Luis Puente-Maestu

Recommendations on the use of exercise testing in clinical practice

Evidence-based recommendations on the clinical use of cardiopulmonary exercise testing (CPET) in lung and heart disease are presented, with reference to the assessment of exercise intolerance, prognostic assessment and the evaluation of therapeutic interventions (e.g. drugs, supplemental oxygen, exercise training). A commonly used grading system for recommendations in evidence-based guidelines was applied, with the grade of recommendation ranging from A, the highest, to D, the lowest. For symptom-limited incremental exercise, CPET indices, such as peak O2 uptake (V′O2), V′O2 at lactate threshold, the slope of the ventilation–CO2 output relationship and the presence of arterial O2 desaturation, have all been shown to have power in prognostic evaluation. In addition, for assessment of interventions, the tolerable duration of symptom-limited high-intensity constant-load exercise often provides greater sensitivity to discriminate change than the classical incremental test. Field-testing paradigms (e.g. timed and shuttle walking tests) also prove valuable. In turn, these considerations allow the resolution of practical questions that often confront the clinician, such as: 1) “When should an evaluation of exercise intolerance be sought?”; 2) “Which particular form of test should be asked for?”; and 3) “What cluster of variables should be selected when evaluating prognosis for a particular disease or the effect of a particular intervention?”

Effect of indacaterol on exercise endurance and lung hyperinflation in COPD

BACKGROUND Indacaterol is a novel, inhaled, once-daily ultra long-acting β(2)-agonist (ultra-LABA) for the treatment of COPD. This study investigated the effect of indacaterol on exercise endurance, and on lung hyperinflation during exercise and at rest in patients with moderate-to-severe COPD. METHODS In this double-blind, placebo-controlled, two-period crossover study (3-week treatment, 3-week washout between treatments), patients were randomized to receive indacaterol 300 μg once-daily or matching placebo. The primary efficacy variable was exercise endurance time after 3 weeks of treatment, measured through constant-load cycle ergometry testing performed at 75% of the peak work rate in a screening incremental exercise test. RESULTS Of 90 patients randomized (mean age: 62.8 years; post-bronchodilator FEV(1): 61.2% predicted and FEV(1)/FVC: 51.6%), 74 completed the study. Pre-treatment exercise tolerance averaged 459 s. Improvement in exercise endurance time was higher with indacaterol 300 μg than with placebo both after the first dose (treatment difference: 101 s; p < 0.001) and after 3 weeks (treatment difference: 111 s; p = 0.011). In addition, indacaterol increased end-exercise inspiratory capacity (IC) versus placebo after 3 weeks (0.28 L, p = 0.002). Significant improvements were also observed in resting IC (0.17 L, p = 0.001), FEV(1) (0.25 L, p < 0.001) and FVC (0.26 L, p < 0.001) with indacaterol compared with placebo at 75 min post-dose after 3 weeks. CONCLUSION In conclusion, indacaterol treatment improved the ability of patients with COPD to exercise. In addition, the improvements observed in resting and end-exercise IC indicate reductions in lung hyperinflation after 3 weeks treatment (ClinicalTrials.gov registration number: NCT00620022).

Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients

Several cellular and molecular alterations have been described in skeletal and respiratory muscles of patients with chronic obstructive pulmonary disease (COPD), but information on potential abnormalities of mitochondrial function is scarce. The aim of the present study was to investigate mitochondrial function in the vastus lateralis (VL) and external intercostalis (EI) of COPD patients. Biopsies from VL and EI were obtained during surgery for lung cancer in 13 patients with mild to moderate COPD (age 68±6 yrs, forced expiratory volume in one second (FEV1) 66±15% predicted) and 19 control subjects (age 67±9 yrs, FEV1 95±18% pred). State 3 and 4 mitochondrial oxygen consumption (V′O2,m), ATP synthesis, citrate synthase, cytochrome oxidase (COX) and complex I–III activities, as well as reactive oxygen species (ROS) production, were determined. In COPD patients, in both muscles, COX activity (VL: COPD 3.0±0.8 versus control 2.0±0.8; EI: 3.7±1.6 versus 2.4±0.9 μmol·min−1·mg−1) and ROS production (VL: 1,643±290 versus 1,285±468; EI: 1,033±210 versus 848±288 arbitrary units) were increased, whereas state 3 V′O2,m was reduced (VL: 2.9±0.3 versus 3.6±0.4; EI: 3.6±0.3 versus 4.1±0.4 mmol·min−1·kg−1). Skeletal muscle mitochondria of patients with chronic obstructive pulmonary disease show electron transport chain blockade and excessive production of reactive oxygen species. The concurrent involvement of both vastus lateralis and external intercostalis suggests a systemic (rather than a local) mechanism(s) already occurring in relatively early stages (Global Initiative for Chronic Obstructive Lung Disease stage II) of the disease.

Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement.

This document reviews 1) the measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and 2) published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches between 1990 and March 2015. Exercise tests are reliable and consistently responsive to rehabilitative and pharmacological interventions. Thresholds for clinically important changes in performance are available for several tests. In pulmonary arterial hypertension, the 6-min walk test (6MWT), peak oxygen uptake and ventilation/carbon dioxide output indices appear to be the variables most responsive to vasodilators. While bronchodilators do not always show clinically relevant effects in chronic obstructive pulmonary disease, high-intensity constant work-rate (endurance) tests (CWRET) are considerably more responsive than incremental exercise tests and 6MWTs. High-intensity CWRETs need to be standardised to reduce interindividual variability. Additional physiological information and responsiveness can be obtained from isotime measurements, particularly of inspiratory capacity and dyspnoea. Less evidence is available for the endurance shuttle walk test. Although the incremental shuttle walk test and 6MWT are reliable and less expensive than cardiopulmonary exercise testing, two repetitions are needed at baseline. All exercise tests are safe when recommended precautions are followed, with evidence suggesting that no test is safer than others. A review of exercise testing to evaluate interventions aimed to improve exercise tolerance in respiratory patients http://ow.ly/U37mQ

Clinical relevance of constant power exercise duration changes in COPD

The endurance time during constant high work-rate exercise (tLIM) is used to assess exercise capacity in patients with chronic obstructive pulmonary disease and as an outcome measure for pulmonary rehabilitation. Our study was designed to establish the minimum clinically important difference for the tLIM. tLIM was measured in 105 patients (86 males) before and after an 8-week outpatient pulmonary rehabilitation programme. Subjects were asked to identify, from a five-point Likert scale, the perceived change in their exercise performance immediately upon completion of the exercise tests. The scale ranged from “better” to “worse”. The mean±sd age was 64±5 yrs, forced expiratory volume in 1 s (FEV1) 47±10% and FEV1/forced vital capacity 54.7±16.3%. Baseline tLIM at 75% of the peak work rate was 397±184 s, which increased by 62±63% after rehabilitation. In subjects who felt their exercise tolerance was “slightly better”, the mean improvement was 34% in the relative improvement over the baseline value (95% CI 29–39)% or 101 (86–116) s compared with 121 (109–134)% in those who reported that their exercise tolerance was “better” and 8 (2–14)% in those who felt their exercise tolerance was “about the same”. Minimum clinically important improvement for tLIM averaged ∼33% of baseline. Patients were able to distinguish at least one further additional level of benefit at 120% of baseline.

