Chronic obstructive pulmonary disease

Bronchodilators accelerate the dynamics of muscle Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from O2 delivery and utilisation during exercise in COPD Danilo C Berton,1 Priscila B Barbosa,1 Luciana S Takara,1 Gaspar R Chiappa,1 Ana Cristina B Siqueira,1 Daniela M Bravo,1 Leonardo F Ferreira,2 J Alberto Neder1

See Editorial, p 573 ABSTRACT (QT), suggesting an important role for the central Background Expiratory flow limitation and cardiovascular adjustments in setting the limits of < Supplementary methods are hyperinflation promote cardiocirculatory perturbations increase in peripheral QO at the onset of exercise. published online only. To view 2 these files please visit the that might impair O2 delivery to locomotor muscles in Further experimental evidence for this contention journal online (http://thorax.bmj. patients with chronic obstructive pulmonary disease was obtained in a subsequent study in which com). (COPD). The hypothesis that decreases in lung hyperinflation a strategy aimed to reduce the resistive work of 1Pulmonary Function and Clinical after the of would improve and dynamic hyperinflation () Exercise Physiology Unit skeletal muscle oxygenation during exercise was tested. simultaneously accelerated the dynamics of QTand (SEFICE), Division of Respiratory 5 Methods Twelve non- or mildly hypoxaemic males QO2 in patients with moderate to severe COPD. Diseases, Department of (forced expiratory volume in 1 s (FEV1)¼38.5612.9% These data prompted the hypothesis that similar Medicine, Federal University of > fi Sao Paulo (UNIFESP), Sa˜o predicted; PaO2 60 mm Hg) underwent constant work ndings would be observed in response to the most Paulo, Brazil rate cycle ergometer exercise tests (70e80% peak) to effective and clinically feasible intervention avail- 2Department of Physiology, the limit of tolerance (Tlim) after inhaled bronchodilators able to alleviate lung hyperinflation and improve University of Kentucky, (salbutamol plus ipratropium) or placebo. Muscle (de) exercise tolerance in these patientsdthat is, inhaled Lexington, Kentucky, USA 167 oxygenation (wfractional O2 extraction) was determined bronchodilators. Correspondence to in the vastus lateralis by changes (D) in the In the present study, therefore, we aimed to Professor J A Neder, Pulmonary deoxyhaemoglobin/myoglobin signal ([HHb]) from near- investigate the effects of acute inhalation of Function and Clinical Exercise b infrared spectroscopy, and cardiac output (QT) was a combination of a short-acting 2-adrenoceptor Physiology Unit (SEFICE), monitored by impedance cardiography. agonist (salbutamol sulfate) and a short-acting Respiratory Division, Department of Medicine, Results Bronchodilators reduced lung hyperinflation and anticholinergic (ipratropium bromide) on key 6 _ Federal University of Sa˜o Paulo increased Tlim compared with placebo (454 131 s vs determinants of QO2 and Vo2 during high-inten- (UNIFESP), Rua Professor 3216140 s, respectively; p<0.05). On-exercise kinetics sity, constant work rate cycling exercise in patients Francisco de Castro 54, Vila _ of QT and pulmonary O2 uptake ðVo2Þ were accelerated with moderate to severe COPD. Confirmation of Clementino, Sa˜o Paulo CEP: D 04020-050, Brazil; with active treatment; [HHb] dynamics, however, were the hypothesis that bronchodilators would slow http://thorax.bmj.com/ [email protected] delayed by w78% and the signal amplitude diminished the dynamics and decrease the amplitude of leg by w21% (p<0.01). Consequently, the ratio between muscle deoxygenation would provide novel _ Received 1 June 2009 Vo2 and D[HHb] dynamics decreased, suggesting evidence that amelioration of the mechanical Accepted 12 January 2010 _ improved microvascular O2 delivery (s-Vo2/MRT-D burden of breathing might positively impact upon ¼ 6 6 < [HHb] 4.48 1.57 s vs 2.08 1.15 s, p 0.05). Of note, the provision of O2 to the working peripheral reductions in lung hyperinflation were related to faster muscles during exercise in patients with COPD. _ QT kinetics and larger decrements in s-Vo2/MRT-D[HHb]

