The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2–3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.

Patients with chronic obstructive pulmonary disease (COPD) have slowed pulmonary O2 uptake (V̇o2p) kinetics during exercise, which may stem from inadequate muscle O2 delivery. However, it is currently unknown how COPD impacts the dynamic relationship between systemic and microvascular O2 delivery to uptake during exercise. We tested the hypothesis that, along with slowed V̇o2p kinetics, COPD patients have faster dynamics of muscle deoxygenation, but slower kinetics of cardiac output (Q̇t) following the onset of heavy-intensity exercise. We measured V̇o2p, Q̇t (impedance cardiography), and muscle deoxygenation (near-infrared spectroscopy) during heavy-intensity exercise performed to the limit of tolerance by 10 patients with moderate-to-severe COPD and 11 age-matched sedentary controls. Variables were analyzed by standard nonlinear regression equations. Time to exercise intolerance was significantly ( P < 0.05) lower in patients and related to the kinetics of V̇o2p ( r = −0.70; P < 0.05). Compared with controls, COPD patients displayed slower kinetics of V̇o2p (42 ± 13 vs. 73 ± 24 s) and Q̇t (67 ± 11 vs. 96 ± 32 s), and faster overall kinetics of muscle deoxy-Hb (19.9 ± 2.4 vs. 16.5 ± 3.4 s). Consequently, the time constant ratio of O2 uptake to mean response time of deoxy-Hb concentration was significantly greater in patients, suggesting a slower kinetics of microvascular O2 delivery. In conclusion, our data show that patients with moderate-to-severe COPD have impaired central and peripheral cardiovascular adjustments following the onset of heavy-intensity exercise. These cardiocirculatory disturbances negatively impact the dynamic matching of O2 delivery and utilization and may contribute to the slower V̇o2p kinetics compared with age-matched controls.

Background: Respiratory muscle unloading during exercise could improve locomotor muscle oxygenation by increasing oxygen delivery (higher cardiac output and/or arterial oxygen content) in patients with chronic obstructive pulmonary disease (COPD). Methods: Sixteen non-hypoxaemic men (forced expiratory volume in 1 s 42.2 (13.9)% predicted) undertook, on different days, two constant work rate (70-80% peak) exercise tests receiving proportional assisted ventilation (PAV) or sham ventilation. Relative changes (D%) in deoxyhaemoglobin (HHb), oxyhaemoglobin (O 2 Hb), tissue oxygenation index (TOI) and total haemoglobin (Hb tot ) in the vastus lateralis muscle were measured by nearinfrared spectroscopy. In order to estimate oxygen delivery (DO 2 est, l/min), cardiac output and oxygen saturation (SpO 2 ) were continuously monitored by impedance cardiography and pulse oximetry, respectively. Results: Exercise tolerance (Tlim) and oxygen uptake were increased with PAV compared with sham ventilation. In contrast, end-exercise blood lactate/Tlim and leg effort/Tlim ratios were lower with PAV (p,0.05). There were no between-treatment differences in cardiac output and SpO 2 either at submaximal exercise or at Tlim (ie, DO 2 est remained unchanged with PAV; p.0.05). Leg muscle oxygenation, however, was significantly enhanced with PAV as the exercise-related decrease in D(O 2 Hb)% was lessened and TOI was improved; moreover, D(Hb tot )%, an index of local blood volume, was increased compared with sham ventilation (p,0.01). Conclusions: Respiratory muscle unloading during highintensity exercise can improve peripheral muscle oxygenation despite unaltered systemic DO 2 in patients with advanced COPD. These findings might indicate that a fraction of the available cardiac output had been redirected from ventilatory to appendicular muscles as a consequence of respiratory muscle unloading.

Blood flow requirements of the respiratory muscles (RM) increase markedly during exercise in chronic heart failure (CHF). We reasoned that if the RM could subtract a fraction of the limited cardiac output (QT) from the peripheral muscles, RM unloading would improve locomotor muscle perfusion. Nine patients with CHF (left ventricle ejection fraction = 26 +/- 7%) undertook constant-work rate tests (70-80% peak) receiving proportional assisted ventilation (PAV) or sham ventilation. Relative changes (Delta%) in deoxy-hemoglobyn, oxi-Hb ([O2Hb]), tissue oxygenation index, and total Hb ([HbTOT], an index of local blood volume) in the vastus lateralis were measured by near infrared spectroscopy. In addition, QT was monitored by impedance cardiography and arterial O2 saturation by pulse oximetry (SpO2). There were significant improvements in exercise tolerance (Tlim) with PAV. Blood lactate, leg effort/Tlim and dyspnea/Tlim were lower with PAV compared with sham ventilation (P < 0.05). There were no significant effects of RM unloading on systemic O2 delivery as QT and SpO2 at submaximal exercise and at Tlim did not differ between PAV and sham ventilation (P > 0.05). Unloaded breathing, however, was related to enhanced leg muscle oxygenation and local blood volume compared with sham, i.e., higher Delta[O2Hb]% and Delta[HbTOT]%, respectively (P < 0.05). We conclude that RM unloading had beneficial effects on the oxygenation status and blood volume of the exercising muscles at similar systemic O2 delivery in patients with advanced CHF. These data suggest that blood flow was redistributed from respiratory to locomotor muscles during unloaded breathing.