Effects of exercise on mitochondrial DNA content in skeletal muscle of patients with COPD

Background Exhausting exercise reduces the mitochondrial DNA (mtDNA) content in the skeletal muscle of healthy subjects due to oxidative damage. Since patients with chronic obstructive pulmonary disease (COPD) suffer enhanced oxidative stress during exercise, it was hypothesised that the mtDNA content will be further reduced. Objective To investigate the effects of exercise above and below the lactate threshold (LT) on the mtDNA content of skeletal muscle of patients with COPD. Methods Eleven patients with COPD (67±8 years; forced expiratory volume in 1 s (FEV1) 45±8%ref) and 10 healthy controls (66±4 years; FEV1 90±7% ref) cycled 45 min above LT (65% peak oxygen uptake (V′o2peak) and another 7 patients (65±6 years; FEV1 50±4%ref) and 7 controls (56±9 years; FEV1 92±6%ref) cycled 45 min below their LT (50% V′o2peak). Biopsies from the vastus lateralis muscle were obtained before exercise, immediately after and 1 h, 1 day and 1 week later to determine by PCR the mtDNA/nuclear DNA (nDNA) ratio (a marker of mtDNA content) and the expression of the peroxisome proliferator-activated receptor-γcoactivator-1α (PGC-1α) mRNA and the amount of reactive oxygen species produced during exercise was estimated from total V′o2. Results Skeletal muscle mtDNA/nDNA fell significantly after exercise above the LT both in controls and in patients with COPD, but the changes were greater in those with COPD. These changes correlated with production of reactive oxygen species, increases in manganese superoxide dismutase and PGC-1α mRNA and returned to baseline values 1 week later. This pattern of response was also observed, albeit minimised, in patients exercising below the LT. Conclusions In patients with COPD, exercise enhances the decrease in mtDNA content of skeletal muscle and the expression of PGC-1α mRNA seen in healthy subjects, probably due to oxidative stress.

Effects of Training on the Tolerance to High-Intensity Exercise in Patients with Severe COPD

Background: There has been no systemic investigation of the effects of training on endurance at different high-intensity work rates in patients with COPD to date. Objectives: We wanted to determine the effects of intense endurance training on tolerance to several high-intensity work rates and to establish the relationship between power (WR) and its tolerable duration (t) (t = W’/(WR – CP), being W’, the curvature constant, thought to be reflective of anaerobic energy availability and/or tolerance to the uncomfortable sensations associated with the high-intensity exercise, and CP the critical power. Methods: We studied 27 patients: age 62 ± 5 years; FEV1 1.2 ± 0.2 liters. Before and after the intervention, the subjects randomly underwent 4 high-intensity constant WR exercise tests. The endurance times of the highest 3 tests were used. Results: Ventilation reached approximately the same level in each of the tests. In response to the training, the average peak increased by 9 ± 5% (p < 0.0001), CP by 14 ± 12% (p < 0.0001) and W’ 18 ± 22% (p = 0.002). In 67% of the patients, CP increased, accompanied by changes in other related physiological variables of aerobic capacity. In the remaining 33%, W’ increased but not CP. Smaller or no changes in the other variables of aerobic capacity were found in those subjects. This latter group was significantly older and had more hyperinflation (i.e. higher RV/TLC%). Conclusions: Our results suggest that neither an incremental nor a single endurance test at constant WR provides an adequate characterisation of exercise tolerance at other WRs. CP and W’ appear to be important parameters characterizing exercise tolerance over a range high-intensity work rates and identifying two distinct types of response to training.

Site of Mitochondrial Reactive Oxygen Species Production in Skeletal Muscle of Chronic Obstructive Pulmonary Disease and Its Relationship with Exercise Oxidative Stress

Exercise triggers skeletal muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD). The objective of this research was to study the specific sites of reactive oxygen species (ROS) production in mitochondria isolated from skeletal muscle of patients with COPD and its relationship with local oxidative stress induced by exercise. Vastus lateralis biopsies were obtained in 16 patients with COPD (66 ± 10 yr; FEV(1), 54 ± 12% ref) and in 14 control subjects with normal lung function who required surgery because of lung cancer (65 ± 7 yr; FEV(1), 91 ± 14% ref) at rest and after exercise. In these biopsies we isolated mitochondria and mitochondrial membrane fragments and determined in vitro mitochondrial oxygen consumption (Mit

A controlled trial of the effects of leg training on breathing pattern and dynamic hyperinflation in severe COPD.

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