J. Alberto Neder

Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD

BACKGROUNDnIt is currently unclear whether the additive effects of a long-acting beta(2)-agonist (LABA) and the antimuscarinic tiotropium bromide (TIO) on resting lung function are translated into lower operating lung volumes and improved exercise tolerance in patients with chronic obstructive pulmonary disease (COPD).nnnMETHODSnOn a double-blind and cross-over study, 33 patients (FEV(1) = 47.4 +/- 12.9% predicted) were randomly allocated to 2-wk formoterol fumarate 12 microg twice-daily (FOR) plus TIO 18 microg once-daily or FOR plus placebo (PLA). Inspiratory capacity (IC) was obtained on constant-speed treadmill tests to the limit of tolerance (Tlim).nnnRESULTSnFOR-TIO was superior to FOR-PLA in increasing post-treatment FEV(1) and Tlim (1.34 +/- 0.42 L vs. 1.25 +/- 0.39 L and 124 +/- 27% vs. 68 +/- 14%, respectively; p < 0.05). FOR-TIO slowed the rate of decrement in exercise IC compared to FOR-PLA (Deltaisotime-rest = -0.27 +/- 0.40 L vs. -0.45 +/- 0.36 L, p < 0.05). In addition, end-expiratory lung volume (% total lung capacity) was further reduced with FOR-TIO (p < 0.05). Of note, patients showing greater increases in Tlim with FOR-TIO (16/26, 61.6%) had more severe airways obstruction and lower exercise capacity at baseline. Improvement in Tlim with FOR-TIO was also related to larger increases in FEV(1) (p < 0.05).nnnCONCLUSIONSnCompared to FOR monotherapy, FOR-TIO further improved effort-induced dynamic hyperinflation and exercise endurance in patients with moderate-to-severe COPD. These beneficial consequences were more likely to be found in severely-disabled patients with larger resting functional responses to the combination therapy.nnnTRIAL REGISTRATIONnClinicaltrials.gov Identifier: NCT00680056 [ClinicalTrials.gov].

Bronchodilators accelerate the dynamics of muscle O2 delivery and utilisation during exercise in COPD

Background Expiratory flow limitation and lung hyperinflation promote cardiocirculatory perturbations that might impair O2 delivery to locomotor muscles in patients with chronic obstructive pulmonary disease (COPD). The hypothesis that decreases in lung hyperinflation after the inhalation of bronchodilators would improve skeletal muscle oxygenation during exercise was tested. Methods Twelve non- or mildly hypoxaemic males (forced expiratory volume in 1u2005s (FEV1)=38.5±12.9% predicted; Pao2>60u2005mm Hg) underwent constant work rate cycle ergometer exercise tests (70–80% peak) to the limit of tolerance (Tlim) after inhaled bronchodilators (salbutamol plus ipratropium) or placebo. Muscle (de)oxygenation (∼fractional O2 extraction) was determined in the vastus lateralis by changes (Δ) in the deoxyhaemoglobin/myoglobin signal ([HHb]) from near-infrared spectroscopy, and cardiac output (QT) was monitored by impedance cardiography. Results Bronchodilators reduced lung hyperinflation and increased Tlim compared with placebo (454±131u2005s vs 321±140u2005s, respectively; p<0.05). On-exercise kinetics of QT and pulmonary O2 uptake (V˙o2) were accelerated with active treatment; Δ[HHb] dynamics, however, were delayed by ∼78% and the signal amplitude diminished by ∼21% (p<0.01). Consequently, the ratio between V˙o2 and Δ[HHb] dynamics decreased, suggesting improved microvascular O2 delivery (τ-V˙o2/MRT-Δ[HHb]=4.48±1.57u2005s vs 2.08±1.15u2005s, p<0.05). Of note, reductions in lung hyperinflation were related to faster QT kinetics and larger decrements in τ-V˙o2/MRT-Δ[HHb] (p<0.01). Conclusions Decreases in operating lung volumes after the inhalation of bronchodilators are associated with faster ‘central’ cardiovascular adjustments to high-intensity exercise with beneficial consequences on muscle oxygenation in patients with moderate to severe COPD.

Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis.

BACKGROUNDnDelayed postexercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. The usefulness of HRR to predict exercise impairment and mortality in patients with pulmonary arterial hypertension (PAH), however, remains largely unexplored.nnnMETHODSnSeventy-two patients with PAH of varied etiology (New York Heart Association classes I-IV) and 21 age- and gender-matched controls underwent a maximal incremental cardiopulmonary exercise test (CPET), with heart rate being recorded up to the fifth minute of recovery.nnnRESULTSnHeart rate recovery was consistently lower in the patients compared with the controls (P < .05). The best cutoff for HRR in 1 minute (HRR(1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR(1 min) ≤ 18 (n = 40), those with HRR(1 min) >18 (n = 32) had better New York Heart Association scores, resting hemodynamics and 6-minute walking distance. In fact, HRR(1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < .05). The single independent predictor of HRR(1 min) ≤ 18 was the 6-minute walking distance (odds ratio [95% CI] 0.99 [0.98-1.00], P < .05). On a multiple regression analysis that considered only CPET-independent variables, HRR(1 min) ≤ 18 was the single predictor of mortality (hazard ratio [95% CI] 1.19 [1.03-1.37], P < .05).nnnCONCLUSIONSnPreserved HRR(1 min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PAH. Conversely, a delayed HRR(1 min) response has negative prognostic implications, a finding likely to be clinically useful when more sophisticated (and costlier) analyses provided by a full CPET are not available.

