Patients with chronic obstructive pulmonary. Endurance shuttle walking test: responsiveness to salmeterol in COPD

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1 Eur Respir J 2008; 31: DOI: / CopyrightßERS Journas Ltd 2008 Endurance shutte waking test: responsiveness to sametero in COPD C. Brouiard*, V. Pepin #, J. Miot*, Y. Lacasse* and F. Matais* ABSTRACT: Few studies have shown that the endurance shutte waking test (ESWT) is responsive to treatment in patients with chronic obstructive pumonary disease (COPD). This exercise test needs to be further investigated because of its reevance for activity of daiy iving. The aim of the present study was to evauate, in patients with COPD, the responsiveness of the ESWT in detecting improvement in waking performance after a singe dose of sametero. In a randomised, doube-bind, pacebo-controed crossover tria, 20 patients with COPD performed two ESWT at 80% of peak capacity 2.5 h after inhaing either a pacebo or 50 mg of sametero. Cardiorespiratory parameters were monitored during each waking test. Inspiratory capacities and Borg ratings for dyspnoea were obtained every other minute throughout the tests. Compared with pacebo, sametero produced a significant change in ung function and a significant improvement in waking performance (mean SD difference in time: s; difference in distance: m). At isotime (the atest exercise time that was reached on both ESWT), a significant reduction in dyspnoea was observed after bronchodiation. Bronchodiation with sametero reduced dyspnoea during waking and improved waking capacity in patients with chronic obstructive pumonary disease. These findings provide further support for the use of the endurance shutte waking test as an evauative too in chronic obstructive pumonary disease. KEYWORDS: Bronchodiators, chronic obstructive pumonary disease, endurance, exercise capacity, exercise testing, sametero AFFILIATIONS *Centre of research, Hôpita Lava, Institut Universitaire de Cardioogie et de Pneumoogie de Université Lava, Quebec City, QC, and # Centre de recherche, Hôpita du Sacré-Coeur de Montrea, Montrea, QC, Canada. CORRESPONDENCE F. Matais Centre de Pneumoogie Hôpita Lava 2725 Chemin Ste-Foy Quebec QC G1V 4G5 Canada Fax: E-mai: francois.matais@ med.uava.ca Received: September Accepted after revision: November Patients with chronic obstructive pumonary disease (COPD) compain of premature exertiona dyspnoea and eg fatigue [1] and exercise intoerance mainy due to a reduced ventiatory capacity, impaired gas exchange and periphera musce dysfunction. Whie short-acting bronchodiators may be sufficient for handing symptoms in the eary phases of the disease process, ong-acting bronchodiators are typicay better suited to treating patients with more advanced disease [2, 3]. Long-acting bronchodiators, such as sametero and tiotropium, have been shown to improve dyspnoea and quaity of ife and to reduce exacerbations in patients with COPD [4 6]. In we-designed, randomised, pacebo-controed cinica trias, these two bronchodiators have aso been convincingy shown to improve the endurance time to submaxima cycing exercise in this patient popuation [7 9]. This benefit can be shown in the few hours foowing the administration of the first dose of the medication [7, 8]. For a given exercise stimuus, ong-acting b 2 -agonists and antichoinergics aso reduce the perception of dyspnoea [8, 9]. Athough the symptomatic and functiona benefit associated with these drugs is fet to be cinicay reevant, it is not known whether the observed improvement in cycing capacity woud transate into better performances in different activities of daiy iving, such as waking. To date, cinica trias assessing the impact of sametero on waking performance in COPD patients have ed to disappointing resuts [6, 10, 11]. However, these trias used the 6-min waking test (6MWT), a test recenty shown to ack sensitivity to bronchodiation [12, 13]. Thus, it is possibe that the impact of sametero on waking performance was underestimated by these cinica trias. Recenty, the endurance shutte waking test (ESWT), an externay paced fied waking test, was found to be responsive to bronchodiation and rehabiitation [13 15]. The present investigation was therefore undertaken to test, in patients with