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Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD
Respiratory Medicine (2012) 106, 1404e1412
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD Nivea D. Canto a, Jorge P. Ribeiro b,c, J. Alberto Neder d, Gaspar R. Chiappa b,* a
Exercise Biochemistry and Physiology Laboratory, Postgraduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Brazil b Exercise Pathophysiology Research Laboratory and Cardiology Division, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, RS, Brazil c Department of Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil d Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Respiratory Division, Department of Medicine, Federal University of Sa˜o Paulo and Paulista School of Medicine (UNIFESP-EPM), Sao Paulo, Brazil Received 17 October 2011; accepted 29 May 2012 Available online 28 June 2012
KEYWORDS Respiratory muscles; Oxygen; Inspiratory muscle strength; Constant work test
Summary Background: The addition of tiotropium bromide (TIO) to formoterol fumarate (FOR) improves exercise performance in patients with chronic obstructive pulmonary disease (COPD). In this study, we test the hypothesis that the addition of TIO to FOR may improve respiratory muscle performance and oxygen uptake kinetics after exercise in patients with COPD. Methods: Thirty eight patients with COPD were randomized to a 2 week treatment with FOR 12 mg twice a day plus TIO 18 mg once a day (FOR þ TIO) or FOR 12 mg twice a day plus placebo (FOR þ PLA) once a day, using a double-blind crossover design. Inspiratory muscle. Strength was measured before, immediately after, as well as 2, 5, and 10 min during recovery of exercise. Time to limit of tolerance on a constant work load exercise test and oxygen uptake kinetics during recovery were evaluated before and after intervention. Results: Only FOR þ TIO improved resting (63 10 cm to 84 11 cmH2O) and post-exercise (49 7 cm to 84 11 cmH2O) maximal inspiratory pressure. Time to limit of tolerance on the constant work load test was increased by FOR þ PLA and by FOR þ TIO, but the size of the increment was significantly larger with FOR þ TIO (40.7 7.6% vs. 84.5 8.2%; p < 0.05). Only FOR þ TIO improved oxygen uptake kinetics during recovery (69 21 to 60 18 s). The improvement in maximal inspiratory pressure (0.78, p < 0.001) and in oxygen uptake kinetics (0.91, p < 0.001) correlated with the change in time to the limit of tolerance. Conclusions: The addition of TIO to FOR improves inspiratory muscle strength and oxygen uptake kinetics after exercise in COPD patients. ª 2012 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ55 51 3359 6332. E-mail address: [email protected] (G.R. Chiappa). 0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2012.05.012
Tiotropium improves inspiratory muscle strength in COPD
Introduction It has been well established that dynamic hyperinflation is a key pathophysiological abnormality associated with effort-induced breathlessnes1 and exercise intolerance in patients with COPD.2 There is also growing evidence that skeletal muscle dysfunction is a major factor contributing to the reduced exercise capacity in COPD patients.3e5 In particular, respiratory muscle weakness may be associated with exercise intolerance and with the degree of dyspnea,6 most likely due to early diaphragmatic fatigue. Moreover, recent data support the view that the rate of decline in oxygen uptake during early recovery from exercise correlates well with exercise tolerance in patients with COPD.3 Previous studies have demonstrated that long-acting-b2 agonists as well as long-acting anticholinergic agents may improve exercise performance in COPD7e9 and recent evidence indicates that the anticholinergic agent tiotropium bromide (TIO) is superior to the b2-agonist salmeterol in improving pulmonary function and preventing exacerbations.10e12 Moreover, the association of bronchodilators of different pharmacological classes may improve efficacy and reduce the risk of side effects, when compared to increasing the dose of a single agent.1 We have previously shown that the addition of TIO to the b2agonist formoterol fumarate (FOR) improves effortinduced dynamic hyperinflation and exercise endurance in patients with moderate-to-severe COPD,1 but little is known on the effects of bronchodilators on respiratory muscle function in this patient population. Indeed, Weiner et al13 and O’Donnell et al37 showed no effect of salmeterol administration on inspiratory muscle strength and endurance in patients with COPD. Therefore, the present trial was conducted to evaluate the effects of the addition of TIO to FOR on inspiratory muscle function and early recovery oxygen uptake kinetics in patients with COPD.
Methods
1405 written, informed consent (UNESC 79/2010) as approved by the Institutional Medical Ethics Committee.
Study design A prospective double-blind, randomized, placebocontrolled, and crossover trial was conducted to compare the use of FOR plus Placebo (FOR þ PLA) and FOR plus TIO (FOR þ TIO). The design of the study was the same to that of our previous trial (Fig. 1).1 In short, after the screening visit the patients entered a run-in period in which they discontinued all long-acting bronchodilators and corticosteroids. If necessary patients could use a short-acting bronchodilator (salbutamol 120 mg/ipratropium 20 mg, Combivent, Boehringer Ingelheim GmbH, Ingelheim, Germany). Patients were then assigned to a 2 week treatment period with FOR dry powder capsules 12 mg BID (Fluir, Mantecorp Plc, Rio de Janeiro, Brazil) plus PLA QD via Handihaler (Boehringer Ingelheim GmbH, Ingelheim, Germany) or the same FOR regimen plus TIO dry powder capsules 18 mg QD via Handihaler (Spiriva, Boehringer Ingelheim GmbH, Ingelheim, Germany). After a 2 week treatment period, patients discontinued all long-acting BD for 7 days and crossed-over for a second 2 week-period on the alternative regimen.1 Throughout this protocol, 5 visits were performed. In the first visit, patients underwent clinical evaluation, pulmonary function testing, blood gas analysis, and a symptomlimited incremental cardiopulmonary exercise test on their current medical regimen. A run-in period of 7 days was allowed for discontinuation of anticholinergic and b-adrenergic bronchodilators and patients were randomized to receive FOR þ PLA or FOR þ TIO for a period of 2 weeks. A 7 day period of washout was allowed and patients were crossed over to receive the alternative treatment regimen for a second 2 week period. Before (visits 2 and 4) and after (visits 3 and 5) the first and the second 2 week intervention period, pulmonary function, and inspiratory strength, as well as a constant work rate test (CWT) to the limit of tolerance (Tlim) were obtained.
Patient population Patients with stable COPD, who met the criteria defined by the Global Initiative for Chronic Obstructive Lung Disease Statement,14 with a long history of smoking (>20 packyears) were recruited for the trial. None of the patients recruited for this study participated in our previous trial.1 Main exclusion criteria were: COPD exacerbation or respiratory infection in the month before recruitment, change in use of oral or inhaled corticosteroids and xanthine agents in the month prior to recruitment, diagnosis of current or previous asthma, allergic rhinitis or other atopic disease and peripheral eosinophilia> 400/mm3, inability to stop the usual bronchodilator therapy prior to initial testing, need for therapy with continuous oxygen, or oxygen saturation <89% at rest, and contraindication for performing a clinical exercise test. Patients who previously used TIO or FOR were not recruited for the study and patients who presented exacerbations during the development of the protocol were withdrawn from the final analysis. All subjects gave
Run-in 7d
Patients
Visit 1
•Clinical evaluation •Lung function • incCPTX
2 wks
Wash out 7d
2 wks
Formoterol + Placebo
Formoterol + Tiotropium
Formoterol + Tiotropium
Formoterol + Placebo
R
Visit 2
•Lung function •ctCPX •PImax
Visit 3
Visit 4
Visit 5
•Lung function pre/post treatment •ctCPX •PImax
Figure 1 Design of the study. IncCPTX Z incremental cardiopulmonary test; ctCPX Z constant cardiopulmonary test; PImax Z inspiratory muscle strength.
1406
Measurements Pulmonary function tests and arterial blood gases Standard pulmonary function tests, including spirometry and diffusing capacity of the lung for CO (DLCO) were performed as previously described,1 using the Vitalograph spirometer (Hand-Held 2021 instrument, Ennis, Ireland) and expressed as percentage of predicted for the adult Brazilian population.15,16 At visit 1, pulmonary function tests were performed before and 20 min after inhalation of salbutamol 400 mg, via metered-dose inhaler. At visits 2 and 4, pulmonary function tests were performed without the administration of long- or short-acting bronchodilators. At visits 3 and 5, pulmonary function tests were performed before (trough effect) and 2 h after (peak effect) the administration of study medications.1,15e17 Arterial partial pressures for O2 and CO2 were obtained during visit 1 from samples taken by radial artery puncture, and analyzed in the ABL 330 system (Radiometer, Copenhagen, Denmark).
