

FM received fees for speaking at conferences sponsored by Boehringer Ingelheim, Pfizer and GlaxoSmithKline. He served on an advisory board for GlaxoSmithKline and Boehringer Ingelheim. He received research grants for participating in multicenter trials sponsored by GlaxoSmithKline, Boehringer Ingelheim, Altana Pharma, Merck, Astra Zeneca, Nycomed and Novartis. He received unrestricted research grant from Boehringer Ingelheim and GlaxoSmithKline. He holds a CIHR/GSK research chair on COPD. AH is an employee of Boehringer Ingelheim. JB has received an educational grant from Acme Pharmaceutical industries; has stocks in excess of £5000 in Grace Bros drugs plc; and travel to the ERS congress was funded by Acme Biotechnologies. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

The authors acknowledge the help of Marthe Bélanger, Marie-Josée Breton, Brigitte Jean and Josée Picard in accomplishing this study. They also thank Gaétan Daigle for his statistical assistance and Eric Nadreau for his help with the exercise tests.