COPD, the hypothesis that the ESWT is responsive in detecting improvement in waking capacity foowing a singe dose of sametero. More specificay, the objectives of the study were: 1) to measure the acute changes in waking performance induced by a singe dose of SUPPORT STATEMENT V. Pepin and F. Matais are research schoars of the Fonds de a Recherche en Santé du Québec (Quebec, Canada). The study s registration number at CinicaTrias.gov is NCT STATEMENT OF INTEREST Statements of interest for J. Miot and F. Matais, and the study itsef can be found at misc/statements.shtm European Respiratory Journa Print ISSN Onine ISSN c EUROPEAN RESPIRATORY JOURNAL VOLUME 31 NUMBER 3 579

2 ENDURANCE SHUTTLE WALKING TEST IN COPD C. BROUILLARD ET AL. sametero against those induced by a pacebo; and 2) to evauate the physioogica (minute ventiation (V9E), oxygen uptake (V9O 2 ), carbon dioxide production (V9CO 2 ), cardiac frequency (fc) and inspiratory capacity) and symptomatic (dyspnoea) responses during each waking test to provide a mechanistic expanation of the findings. METHODS Subjects Patients with cinicay stabe COPD participated in the study. Incusion criteria were as foows: 1) age o50 yrs; 2) current or past smoking history of o10 pack-yrs; 3) forced expiratory voume in one second (FEV1) f70% of the predicted vaue; 4) FEV1/forced vita capacity (FVC) f70%; 5) no acute COPD exacerbation within the preceding 2 months; 6) no history of asthma; 7) no significant arteria oxygen desaturation (,85%) at rest or during exercise; and 8) no other active condition that coud infuence exercise toerance. Patients on ong-acting antichoinergics were excuded from the study due to the ong wash-out period required for this medication. No participant was invoved in pumonary rehabiitation in the previous year. The research protoco was approved by the Institutiona Ethics Committee (Hôpita Lava, Quebec City, QC, Canada) and a signed, informed consent was obtained from each subject. Study design The study required five visits to the research faciity. Each visit was separated by o48 h and f4 days. The first visit incuded a baseine assessment of pumonary function and an incrementa shutte waking test (ISWT). The foowing two visits (visits 2 and 3) were used to famiiarise participants to the ESWT. The goa of the famiiarisation was to reduce the earning effect that typicay occurs when an individua competes the same endurance test severa times [8]. Patients whose ESWT at visit 2 and 3 were not reproducibe (when the difference in endurance time between visit 2 and 3 was.2 min) or onger than 20 min were excuded. For the remaining two visits (visits 4 and 5), subjects entered a crossover design where they competed one ESWT at each visit, min after the inhaation of 50 mg of sametero or the inhaation of a pacebo. Pumonary function tests were performed before (pre-dose) and min after (post-dose) the inhaation of the pacebo or sametero. The medication was administered in a randomised and doube-bind fashion using the Diskus1 (GaxoSmithKine, Ware, UK) device, which was identica in appearance between pacebo and active medication. Treatment sequence was determined using a random number tabe. A visits were conducted at the same time of the day for each subject. Subjects remained on their usua medication between visits. Short-acting b 2 -agonists and short-acting antichoinergics were stopped 6 h preceding visits 2 5, whie theophyines and ong-acting b 2 -agonists were stopped 48 h before visits 4 and 5. Inhaed sabutamo (short-acting b 2 -agonist) was used as rescue medication when subjects had to stop their medication for 48 h. Finay, subjects were asked to avoid smoking, caffeine, dark chocoate, coa beverages, heavy meas, acoho and major physica exertion prior to visits because these factors can infuence exercise performance. Pumonary function testing Standard pumonary function tests, incuding spirometry, ung voumes and diffusing capacity of the ung for carbon monoxide were measured according to previousy described guideines [16]. Resuts were compared with predicted norma vaues from the European Community for Coa and Stee/ European Respiratory Society [17]. Maximum vountary ventiation was estimated by mutipying FEV1 by 35 [18]. Incrementa waking exercise test Peak