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 O 2 uptake (V9O 2 ), V9O 2 at lactate threshold, the slope of the ventilation-CO 2 output relationship and the presence of arterial O 2 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?''

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. @ERSpublications A review of exercise testing to evaluate interventions aimed to improve exercise tolerance in respiratory 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 (FEV(1)) 66+/-15% predicted) and 19 control subjects (age 67+/-9 yrs, FEV(1) 95+/-18% pred). State 3 and 4 mitochondrial oxygen consumption (V'(O(2),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 micromol 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'(O(2),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.

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).

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New Findings r What is the central question of this study?We explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles, and whether signalling pathways, proteasome and oxidative stress influence that process. r What is the main finding and what is its importance?In cancer cachectic mice, MRC complexes and oxygen consumption were decreased in the diaphragm and gastrocnemius. Blockade of nuclear factor-κB and mitogen-activated protein kinase actions partly restored the muscle mass and force and corrected the MRC dysfunction, while concomitantly reducing tumour burden. Antioxidants improved mitochondrial oxygen consumption without eliciting effects on the loss of muscle mass and force or the tumour size, whereas bortezomib reduced tumour burden without influencing muscle mass and strength or MRC function.Abnormalities in mitochondrial content, morphology and function have been reported in several muscle-wasting conditions. We specifically explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles, and whether signalling pathways, proteasomes and oxidative stress may influence that process. We evaluated complex I, II and IV enzyme activities (specific activity assays) and MRC oxygen consumption (polarographic measurements) in diaphragm and gastrocnemius of cachectic mice bearing the LP07 lung tumour, with and without treatment with N -acetylcysteine, bortezomib and nuclear factor-κB (sulfasalazine) and mitogen-activated protein kinases (MAPK, U0126) inhibitors (n = 10 per group for all groups). Whole-body and muscle weights and limb muscle force were also assessed in all rodents at baseline and after 1 month. Compared with control animals, cancer cachectic mice showed a significant reduction in body weight gain, smaller sizes of the diaphragm and gastrocnemius, lower muscle strength, decreased activity of complexes I, II and IV and decreased oxygen consumption in both muscles. Blockade of nuclear factor-κB and MAPK actions restored muscle mass and force and corrected the MRC dysfunction in both muscles, while partly reducing tumour burden.

The effects of two 8 week programmes of reconditioning in chronic obstructive pulmonary disease (COPD) patients were studied. Forty one subjects (mean+/-SD) 644.5) yrs; forced expiratory volume in one second (FEV1) 1.09+/-0.16 L; 40.6+/-6.2% predicted were randomly assigned either to supervised training on a treadmill, 4 days x week(-1) (group S; n=21) or walking 3 or 4 km in 1 h 4 days x week(-1), self-monitored with a pedometer, with weekly visits to encourage adherence (group SM; n=20). Patients were evaluated with the chronic respiratory diseases questionnaire (CRQ) and two exercise tests on a treadmill: incremental (IT) and constant (CT), above lactic threshold or 70% of maximal oxygen uptake (VO2, max) with arterial blood lactate determinations. Estimated mean work rate of training was 69+/-27 W and 25+/-5 W respectively for groups S and SM. Both types of training produced similar changes in the four dimensions of the CRQ. In group S reconditioning yielded significant (p<0.05) increases in VO2, max and increases in duration, with decreased lactate accumulation, ventilation, CO2 output (VCO2), heart rate (HR) and diastolic blood pressure (DBP) at the end of CT. They also adopted a deeper slower pattern of breathing during exercise. The SM group showed significant (p<0.05) increases in duration, lower HR and DBP at the end of CT. Significantly (p<0.05) different effects between S and SM programmes were changes in VO2, max 100+/-101 mL x min(-1) versus 5+/-101 mL x min(-1)), duration of the CT (8.1+/-4.4 min versus 3.9+/-4.7 min), VCO2 (-94+/-153 mL x min(-1) versus 48+/-252 mL x min(-1)), lactate accumulation (-1.3+/-2.2 mmol x L(-1) versus 0+/-1.2 mmol x L(-1) and respiratory rate at the end of CT (4.3+/-3.4 min(-1) versus -1+/-4.2 min(-1)). Supervised, intense training yields physiological improvements in severe chronic obstructive pulmonary disease patients not induced by self-monitored training. The self-monitored, less intense training, increases submaximal exercise endurance, although to a lesser degree.