Scaling skeletal muscle function to mass in patients with moderate-to-severe COPD

Skeletal muscle performance and muscle mass are commonly reduced in patients with advanced chronic obstructive pulmonary disease (COPD). It is currently unclear, however, whether negative changes in muscle structure and function are proportionately related to each other in these patients. In a cross-sectional study, 39 patients (post-bronchodilator FEV1xa0=xa049.7xa0±xa015.5% pred) and 17 controls were submitted to knee isokinetic dynamometry [peak torque (PT), isometric strength (IS), and total work (TW)] and dual energy X-ray absorptiometry for the evaluation of leg muscle mass (LMM). Muscle function (F) was normalised for LMM by using ratio standards (F·LMM−1), power function ratios (F·LMM−b, where b is usuallyxa0≠xa01), and analysis of covariance (ANCOVA). Patients with COPD presented with reduced PT, IS, TW, and LMM as compared to controls: there were significant linear correlations among these variables in both groups (Pxa0<xa00.05). Ratio standards of PT·LMM−1 and TW·LMM−1 were, on average, 14% lower in patients than controls (Pxa0<xa00.01). The coefficients for allometric correction of IS and TW were significantly higher in patients as compared to controls (0.975 vs. 0.603 and 1.471 vs. 0.824, respectively, Pxa0<xa00.05), i.e. more LMM was needed to generate a given functional output in patients than normal subjects. In addition, adjusted means of muscle function variables by ANCOVA were 11–18% lower for patients than controls with LMM as the covariate (Pxa0<xa00.05). We conclude that factors other than simple atrophy (i.e. mass-independent mechanisms) might play a role in explaining the COPD-related skeletal muscle dysfunction.

Alternative strategies for exercise critical power estimation in patients with COPD

Exercise critical power (CP) has been shown to represent the highest sustainable work rate (WR) in patients with chronic obstructive pulmonary disease (COPD). Parameter estimation, however, depends on 4 high-intensity tests performed, on different days, to the limit of tolerance (Tlim). In order to establish a milder protocol that would be more suitable for disabled patients, we contrasted CP derived from 4, 3 and 2 tests (CP4, CP3 and CP2) in 8 males with moderate COPD. In addition, CP was calculated from 2 single-day tests performed on an inverse sequence (CP2AB and CP2BA): CP values within 5xa0W from CP4 were assumed as “clinically-acceptable” estimates. We found that [CP4–CP3] and [CP4–CP2] differences were within 5xa0W in 8 and 6 patients, respectively (95% confidence interval of the differences=−1.3 to 3.5xa0W and −11.5 to 6.5xa0W). There was a systematic decline on Tlim when an exercise bout was performed after a previous test on the same day (P<0.05). Consequently, substantial differences were found between CP4 and any of the CP estimates obtained from single-day tests. In conclusion, clinically-acceptable estimates of CP can be obtained by using 3 or, in most circumstances, 2 constant WR tests in patients with moderate COPD—provided that they are not performed on the same day.

Effects of oxygen supplementation on cerebral oxygenation during exercise in chronic obstructive pulmonary disease patients not entitled to long-term oxygen therapy.

Background:u2002 The rate of change (Δ) in cerebral oxygenation (COx) during exercise is influenced by blood flow and arterial O2 content (CaO2). It is currently unclear whether ΔCOx would (i) be impaired during exercise in patients with chronic obstructive pulmonary disease (COPD) who do not fulfil the current criteria for long‐term O2 therapy but present with exercise‐induced hypoxaemia and (ii) improve with hyperoxia (FIO2u2003=u20030·4) in this specific sub‐population.

Kinetics of skeletal muscle O2 delivery and utilization at the onset of heavy-intensity exercise in pulmonary arterial hypertension

Impaired O2 delivery relative to O2 demands at the onset of exercise might influence the response profile of muscle fractional O2 extraction (≅Δ[deoxy-Hb/Mb] by near-infrared spectroscopy) either by accelerating its rate of increase or creating an “overshoot” (OS) in patients with pulmonary arterial hypertension (PAH). We therefore assessed the kinetics of O2 uptake

Constant Work-Rate Test to Assess the Effects of Intradialytic Aerobic Training in Mildly Impaired Patients With End-Stage Renal Disease: A Randomized Controlled Trial

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