waking capacity was determined with the ISWT [19], which was performed in an encosed corridor on a fat 10 m- ong course. The course was identified by two cones, each positioned 0.5 m from either end to aow patients to wak in a circe and thereby avoid the need for abrupt changes in direction. Patients had to foow the rhythm dictated by the audio signa. Waking speed was initiay set at 0.5 m?s -1 and subsequenty increased by 0.17 m?s -1 every minute unti the patient reached a symptom-imited maximum. Encouragement was provided during the test and patients received standardised instructions to wak for as ong as possibe. Endurance waking exercise test Endurance waking capacity was determined with the ESWT. The ESWT was performed on the same course as the ISWT in accordance with pubished guideines [20]. After 1.5 min of warm up, waking speed was set at the speed corresponding to 80% of peak V9O 2, as predicted from the ISWT [20]. Before each ESWT, patients received standardised instructions to wak for as ong as possibe, athough there was a predetermined 20- min maximum. No encouragement was provided during these tests to avoid any potentia confounding effect on exercise performance [21]. Reproducibiity criteria were set at f2 min or 10% between consecutive ESWT. Physioogica measures During each exercise test, gas exchange parameters (V9O 2, V9CO 2, V9E and arteria oxygen saturation measured by puse oximetry), respiratory frequency (fr), tida voume (VT) and fc were monitored breath by breath with a portabe teemetric system (Oxycon Mobie; Viasys Heathcare GmbH, Hoechberg, Germany). This system is both ight (950 g incuding bet, battery and mask) and compact, and consists of a facemask, fc monitor, battery, transmitting unit (containing the O 2 and CO 2 gas anaysers) and receiving unit. The voume sensor and gas anaysers were caibrated before each test. Patients were asked to perform inspiratory capacity manoeuvres at 2-min intervas during the exercise period. This was carried out to foow changes in operationa ung voumes occurring during exercise, as described previousy [22]. When end-expiratory voume was stabe, as indicated by rea-time fow voume oops, subjects were asked, at the end of a norma expiration, to take a deep inspiration to tota ung capacity. Subjective measures Dyspnoea and perception of eg fatigue were evauated at rest and at end exercise using the modified 10-point Borg scae [23]. Dyspnoea was aso evauated at 2-min intervas during the exercise tests. At the end of each test, patients were asked to identify the main reason for which they stopped the test. 580 VOLUME 31 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

3 C. BROUILLARD ET AL. ENDURANCE SHUTTLE WALKING TEST IN COPD Statistica anaysis Resuts are reported as mean SD, uness otherwise stated. The eve of significance of a50.05 was used for a anayses. The endurance time was defined as the duration of waking at 80% maximum capacity, excuding the 1.5-min warm-up period. Comparisons of the vaues observed with sametero and pacebo were made using a 262 crossover design in which the period, sequence and treatment effects were considered. In order to study possibe determinants of the improved waking capacity after bronchodiation, mutipe regression anaysis was performed using the changes in waking endurance time as the dependant variabe and the post-bronchodiator changes in FEV1, FVC, functiona residua capacity, inspiratory capacity and dyspnoea at isotime during exercise as independant variabes. Isotime was defined as the atest exercise time that was reached on both ESWT. The sampe size cacuation was based on the assumption that the improvement in the waking endurance time with sametero shoud be at east of simiar magnitude to that of ipratropium bromide ( s) [14]. It was cacuated that 20 patients woud be needed to compete the study with a power of 0.85 and a type-i error of RESULTS Subjects The study fow chart is presented in figure 1. In tota, 28 patients initiay vounteered to participate in the study but ony 20 patients were actuay randomised at visit 4 and received the study medication. These patients a competed the study. The foowing resuts pertain to this popuation. Subject characteristics are presented in tabe 1. Of the study group, 30% were