< on September 25, 2021 by guest. Protected copyright. (p 0.01). METHODS Decreases in operating after Conclusions Subjects the inhalation of bronchodilators are associated with faster Twelve males with moderate to severe, stable ‘central’ cardiovascular adjustments to high-intensity COPD (forced expiratory volume in 1 s (FEV )/ exercise with beneficial consequences on muscle 1 forced (FVC) <0.7 and post- oxygenation in patients with moderate to severe COPD. < bronchodilator FEV1 60% predicted), and resting > PaO2 60 mm Hg, volunteered to participate in the study. Patients were recruited from the COPD INTRODUCTION Outpatients Clinic of the Sao Paulo Hospital Exercise intolerance is a multifactorial construct in (Brazil), a University-based teaching hospital. patients with chronic obstructive pulmonary Subjects were free of echo Doppler cardiographic e disease (COPD).1 3 In fact, recent studies from our evidence of severe and left laboratory suggest that expiratory flow limitation ventricular dysfunction. No patient has ever been and lung hyperinflation are related to sluggish enrolled in a programme. central cardiovascular adjustments at the onset of All participants signed a written informed consent exercise which might impair the balance between form. The study protocol was approved by the ð _ Þ O2 delivery (QO2) and uptake Vo2 in the exer- Institutional Medical Ethics Committee. cising muscles of patients with COPD.45The result, then, is faster and heightened muscle deox- Study protocol ygenation measured by near-infrared spectroscopy This was a double-blinded, placebo-controlled _ (NIRS) in patients compared with age-matched crossover study. After determination of peak ðVo2Þ controls.4 Interestingly, these abnormalities were on a maximal incremental cycle ergometer exercise closely related to slower kinetics of cardiac output test, subjects were randomly assigned to inhale