Inspiratory muscle strength Maximal inspiratory pressure (PImax) was measured at visits 2 and 4 without the administration of long- or short-acting bronchodilators and at trough on visits 3 and 5. PImax was measured using a pressure transducer (MVD-500 V.1.1 Microhard System, Globalmed, Porto Alegre, Brazil), as previously described.18 The baseline PImax measurements were repeated at least 12 times to find the mean 6 measurements with less than 10% of variation.19 PImax was also measured once immediately after Tlim, and on the 2nd, 5th and 10th minute after the CWT.
Exercise tests All exercise tests were performed on an electronically braked cycle ergometer (Inbrasport, Porto Alegre, Brazil) at 60 rpm. Standard metabolic and ventilatory responses were measured breath-by-breath using a calibrated, computer-based system (K4b,2 Cosmed, Rome, Italy). Arterial oxyhemoglobin saturation (SpO2) was determined by pulse oximetry (POX 010e340, Mediaid, Torrance, USA). The incremental exercise test started with 2 min unloaded cycling and increments of 5e10 W per min were added until exhaustion. Gas exchange variables were averaged _ 2peak ) was defined as every 5 s, and peak oxygen uptake (VO the highest value achieved during the test. Peak gas exchange values are expressed as percentage of predicted _ 2 at the first ventilatory for the Brazilian population.20 VO threshold was estimated by the V-slope method as previously described.17 Heart rate (HR) was determined using the ReR intervals from a 12-lead electrocardiogram. Subjects were also asked to rate their ‘shortness of breath’ at exercise cessation using the 0e10 Borg’s category-ratio scale.21 The CWT to Tlim was performed at visits 2 and 4 without the administration of long- or short-acting bronchodilators and at trough effect on visits 3 and 5. The constant power _ 2 that exceeded the first output was chosen to elicit an VO
N.D. Canto et al. ventilatory threshold by a value of 60% of the difference _ 2peak and ventilatory threshold VO _ 2 (w80% between VO 22 peak work rate). Tlim was defined as the point in time when patients signaled to stop exercising or could not maintain the required pedaling rate for 10 s, despite being encouraged by the investigators. Serial inspiratory capacity (IC) maneuvers were performed every 2 min during the test. Assuming that total lung capacity (TLC) remains constant during exercise, IC maneuvers provide an estimate of end-expiratory lung volume (EELV Z TLC e IC).2,23e25
_ 2 kinetics Off-transient VO _ 2 data during recovery of from CWT Breath-by-breath VO were interpolated second-by-second (SigmaPlot 11.0, Systat Software, San Jose, CA) and oxygen uptake kinetics during recovery were calculated as previously described.22,26 In short, the time constant of the decay in _ 2 during recovery from CWE (tVO _ 2off ) was determined by VO fitting an exponential curve, using the value at the end of exercise as baseline. The equation applied27,28 was: _ 2 ðtÞZVO _ 2 base þ DVO _ 2 et=t 1 VO _ 2 ðtÞ is the VO _ 2 at time t, VO _ 2 base is the VO _ 2 at Where VO _ the end of exercise, DVO2 is the amplitude of the response during recovery, and t is the time constant. The time constant was derived by nonlinear regression using leastsquares and iterative techniques.
Statistical analysis Considering the 2 2 crossover design, a sample size of 30 patients was estimated to detect a between-treatment difference in post-exercise PImax of 25% with b and a errors set at 15% and 5%, respectively. Data are reported as mean SD or median (range). Repeated measures analysis of variance (ANOVA) was used to test for significant differences at different visits and time points, according to each treatment. Non-paired or paired t-tests were used as appropriate. Pearson’s product moment correlation was used to assess the level of association between continuous variables. Differences were declared significant if p < 0.05.
Results Fig. 1 shows the design of the study. Forty nine patients were assessed for eligibility. Five patients did not meet inclusion criteria and 3 refused to participate. Therefore, 41 patients were randomized. Twenty one patients were randomized to first receive FOR þ TIO, but 1 patient had an exacerbation during the first intervention period and another patient had an exacerbation during the washout period. Twenty patients were randomized to first receive FOR þ PLA, but 1 patient had an exacerbation during the first intervention period. Therefore, 19 patients in each group crossed to the second part of the trial and all completed the study.
Tiotropium improves inspiratory muscle strength in COPD
Baseline pulmonary function and maximal exercise capacity As shown in Table 1, patients with COPD had moderate-tosevere airflow obstruction with increased static lung volumes and reductions in DLCO. They had mild reduction in resting PaO2 and SaO2, but normal PaCO2. Exercise tolerance was markedly reduced, most likely due to pulmonaryventilatory limitation, as suggested by increased VE peak/ MVV. Breathlessness and leg effort were similarly described as the exercise-limiting symptoms.
Pulmonary function Table 2 shows the results of pulmonary function test before and after 2 weeks of treatment, including effects at trough (before medication) and at peak (2 h after medication).
Table 1
Baseline characteristics. Values
Age, years Body Mass Index, kg m2 Pulmonary Function FEV1, L (%predicted) FVC, L (%predicted) FEV1/FVC IC, L (%predicted) TLC, L (%predicted) RV, L (%predicted) DLCO, (% predicted) Arterial blood gases PaO2, mmHg SaO2, % PaCO2, mmHg Cardiopulmonary exercise testing _ 2 peak, ml min-1 VO _ 2 peak, % of predicted VO _ 2 peak, ml min-1 VCO RER peak _ peak, L min1 VE _ peak/MVV VE VT peak, L f peak, rpm SpO2 peak, % HR peak, % predicted Borg dyspnea scores Borg leg effort scores
56 7 25 3 1.21 0.33 2.66 0.48 0.45 0.14 2.02 0.34 6.02 0.99 3.01 0.43 55 14
(44 9) (42 8) (78 18) (108 12) (168 48)
69 8 92 2 39.5 4.5 988 183 60 12 961 350 0.97 0.09 37 8 0.71 0.12 1.12 0.18 34 6 89 4 88 10 7 (4e9) 6 (1e10)
Values are means standard deviation, except for symptoms (median and range). Definition of abbreviations: FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity; IC Z inspiratory capacity; TLC Z total lung capacity; RV Z residual volume; DLCO Z lung diffusing capacity for carbon monoxide; Pa Z arterial partial _ 2 Z oxygen uptake; pressure; Sa Z arterial saturation. VO _ 2 Z carbon dioxide output; RER Z ratio exchange ratio; VCO _ Z minute ventilation; MVV Z maximal voluntary ventilation; VE VT Z tidal volume; f Z respiratory frequency; SpO2 Z oxyhemoglobin saturation by pulse oximetry; HR Z heart rate.
1407 Both interventions resulted in improvement in FEV1, FVC, IC and EELV, but FOR-TIO led to greater changes in FEV1, IC and EELV than FOR-PLA.
Inspiratory muscle strength Fig. 2 shows PImax evaluated at rest, at the end of CWT, and at 2, 5, and 10 min during recovery. FOR þ TIO improved PImax at rest, immediately after exercise and during recovery, while FOR þ PLA improved PImax only at 10 min during recovery. Overall, FOR þ TIO resulted in significantly larger increments in PImax at all points of comparison.
Constant work exercise test After 2 weeks of intervention, Tlim during CWT was increased by FOR þ PLA (501 178 s to 702 145 s; p < 0.05) and by FOR þ TIO (488 150 s vs. 899 123; p < 0.05), but the size of the increment was significantly larger with FOR þ TIO (40.7 7.6% vs. 84.5 8.2%; _ 2 , VCO _ 2 , V_ E , and p < 0.05). As shown in Table 3, at Tlim, VO VT were increased only by FOR þ TIO, while respiratory exchange ratio, breathing frequency, heart rate, and scores for dyspnea and leg effort were unchanged by either intervention. V_ E =MVV, VT, EELV, and IC were improved by both interventions, but FOR þ TIO resulted in a significantly larger effect. _ 2 kinetics after constant work exercise was Pulmonary VO improved only with FOR þ TIO. Fig. 3 depicts the responses of a representative patient, and Table 4 shows that the amplitude increased while the time constant and the time _ 2 kinetics decreased with FOR þ TIO. delay of recovery VO Considering all patients in the analyses, at baseline, PImax was significantly correlated to Tlim (0.51, p < 0.01) _ 2off and to tO2off (0.65, p < 0.01). Likewise, baseline tVO
was significantly correlated to Tlim (0.77, p < 0.001). The change in PImax after intervention correlated with the change in Tlim (0.78, p < 0.001) and with the change in _ 2off (0.83, p < 0.001). Finally, the change in tVO _ 2off tVO with intervention was significantly correlated with the change in Tlim (0.91, p < 0.001).