femaes. Patients had, on average, moderate-to-severe airfow obstruction with mid hyperinfation and gas trapping at rest. Pumonary function Pre- and post-dose pumonary function measurements are shown in tabe 2. Significant drug effects were found after treatment with sametero compared with pacebo. The preand post-bronchodiator improvements in FEV1 and FVC and reduction in residua voume were significanty arger for sametero compared with pacebo (tabe 2). Endurance time and waking distance No sequence or carry-over effect was observed in the present investigation. There was a significant improvement in waking performance (difference in endurance time sametero-pacebo: s; p50.02) and waking distance (difference in waking distance sametero-pacebo: m; p50.02) with sametero inhaation. Individua data for changes in endurance time from the pacebo to the sametero condition for the ESWT are shown in figure 2. In mutipe regression anaysis, the change in Borg at isotime and post-bronchodiator increase in FVC expained 71% of the variance in the endurance time with bronchodiation. The post-bronchodiator changes in FEV1 or inspiratory capacity did not improve the abiity to predict the changes in endurance time in the mutipe regression anaysis. Physioogica response Time course and end-exercise vaues for dyspnoea under the pacebo and sametero conditions are shown in figure 3. Sametero significanty reduced dyspnoea at isotime (difference in dyspnoea sametero-pacebo: ; p50.006), as TABLE 1 Subject characteristics and data at peak exercise Screened (n=56) Evauated at visit 1 3 (n=28) Randomised at visit 4 (n=20) Patients not evauated (n=28) Recent exacerbation (n=6) Coud not be reached (n=3) Refusa (n=13) Use of tiotropium (n=1) Contraindication to exercise (n=5) Patients excuded (n=8) Refusa (n=3) FEV1 >70% predicted (n=2) Exercise duration >20 min (n=2) Exercise not reproducibe (n=1) Vaue % predicted Subjects 20 Femaes 6 (30) Age yrs 65 6 BMI kg?m FEV1 L FVC L FEV1/FVC % TLC L IC L FRC L RV L Sp,O2 % rest DL,CO % pred Peak V9O 2 ml?kg -1?min Peak V9O2 L?min Peak V9E L?min V9E/MVV peak % Peak fc beats?min Competed the study (n=20) FIGURE 1. Fow chart of the study. FEV1: forced expiratory voume in one second. Data are presented as n, n (%) and mean SD. BMI: body mass index; FEV1: forced expiratory voume in one second; FVC: forced vita capacity; TLC: tota ung capacity; IC: inspiratory capacity; FRC: functiona residua capacity; RV: residua voume; Sp,O 2: puse oxygen saturation; DL,CO: diffusing capacity of the ung for carbon monoxide; V9O2: oxygen uptake; V9E: minute ventiation; MVV: maximum vountary ventiation; fc: cardiac frequency. c EUROPEAN RESPIRATORY JOURNAL VOLUME 31 NUMBER 3 581

4 ENDURANCE SHUTTLE WALKING TEST IN COPD C. BROUILLARD ET AL. TABLE 2 Pre- and post-dose pumonary function measurements Pacebo Sametero DSametero (post-pre) Dpacebo (post-pre) Pre Post Pre Post FEV1 L # FVC L # FRC L TLC L RV L * IC L Data are presented as mean SD. FEV1: forced expiratory voume in one second; FVC: forced vita capacity; FRC: functiona residua capacity; TLC: tota ung capacity; RV: residua voume; IC: inspiratory capacity. *: p,0.05; # :p, shown in tabe 3 and figure 3. The cardiorespiratory response to ESWT was simiar between the pacebo and sametero conditions. Interestingy, patients were abe to reach greater VT ( L; p50.005) at end exercise after sametero. Endexercise dyspnoea was simiar between the two conditions. Inspiratory capacity measurement whie waking was chaenging and some patients were unabe to perform the manoeuvres. In others, a drift in the end expiratory ung voume was observed, preventing reiabe estimation of inspiratory capacity. In the eight out of 20 patients in whom this procedure was competed, inspiratory capacity at isotime was 220 ml greater with sametero compared with pacebo (p50.07). Locus of symptom imitation The perception of dyspnoea and eg fatigue at end exercise was not significanty atered by sametero. During the sametero condition, 12 patients (60%) cited dyspnoea as the main imiting factor, whereas four (20%) cited eg fatigue and four (20%) the combination of both symptoms. For the pacebo condition, 14 patients (70%) cited dyspnoea, two (10%) eg fatigue and four (20%) the combination of both