588 Thorax 2010;65:588e593. doi:10.1136/thx.2009.120857 Chronic obstructive pulmonary disease

m m fi salbutamol sulfate 120 g plus ipratropium bromide 20 g per 180 s of exercise, metabolic and NIRS data were tted by the Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from actuation, via a metered dose inhaler (MDI; Combivent, Boeh- following monoexponential equation from the start of exercise ringer Ingelheim, Germany) or Combivent placebo via an MDI to the third minute16:   each on a different day. At these visits, patients performed ðtTDpÞ ½Y ¼½Y þ Ap e sp a total of four transitions from baseline pedalling to 70e80% ðtÞ ðbÞ 1 peak work rate. The initial test was performed to the limit of b p tolerance (Tlim, min) 20 min after the inhalation of broncho- where and refer to baseline unloaded cycling and primary component, respectively; A, TD and s are the amplitude, time dilators or placebo. Patients rested for 1 h before performing an _ additional 4 min exercise test. Thus, there were two on-exercise delay and time constant of the exponential response. For Vo2 fi repetitions per day. Data from same-day transitions were aver- analysis we deleted the data relative to the rst 20 s after exer- d s _ aged to reduce data noise for the kinetic analyses (see details cise onset that is, the cardiodynamic phase. Therefore, Vo2 represents the time course of the primary componentdan below). Additional details are described in the supplement _ 17 available online. estimate of the muscle Vo2 kinetics. The overall kinetics of [HHb] were determined by the mean response time ¼s s _ Measurements (MRT +TD). The ratio -Vo2/MRT-[HHb] was used as Pulmonary function tests a semiquantitative index of microvascular QO2 kinetics, with 45 , single-breath lung , static lung higher values indicating slower QO2. Based on our experience with NIRS in patients with COPD,4518and previous findings volumes by body plethysmography and arterial blood gases were 19 measured at baseline. Recorded values were compared with with other disease populations, we systematically examined ‘ ’ D those predicted for the adult Brazilian population.8 9 whether there was an overshoot in [HHb] after the initial fast response (see the Results section). In the case of a discernible ‘ ’ Exercise tests overshoot in the two interventions, we used the area under the ‘overshoot’ as an additional index of impaired microvascular Standard metabolic and ventilatory responses were measured 12 breath-by-breath using a calibrated, computer-based system QO2. Additional information on kinetic analyses are detailed in the supplement online. (CardiO2 System, Medical Graphics, St Paul, Minnesota, USA). A period of 3 min unloaded exercise preceded the imposition of the selected work rate. Serial inspiratory capacity (IC, litres) Statistical analysis manoeuvres were performed during the test. Assuming that total Statistical analysis was performed using SPSS 15.0. We planned lung capacity (TLC) remains constant during exercise, IC to evaluate 12 patients based on our previous results in a similar manoeuvres provide an estimate of end-expiratory lung volume.10 transversal and crossover study with heliox in patients with COPD.5 Paired t test was used to contrast within-subject exer- Skeletal muscle oxygenation cise responses with the exception of symptom scores (Wilcoxon fi signed-rank test). A one-way repeated measures analysis of Skeletal muscle oxygenation pro les of the left vastus lateralis http://thorax.bmj.com/ D were evaluated with a commercially available NIRS system variance (ANOVA) was used to compare [HHb] at quartiles of d (Hamamatsu NIRO 200, Hamamatsu Photonics KK, Japan). isotime that is, the shortest Tlim between the two interven- e The (deoxyhemoglobin (Hb)/myoglobin (Mb) signal ([HHb], tions on a given subject. Pearson product moment correlation mM/cm) during exercise has been considered a proxy of frac- was used to assess the level of association between continuous fl variables. The level of statistical significance was set at p<0.05 tional O2 extraction in the microcirculation, re ecting the balance between O delivery and utilisation11 12dthat is, for all tests. _ 2 D[HHb]yVo2=QO2. Additional details are described in the supplement online. RESULTS on September 25, 2021 by guest. Protected copyright. Subject characteristics and maximum exercise capacity Central haemodynamics On average, patients had severe airflow obstruction and lung Cardiac output (QT, l/min) and stroke volume (SV, ml) were diffusing capacity for carbon monoxide (DLCO) impairment measured throughout the constant work rate test using with increased static lung volumes and normal arterial blood impedance cardiography (PhysioFlow PF-0, Manatec Biomedical, gases at rest (table 1). All patients showed reduced maximal _ Macheren, France).13 This methodology is different from exercise capacity (peak Vo <83% predicted) (table 1)20 with _ 2 previously used impedance systems as its algorithm does not increased peak VE/MVV ratio (>0.8). Although dyspnoea was require basal thoracic impedance measurement (Z0). Consid- the main limiting symptom in 8/12 patients, Borg scores for leg ering, however, the controversy on the accuracy of the system effort did not differ more than 2 units from the Borg dyspnoea in providing reliable absolute values of SV in patients with ratings in these patients. COPD,14 15 exercise haemodynamic data were also expressed as ‘D’ from baseline. Additional information on response character- Effects of bronchodilators on pulmonary function and exercise istics and system validation are detailed in the supplement online. tolerance Treatment with bronchodilators increased FEV1 and IC Kinetics analysis compared with placebo (1.3060.50 litres vs 1.1760.56 litres _ 6 6 < The breath-by-breath Vo2, D[HHb] and haemodynamic (QT, SV and 2.28 0.83 litres vs 1.89 0.73 litres, respectively; p 0.001 and heart rate (HR)) data from same-day exercise bouts were for both comparisons). The criteria for a ‘positive’ bronchodi- $ 21 linearly interpolated to provide second-by-second values and, for lator response (FEV1 change 12% and 200 ml) were obtained each individual, the repetitions were time aligned to the start of in 7/12 patients, with FEV1 increases being closely related to exercise and ensemble averaged (SigmaPlot 10.0, Systat Soft- changes in FVC. ware). The kinetic behaviour of haemodynamic data was esti- The subjects exercised at 53610 W. Exercise tolerance (Tlim) t 6 mated by calculation of the half-time of response ( 1/2, s). After was improved after treatment with bronchodilators (321 140 s checking that a slow component was not discernible in the first vs 4546131 s, for placebo and bronchodilators, respectively;

Thorax 2010;65:588e593. doi:10.1136/thx.2009.120857 589 Chronic obstructive pulmonary disease