Discussion In this randomized, crossover trial, we have shown that the addition of TIO to FOR improved inspiratory strength at rest and after exercise and accelerated recovery oxygen in patients with COPD. Moreover, in a different group of patients, we confirmed the findings of our previous trial,1 by showing that the addition of TIO to FOR improved exercise performance and effort-induced dynamic hyperinflation. To our knowledge, this is the first evidence that the addition of TIO to FOR improves respiratory muscle performance and recovery from exhaustive exercise in this patient population. Weiner et al13 found no improvement in inspiratory muscle strength and endurance after 6 weeks of treatment of salmeterol in patients with COPD. In agreement with those results, our patients also showed no improvement in inspiratory strength after 2 weeks of FOR, but the addition
1408 Table 2
N.D. Canto et al. Pulmonary function before and after 2 weeks of treatment. Formoterol þ placebo Before
Formoterol þ tiotropium
After 2 weeks Trough
FEV1, L FEV1, % pred FVC, L FVC, % pred FEV1/FVC, % IC, L IC, % pred EELV, L
1.09 40 2.55 69 40 1.66 61 4.35
0.21 11 0.66 10 8 0.45 45 0.77
1.11 41 2.56 70 42 1.78 65 4.24
Before
After 2 weeks
Peak 0.22 9 0.48 12 10 0.88 15 0.81
1.21 45 2.66 74 43 2.02 73 3.98
Trough
a,b
0.29 14a,b 0.98a,b 11a,b 15 0.49a,b 13a,b 0.67a,b
1.07 40 2.51 67 41 1.68 62 4.34
0.25 11 0.57 13 7 0.41 33 0.59
1.11 42 2.60 73 42 1.75 67 4.28
Peak 0.12 10 0.45 11 11 0.43 18 0.83
1.25 46 2.75 77 44 2.16 78 3.85
0.32a,b,c 12a,b 0.91a,b 12a,b 10 0.77a,b,c 13a,b,c 0.77a,b,c
Values are means SD. Definition of abbreviations: FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity; IC Z inspiratory capacity; EELV Z end-expiratory lung volume. a p < 0.05 from before within a given treatment. b p < 0.05 from trough within a given treatment. c p < 0.05 between-treatment comparison.
of TIO resulted in an increment of PImax of similar magnitude to that obtained by Weiner et al12 with inspiratory muscle training in their patients. Inspiratory muscle training may improve PImax by several mechanisms, including diaphragm hypertrophy,29 metabolic,30 and neuromuscular adaptations.31 Previous studies have demonstrated that b2-agonists may increase the maximal force generated by the diaphragm32,33 by affecting its length and geometry,34 which is mostly determined by lung volume.33 Furthermore, there is evidence that b2-agonists increase fat and carbohydrate oxidation, resulting in stimulation of hepatic glucose production.35,36 Despite these potential mechanisms for improvement in inspiratory muscle strength, we found that FOR administration had no significant effect on resting or post-exercise PImax (Fig. 2, left panel). In contrast, the addition of TIO resulted in a larger increment in FEV1 and inspiratory capacity (Table 2), as well as a significant improvement in resting PImax (Fig. 2). O’Donnell et al37 compared the effects of TIO to placebo
administered for 7e10 days in 11 patients with COPD. In contrast to our findings, they failed to demonstrate improvement in maximal inspiratory sniff pressure, which corrects for changes in operating volumes. Our trial included a much larger number of patients (38) and intervention was used for two weeks, therefore with a larger power to detect changes. Moreover, patients in both groups received FOR, reducing even more the possibility of a placebo effect. The mechanisms by which the addition of TIO might improve PImax at rest are not readily apparent from our data and we can only speculate on possible explanations. Since static maximal inspiratory pressure measured at the mouth does not correct for operating volumes, it is conceivable that changes in inspiratory volumes might have improved the length and geometry of the diaphragm, resulting in increased force as measured by PImax. This is partially supported by the finding of a small but significant larger improvement in EELV (Table 2) with the addition of TIO during the evaluation at rest.
Figure 2 Maximal inspiratory pressure (PImax) at rest, immediately constant work exercise, and at 2, 5 and 10 min during recovery before (open circles) and after (closed circles) intervention for the formoterol plus placebo (left panel) and for formoterol plus tiotropium (right panel). *P < 0.05 from baseline; yP < 0.05 between-treatment comparison.
Tiotropium improves inspiratory muscle strength in COPD
1409
Table 3 Measurements at the time to the limit of tolerance in the constant work tests before and after 2 weeks of intervention. Formoterol þ placebo Metabolic _ 2 , ml min1 VO _VCO2 , ml min1 RER Ventilatory V_ E , L min1 V_ E =MVV VT, L f, rpm IC, L EELV, L SpO2, % Cardiac HR, bpm HR, % pred Subjective Borg dyspnoea scores Borg leg effort scores
Formoterol þ tiotropium
Before
2 weeks
Before
2 weeks
1058 302 1004 299 0.94 0.08
1081 280 972 272 0.89 0.06
1010 260 947 275.0 0.93 0.08
1131 294a 1021 306.9 0.92 0.06
33.5 0.81 1.09 30 1.41 3.85 85
11.7 0.18 0.3 8 0.4 0.67 6
34.4 0.76 1.16 30 1.56 3.71 86
127 16 82 10 7 (3e10) 5 (0e10)
11.3 0.13a 0.3a 7 0.4a 0.54 6a
130 20 83 12 9 (1e10) 3.5 (0e10)
32.7 0.85 1.04 31 1.41 3.91 86
11.2 0.19 0.3 8 0.4 0.75 6
129 20 83 12 9 (3e10) 5 (0e10)
36.5 0.73 1.24 30 1.60 3.45 88
12.3b 0.14a,b 0.3a,b 9 0.3a,b 0.51a,b 6a
128 19 82 11 9 (1e10) 5.5 (0e10)
_ 2 Z oxygen uptake; VCO _ 2 Z carbon Values are means SD except for symptoms (median and ranges). Definition of abbreviations: VO dioxide output; RER Z respiratory exchange rate; VE Z minute ventilation; MVV Z maximal voluntary ventilation; VT Z tidal volume; f Z respiratory rate; IC Z inspiratory capacity; HR Z heart rate; SpO2 Z oxyhemoglobin saturation by pulse oximetry. a p < 0.05 from baseline. b p < 0.05 between-treatment comparison.
The measurement of PImax after exercise has been previously evaluated by randomized studies as a reliable indicator of inspiratory muscle fatigue.17 Previous studies have reported that exhaustive exercise may lead to a decline in PImax immediately after exercise in healthy subjects.38 This also happens to patients with chronic heart failure,6 especially those with inspiratory muscle weakness.18 In some COPD patients, inspiratory muscle function may be impaired, mainly due to dynamic hyperinflation.39,40 This may cause shortening of the diaphragm,
changing length-tension properties and decreasing PImax. Dynamic hyperinflation may also evoke reduction in inspiratory muscle strength by the abolition of the zone of apposition of the costal portion of the diaphragm with the rib cage, resulting in less lateral expansion of the thoracic cage during inspiration and inward recoil of the chest wall, which means that inspiratory muscles work not only against the lung elastic recoil but also against the elastic recoil of the chest wall.41 Exercise induces an increase in diaphragm work, which has to overcome the increase
_ 2 kinetics (off-transient) after constant work rate exercise in a representative patient with COPD. Panel A Figure 3 Pulmonary VO _ 2 kinetics before (continuous line) and after 2 weeks (dashed line) of formoterol plus placebo. Panel B shows interpolated shows VO _ 2 kinetics before (continuous line) and after 2 weeks (dashed line) of formoterol plus tiotroprium. Note the faster kinetics offVO transient [smaller time constant (t) of primary component].
1410 Table 4
N.D. Canto et al. Recovery measurements after constant work exercise before and after 2 weeks of intervention.
