Ventilation/carbon dioxide output relationships during exercise in health.

"Ventilatory efficiency" is widely used in cardiopulmonary exercise testing to make inferences regarding the normality (or otherwise) of the arterial CO2 tension (P aCO2 ) and physiological dead-space fraction of the breath (V D/V T) responses to rapid-incremental (or ramp) exercise. It is quantified as: 1) the slope of the linear region of the relationship between ventilation (V'E) and pulmonary CO2 output (V'CO2 ); and/or 2) the ventilatory equivalent for CO2 at the lactate threshold (V'E/V'CO2 [Formula: see text]) or its minimum value (V'E/V'CO2 min), which occurs soon after [Formula: see text] but before respiratory compensation. Although these indices are normally numerically similar, they are not equally robust. That is, high values for V'E/V'CO2 [Formula: see text] and V'E/V'CO2 min provide a rigorous index of an elevated V D/V T when P aCO2 is known (or can be assumed) to be regulated. In contrast, a high V'E-V'CO2 slope on its own does not, as account has also to be taken of the associated normally positive and small V'E intercept. Interpretation is complicated by factors such as: the extent to which P aCO2 is actually regulated during rapid-incremental exercise (as is the case for steady-state moderate exercise); and whether V'E/V'CO2 [Formula: see text] or V'E/V'CO2 min provide accurate reflections of the true asymptotic value of V'E/V'CO2 , to which the V'E-V'CO2 slope approximates at very high work rates.

Reply to Garcia-Tabar et al.: Quality control of open-circuit respirometry: real-time, laboratory-based systems. Let us spread "good practice".

PURPOSE: This article is in response to the Letter of Garcia-Tabar et al. [Eur J Appl Physiol (in press), 2018] relating to the issue of post-test sensor calibration 'verification'. This issue is poorly addressed in contemporary patient-related position statements on cardiopulmonary exercise testing (CPET). METHODS: Post-test sensor calibration verification approaches were compared. RESULT: The potential impact on data quality of changing sensor calibration during the course of an exercise test was described. CONCLUSION: It is recommended that post-test sensor calibration verification be incorporated into existing CPET 'best practice'.

Open-circuit respirometry: real-time, laboratory-based systems.

This review explores the conceptual and technological factors integral to the development of laboratory-based, automated real-time open-circuit mixing-chamber and breath-by-breath (B × B) gas-exchange systems, together with considerations of assumptions and limitations. Advances in sensor technology, signal analysis, and digital computation led to the emergence of these technologies in the mid-20th century, at a time when investigators were beginning to recognise the interpretational advantages of nonsteady-state physiological-system interrogation in understanding the aetiology of exercise (in)tolerance in health, sport, and disease. Key milestones include the 'Auchincloss' description of an off-line system to estimate alveolar O2 uptake B × B during exercise. This was followed by the first descriptions of real-time automated O2 uptake and CO2 output B × B measurement by Beaver and colleagues and by Linnarsson and Lindborg, and mixing-chamber measurement by Wilmore and colleagues. Challenges to both approaches soon emerged: e.g., the influence of mixing-chamber washout kinetics on mixed-expired gas concentration determination, and B × B alignment of gas-concentration signals with respired flow. The challenging algorithmic and technical refinements required for gas-exchange estimation at the alveolar level have also been extensively explored. In conclusion, while the technology (both hardware and software) underpinning real-time automated gas-exchange measurement has progressively advanced, there are still concerns regarding accuracy especially under the challenging conditions of changing metabolic rate.

Exercise Testing, Supplemental Oxygen, and Hypoxia.

Cardiopulmonary exercise testing (CPET) in hyperoxia and hypoxia has several applications, stemming from characterization of abnormal physiological response profiles associated with exercise intolerance. As altered oxygenation can impact the performance of gas-concentration and flow sensors and pulmonary gas exchange algorithms, integrated CPET system function requires validation under these conditions. Also, as oxygenation status can influence peak [Formula: see text]o2, care should be taken in the selection of work-rate incrementation rates when CPET performance is to be compared with normobaria at sea level. CPET has been used to evaluate the effects of supplemental O2 on exercise intolerance in chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, and cystic fibrosis at sea level. However, identification of those CPET indices likely to be predictive of supplemental O2 outcomes for exercise tolerance at altitude in such patients is lacking. CPET performance with supplemental O2 in respiratory patients residing at high altitudes is also poorly studied. Finally, CPET has the potential to give physiological and clinical information about acute and chronic mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. It may also translate high-altitude acclimatization and adaptive processes in healthy individuals into intensive care medical practice.

A 'ramp-sprint' protocol to characterise indices of aerobic function and exercise intensity domains in a single laboratory test.