Table 1 Resting characteristics and responses to Table 2 Isotime values of selected physiological and perceptual Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from incremental exercise (n¼12) responses during high-intensity, constant work rate exercise after Variables Values placebo or bronchodilators (n¼12) Variables Placebo Bronchodilators P Value Demography/anthropometric Age (years) 65.366.5 Metabolic _ Body mass 23.464.0 Vo2 (ml/min) 2 index (kg/m ) Exercise 11076300 11806355 0.94 Pulmonary function D exerciseerest 8086128 8356141 0.86 6 _ FEV1,% 38.5 12.9 VCO2 (ml/min) 11106293 12216335 0.88 predicted RER 1.0060.07 1.0460.08 0.90 6 FVC, % predicted 80.1 9.7 Ventilatory/gas exchange 6 TLC, % predicted 125.4 5.8 VE_ (l/min) 37.6615.8 41.3617.4 0.02 6 RV, % predicted 192.1 35.6 VE/MVV_ 0.8760.10 0.8860.11 0.90 6 IC, % predicted 70.1 15.9 ƒ (respirations/min) 31643165 0.95 6 DLCO,% 43.4 14.2 VT (litres) 1.2460.46 1.3460.50 0.02 predicted IC (litres) PaO mm Hg 7068 2 Exercise 1.6760.58 2.02 6 0.65 0.02 SaO ,% 9464 2 D exerciseerest 0.2960.18 0.2560.20 0.78 PaCO mm Hg 3965 2 IRV (litres) 0.4860.17 0.3260.15 0.01 Peak exercise SpO (%) 91639062 0.88 Power W 72619 2 Cardiovascular Vo_ ml/min 12156185 2 QT (l/min) Vo_ , % predicted 58.7615.1 2 Exercise 11.763.1 11.662.9 0.92 VE_ l/min 40.8614.0 D exerciseeest 4.461.0 4.360.9 0.87 VE_ /MVV 0.8760.18 HR (bpm) HR beats/min 135624 Exercise 133622 134624 0.68 Borg dyspnoea 8(6e10) D e 6 6 scores exercise rest 54 18 52 14 0.74 Borg leg effort 7(5e9) SV (ml) scores Exercise 89618 88616 0.81 D exerciseerest 28615 26619 0.75 Values are means6SD. DLCO, lung diffusing capacity for carbon monoxide; FEV1, forced Subjective expiratory volume in 1 s; FVC, forced vital capacity; HR, heart rate; Dyspnoea scores 8 (6e10) 6 (4e8) 0.03 IC, inspiratory capacity; MVV, maximal voluntary ventilation; Pa, arterial Leg effort scores 7 (4e9) 5 (3e8) 0.04 ; RV, residual volume; Sa, arterial saturation; TLC, total _ _ lung capacity; Vco2, carbon dioxide output; VE, ; Values are means 6 SD, with the exception of subjective variables (median and range). http://thorax.bmj.com/ _ Vo2, oxygen uptake. bpm, beats per minute; ƒ, breathing frequency; HR, heart rate; IC, inspiratory capacity; IRV, inspiratory reserve volume; QT, cardiac output; RER, respiratory exchange rate; _ SpO , by ; SV, stroke volume; Vco , carbon dioxide output; p¼0.01). Increases in pre-exercise IC were significantly related to _ 2 _ 2 VE, minute ventilation; Vo2, oxygen uptake; VT, . D (bronchodilatorseplacebo) TLim (r¼0.72 (95% CI 0.31 to 0.91); p¼0.04). As previously described,13 increases in IC during 4 5 exercise were accompanied by larger tidal and inspiratory reserve of impaired microvascular QO2 decreased after the inhalation volumes and lower dyspnoea scores at isotime (table 2). In of bronchodilators (4.4861.57 s vs 2.0861.15 s, for placebo and fi < contrast, there were no signi cant effects of bronchodilators on bronchodilators, respectively; p 0.001). There was a close on September 25, 2021 by guest. Protected copyright. > t s _ mean SpO2 values (table 2), and improvements in SpO2 3% at association between reductions in 1/2QT and lower -VO2/ isotime were found in only 3/12 patients. Similarly, there were MRT-D[HHb] values after active treatment (r¼0.88 (95% no significant between-interventions differences in the cardio- CI¼0.64 to 0.96); p¼0.008). Furthermore, the area under the vascular responses at the individual isotime (table 2). ‘overshoot’ of the D[HHb] response, a pattern of abnormality 12 ¼ associated with impaired microvascular QO2 decreased (n 3; Kinetics response to exercise p¼0.04) or disappeared (n¼4) after treatment Treatment with bronchodilators accelerated the central haemo- compared with placebo. fl dynamic responses at the onset of exercise (t QT¼ 75.9610.3 s Interestingly, the decrease in lung hyperin ation (ie, higher 1/2 fi fi _ vs 58.9618.9 s (p¼0.02), t HR¼ 78.2613.0 s vs 62.5 615.5 s IC) was signi cantly related to faster QT ( gure 2A) and Vo2 1/2 ¼ ¼ (p¼0.03), t SV¼51.068.1 s vs 40.6610.3 s (p¼0.02) for kinetics (r 0.73 (95% CI 0.34 to 0.91); p 0.03) but slower 1/2 _ ¼ placebo and bronchodilators, respectively). In relation to the Vo rates of muscle deoxygenation (MRT-[HHb], r 0.78 (95% CI 2 ¼ response, there were no significant differences in baseline 0.40 to 0.92); p 0.03). Therefore, patients with larger (unload exercise) and amplitude comparing bronchodilators and increases in IC after the inhalation of bronchodilators had s _ D fi placebo (5086147 ml/min vs 5286117 ml/min (p¼0.87) and greater decrements in -Vo2/MRT- [HHb] ( gure 2B). 554698 ml/min vs 5326108 ml/min (p¼0.90)). In contrast, the ‘ ’ _ fi dynamics of the primary component of VO2 were signi cantly Muscle oxygenation and leg effort scores at steady-state faster after bronchodilation (table 3). exercise Bronchodilators slowed the kinetics of leg muscle deoxygen- The amplitude of D[HHb] after the initial ‘fast’ response was ation compared with placebo (figure 1, table 3), despite no significantly reduced with bronchodilators compared with significant effects on baseline D[HHb] (3615 mM/cm vs placebo (1856115 mM/cm vs 1536108 mM/cm; p¼0.009), 2613 mM/cm; p¼0.83). Therefore, sD[HHb] post- remaining lower throughout exercise (figure 3). D[HHb] at bronchodilators was, on average, twofold the postplacebo value isotime was significantly related to larger postbronchodilator _ (table 3). Consequently, the s-Vo2/MRT-D[HHb] ratio, an index increases in IC (r¼0.82 (95% CI 0.62 to 0.94); p¼0.01) and