Variable
Formoterol þ placebo Before
Off-transient _ 2ðoffÞ VO A t TD MRT
1058 710 72.1 16.5 88
Formoterol þ tiotropium 2 weeks
302 105 18.7 5.2 6.8
1081 698 66.1 17.2 81
Before
280 88 15.3 4.5 9.7
1010 678 68.9 18.8 86
2 weeks 260 125 21.1 7.4 5.7
1131 801 60.4 14.2 71
294a,b,c 123a,b,c 17.8a,b,c 5.6a 8.1a,b,c
_ 2ðoffÞ Z oxygen uptake at the end of exercise (mL min1); A Z amplitude; Values are means SD. Definition of abbreviations: VO t Z time constant; TD Z time delay; MRT Z Mean response time (t þ TD). a p < 0.05 from basal within a given treatment. b p < 0.05 post vs. pre within a given treatment. c p < 0.05 between-treatment comparison.
elastic load and intrinsic positive end-expiratory pressure, by generating an abnormally higher proportion of PImax in terms of pleural pressure swings for a given tidal volume (called “ventilatory effort”).42 This may affect the pattern of breathing, causing dyspnea and higher dynamic hyperinflation, and potentially induces respiratory muscle fatigue.31 This response may be associated with increased end-expiratory lung volume (EELV) and reduction in exercise tolerance (inspiratory capacity to total lung capacity ratio, IC/TLC 0.28).43 In our study, we showed a reduction in PImax immediately after CWT in both treatments, which may reflect high-frequency fatigue of the respiratory muscles. The correlation between the change in PImax after intervention and the improvement in Tlim (r Z 0.72) suggests that in the change inspiratory muscle strength after TIO administration is a major determinant to the improvement in exercise performance in patients with COPD. In healthy subjects, the time required for the return of PImax to pre-exercise values is 2 min38 In previous reports, we and others have demonstrated that the time of recovery is prolonged in chronic heart failure patients with inspiratory muscle weakness.18,38 In the present study, it was observed that FOR þ TIO therapy reduced the recovery time of inspiratory muscle strength, which is suggestive with delayed development in diaphragmatic fatigue.38 This effect was present despite a longer exercise duration, higher metabolic rate and smaller ventilatory effort. It is important to remember that recovery of muscle energy stores depends on intrinsic histologic44 and biochemical muscle alterations, impaired O2 delivery to skeletal muscles and vascular dysfunction.22,45 Accordingly, we have demonstrated that patients with moderate to severe COPD have impaired central and peripheral cardiovascular responses to exercise that lead to slower kinetics of cardiac output and faster muscle deoxygenation profile following the onset of heavy-intensity exercise.22 In a previous study, we showed that the administration of inhaled short-acting bronchodilators reduces lung hyperinflation and the amplitude of muscle deoxygenation during high-intensity cycling exercise in patients with moderate to severe COPD, which are linked with faster on-exercise kinetics of cardiac output.17 The importance of the inspiratory _ 2 kinetics after exercise is underscored by the muscles in VO
high correlation between the change in PImax and the _ 2off (r Z 0.83) after intervention in improvement in tVO our patients. The potential limitation of our study lies in crossover design and small number of patients. Therefore further larger clinical trials with parallel design should be conducted to evaluate the effects of the addition of TIO to FOR on functional capacity and quality of life in patients with COPD. However, special care was taken to allow for an appropriate washout period between interventions, reducing the possibility of a carry-over effect. Moreover, we were able the reproduce the results or our previous trial1 in a different group of COPD patients, underscoring the consistency of our findings. Since the improvement of inspiratory muscle strength by the addition of TIO is in disagreement with the results of the smaller trial by O’Donnel et al,37 this particular subject should further evaluated, including studies to address the mechanism by which TIO may improve inspiratory muscle strength in COPD. In our study, we measured PImax for assessment inspiratory muscle strength, while O’Donnel et al,37 measured maximal inspiratory sniff esophageal pressure. Despite the known limitations of using a volitional test such as PImax46 as a measure of inspiratory muscle strength after exercise, the randomized, crossover design of the present study strongly indicates that TIO administration resulted in improvement in inspiratory muscle strength. Our results may have clinical implications. Previous studies have demonstrated success in enhancing exercise tolerance with TIO in COPD patients.1,46,47 The results of the present and as well as our previous trial1 underscore the usefulness of adding TIO to FOR to improve exercise performance in this patient population. Moreover, the improvement in oxygen uptake kinetics during recovery may impact on capacity of patients to perform intermittent exercise, which is used in daily activities. However, future large clinical trials should be conducted to test the hypothesis that this combined intervention may impact on clinical outcomes. In conclusion, the addition of TIO to FOR improves preand post-exercise inspiratory muscle strength and accelerates recovery oxygen uptake kinetics in patients with COPD. These physiological effects may partially explain the
Tiotropium improves inspiratory muscle strength in COPD
1411
improvement in exercise performance induced by the addition of TIO to FOR. 12.
Conflict of interest statement 13.
None of the authors have any potential conflict of interest related to the contents of this paper. Paulo J. C. Vieira is supported by a Doctoral Scholarship and Gaspar R. Chiappa receives a Post-doctoral Fellowship from the Brazilian Research Council (CNPq), Brasilia, Brazil.
14.
15.
Acknowledgements 16.
The authors would like to thank all colleagues from the Exercise Biochemistry and Physiology Laboratory for their friendly collaboration. Add JPR and JAN are an Established Investigator (level II) of the CNPq (Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo ´gico), Brazil. GRC was supported by a PhD Fellowship Grant from CAPES (Coordenac ¸˜ ao de Aperfeic ¸oamento de Pessoal de Nı´vel Superior), Brazil.
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18.
19.
References 1. Berton DC, Reis M, Siqueira AC, et al. Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD. Respir Med 2010;104(9):1288e96. 2. O’Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3(2):180e4. 3. Okamoto T, Kanazawa H, Hirata K, Yoshikawa J. Evaluation of oxygen uptake kinetics and oxygen kinetics of peripheral skeletal muscle during recovery from exercise in patients with chronic obstructive pulmonary disease. Clin Physiol Funct Imaging 2003;23(5):257e62. 4. Neder JA. On the issue of exercise normalcy. Eur Respir J 2009; 34(1):286e7. author reply 287e288. 5. Neder JA. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles vs. lower limb muscle dysfunction vs. dynamic hyperinflation. Interpretation of exercise intolerance in COPD requires an integrated, multisystemic approach. J Appl Physiol 2008;105(2):758e9. 6. Mancini DM, Henson D, LaManca J, Levine S. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 1992;86(3):909e18. 7. van der Vaart H, Postma DS, Grevink R, Roemer W, Ten Hacken N. Bronchodilation improves endurance but not muscular efficiency in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2011;6:229e35. 8. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24(1):86e94. 9. Maltais F, Hamilton A, Marciniuk D, et al. Improvements in symptom-limited exercise performance over 8 h with oncedaily tiotropium in patients with COPD. Chest 2005;128(3): 1168e78. 10. Briggs Jr DD, Covelli H, Lapidus R, Bhattycharya S, Kesten S, Cassino C. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD. Pulm Pharmacol Ther 2005;18(6):397e404. 11. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months
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with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58(5):399e404. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364(12):1093e103. Weiner P, Magadle R, Berar-Yanay N, Davidovich A, Weiner M. The cumulative effect of long-acting bronchodilators, exercise, and inspiratory muscle training on the perception of dyspnea in patients with advanced COPD. Chest 2000;118(3):672e8. Fabbri LM, Hurd SS. Global Strategy for the diagnosis, Management and prevention of COPD: 2003 update. Eur Respir J 2003;22(1):1e2. Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung function tests. I. Static volumes. Braz J Med Biol Res 1999;32(6):703e17. Neder JA, Andreoni S, Peres C, Nery LE. Reference values for lung function tests. III. Carbon monoxide diffusing capacity (transfer factor). Braz J Med Biol Res 1999;32(6):729e37. Berton DC, Barbosa PB, Takara LS, et al. Bronchodilators accelerate the dynamics of muscle O2 delivery and utilisation during exercise in COPD. Thorax 2010;65(7):588e93. Dall’Ago P, Chiappa GR, Guths H, Stein R, Ribeiro JP. Inspiratory muscle training in patients with heart failure and inspiratory muscle weakness: a randomized trial. J Am Coll Cardiol 2006;47(4):757e63. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166(4):518e624. Neder JA, Nery LE, Castelo A, et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomised study. Eur Respir J 1999;14(6):1304e13. Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995; 152(6 Pt 1):2021e31. Chiappa GR, Borghi-Silva A, Ferreira LF, et al. Kinetics of muscle deoxygenation are accelerated at the onset of heavy-intensity exercise in patients with COPD: relationship to central cardiovascular dynamics. J Appl Physiol 2008;104(5):1341e50. O’Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23(6):832e40. Neder JA, Fuld JP, Overend T, et al. Effects of formoterol on exercise tolerance in severely disabled patients with COPD. Respir Med 2007;101(10):2056e64. Cooper CB. Airflow obstruction and exercise. Respir Med 2009; 103(3):325e34. Chiappa GR, Queiroga Jr F, Meda E, et al. Heliox improves oxygen delivery and utilization during dynamic exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;179(11):1004e10. Linnarsson D. Dynamics of pulmonary gas exchange and heart rate changes at start and end of exercise. Acta Physiol Scand Suppl 1974;415:1e68. Ozyener F, Rossiter HB, Ward SA, Whipp BJ. Influence of exercise intensity on the on- and off-transient kinetics of pulmonary oxygen uptake in humans. J Physiol 2001;533(Pt 3): 891e902. Chiappa GR, Roseguini BT, Vieira PJ, et al. Inspiratory muscle training improves blood flow to resting and exercising limbs in patients with chronic heart failure. J Am Coll Cardiol 2008; 51(17):1663e71. Ribeiro JP, Chiappa GR, Neder JA, Frankenstein L. Respiratory muscle function and exercise intolerance in heart failure. Curr Heart Fail Rep 2009;6(2):95e101. Gosselink R, De Vos J, van den Heuvel SP, Segers J, Decramer M, Kwakkel G. Impact of inspiratory muscle training in patients with COPD: what is the evidence? Eur Respir J 2011; 37(2):416e25.