PURPOSE: The lactate threshold (LT), critical power (CP) and maximum oxygen uptake (VO2max) together partition exercise intensity domains by their common physiological, biochemical and perceptual response characteristics. CP is the greatest power output attainable immediately following intolerance at VO2peak, and the asymptote of 3 min all-out exercise. Thus we reasoned that a maximal 'sprint' immediately following standard ramp-incremental exercise would allow characterisation of the three aerobic indices in a single test. METHODS: Ten healthy men (23 ± 3 year, mean ± SD) performed 9 cycle-ergometry tests on different days: (A) two ramp-incremental tests to intolerance (20 W min(-1)), immediately followed by a 3 min maximal, variable-power effort ramp-sprint test (RST) for LT, VO2peak and sprint-phase power (SP) determination; (B) four constant-power tests for CP and VO2max determination; (C) constant-power tests at 10 W below LT, and 10 W below and above SP to verify intensity domain characterisation. Capillary [lactate] and breath-by-breath VO2 were measured. RESULTS: Reproducibility of LT, SP and VO2max measurements between RST repeats was within 5% or less (r ≥ 0.991, p < 0.001). CP (257 ± 46 W) was not different (p = 0.72) from SP (258 ± 42 W). Exercise 10 W below LT and SP resulted in steady state VO2 and [lactate]. VO2max (4.0 ± 0.6 L min(-1)), peak [lactate] (11 ± 2 mM) and intolerance were reached 19 ± 5 min into exercise at 10 W above SP. CONCLUSIONS: These data suggest that the key indices of aerobic function may be accurately and reliably estimated during a single exercise test. This test may provide a basis for simplifying assessment and prescription of exercise training and experimental interventions.

Muscle metabolism and activation heterogeneity by combined 31P chemical shift and T2 imaging, and pulmonary O2 uptake during incremental knee-extensor exercise.

The integration of skeletal muscle substrate depletion, metabolite accumulation, and fatigue during large muscle-mass exercise is not well understood. Measurement of intramuscular energy store degradation and metabolite accumulation is confounded by muscle heterogeneity. Therefore, to characterize regional metabolic distribution in the locomotor muscles, we combined 31P magnetic resonance spectroscopy, chemical shift imaging, and T2-weighted imaging with pulmonary oxygen uptake during bilateral knee-extension exercise to intolerance. Six men completed incremental tests for the following: (1) unlocalized 31P magnetic resonance spectroscopy; and (2) spatial determination of 31P metabolism and activation. The relationship of pulmonary oxygen uptake to whole quadriceps phosphocreatine concentration ([PCr]) was inversely linear, and three of four knee-extensor muscles showed activation as assessed by change in T2. The largest changes in [PCr], [inorganic phosphate] ([Pi]) and pH occurred in rectus femoris, but no voxel (72 cm3) showed complete PCr depletion at exercise cessation. The most metabolically active voxel reached 11 ± 9 mM [PCr] (resting, 29 ± 1 mM), 23 ± 11 mM [Pi] (resting, 7 ± 1 mM), and a pH of 6.64 ± 0.29 (resting, 7.08 ± 0.03). However, the distribution of 31P metabolites and pH varied widely between voxels, and the intervoxel coefficient of variation increased between rest (∼10%) and exercise intolerance (∼30-60%). Therefore, the limit of tolerance was attained with wide heterogeneity in substrate depletion and fatigue-related metabolite accumulation, with extreme metabolic perturbation isolated to only a small volume of active muscle (<5%). Regional intramuscular disturbances are thus likely an important requisite for exercise intolerance. How these signals integrate to limit muscle power production, while regional "recruitable muscle" energy stores are presumably still available, remains uncertain.

Respiratory and sleep disorders in mucopolysaccharidosis.

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.

The contribution of "resting" body muscles to the slow component of pulmonary oxygen uptake during high-intensity cycling.