590 Thorax 2010;65:588e593. doi:10.1136/thx.2009.120857 Chronic obstructive pulmonary disease

ð_ Þ

Table 3 Comparative effects of inhaled placebo vs bronchodilators (BDs) on selected parameters of the kinetics of pulmonary oxygen uptake Vo2 Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from and deoxyhaemoglobin (D[HHb]) in the vastus lateralis at the onset of high-intensity, constant work rate exercise (n¼ 12) TD (s) s (s) MRT (s) Placebo BDs p Value Placebo BDs p Value Placebo BDs p Value _ Vo2 ml/min 23.267.5 20.367.1 0.67 89.4620.1 69.8615.4 0.01 106.3618.0 84.1612.2 0.003 D[HHb] mM/cm 10.262.3 10.161.7 0.94 4.961.8 9.163.2 0.001 15.763.0 19.863.2 0.007 Values are means 6 SD. MRT, mean response time; TD, time delay; s, time constant. improvements in Tlim (r¼0.80 (95% CI¼0.54 to 0.92); (3) lower leg effort scores. The relationship between lower oper- p¼0.01). Leg effort scores at isotime were also lower after active ating lung volumes after bronchodilators (ie, larger IC) with faster treatment compared with placebo (table 2) and they were ‘central’ haemodynamic adjustments to exercise (QT) and _ marginally related to changes in Tlim (r¼0.53; p¼0.08). improved muscle oxygenation (s-Vo2/MRT-D[HHb]) suggest a mechanistic link between dynamic hyperinflation and impair- DISCUSSION ed QO2 in these patients. Our data, therefore, provide novel This seems to constitute the first study to investigate the effects of evidence that by alleviating the mechanical burden of breathing inhaled bronchodilators on the determinants of (estimated) in patients with COPD pharmacological bronchodilation promotes an enhancement of O2 delivery to the working periph- microvascular O2 delivery (QO2) and utilisation (phase II _ eral muscles. pulmonary Vo2 kinetics) during exercise in patients with COPD. The main novel findings of the present study are that treatment with inhaled bronchodilators to reduce airflow obstruction and lung hyperinflation were associated with: (1) faster on-exercise _ dynamics of QT and Vo2; (2) slower kinetics and decreased amplitude of muscle deoxygenation, estimated by D[HHb]; and http://thorax.bmj.com/ on September 25, 2021 by guest. Protected copyright.