1412 32. Man WD, Mustfa N, Nikoletou D, et al. Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 2004;59(6):471e6. 33. Aubier M, Viires N, Murciano D, Medrano G, Lecocguic Y, Pariente R. Effects and mechanism of action of terbutaline on diaphragmatic contractility and fatigue. J Appl Physiol 1984; 56(4):922e9. 34. Grassino A, Goldman MD, Mead J, Sears TA. Mechanics of the human diaphragm during voluntary contraction: statics. J Appl Physiol 1978;44(6):829e39. 35. Kendall MJ, Clark NW, Haffner CA, Kong J, Hughes BA. Investigation of the effects of beta-2 stimulation on free fatty acids in man. J Clin Pharm Ther 1991;16(1):31e40. 36. Collomp K, Panse B, Candau R, Lecoq AM, De Ceaurriz J. Beta-2 agonists and exercise performance in humans. Sci Sport 2010; 25(6):281e90. 37. O’Donnell DE, Hamilton AL, Webb KA. Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD. J Appl Physiol 2006;101(4):1025e35. 38. Nanas S, Nanas J, Kassiotis C, et al. Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation 1999;100(5):503e8. 39. Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Diaphragm strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154(5):1310e7.
N.D. Canto et al. 40. Newell SZ, McKenzie DK, Gandevia SC. Inspiratory and skeletal muscle strength and endurance and diaphragmatic activation in patients with chronic airflow limitation. Thorax 1989;44(11): 903e12. 41. Hamid Q, Shannon J, Martin J. Physiologic basis of respiratory disease. BC Decker, Inc; 2005. 42. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation. The role of lung hyperinflation. Am Rev Respir Dis 1993;148(5):1351e7. 43. Albuquerque AL, Nery LE, Villaca DS, et al. Inspiratory fraction and exercise impairment in COPD patients GOLD stages II-III. Eur Respir J 2006;28(5):939e44. 44. Casaburi R. Skeletal muscle function in COPD. Chest 2000; 117(5 Suppl. 1):267Se71S. 45. Maltais F, LeBlanc P, Jobin J, Casaburi R. Peripheral muscle dysfunction in chronic obstructive pulmonary disease. Clin Chest Med 2000;21(4):665e77. 46. Troosters T, Weisman I, Dobbels F, Giardino N, Valluri SR. Assessing the impact of tiotropium on lung function and Physical activity in GOLD Stage II COPD patients who are Naive to Maintenance respiratory therapy: a study protocol. Open Respir Med J 2011;5:1e9. 47. Ambrosino N, Foglio K, Balzano G, Paggiaro PL, Lessi P, Kesten S. Tiotropium and exercise training in COPD patients: effects on dyspnea and exercise tolerance. Int J Chron Obstruct Pulmon Dis 2008;3(4):771e80.
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Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD Nivea D. Canto a, Jorge P. Ribeiro b,c, J. Alberto Neder d, Gaspar R. Chiappa b,* a
Exercise Biochemistry and Physiology Laboratory, Postgraduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Brazil b Exercise Pathophysiology Research Laboratory and Cardiology Division, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, RS, Brazil c Department of Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil d Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Respiratory Division, Department of Medicine, Federal University of Sa˜o Paulo and Paulista School of Medicine (UNIFESP-EPM), Sao Paulo, Brazil Received 17 October 2011; accepted 29 May 2012 Available online 28 June 2012
KEYWORDS Respiratory muscles; Oxygen; Inspiratory muscle strength; Constant work test
Summary Background: The addition of tiotropium bromide (TIO) to formoterol fumarate (FOR) improves exercise performance in patients with chronic obstructive pulmonary disease (COPD). In this study, we test the hypothesis that the addition of TIO to FOR may improve respiratory muscle performance and oxygen uptake kinetics after exercise in patients with COPD. Methods: Thirty eight patients with COPD were randomized to a 2 week treatment with FOR 12 mg twice a day plus TIO 18 mg once a day (FOR þ TIO) or FOR 12 mg twice a day plus placebo (FOR þ PLA) once a day, using a double-blind crossover design. Inspiratory muscle. Strength was measured before, immediately after, as well as 2, 5, and 10 min during recovery of exercise. Time to limit of tolerance on a constant work load exercise test and oxygen uptake kinetics during recovery were evaluated before and after intervention. Results: Only FOR þ TIO improved resting (63 10 cm to 84 11 cmH2O) and post-exercise (49 7 cm to 84 11 cmH2O) maximal inspiratory pressure. Time to limit of tolerance on the constant work load test was increased by FOR þ PLA and by FOR þ TIO, but the size of the increment was significantly larger with FOR þ TIO (40.7 7.6% vs. 84.5 8.2%; p < 0.05). Only FOR þ TIO improved oxygen uptake kinetics during recovery (69 21 to 60 18 s). The improvement in maximal inspiratory pressure (0.78, p < 0.001) and in oxygen uptake kinetics (0.91, p < 0.001) correlated with the change in time to the limit of tolerance. Conclusions: The addition of TIO to FOR improves inspiratory muscle strength and oxygen uptake kinetics after exercise in COPD patients. ª 2012 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ55 51 3359 6332. E-mail address: [email protected] (G.R. Chiappa). 0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2012.05.012
Tiotropium improves inspiratory muscle strength in COPD
Introduction It has been well established that dynamic hyperinflation is a key pathophysiological abnormality associated with effort-induced breathlessnes1 and exercise intolerance in patients with COPD.2 There is also growing evidence that skeletal muscle dysfunction is a major factor contributing to the reduced exercise capacity in COPD patients.3e5 In particular, respiratory muscle weakness may be associated with exercise intolerance and with the degree of dyspnea,6 most likely due to early diaphragmatic fatigue. Moreover, recent data support the view that the rate of decline in oxygen uptake during early recovery from exercise correlates well with exercise tolerance in patients with COPD.3 Previous studies have demonstrated that long-acting-b2 agonists as well as long-acting anticholinergic agents may improve exercise performance in COPD7e9 and recent evidence indicates that the anticholinergic agent tiotropium bromide (TIO) is superior to the b2-agonist salmeterol in improving pulmonary function and preventing exacerbations.10e12 Moreover, the association of bronchodilators of different pharmacological classes may improve efficacy and reduce the risk of side effects, when compared to increasing the dose of a single agent.1 We have previously shown that the addition of TIO to the b2agonist formoterol fumarate (FOR) improves effortinduced dynamic hyperinflation and exercise endurance in patients with moderate-to-severe COPD,1 but little is known on the effects of bronchodilators on respiratory muscle function in this patient population. Indeed, Weiner et al13 and O’Donnell et al37 showed no effect of salmeterol administration on inspiratory muscle strength and endurance in patients with COPD. Therefore, the present trial was conducted to evaluate the effects of the addition of TIO to FOR on inspiratory muscle function and early recovery oxygen uptake kinetics in patients with COPD.
Methods
1405 written, informed consent (UNESC 79/2010) as approved by the Institutional Medical Ethics Committee.
