Daniela M. Bravo

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

BACKGROUND It 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). METHODS On 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). RESULTS FOR-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). CONCLUSIONS Compared 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. TRIAL REGISTRATION Clinicaltrials.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 1 s (FEV1)=38.5±12.9% predicted; Pao2>60 mm 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±131 s vs 321±140 s, 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±1.57 s vs 2.08±1.15 s, 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.

Kinetics analysis of muscle arterial–venous O2 difference profile during exercise

Muscle vascular dysfunction, a hallmark of chronic diseases such as heart failure and diabetes, impairs the matching of blood flow (Q(m)) to O(2) utilization (V(O(2m))) following exercise onset. One recently described consequence of this behavior is that arterial-venous O(2) difference [(a-v)(O(2)), the mirror image of muscle vascular oxygenation] transiently overshoots the subsequent steady-state and, in so doing, may provide important information regarding Q(m) versus V(O(2m)) dynamics. Using computer simulations, we tested the hypothesis that key parameters of the (a-v)(O(2)) overshoot - peak response, downward time constant (tau(D)), and total area - would relate quantitatively to Q(m) kinetics. Our results demonstrated significant proportionality (all p<0.01) between Q(m) mean response time and peak (r(2)=0.56), tau(D) (r(2)=72) and total area (r(2)=0.97) of (a-v)(O(2)) overshoot. These results suggest that analysis of (a-v)(O(2)) or its proxy, muscle vascular oxygenation [measured using near-infrared spectroscopy or phosphorescence quenching], provides valuable information regarding blood flow and vascular function particularly in reference to V(O(2m)) kinetics.

Signal-morphology impedance cardiography during incremental cardiopulmonary exercise testing in pulmonary arterial hypertension.

Haemodynamic responses to exercise are related to physical impairment and worse prognosis in patients with pulmonary arterial hypertension (PAH). It is clinically relevant, therefore, to investigate the practical usefulness of non‐invasive methods of monitoring exercise haemodynamics in this patient population.

Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption (V˙O2) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

Excess ventilation in COPD: Implications for dyspnoea and tolerance to interval exercise

Interval exercise delays critical mechanical-ventilatory constraints with positive consequences on Dyspnoea and exercise tolerance in COPD. We hypothesized that those advantages of interval exercise would be partially off-set in patients showing excessive ventilation (V˙E) to metabolic demand (V˙CO2). Sixteen men (FEV1 = 42.3 ± 8.9%) performed, on different days, 30 s and 60 s bouts at 100% peak (on) interspersed by moderate exercise at 40% (off). Nine patients did not sustain exercise for 30 min irrespective of on duration. They presented with higher V˙E/V˙CO2 nadir (35 ± 3 vs. 30 ± 5) and dead space/tidal volume (0.39 ± 0.05 vs. 0.34 ± 0.06) compared to their counterparts (p < 0.05). [Lactate], operating lung volumes and symptom burden (dyspnoea and leg effort) were also higher (p < 0.05). Unloading off decreased the metabolic-ventilatory demands, thereby allowing 7/9 patients to exercise for 30 min. Increased wasted ventilation accelerates the rate at which critical mechanical constraints and limiting dyspnoea are reached during interval exercise in patients with COPD.