symptoms. Endurance time s Pacebo # Sametero FIGURE 2. Individua data for changes in endurance time from the pacebo to the sametero condition for the endurance shutte waking test. The group mean for each experimenta condition is represented by the horizonta bars. # : end exercise endurance time p DISCUSSION The major finding of the present study was that the ESWT enabed the detection of functiona changes after bronchodiation in patients with COPD. In addition to the improvement in waking endurance time with sametero, a reduction in dyspnoea at a given exercise time and a tendency toward reduced dynamic hyperinfation during waking were aso observed. There is growing interest in demonstrating the efficacy of bronchodiation on functiona status in patients with COPD [7 9]. To this end, the utiity and responsiveness of constant workrate cycing exercise to pharmacotherapy have been confirmed in arge cinica trias [7 9]. Despite providing convincing physioogica evidence of the efficacy of bronchodiation in patients with COPD, the cinica reevance of these findings may be questioned since cycing is not a typica activity of daiy iving in patients with COPD [24]. Waking woud appear an obvious aternative to cycing in order to address the imitation of cycing-based indices of exercise capacity. Athough the initia experience with the 6MWT to evauate the effects of bronchodiation was disappointing [12], PEPIN and co-workers [13, 14] have reported more encouraging resuts using the ESWT. In these investigations, the ESWT has proved to be sensitive to acute bronchodiation and more responsive to this intervention than the 6MWT [13, 14]. The current state of knowedge about the efficacy of sametero in improving waking capacity is consistent with these notions. Three previous investigations reported that sametero did not improve 6-min waking distance, casting doubt on the efficacy of this medication in improving functiona status [6, 10, 11]. In contrast, by using a waking protoco with better evauative properties than the 6MWT, the present investigation confirms that a ong-acting b 2 -agonist may improve waking capacity in patients with COPD. This indicates that the evauative properties of a given exercise test have to be considered when designing cinica trias. The ESWT was initiay deveoped as a simpe fied exercise test for the measurement of response to therapy in patients with COPD [20]. The use of portabe technoogy, now aowing a detaied physioogica evauation during waking and the assessment of dyspnoea perception, makes it possibe to expore possibe mechanisms of improvement in waking 582 VOLUME 31 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

5 C. BROUILLARD ET AL. ENDURANCE SHUTTLE WALKING TEST IN COPD Dyspnoea Borg n n # 0 Rest Time min FIGURE 3. Time course ($ and #) and peak end exercise vaues (& and h) for dyspnoea under the pacebo ($ and &) and sametero (# and h) conditions for the endurance shutte waking test. At 4 min, dyspnoea scores were avaiabe for 19 out of 20 patients. There was a significant reduction in dyspnoea at isotime. Data are presented as mean SD. # :p TABLE 3 End exercise and isotime measurements during the endurance shutte waking test End exercise Isotime Pacebo Sametero Pacebo Sametero Exercise time s " Distance m " Dyspnoea Borg Leg discomfort Borg V9O 2 m?kg -1?min V9O2 L?min V9CO2 L?min V9E L?min V9E/MVV # % RER fr breaths?min VT L IC L e fc beats?min Sp,O 2 % capacity as it is often carried out during cycing [7 9]. The changes in breathing pattern with sower fr and arger VT were sma but consistent in magnitude with previous reports [7 9]. An interesting novety of the present investigation was the possibiity of performing, in a subset of patients, repeated measurements of inspiratory capacity whie they were actuay waking in the corridor and of monitoring the degree of dynamic hyperinfation occurring during waking exercise. The magnitude of improvement in inspiratory capacity with bronchodiation was consistent with previous cinica trias [7 9]. Reduced perception of dyspnoea at isotime with bronchodiation together with the improvement in FVC, a refection of more compete ung emptying and reduced gas trapping, were important determinants of the improvement in endurance time, as indicated by the mutipe