Study design A prospective double-blind, randomized, placebocontrolled, and crossover trial was conducted to compare the use of FOR plus Placebo (FOR þ PLA) and FOR plus TIO (FOR þ TIO). The design of the study was the same to that of our previous trial (Fig. 1).1 In short, after the screening visit the patients entered a run-in period in which they discontinued all long-acting bronchodilators and corticosteroids. If necessary patients could use a short-acting bronchodilator (salbutamol 120 mg/ipratropium 20 mg, Combivent, Boehringer Ingelheim GmbH, Ingelheim, Germany). Patients were then assigned to a 2 week treatment period with FOR dry powder capsules 12 mg BID (Fluir, Mantecorp Plc, Rio de Janeiro, Brazil) plus PLA QD via Handihaler (Boehringer Ingelheim GmbH, Ingelheim, Germany) or the same FOR regimen plus TIO dry powder capsules 18 mg QD via Handihaler (Spiriva, Boehringer Ingelheim GmbH, Ingelheim, Germany). After a 2 week treatment period, patients discontinued all long-acting BD for 7 days and crossed-over for a second 2 week-period on the alternative regimen.1 Throughout this protocol, 5 visits were performed. In the first visit, patients underwent clinical evaluation, pulmonary function testing, blood gas analysis, and a symptomlimited incremental cardiopulmonary exercise test on their current medical regimen. A run-in period of 7 days was allowed for discontinuation of anticholinergic and b-adrenergic bronchodilators and patients were randomized to receive FOR þ PLA or FOR þ TIO for a period of 2 weeks. A 7 day period of washout was allowed and patients were crossed over to receive the alternative treatment regimen for a second 2 week period. Before (visits 2 and 4) and after (visits 3 and 5) the first and the second 2 week intervention period, pulmonary function, and inspiratory strength, as well as a constant work rate test (CWT) to the limit of tolerance (Tlim) were obtained.
Patient population Patients with stable COPD, who met the criteria defined by the Global Initiative for Chronic Obstructive Lung Disease Statement,14 with a long history of smoking (>20 packyears) were recruited for the trial. None of the patients recruited for this study participated in our previous trial.1 Main exclusion criteria were: COPD exacerbation or respiratory infection in the month before recruitment, change in use of oral or inhaled corticosteroids and xanthine agents in the month prior to recruitment, diagnosis of current or previous asthma, allergic rhinitis or other atopic disease and peripheral eosinophilia> 400/mm3, inability to stop the usual bronchodilator therapy prior to initial testing, need for therapy with continuous oxygen, or oxygen saturation <89% at rest, and contraindication for performing a clinical exercise test. Patients who previously used TIO or FOR were not recruited for the study and patients who presented exacerbations during the development of the protocol were withdrawn from the final analysis. All subjects gave
Run-in 7d
Patients
Visit 1
•Clinical evaluation •Lung function • incCPTX
2 wks
Wash out 7d
2 wks
Formoterol + Placebo
Formoterol + Tiotropium
Formoterol + Tiotropium
Formoterol + Placebo
R
Visit 2
•Lung function •ctCPX •PImax
Visit 3
Visit 4
Visit 5
•Lung function pre/post treatment •ctCPX •PImax
Figure 1 Design of the study. IncCPTX Z incremental cardiopulmonary test; ctCPX Z constant cardiopulmonary test; PImax Z inspiratory muscle strength.
1406
Measurements Pulmonary function tests and arterial blood gases Standard pulmonary function tests, including spirometry and diffusing capacity of the lung for CO (DLCO) were performed as previously described,1 using the Vitalograph spirometer (Hand-Held 2021 instrument, Ennis, Ireland) and expressed as percentage of predicted for the adult Brazilian population.15,16 At visit 1, pulmonary function tests were performed before and 20 min after inhalation of salbutamol 400 mg, via metered-dose inhaler. At visits 2 and 4, pulmonary function tests were performed without the administration of long- or short-acting bronchodilators. At visits 3 and 5, pulmonary function tests were performed before (trough effect) and 2 h after (peak effect) the administration of study medications.1,15e17 Arterial partial pressures for O2 and CO2 were obtained during visit 1 from samples taken by radial artery puncture, and analyzed in the ABL 330 system (Radiometer, Copenhagen, Denmark).
Inspiratory muscle strength Maximal inspiratory pressure (PImax) was measured at visits 2 and 4 without the administration of long- or short-acting bronchodilators and at trough on visits 3 and 5. PImax was measured using a pressure transducer (MVD-500 V.1.1 Microhard System, Globalmed, Porto Alegre, Brazil), as previously described.18 The baseline PImax measurements were repeated at least 12 times to find the mean 6 measurements with less than 10% of variation.19 PImax was also measured once immediately after Tlim, and on the 2nd, 5th and 10th minute after the CWT.
Exercise tests All exercise tests were performed on an electronically braked cycle ergometer (Inbrasport, Porto Alegre, Brazil) at 60 rpm. Standard metabolic and ventilatory responses were measured breath-by-breath using a calibrated, computer-based system (K4b,2 Cosmed, Rome, Italy). Arterial oxyhemoglobin saturation (SpO2) was determined by pulse oximetry (POX 010e340, Mediaid, Torrance, USA). The incremental exercise test started with 2 min unloaded cycling and increments of 5e10 W per min were added until exhaustion. Gas exchange variables were averaged _ 2peak ) was defined as every 5 s, and peak oxygen uptake (VO the highest value achieved during the test. Peak gas exchange values are expressed as percentage of predicted _ 2 at the first ventilatory for the Brazilian population.20 VO threshold was estimated by the V-slope method as previously described.17 Heart rate (HR) was determined using the ReR intervals from a 12-lead electrocardiogram. Subjects were also asked to rate their ‘shortness of breath’ at exercise cessation using the 0e10 Borg’s category-ratio scale.21 The CWT to Tlim was performed at visits 2 and 4 without the administration of long- or short-acting bronchodilators and at trough effect on visits 3 and 5. The constant power _ 2 that exceeded the first output was chosen to elicit an VO
N.D. Canto et al. ventilatory threshold by a value of 60% of the difference _ 2peak and ventilatory threshold VO _ 2 (w80% between VO 22 peak work rate). Tlim was defined as the point in time when patients signaled to stop exercising or could not maintain the required pedaling rate for 10 s, despite being encouraged by the investigators. Serial inspiratory capacity (IC) maneuvers were performed every 2 min during the test. Assuming that total lung capacity (TLC) remains constant during exercise, IC maneuvers provide an estimate of end-expiratory lung volume (EELV Z TLC e IC).2,23e25
_ 2 kinetics Off-transient VO _ 2 data during recovery of from CWT Breath-by-breath VO were interpolated second-by-second (SigmaPlot 11.0, Systat Software, San Jose, CA) and oxygen uptake kinetics during recovery were calculated as previously described.22,26 In short, the time constant of the decay in _ 2 during recovery from CWE (tVO _ 2off ) was determined by VO fitting an exponential curve, using the value at the end of exercise as baseline. The equation applied27,28 was: _ 2 ðtÞZVO _ 2 base þ DVO _ 2 et=t 1 VO _ 2 ðtÞ is the VO _ 2 at time t, VO _ 2 base is the VO _ 2 at Where VO _ the end of exercise, DVO2 is the amplitude of the response during recovery, and t is the time constant. The time constant was derived by nonlinear regression using leastsquares and iterative techniques.
Statistical analysis Considering the 2 2 crossover design, a sample size of 30 patients was estimated to detect a between-treatment difference in post-exercise PImax of 25% with b and a errors set at 15% and 5%, respectively. Data are reported as mean SD or median (range). Repeated measures analysis of variance (ANOVA) was used to test for significant differences at different visits and time points, according to each treatment. Non-paired or paired t-tests were used as appropriate. Pearson’s product moment correlation was used to assess the level of association between continuous variables. Differences were declared significant if p < 0.05.
Results Fig. 1 shows the design of the study. Forty nine patients were assessed for eligibility. Five patients did not meet inclusion criteria and 3 refused to participate. Therefore, 41 patients were randomized. Twenty one patients were randomized to first receive FOR þ TIO, but 1 patient had an exacerbation during the first intervention period and another patient had an exacerbation during the washout period. Twenty patients were randomized to first receive FOR þ PLA, but 1 patient had an exacerbation during the first intervention period. Therefore, 19 patients in each group crossed to the second part of the trial and all completed the study.
Tiotropium improves inspiratory muscle strength in COPD
Baseline pulmonary function and maximal exercise capacity As shown in Table 1, patients with COPD had moderate-tosevere airflow obstruction with increased static lung volumes and reductions in DLCO. They had mild reduction in resting PaO2 and SaO2, but normal PaCO2. Exercise tolerance was markedly reduced, most likely due to pulmonaryventilatory limitation, as suggested by increased VE peak/ MVV. Breathlessness and leg effort were similarly described as the exercise-limiting symptoms.
Pulmonary function Table 2 shows the results of pulmonary function test before and after 2 weeks of treatment, including effects at trough (before medication) and at peak (2 h after medication).