Figure 2 Increases in inspiratory capacity (IC) with inhaled broncho- dilators (D¼bronchodilatoreplacebo) were associated with faster _ Figure 1 Comparative effects of inhaled placebo (A) and bronchodi- cardiac output (QT) kinetics (A) and larger decrements in s-ðVo2Þ/MRT- lators (B) on changes in deoxyhaemoglobin (D[HHb] by near-infrared [HHb]) (B). Collectively, these data suggest that improvement in central spectroscopy) in the vastus lateralis in a patient with severe COPD. Note cardiovascular adjustments after reduction in the operating lung volumes that bronchodilation was associated with slower D[HHb] adjustments. with inhaled bronchodilators (A) led to faster dynamics of microvascular These data are consistent with improved microvascular O delivery to O delivery (B). t , half-time; s, time constant; MRT, mean response 2 2 _ 1/2 the peripheral muscles after bronchodilation. TD, time delay; s, time time; Vo2, oxygen uptake; [HHb], deoxyhaemoglobin by near-infrared constant; MRT, mean response time. spectroscopy.

Thorax 2010;65:588e593. doi:10.1136/thx.2009.120857 591 Chronic obstructive pulmonary disease

in slower kinetics and lower amplitude of muscle deoxygenation Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from (table 3 and figure 3, respectively). In addition, bronchodilators lessened or eliminated the ‘overshoots’ in D[HHb], further indicating that muscle oxygenation improved after active treatment. Although the precise mechanism(s) leading to enhanced leg oxygenation could not be determined in this non- invasive study, it is noteworthy that active treatment acceler- ated the kinetics of the ‘central’ haemodynamic adjustments to exercise. In this context, a decrease in the operating lung volumes might have been associated with increased reliance of parasympathetic control of HR,26 an effect that could be related to less airways compression27 and lower pulmonary arterial pressure.28 Reduction in air trapping and expiratory positive pleural pressure may have increased venous return, decreased pulmonary vascular resistance and lessened the compression of the left ventricle by the overfilled right ventricle.29 As there was a close association between faster QT kinetics and _ reductions in s-ðVo2Þ/MRT-D[HHb], an index of impaired 45 Figure 3 Effects of inhaled bronchodilators (filled symbols) and placebo microvascular QO2 it is likely that the slower changes in muscle (open symbols) on skeletal muscle deoxyhaemoglobin (D[HHb], % of deoxygenation were driven by quicker ‘central’ haemodynamic maximal value obtained on a previous leg occlusion) in the vastus responses at the onset of exercise. Consistent with this notion, lateralis at standardised time points during high-intensity exercise. Laveneziana and colleagues recently found significant correlations Isotime, the shortest exercise test between the two interventions on _ between faster HR dynamics and improved Vo kinetics after a given subject. Values are mean and standard error. 2 inhaled bronchodilators in patients with moderate COPD ¼ 6 30 (FEV1 57 19% predicted). INTERPRETING THE KINETICS OF MUSCLE OXYGENATION Other potential mechanisms for the faster on-exercise DURING EXERCISE dynamics of QTand improved muscle oxygenation are related to the pharmacological properties of the bronchodilators. Although NIRS is a non-invasive technique that allows continuous the limited available evidence suggests that inhaled bronchodi- measurement of key determinants of peripheral muscle lators have few haemodynamic effects during exercise in oxygenation during exercise. The time course of D[HHb] reflects _ patients with COPD,6 28 their role in modulating skeletal muscle the local balance between QO2 and Vo2 in the area under fl 11 12 D blood ow at the exercise transient in animals