regression anaysis. The present study confirms that the ESWT, in conjunction with a portabe exercise circuit, is an appropriate exercise modaity for the assessment of the functiona and physioogica responses to bronchodiation. An interesting feature of waking is that it induces ess eg fatigue compared with other exercise modaities, such as cycing [14, 25]. This coud be important given that the occurrence of eg fatigue during exercise may prevent bronchodiation from fuy transating into better exercise capacity [26]. Indeed, in patients predominanty imited by quadriceps musce fatigue during cycing, the administration of a bronchodiator has been shown not to transate into improvements in exercise toerance [26]. Other advantages of the ESWT incude the fact that it may show, more consistenty than cycing, the functiona gain associated with bronchodiation [14] and that it is reevant for daiy iving. Nevertheess, it is important to appreciate the potentia shortcomings of waking as an evauating exercise modaity. Inspiratory capacity and dyspnoea are more difficut to assess during free waking compared with during stationary cycing. Aso, the pattern of ower imb musces recruitment is not as Data are presented as mean SD. V9O 2: oxygen uptake; V9CO 2: carbon dioxide output; V9E: minute ventiation; MVV: maximum vountary ventiation; RER: respiratory exchange ratio; fr: respiratory frequency; VT: tida voume; IC: inspiratory capacity; fc: cardiac frequency; Sp,O 2: puse oxygen saturation. # : MVV was cacuated from the post-bronchodiator forced expiratory voume in one second vaue obtained at the pacebo visit; " : p50.02; + : p50.006; 1 :p50.005; e : due to technica reasons, IC data are ony avaiabe for eight out of 20 patients (p50.07). we controed during waking than cycing. For instance, stride ength and strategies during turning, which may infuence the metaboic requirements, cannot be easiy controed from one waking test to the other. Despite this, waking appears to be a promising strategy for future cinica trias aiming to evauate the impact of pharmacotherapy on functiona status in patients with COPD. In the absence of a minima cinicay important difference for the ESWT, the significance of changes observed with treatment is difficut to interpret. Preiminary resuts from the current authors aboratory indicate that an 85-s improvement in ESWT is ikey to be perceived positivey by patients [27]. As such, it is possibe that the average gain in waking endurance obtained with sametero was not ony statisticay significant but aso cinicay meaningfu. Further investigation is necessary to better appreciate the cinica significance of the gain in waking capacity reported in the present study. In concusion, the present study demonstrates the abiity of sametero to improve waking capacity in patients with chronic obstructive pumonary disease. The study extends the resuts of previous investigations about the evauative properties of the endurance shutte waking test in patients with chronic obstructive pumonary disease. This exercise modaity can be used to assess endurance to constant work rate waking exercise. Detaied physioogica evauation can aso be obtained during free waking when couped with a portabe exercise circuit. c EUROPEAN RESPIRATORY JOURNAL VOLUME 31 NUMBER 3 583

6 ENDURANCE SHUTTLE WALKING TEST IN COPD C. BROUILLARD ET AL. ACKNOWLEDGEMENTS The authors acknowedge the hep of M. Béanger, M-J. Breton, B. Jean and J. Picard in performing the study and É. Nadreau (a Centre de Recherche, Hôpita Lava, Institut Universitaire de Cardioogie et de Pneumoogie de Université Lava, Quebec City, QC, Canada) for technica assistance. They aso thank G. Daige (Université Lava, Quebec City) for statistica assistance. REFERENCES 1 Hamiton AL, Kiian KJ, Summers E, Jones NL. Musce strength, symptom intensity and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995; 152: Goba Initiative for Chronic Obstructive Lung Disease. Goba Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pumonary Disease Date ast accessed: January 8, Date ast updated: December O Donne DE, Aaron S, Bourbeau J, et a. Canadian Thoracic Society recommendations for management of chronic obstructive pumonary disease: 2007 update. 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