Table 1
Baseline characteristics. Values
Age, years Body Mass Index, kg m2 Pulmonary Function FEV1, L (%predicted) FVC, L (%predicted) FEV1/FVC IC, L (%predicted) TLC, L (%predicted) RV, L (%predicted) DLCO, (% predicted) Arterial blood gases PaO2, mmHg SaO2, % PaCO2, mmHg Cardiopulmonary exercise testing _ 2 peak, ml min-1 VO _ 2 peak, % of predicted VO _ 2 peak, ml min-1 VCO RER peak _ peak, L min1 VE _ peak/MVV VE VT peak, L f peak, rpm SpO2 peak, % HR peak, % predicted Borg dyspnea scores Borg leg effort scores
56 7 25 3 1.21 0.33 2.66 0.48 0.45 0.14 2.02 0.34 6.02 0.99 3.01 0.43 55 14
(44 9) (42 8) (78 18) (108 12) (168 48)
69 8 92 2 39.5 4.5 988 183 60 12 961 350 0.97 0.09 37 8 0.71 0.12 1.12 0.18 34 6 89 4 88 10 7 (4e9) 6 (1e10)
Values are means standard deviation, except for symptoms (median and range). Definition of abbreviations: FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity; IC Z inspiratory capacity; TLC Z total lung capacity; RV Z residual volume; DLCO Z lung diffusing capacity for carbon monoxide; Pa Z arterial partial _ 2 Z oxygen uptake; pressure; Sa Z arterial saturation. VO _ 2 Z carbon dioxide output; RER Z ratio exchange ratio; VCO _ Z minute ventilation; MVV Z maximal voluntary ventilation; VE VT Z tidal volume; f Z respiratory frequency; SpO2 Z oxyhemoglobin saturation by pulse oximetry; HR Z heart rate.
1407 Both interventions resulted in improvement in FEV1, FVC, IC and EELV, but FOR-TIO led to greater changes in FEV1, IC and EELV than FOR-PLA.
Inspiratory muscle strength Fig. 2 shows PImax evaluated at rest, at the end of CWT, and at 2, 5, and 10 min during recovery. FOR þ TIO improved PImax at rest, immediately after exercise and during recovery, while FOR þ PLA improved PImax only at 10 min during recovery. Overall, FOR þ TIO resulted in significantly larger increments in PImax at all points of comparison.
Constant work exercise test After 2 weeks of intervention, Tlim during CWT was increased by FOR þ PLA (501 178 s to 702 145 s; p < 0.05) and by FOR þ TIO (488 150 s vs. 899 123; p < 0.05), but the size of the increment was significantly larger with FOR þ TIO (40.7 7.6% vs. 84.5 8.2%; _ 2 , VCO _ 2 , V_ E , and p < 0.05). As shown in Table 3, at Tlim, VO VT were increased only by FOR þ TIO, while respiratory exchange ratio, breathing frequency, heart rate, and scores for dyspnea and leg effort were unchanged by either intervention. V_ E =MVV, VT, EELV, and IC were improved by both interventions, but FOR þ TIO resulted in a significantly larger effect. _ 2 kinetics after constant work exercise was Pulmonary VO improved only with FOR þ TIO. Fig. 3 depicts the responses of a representative patient, and Table 4 shows that the amplitude increased while the time constant and the time _ 2 kinetics decreased with FOR þ TIO. delay of recovery VO Considering all patients in the analyses, at baseline, PImax was significantly correlated to Tlim (0.51, p < 0.01) _ 2off and to tO2off (0.65, p < 0.01). Likewise, baseline tVO
was significantly correlated to Tlim (0.77, p < 0.001). The change in PImax after intervention correlated with the change in Tlim (0.78, p < 0.001) and with the change in _ 2off (0.83, p < 0.001). Finally, the change in tVO _ 2off tVO with intervention was significantly correlated with the change in Tlim (0.91, p < 0.001).
Discussion In this randomized, crossover trial, we have shown that the addition of TIO to FOR improved inspiratory strength at rest and after exercise and accelerated recovery oxygen in patients with COPD. Moreover, in a different group of patients, we confirmed the findings of our previous trial,1 by showing that the addition of TIO to FOR improved exercise performance and effort-induced dynamic hyperinflation. To our knowledge, this is the first evidence that the addition of TIO to FOR improves respiratory muscle performance and recovery from exhaustive exercise in this patient population. Weiner et al13 found no improvement in inspiratory muscle strength and endurance after 6 weeks of treatment of salmeterol in patients with COPD. In agreement with those results, our patients also showed no improvement in inspiratory strength after 2 weeks of FOR, but the addition
1408 Table 2
N.D. Canto et al. Pulmonary function before and after 2 weeks of treatment. Formoterol þ placebo Before
Formoterol þ tiotropium
After 2 weeks Trough
FEV1, L FEV1, % pred FVC, L FVC, % pred FEV1/FVC, % IC, L IC, % pred EELV, L
1.09 40 2.55 69 40 1.66 61 4.35
0.21 11 0.66 10 8 0.45 45 0.77
1.11 41 2.56 70 42 1.78 65 4.24
Before
After 2 weeks
Peak 0.22 9 0.48 12 10 0.88 15 0.81
1.21 45 2.66 74 43 2.02 73 3.98
Trough
a,b
0.29 14a,b 0.98a,b 11a,b 15 0.49a,b 13a,b 0.67a,b
1.07 40 2.51 67 41 1.68 62 4.34
0.25 11 0.57 13 7 0.41 33 0.59
1.11 42 2.60 73 42 1.75 67 4.28
Peak 0.12 10 0.45 11 11 0.43 18 0.83
1.25 46 2.75 77 44 2.16 78 3.85
0.32a,b,c 12a,b 0.91a,b 12a,b 10 0.77a,b,c 13a,b,c 0.77a,b,c
Values are means SD. Definition of abbreviations: FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity; IC Z inspiratory capacity; EELV Z end-expiratory lung volume. a p < 0.05 from before within a given treatment. b p < 0.05 from trough within a given treatment. c p < 0.05 between-treatment comparison.
of TIO resulted in an increment of PImax of similar magnitude to that obtained by Weiner et al12 with inspiratory muscle training in their patients. Inspiratory muscle training may improve PImax by several mechanisms, including diaphragm hypertrophy,29 metabolic,30 and neuromuscular adaptations.31 Previous studies have demonstrated that b2-agonists may increase the maximal force generated by the diaphragm32,33 by affecting its length and geometry,34 which is mostly determined by lung volume.33 Furthermore, there is evidence that b2-agonists increase fat and carbohydrate oxidation, resulting in stimulation of hepatic glucose production.35,36 Despite these potential mechanisms for improvement in inspiratory muscle strength, we found that FOR administration had no significant effect on resting or post-exercise PImax (Fig. 2, left panel). In contrast, the addition of TIO resulted in a larger increment in FEV1 and inspiratory capacity (Table 2), as well as a significant improvement in resting PImax (Fig. 2). O’Donnell et al37 compared the effects of TIO to placebo
administered for 7e10 days in 11 patients with COPD. In contrast to our findings, they failed to demonstrate improvement in maximal inspiratory sniff pressure, which corrects for changes in operating volumes. Our trial included a much larger number of patients (38) and intervention was used for two weeks, therefore with a larger power to detect changes. Moreover, patients in both groups received FOR, reducing even more the possibility of a placebo effect. The mechanisms by which the addition of TIO might improve PImax at rest are not readily apparent from our data and we can only speculate on possible explanations. Since static maximal inspiratory pressure measured at the mouth does not correct for operating volumes, it is conceivable that changes in inspiratory volumes might have improved the length and geometry of the diaphragm, resulting in increased force as measured by PImax. This is partially supported by the finding of a small but significant larger improvement in EELV (Table 2) with the addition of TIO during the evaluation at rest.
Figure 2 Maximal inspiratory pressure (PImax) at rest, immediately constant work exercise, and at 2, 5 and 10 min during recovery before (open circles) and after (closed circles) intervention for the formoterol plus placebo (left panel) and for formoterol plus tiotropium (right panel). *P < 0.05 from baseline; yP < 0.05 between-treatment comparison.