is still contro- investigation. Previous studies have shown that [HHb] 31 versial. Additional studies, therefore, are warranted to address http://thorax.bmj.com/ provides a surrogate of fractional O extraction,22 23 and its 2 this specific issue in patients with COPD. measurement in parallel with (muscle) phase II of the kinetics of _ Interestingly, D[HHb] remained lower during steady-state pulmonary Vo2 can be used to make useful inferences regarding 4511122223 exercise after the inhalation of bronchodilators (figure 3) despite microvascular QO2 via the Fick principle. Therefore, no significant increases in QT or SpO (table 2). This finding the muscle haemodynamic response at the onset of exercise is 2 raises the intriguing hypothesis that alleviation of the respira- characterised by an initial ‘phase I’ response centrally related to tory muscle work with bronchodilators may have redirected the mechanical effect of muscle contraction (ie, muscle pump) a fraction of the QT from these muscles back to the appendic- and a slower ‘phase II’ matched with metabolic demand. _ ular muscles. In fact, we previously reported that respiratory on September 25, 2021 by guest. Protected copyright. Conversely, muscle ðVo Þ response seems to be well charac- 2 muscle unloading by proportional assisted ventilation increased terised by a single monoexponential function from the start of microvascular QO at the same QT, suggesting improved exercise.24 Therefore, the resulting response of fractional O 2 2 due to blood flow redistribution from respiratory to extraction (w[HHb]) encompasses an early delay where O 2 working peripheral muscles.18 Further studies are needed to delivery meets (or exceeds) demand (TD) and a rapidly apportion the role of lower operating lung volumes and increasing response when the dynamics of capillary flow blood _ improved muscle oxygenation in enhancing exercise tolerance in are slower than the rate of change in Vo .11 12 Consequently, the 2 patients with COPD. overall [HHb] kinetics are expected to be inversely related to the dynamics of QO .4511122223 2 STUDY LIMITATIONS In some specific circumstances, this pattern of response is e Constant work rate exercise tests at 70e80% peak have been further complicated by a transient ‘overshoot’ in D[HHb],25 27 recognised as the most sensitive testing modality to unravel the indicating an increase in fractional O extraction above the 2 functional benefits of bronchodilators.32 However, our findings steady-state level due to impaired phase II blood flow relative to _ may not be relevant to milder exercise intensities where lower muscle Vo .12 Consistent with these assumptions, previous 2 ventilatory requirements may decrease, or even abolish, the studies found an ‘overshoot’ in D[HHb] in patients with type 2 beneficial effects of bronchodilators on muscle deoxygenation. diabetes,25 chronic heart failure19 and COPD.4 The effects of We also recognise that the use of cycling instead of walking may bronchodilators on these complex inter-relationships, however, have contributed to magnify the positive effects of bronchodi- have not been previously investigated in patients with COPD. lation on exercise tolerance, as contractile fatigue33 and the sense of leg effort34 are more relevant contributors to decrease exercise EFFECTS OF BRONCHODILATORS ON LEG O2 DELIVERY capacity in the former modality. It should also be acknowledged The present study provides novel evidence that alleviation of that our non-hypercapnic patients with advanced COPD were airflow obstruction after pharmacological bronchodilation, with severely hyperinflated and they presented with substantial fl d fi consequent reductions in lung hyperin ation (table 2), resulted reductions in DLCO (table 1) that is, a disease pro le more