Oxygen uptake (VO2) kinetics during moderate constant-workrate (WR) exercise (>lactate-threshold (θL)) are well described as exponential. AboveθL, these kinetics are more complex, consequent to the development of a delayed slow component (VO2sc), whose aetiology remains controversial. To assess the extent of the contribution to the VO2sc from arm muscles involved in postural stability during cycling, six healthy subjects completed an incremental cycle-ergometer test to the tolerable limit for estimation of θL and determination of peak VO2. They then completed two constant-WR tests at 90% of θL and two at 80% of ∆ (difference between θL and VO2peak). Gas exchange variables were derived breath-by-breath. Local oxygenation profiles of the vastus lateralis and biceps brachii muscles were assessed by near-infrared spectroscopy, with maximal voluntary contractions (MVC) of the relevant muscles being performed post-exercise to provide a frame of reference for normalising the exercise-related oxygenation responses across subjects. Above supra-θL, VO2 rose in an exponential-like fashion ("phase 2), with a delayed VO2sc subsequently developing. This was accompanied by an increase in [reduced haemoglobin] relative to baseline (∆[Hb]), which attained 79 ± 13 % (mean, SD) of MVC maximum in vastus lateralis at end-exercise and 52 ± 27 % in biceps brachii. Biceps brachii ∆[Hb] was significantly correlated with VO2 throughout the slow phase. In contrast, for sub- L exercise, VO2 rose exponentially to reach a steady state with a more modest increase in vastus lateralis ∆[Hb] (30 ± 11 %); biceps brachii ∆[Hb] was minimally affected (8 ± 2 %). That the intramuscular O2 desaturation profile in biceps brachii was proportional to that for VO2sc during supra-θL cycle ergometry is consistent with additional stabilizing arm work contributing to the VO2sc.

Pulmonary O2 uptake kinetics as a determinant of high-intensity exercise tolerance in humans.

Tolerance to high-intensity constant-power (P) exercise is well described by a hyperbola with two parameters: a curvature constant (W') and power asymptote termed "critical power" (CP). Since the ability to sustain exercise is closely related to the ability to meet the ATP demand in a steady state, we reasoned that pulmonary O(2) uptake (Vo(2)) kinetics would relate to the P-tolerable duration (t(lim)) parameters. We hypothesized that 1) the fundamental time constant (τVo(2)) would relate inversely to CP; and 2) the slow-component magnitude (ΔVo(2sc)) would relate directly to W'. Fourteen healthy men performed cycle ergometry protocols to the limit of tolerance: 1) an incremental ramp test; 2) a series of constant-P tests to determine Vo(2max), CP, and W'; and 3) repeated constant-P tests (WR(6)) normalized to a 6 min t(lim) for τVo(2) and ΔVo(2sc) estimation. The WR(6) t(lim) averaged 365 ± 16 s, and Vo(2max) (4.18 ± 0.49 l/min) was achieved in every case. CP (range: 171-294 W) was inversely correlated with τVo(2) (18-38 s; R(2) = 0.90), and W' (12.8-29.9 kJ) was directly correlated with ΔVo(2sc) (0.42-0.96 l/min; R(2) = 0.76). These findings support the notions that 1) rapid Vo(2) adaptation at exercise onset allows a steady state to be achieved at higher work rates compared with when Vo(2) kinetics are slower; and 2) exercise exceeding this limit initiates a "fatigue cascade" linking W' to a progressive increase in the O(2) cost of power production (Vo(2sc)), which, if continued, results in attainment of Vo(2max) and exercise intolerance. Collectively, these data implicate Vo(2) kinetics as a key determinant of high-intensity exercise tolerance in humans.

Oxygen uptake kinetics during incremental- and decremental-ramp cycle ergometry.

The pulmonary oxygen uptake (VO2) response to incremental-ramp cycle ergometry typically demonstrates lagged-linear first-order kinetics with a slope of ~10-11 ml·min(-1)·W(-1), both above and below the lactate threshold (θL), i.e. there is no discernible VO2 slow component (or "excess" VO2) above θL. We were interested in determining whether a reverse ramp profile would yield the same response dynamics. Ten healthy males performed a maximum incremental -ramp (15-30 W·min(-1), depending on fitness). On another day, the work rate (WR) was increased abruptly to the incremental maximum and then decremented at the same rate of 15-30 W.min(-1) (step-decremental ramp). Five subjects also performed a sub-maximal ramp-decremental test from 90% of θL. VO2 was determined breath-by-breath from continuous monitoring of respired volumes (turbine) and gas concentrations (mass spectrometer). The incremental-ramp VO2-WR slope was 10.3 ± 0.7 ml·min(-1)·W(-1), whereas that of the descending limb of the decremental ramp was 14.2 ± 1.1 ml·min(-1)·W(-1) (p < 0.005). The sub-maximal decremental-ramp slope, however, was only 9. 8 ± 0.9 ml·min(-1)·W(-1): not significantly different from that of the incremental-ramp. This suggests that the VO2 response in the supra-θL domain of incremental-ramp exercise manifest not actual, but pseudo, first-order kinetics. Key pointsThe slope of the decremental-ramp response is appreciably greater than that of the incremental.The response dynamics in supra-θL domain of the incremental-ramp appear not to manifest actual first-order kinetics.The mechanisms underlying the different dynamic response behaviour for incremental and decremental ramps are presently unclear.

