Harry B. Rossiter

Influence of exercise intensity on the on- and off-transient kinetics of pulmonary oxygen uptake in humans

1 The maximal oxygen uptake (V̇O2,peak) during dynamic muscular exercise is commonly taken as a crucial determinant of the ability to sustain high‐intensity exercise. Considerably less attention, however, has been given to the rate at which V̇O2 increases to attain this maximum (or to its submaximal requirement), and even less to the kinetic features of the response following exercise. 2 Six, healthy, male volunteers (aged 22 to 58 years), each performed 13 exercise tests: initial ramp‐incremental cycle ergometry to the limit of tolerance and subsequently, on different days, three bouts of square‐wave exercise each at moderate, heavy, very heavy and severe intensities. Pulmonary gas exchange variables were determined breath by breath throughout exercise and recovery from the continuous monitoring of respired volumes (turbine) and gas concentrations (mass spectrometer). 3 For moderate exercise, the V̇O2 kinetics were well described by a simple mono‐exponential function, following a short cardiodynamic phase, with the on‐ and off‐transients having similar time constants (τ1); i.e. τ1,on averaged 33 ± 16 s (± S.D.) and τ1,off 29 ± 6 s. 4 The on‐transient V̇O2 kinetics were more complex for heavy exercise. The inclusion of a second slow and delayed exponential component provided an adequate description of the response; i.e. τ1,on= 32 ± 17 s and τ2,on= 170 ± 49 s. The off‐transient V̇O2 kinetics, however, remained mono‐exponential (τ1,off= 42 ± 11 s). 5 For very heavy exercise, the on‐transient V̇O2 kinetics were also well described by a double exponential function (τ1,on= 34 ± 11 s and τ2,on= 163 ± 46 s). However, a double exponential, with no delay, was required to characterise the off‐transient kinetics (i.e. τ1,off= 33 ± 5 s and τ2,off= 460 ± 123 s). 6 At the highest intensity (severe), the on‐transient V̇O2 kinetics reverted to a mono‐exponential profile (τ1,on= 34 ± 7 s), while the off‐transient kinetics retained a two‐component form (τ1,off= 35 ± 11 s and τ2,off= 539 ± 379 s). 7 We therefore conclude that the kinetics of V̇O2 during dynamic muscular exercise are strikingly influenced by the exercise intensity, both with respect to model order and to dynamic asymmetries between the on‐ and off‐transient responses.

Dynamic asymmetry of phosphocreatine concentration and O2 uptake between the on- and off-transients of moderate- and high-intensity exercise in humans

The on‐ and off‐transient (i.e. phase II) responses of pulmonary oxygen uptake (V̇O2) to moderate‐intensity exercise (i.e. below the lactate threshold, θL) in humans has been shown to conform to both mono‐exponentiality and ‘on‐off’ symmetry, consistent with a system manifesting linear control dynamics. However above θL the V̇O2 kinetics have been shown to be more complex: during high‐intensity exercise neither mono‐exponentiality nor ‘on‐off’ symmetry have been shown to appropriately characterise the V̇O2 response. Muscle [phosphocreatine] ([PCr]) responses to exercise, however, have been proposed to be dynamically linear with respect to work rate, and to demonstrate ‘on‐off’ symmetry at all work intenisties. We were therefore interested in examining the kinetic characteristics of the V̇O2 and [PCr] responses to moderate‐ and high‐intensity knee‐extensor exercise in order to improve our understanding of the factors involved in the putative phosphate‐linked control of muscle oxygen consumption. We estimated the dynamics of intramuscular [PCr] simultaneously with those of V̇O2 in nine healthy males who performed repeated bouts of both moderate‐ and high‐intensity square‐wave, knee‐extension exercise for 6 min, inside a whole‐body magnetic resonance spectroscopy (MRS) system. A transmit‐receive surface coil placed under the right quadriceps muscle allowed estimation of intramuscular [PCr]; V̇O2 was measured breath‐by‐breath using a custom‐designed turbine and a mass spectrometer system. For moderate exercise, the kinetics were well described by a simple mono‐exponential function (following a short cardiodynamic phase for V̇O2,), with time constants (τ) averaging: τV̇O2,on 35 ± 14 s (±s.d.), τ[PCr]on 33 ± 12 s, τV̇O2,off 50 ± 13 s and τ[PCr]off 51 ± 13 s. The kinetics for both V̇O2 and [PCr] were more complex for high‐intensity exercise. The fundamental phase expressing average τ values of τV̇O2,on 39 ± 4 s, τ[PCr]on 38 ± 11 s, τV̇O2,off 51 ± 6 s and τ[PCr]off 47 ± 11 s. An associated slow component was expressed in the on‐transient only for both V̇O2 and [PCr], and averaged 15.3 ± 5.4 and 13.9 ± 9.1 % of the fundamental amplitudes for V̇O2 and [PCr], respectively. In conclusion, the τ values of the fundamental component of [PCr] and V̇O2 dynamics cohere to within 10 %, during both the on‐ and off‐transients to a constant‐load work rate of both moderate‐ and high‐intensity exercise. On average, ≈90 % of the magnitude of the V̇O2 slow component during high‐intensity exercise is reflected within the exercising muscle by its [PCr] response.