Exercise ventilation (') relative to carbon dioxide output (' ) is particularly relevant to patients limited by the respiratory system, those with chronic obstructive pulmonary disease (COPD). High'-' (poor ventilatory efficiency) has been found to be a key physiological abnormality in symptomatic patients with largely preserved forced expiratory volume in 1 s (FEV). Establishing an association between high '-' and exertional dyspnoea in mild COPD provides evidence that exercise intolerance is not a mere consequence of detraining. As the disease evolves, poor ventilatory efficiency might help explaining "out-of-proportion" breathlessness (to FEV impairment). Regardless, disease severity, cardiocirculatory co-morbidities such as heart failure and pulmonary hypertension have been found to increase '-' In fact, a high '-' has been found to be a powerful predictor of poor outcome in lung resection surgery. Moreover, a high '-' has added value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of COPD severity. Documenting improved ventilatory efficiency after lung transplantation and lung volume reduction surgery provides objective evidence of treatment efficacy. Considering the usefulness of exercise ventilatory efficiency in different clinical scenarios, the '-' relationship should be valued in the interpretation of cardiopulmonary exercise tests in patients with mild-to-end-stage COPD.

Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple “non-invasive” assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions.

Severity of resting functional impairment only partially predicts the increased risk of death in chronic obstructive pulmonary disease (COPD). Increased ventilation during exercise is associated with markers of disease progression and poor prognosis, including emphysema extension and pulmonary vascular impairment. Whether excess exercise ventilation would add to resting lung function in predicting mortality in COPD, however, is currently unknown. After an incremental cardiopulmonary exercise test, 288 patients (forced expiratory volume in one second ranging from 18% to 148% predicted) were followed for a median (interquartile range) of 57 (47) months. Increases in the lowest (nadir) ventilation to CO2 output (VCO2) ratio determined excess exercise ventilation. Seventy-seven patients (26.7%) died during follow-up: 30/77 (38.9%) deaths were due to respiratory causes. Deceased patients were older, leaner, had a greater co-morbidity burden (Charlson Index) and reported more daily life dyspnea. Moreover, they had poorer lung function and exercise tolerance (p < 0.05). A logistic regression analysis revealed that ventilation/VCO2 nadir was the only exercise variable that added to age, body mass index, Charlson Index and resting inspiratory capacity (IC)/total lung capacity (TLC) ratio to predict all-cause and respiratory mortality (p < 0.001). Kaplan-Meier analyses showed that survival time was particularly reduced when ventilation/VCO2 nadir > 34 was associated with IC/TLC ≤ 0.34 or IC/TLC ≤ 0.31 for all-cause and respiratory mortality, respectively (p < 0.001). Excess exercise ventilation is an independent prognostic marker across the spectrum of COPD severity. Physiological abnormalities beyond traditional airway dysfunction and lung mechanics are relevant in determining the course of the disease.

Sperandio PA, Oliveira MF, Rodrigues MK, Berton DC, Treptow E, Nery LE, Almeida DR, Neder JA. Sildenafil improves microvascular O 2 delivery-to-utilization matching and accelerates exercise O 2 uptake kinetics in chronic heart failure. Am J Physiol Heart Circ Physiol 303: H1474 -H1480, 2012. First published September 28, 2012; doi:10.1152/ajpheart.00435.2012 can temporally and spatially match microvascular oxygen (O 2) delivery (Q O2mv) to O2 uptake (V O2) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Q O2mv-to-O2 utilization matching and V O2 kinetics, 10 males with CHF (ejection fraction ϭ 27 Ϯ 6%) undertook constant work-rate exercise (70 -80% peak). Breath-bybreath V O2, fractional O2 extraction in the vastus lateralis {ϳdeoxy-genated hemoglobin ϩ myoglobin ([deoxy-Hb ϩ Mb]) by nearinfrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ϳ20%, an effect that was related to faster onand off-exercise V O2 kinetics (P Ͻ 0.05). Active treatment, however, failed to accelerate CO dynamics (P Ͼ 0.05). On-exercise [deoxy-Hb ϩ Mb] kinetics were slowed by sildenafil (ϳ25%), and a subsequent response "overshoot" (n ϭ 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb ϩ Mb] recovery was faster with sildenafil (ϳ15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise V O2 kinetics, blunted oscillations in ventilation (n ϭ 9), and greater exercise capacity (P Ͻ 0.05). Sildenafil intake enhanced intramuscular Q O2mv-to-V O2 matching with beneficial effects on V O2 kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects.sildenafil; blood flow; heart failure; hemodynamics; near-infrared spectroscopy; oxygen consumption; kinetics THE INABILITY TO MAINTAIN an adequate driving pressure for blood-myocite oxygen (O 2 ) diffusion [i.e., microvascular partial pressure of O 2 (PO 2mv )] is paramount to explain the slowness of exercise O 2 uptake (V O 2 ) kinetics in patients with chronic heart failure [CHF; as recently reviewed by Poole and colleagues (34)]. To keep a sufficiently high PO 2mv , however, O 2 delivery should be spatially and temporally matched to V O 2 of individual fibers. In this context, seminal studies found that intramuscular PO 2mv in rodents with CHF was critically low either at rest-to-contractions transition (7,14) or during early recovery (12), i.e., when V O 2 should be increasing or decreasing most rapidly, respectively. Importantly, it was demonstrated that reduced nitric oxide (NO) bioavailability exerted a key mechanistic role on on-and off-exercise O 2 delivery-toutilization uncoupling in these animal preparations (24,25).In intact humans with CHF, previous studies have concomitant...