Influence of cycling history on the ventilatory response to cycle-ergometry in humans: a role for respiratory memory?

The ventilatory (V' E) mechanisms subserving stability of alveolar and arterial PCO2 (PACO2, PaCO2) during moderate exercise (< lactate threshold, thetaL) remain controversial. As long-term modulation has been argued to be an important contributor to this control process, we proposed that subjects with no experience of cycling (NEx) might provide insight into this issue. With no exercise familiarization, 9 sedentary NEx subjects and 9 age-, sex-, and activity-matched controls (C) who had cycled regularly for recreational purposes since childhood completed a square-wave (6-min stage) cycle-ergometry test: 10 W-WR1-WR2-WR1-10 W; WR1 range 25-45 W, WR2 range 50-90 W. WRs were subsequently confirmed to

Kinetics of the ventilatory and metabolic responses to moderate-intensity exercise in humans following prior exercise-induced metabolic acidaemia.

As the time constant of the phase 2 (ø2) ventilatory response (tauV'(E)) to moderate exercise (< lactate threshold, thetaL) is reduced by exogenous procedures that augment peripheral (carotid) chemosensitivity (hypoxia; chronic metabolic acidaemia), we examined whether an acute endogenous metabolic acidaemia had a similar effect. Six subjects completed two tests (A, B), each comprising two 6-min bouts separated by a 6-min "0" W recovery: A:- 90% thetaL, 90% thetaL; B:- supra-thetaL (50% between thetaL and peak V'O2), 90% thetaL. For Protocol A, the bout 2 sub-thetaL tauV'E was similar to bout 1. However, for Protocol B, where the initial supra-thetaL metabolic acidaemia was still evident at the end of the subsequent sub-thetaL bout, the sub-thetaL tauV'E was shorter; tauV'E/tauV'O2 and tauV'E/tauV'CO2 were reduced; and the transient end-tidal PO2undershoot was less marked. We conclude that an acute, endogenous metabolic acidaemia speeds ø2 V'(E) kinetics in moderate exercise, consistent with carotid chemoreception contributing to the tightness of arterial pH-CO2 regulation and the magnitude of the transient arterial hypoxaemia.

Ventilatory control during intermittent high-intensity exercise in humans.

Intermittent supra-maximal cycling of varying work: recovery durations was used to explore the kinetics of respiratory compensation for the metabolic acidosis of high-intensity exercise (> lactate threshold, thetaL). For a 10:20s duty-cycle, blood [lactate] ([L-]) was not increased, and there was no evidence of respiratory compensation (RC); i.e, no increase in the ventilation (VE)-CO2 output (Vco2) slope, nor fall in end-tidal PCO2 (PETCO2). For longer duty-cycles, [L-] was elevated, stabilizing (30s:60 s exercise) or rising progressively (60s:120s, 90s: 180s exercise). In addition, Vco2 and VE now oscillated with WR, with evidence of delayed RC (progressive increase in VE - VCO2 slope; decrease in PETCO2) being more marked with longer duty-cycles. These results, which extend earlier findings with supra- thetaL step and ramp exercise, are not consistent with an appreciable contribution to RC from zero-order central command or peripheral neurogenesis. The reasons for the slow RC kinetics are unclear, but may reflect in part the H(+)-signal transduction properties of carotid chemoreceptors.

Effects of formoterol on exercise tolerance in severely disabled patients with COPD.

OBJECTIVE: We wished to evaluate the effects of inhaled formoterol, a long-acting beta(2)-adrenergic agonist, on exercise tolerance and dynamic hyperinflation (DH) in severely disabled chronic obstructive pulmonary disease (COPD) patients. DESIGN: In a two-period, crossover study, 21 patients with advanced COPD (FEV(1)=38.8+/-11.7% predicted, 16 patients GOLD stages III-IV) were randomly allocated to receive inhaled formoterol fumarate 12 microg twice daily for 14 days followed by placebo for 14 days, or vice versa. Patients performed constant work-rate cardiopulmonary exercise tests to the limit of tolerance (Tlim) on a cycle ergometer: inspiratory capacity (IC) was obtained at rest and each minute during exercise. Baseline and transitional dyspnoea indices (BDI and TDI) were also recorded. RESULTS: Eighteen patients completed both treatment periods. Formoterol treatment was associated with an estimated increase of 130 s in Tlim compared with placebo (P=0.052): this corresponded to a 37.8% improvement over placebo (P=0.012). Enhanced exercise tolerance after bronchodilator was associated with diminished DH marked by higher inspiratory reserve and tidal volumes at isotime and exercise cessation (P<0.05). There was no significant difference between formoterol and placebo on exercise dyspnoea ratings; however, all domains of the TDI improved (P