Inferences from pulmonary O2 uptake with respect to intramuscular [phosphocreatine] kinetics during moderate exercise in humans

1 In the non‐steady state of moderate intensity exercise, pulmonary O2 uptake (V̇p,O2) is temporally dissociated from muscle O2 consumption (V̇m,O2) due to the influence of the intervening venous blood volume and the contribution of body O2 stores to ATP synthesis. A monoexponential model of V̇p,O2 without a delay term, therefore, implies an obligatory slowing of V̇p,O2 kinetics in comparison to V̇m,O2. 2 During moderate exercise, an association of V̇m,O2 and [phosphocreatine] ([PCr]) kinetics is a necessary consequence of the control of muscular oxidative phosphorylation mediated by some function of [PCr]. It has also been suggested that the kinetics of V̇p,O2 will be expressed with a time constant within 10 % of that of V̇m,O2. 3 V̇p,O2 and intramuscular [PCr] kinetics were investigated simultaneously during moderate exercise of a large muscle mass in a whole‐body NMR spectrometer. Six healthy males performed prone constant‐load quadriceps exercise. A transmit‐receive coil under the right quadriceps allowed determination of intramuscular [PCr]; V̇p,O2 was measured breath‐by‐breath, in concert with [PCr], using a turbine and a mass spectrometer system. 4 Intramuscular [PCr] decreased monoexponentially with no delay in response to exercise. The mean of the time constants (τPCr) was 35 s (range, 20–64 s) for the six subjects. 5 Two temporal phases were evident in the V̇p,O2 response. When the entire V̇p,O2 response was modelled to be exponential with no delay, its time constant (τ′V̇p,O2) was longer in all subjects (group mean = 62 s; range, 52–92 s) than that of [PCr], reflecting the energy contribution of the O2 stores. 6 Restricting the V̇p,O2 model fit to phase II resulted in matching kinetics for V̇p,O2 (group mean τV̇p,O2= 36 s; range, 20–68 s) and [PCr], for all subjects. 7 We conclude that during moderate intensity exercise the phase II τV̇p,O2 provides a good estimate of τPCr and by implication that of V̇m,O2 (τV̇m,O2).

Effects of prior exercise on oxygen uptake and phosphocreatine kinetics during high‐intensity knee‐extension exercise in humans