Tiotropium improves inspiratory muscle strength in COPD
1409
Table 3 Measurements at the time to the limit of tolerance in the constant work tests before and after 2 weeks of intervention. Formoterol þ placebo Metabolic _ 2 , ml min1 VO _VCO2 , ml min1 RER Ventilatory V_ E , L min1 V_ E =MVV VT, L f, rpm IC, L EELV, L SpO2, % Cardiac HR, bpm HR, % pred Subjective Borg dyspnoea scores Borg leg effort scores
Formoterol þ tiotropium
Before
2 weeks
Before
2 weeks
1058 302 1004 299 0.94 0.08
1081 280 972 272 0.89 0.06
1010 260 947 275.0 0.93 0.08
1131 294a 1021 306.9 0.92 0.06
33.5 0.81 1.09 30 1.41 3.85 85
11.7 0.18 0.3 8 0.4 0.67 6
34.4 0.76 1.16 30 1.56 3.71 86
127 16 82 10 7 (3e10) 5 (0e10)
11.3 0.13a 0.3a 7 0.4a 0.54 6a
130 20 83 12 9 (1e10) 3.5 (0e10)
32.7 0.85 1.04 31 1.41 3.91 86
11.2 0.19 0.3 8 0.4 0.75 6
129 20 83 12 9 (3e10) 5 (0e10)
36.5 0.73 1.24 30 1.60 3.45 88
12.3b 0.14a,b 0.3a,b 9 0.3a,b 0.51a,b 6a
128 19 82 11 9 (1e10) 5.5 (0e10)
_ 2 Z oxygen uptake; VCO _ 2 Z carbon Values are means SD except for symptoms (median and ranges). Definition of abbreviations: VO dioxide output; RER Z respiratory exchange rate; VE Z minute ventilation; MVV Z maximal voluntary ventilation; VT Z tidal volume; f Z respiratory rate; IC Z inspiratory capacity; HR Z heart rate; SpO2 Z oxyhemoglobin saturation by pulse oximetry. a p < 0.05 from baseline. b p < 0.05 between-treatment comparison.
The measurement of PImax after exercise has been previously evaluated by randomized studies as a reliable indicator of inspiratory muscle fatigue.17 Previous studies have reported that exhaustive exercise may lead to a decline in PImax immediately after exercise in healthy subjects.38 This also happens to patients with chronic heart failure,6 especially those with inspiratory muscle weakness.18 In some COPD patients, inspiratory muscle function may be impaired, mainly due to dynamic hyperinflation.39,40 This may cause shortening of the diaphragm,
changing length-tension properties and decreasing PImax. Dynamic hyperinflation may also evoke reduction in inspiratory muscle strength by the abolition of the zone of apposition of the costal portion of the diaphragm with the rib cage, resulting in less lateral expansion of the thoracic cage during inspiration and inward recoil of the chest wall, which means that inspiratory muscles work not only against the lung elastic recoil but also against the elastic recoil of the chest wall.41 Exercise induces an increase in diaphragm work, which has to overcome the increase
_ 2 kinetics (off-transient) after constant work rate exercise in a representative patient with COPD. Panel A Figure 3 Pulmonary VO _ 2 kinetics before (continuous line) and after 2 weeks (dashed line) of formoterol plus placebo. Panel B shows interpolated shows VO _ 2 kinetics before (continuous line) and after 2 weeks (dashed line) of formoterol plus tiotroprium. Note the faster kinetics offVO transient [smaller time constant (t) of primary component].
1410 Table 4
N.D. Canto et al. Recovery measurements after constant work exercise before and after 2 weeks of intervention.
Variable
Formoterol þ placebo Before
Off-transient _ 2ðoffÞ VO A t TD MRT
1058 710 72.1 16.5 88
Formoterol þ tiotropium 2 weeks
302 105 18.7 5.2 6.8
1081 698 66.1 17.2 81
Before
280 88 15.3 4.5 9.7
1010 678 68.9 18.8 86
2 weeks 260 125 21.1 7.4 5.7
1131 801 60.4 14.2 71
294a,b,c 123a,b,c 17.8a,b,c 5.6a 8.1a,b,c
_ 2ðoffÞ Z oxygen uptake at the end of exercise (mL min1); A Z amplitude; Values are means SD. Definition of abbreviations: VO t Z time constant; TD Z time delay; MRT Z Mean response time (t þ TD). a p < 0.05 from basal within a given treatment. b p < 0.05 post vs. pre within a given treatment. c p < 0.05 between-treatment comparison.
elastic load and intrinsic positive end-expiratory pressure, by generating an abnormally higher proportion of PImax in terms of pleural pressure swings for a given tidal volume (called “ventilatory effort”).42 This may affect the pattern of breathing, causing dyspnea and higher dynamic hyperinflation, and potentially induces respiratory muscle fatigue.31 This response may be associated with increased end-expiratory lung volume (EELV) and reduction in exercise tolerance (inspiratory capacity to total lung capacity ratio, IC/TLC 0.28).43 In our study, we showed a reduction in PImax immediately after CWT in both treatments, which may reflect high-frequency fatigue of the respiratory muscles. The correlation between the change in PImax after intervention and the improvement in Tlim (r Z 0.72) suggests that in the change inspiratory muscle strength after TIO administration is a major determinant to the improvement in exercise performance in patients with COPD. In healthy subjects, the time required for the return of PImax to pre-exercise values is 2 min38 In previous reports, we and others have demonstrated that the time of recovery is prolonged in chronic heart failure patients with inspiratory muscle weakness.18,38 In the present study, it was observed that FOR þ TIO therapy reduced the recovery time of inspiratory muscle strength, which is suggestive with delayed development in diaphragmatic fatigue.38 This effect was present despite a longer exercise duration, higher metabolic rate and smaller ventilatory effort. It is important to remember that recovery of muscle energy stores depends on intrinsic histologic44 and biochemical muscle alterations, impaired O2 delivery to skeletal muscles and vascular dysfunction.22,45 Accordingly, we have demonstrated that patients with moderate to severe COPD have impaired central and peripheral cardiovascular responses to exercise that lead to slower kinetics of cardiac output and faster muscle deoxygenation profile following the onset of heavy-intensity exercise.22 In a previous study, we showed that the administration of inhaled short-acting bronchodilators reduces lung hyperinflation and the amplitude of muscle deoxygenation during high-intensity cycling exercise in patients with moderate to severe COPD, which are linked with faster on-exercise kinetics of cardiac output.17 The importance of the inspiratory _ 2 kinetics after exercise is underscored by the muscles in VO
high correlation between the change in PImax and the _ 2off (r Z 0.83) after intervention in improvement in tVO our patients. The potential limitation of our study lies in crossover design and small number of patients. Therefore further larger clinical trials with parallel design should be conducted to evaluate the effects of the addition of TIO to FOR on functional capacity and quality of life in patients with COPD. However, special care was taken to allow for an appropriate washout period between interventions, reducing the possibility of a carry-over effect. Moreover, we were able the reproduce the results or our previous trial1 in a different group of COPD patients, underscoring the consistency of our findings. Since the improvement of inspiratory muscle strength by the addition of TIO is in disagreement with the results of the smaller trial by O’Donnel et al,37 this particular subject should further evaluated, including studies to address the mechanism by which TIO may improve inspiratory muscle strength in COPD. In our study, we measured PImax for assessment inspiratory muscle strength, while O’Donnel et al,37 measured maximal inspiratory sniff esophageal pressure. Despite the known limitations of using a volitional test such as PImax46 as a measure of inspiratory muscle strength after exercise, the randomized, crossover design of the present study strongly indicates that TIO administration resulted in improvement in inspiratory muscle strength. Our results may have clinical implications. Previous studies have demonstrated success in enhancing exercise tolerance with TIO in COPD patients.1,46,47 The results of the present and as well as our previous trial1 underscore the usefulness of adding TIO to FOR to improve exercise performance in this patient population. Moreover, the improvement in oxygen uptake kinetics during recovery may impact on capacity of patients to perform intermittent exercise, which is used in daily activities. However, future large clinical trials should be conducted to test the hypothesis that this combined intervention may impact on clinical outcomes. In conclusion, the addition of TIO to FOR improves preand post-exercise inspiratory muscle strength and accelerates recovery oxygen uptake kinetics in patients with COPD. These physiological effects may partially explain the
Tiotropium improves inspiratory muscle strength in COPD
1411
improvement in exercise performance induced by the addition of TIO to FOR. 12.
Conflict of interest statement 13.
None of the authors have any potential conflict of interest related to the contents of this paper. Paulo J. C. Vieira is supported by a Doctoral Scholarship and Gaspar R. Chiappa receives a Post-doctoral Fellowship from the Brazilian Research Council (CNPq), Brasilia, Brazil.
14.
15.
Acknowledgements 16.
The authors would like to thank all colleagues from the Exercise Biochemistry and Physiology Laboratory for their friendly collaboration. Add JPR and JAN are an Established Investigator (level II) of the CNPq (Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo ´gico), Brazil. GRC was supported by a PhD Fellowship Grant from CAPES (Coordenac ¸˜ ao de Aperfeic ¸oamento de Pessoal de Nı´vel Superior), Brazil.
17.
18.
19.
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