592 Thorax 2010;65:588e593. doi:10.1136/thx.2009.120857 Chronic obstructive pulmonary disease

9. Neder JA, Andreoni S, Peres C, et al. Reference values for lung function tests. III. compatible with the emphysematous subtype. Consequently, Thorax: first published as 10.1136/thx.2009.120857 on 13 July 2010. Downloaded from Carbon monoxide diffusing capacity (transfer factor). Braz J Med Biol Res our results should be cautiously extrapolated to other COPD e fi 1999;32:729 37. phenotypes. Finally, most of the correlation coef cients had 10. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, wide confidence intervals, a likely consequence of the small and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir sample size. Therefore, it is advisable that these specific results Crit Care Med 1998;158:1557e65. fi 11. Poole DC, Behnke BJ, Padilla DJ. Dynamics of muscle microcirculatory oxygen be con rmed in larger studies. exchange. Med Sci Sports Exerc 2005;37:1559e66. 12. Ferreira LF, Townsend DK, Lutjemeier BJ, et al. Muscle capillary blood flow kinetics estimated from pulmonary O2 uptake and near-infrared spectroscopy. J Appl Physiol CONCLUSIONS 2005;98:1820e8. The present study showed that administration of inhaled short- 13. Charloux A, Lonsdorfer-Wolf E, Richard R, et al. A new impedance cardiograph device acting bronchodilators to reduce lung hyperinflation slowed the for the non-invasive evaluation of cardiac output at rest and during exercise: comparison with the “direct” Fick method. Eur J Appl Physiol 2000;82:313e20. dynamics and reduced the amplitude of muscle deoxygenation 14. Bougault V, Lonsdorfer-Wolf E, Charloux A, et al. Does thoracic bioimpedance during high-intensity cycling exercise in patients with moderate accurately determines cardiac output in COPD patients during maximal or intermittent to severe COPD. Considering that these findings were associated exercise? Chest 2005;127:1122e31. 15. Kemps HM, Thijssen EJ, Schep G, et al. Evaluation of two methods for continuous with faster on-exercise kinetics of QT and the ‘metabolic’ phase _ cardiac output assessment during exercise in chronic patients. J Appl of pulmonary Vo2, our data are consistent with a speeding and Physiol 2008;105:1822e9. 16. Whipp BJ, Ward SA, Lamarra N, et al. Parameters of ventilatory and gas exchange heightening of O2 delivery to skeletal muscles of patients with dynamics during exercise. J Appl Physiol 1982;52:1506e13. COPD treated with inhaled bronchodilators. 17. Poole DC, Barstow TJ, McDonough P, et al. Control of oxygen uptake during exercise. Med Sci Sports Exerc 2008;40:462e74. Acknowledgements The authors would like to thank all colleagues from the 18. Borghi-Silva A, Oliveira CC, Carrascosa C, et al. Respiratory muscle unloading Pulmonary Function and Clinical Exercise Physiology Unit (Division of Respiratory improves leg muscle oxygenation during exercise in patients with COPD. Thorax Diseases, Federal University of Sao Paulo (UNIFESP), Brazil) for their friendly 2008;63:910e15. collaboration. More importantly, however, they are indebted to the patients for their 19. Sperandio PA, Borghi-Silva A, Barroco A, et al. Microvascular oxygen effort and enthusiastic cooperation throughout the study. delivery-to-utilization mismatch at the onset of heavy intensity exercise in optimally- treated patients with CHF. Am J Physiol Heart Circ Physiol 2009;297:H1720e8. Funding DCB was suppported by a Doctoral Research Fellowship from Coordenadoria 20. Neder JA, Nery LE, Castelo A, et al. Prediction of metabolic and cardiopulmonary de Aperfeic¸oamento do Pessoal de Nı´vel Superior (CAPES), Brazil. GRC was responses to maximum cycle ergometry: a randomised study. Eur Respir J suppported by a Postdoctoral Research Fellowship from Fundac¸a˜o de Amparo` a 1999;14:1304e13. Pesquisa do Estado de Sa˜o Paulo (FAPESP), Brazil. JAN is an Investigator of the 21. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Brazil. The tests. Eur Respir J 2005;26:948e68. study was supported by a Research Grant from FAPESP, Brazil. 22. Grassi B, Gladden LB, Samaja M, et al. Faster adjustment of O2 delivery does not affect VO2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 1998;85:1394e403. Competing interests None. 23. Ferreira LF, Poole DC, Barstow TJ. Muscle blood floweO2 uptake interaction and their relation to on-exercise dynamic of O2 exchange. Respir Physiol Neurobiol Ethics approval This study was conducted with the approval of the Institutional e Medical Ethics Committee. 2005;147:91 103. 24. Saltin B. Exercise hyperaemia: magnitude and aspects on regulation in humans. Provenance and peer review Not commissioned; externally peer reviewed. J Physiol 2007;583:819e23. 25. Bauer TA, Reusch JE, Levi M, et al. 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