1 A prior bout of high‐intensity square‐wave exercise can increase the temporal adaptation of pulmonary oxygen uptake (V̇O2) to a subsequent bout of high‐intensity exercise. The mechanisms controlling this adaptation, however, are poorly understood. 2 We therefore determined the dynamics of intramuscular [phosphocreatine] ([PCr]) simultaneously with those of V̇O2 in seven males who performed two consecutive bouts of high‐intensity square‐wave, knee‐extensor exercise in the prone position for 6 min with a 6 min rest interval. A magnetic resonance spectroscopy (MRS) transmit‐receive surface coil under the quadriceps muscle allowed estimation of [PCr]; V̇O2 was measured breath‐by‐breath using a custom‐designed turbine and a mass spectrometer system. 3 The V̇O2 kinetics of the second exercise bout were altered compared with the first such that (a) not only was the instantaneous rate of V̇O2 change (at a given level of V̇O2) greater but the phase II τ was also reduced ‐ averaging 46.6 ± 6.0 s (bout 1) and 40.7 ± 8.4 s (bout 2) (mean ±s.d.) and (b) the magnitude of the later slow component was reduced. 4 This was associated with a reduction of, on average, 16.1 % in the total exercise‐induced [PCr] decrement over the 6 min of the exercise, of which 4.0 % was due to a reduction in the slow component of [PCr]. There was no discernable alteration in the initial rate of [PCr] change. The prior exercise, therefore, changed the multi‐compartment behaviour towards that of functionally first‐order dynamics. 5 These observations demonstrate that the V̇O2 responses relative to the work rate input for high‐intensity exercise are non‐linear, as are, it appears, the putative phosphate‐linked controllers for which [PCr] serves as a surrogate.

Exercise: Kinetic Considerations for Gas Exchange

The activities of daily living typically occur at metabolic rates below the maximum rate of aerobic energy production. Such activity is characteristic of the nonsteady state, where energy demands, and consequential physiological responses, are in constant flux. The dynamics of the integrated physiological processes during these activities determine the degree to which exercise can be supported through rates of O₂ utilization and CO₂ clearance appropriate for their demands and, as such, provide a physiological framework for the notion of exercise intensity. The rate at which O₂ exchange responds to meet the changing energy demands of exercise--its kinetics--is dependent on the ability of the pulmonary, circulatory, and muscle bioenergetic systems to respond appropriately. Slow response kinetics in pulmonary O₂ uptake predispose toward a greater necessity for substrate-level energy supply, processes that are limited in their capacity, challenge system homeostasis and hence contribute to exercise intolerance. This review provides a physiological systems perspective of pulmonary gas exchange kinetics: from an integrative view on the control of muscle oxygen consumption kinetics to the dissociation of cellular respiration from its pulmonary expression by the circulatory dynamics and the gas capacitance of the lungs, blood, and tissues. The intensity dependence of gas exchange kinetics is discussed in relation to constant, intermittent, and ramped work rate changes. The influence of heterogeneity in the kinetic matching of O₂ delivery to utilization is presented in reference to exercise tolerance in endurance-trained athletes, the elderly, and patients with chronic heart or lung disease.

Skeletal Muscle Fatigue and Decreased Efficiency: Two Sides of the Same Coin?

During high-intensity submaximal exercise, muscle fatigue and decreased efficiency are intertwined closely, and each contributes to exercise intolerance. Fatigue and muscle inefficiency share common mechanisms, for example, decreased “metabolic stability,” muscle metabolite accumulation, decreased free energy of adenosine triphosphate breakdown, limited O2 or substrate availability, increased glycolysis, pH disturbance, increased muscle temperature, reactive oxygen species production, and altered motor unit recruitment patterns.

The effect of resistive breathing on leg muscle oxygenation using near-infrared spectroscopy during exercise in men

The effect of added respiratory work on leg muscle oxygenation during constant‐load cycle ergometry was examined in six healthy adults. Exercise was initiated from a baseline of 20 W and increased to a power output corresponding to 90% of the estimated lactate threshold (moderate exercise) and to a power output yielding a tolerance limit of 11.8 min (± 1.4, S.D.) (heavy exercise). Ventilation and pulmonary gas exchange were measured breath‐by‐breath. Profiles of leg muscle oxygenation were determined throughout the protocol using near‐infrared (NIR) spectroscopy (Hamamatsu NIRO 500) with optodes aligned midway along the vastus lateralis of the dominant leg. Four conditions were tested: (i) control (Con) where the subjects breathed spontaneously throughout, (ii) controlled breathing (Con Br) where breathing frequency and tidal volume were matched to the Con profile, (iii) increased work of breathing (Resist Br) in which a resistance of 7 cmH2O l−1 s−1 was inserted into the mouthpiece assembly, and (iv) partial leg blood flow occlusion (Leg Occl), where muscle perfusion was reduced by inflating a pressure cuff (∼90 mmHg) around the upper right thigh. During Resist Br and Leg Occl, subjects controlled their breathing pattern to reproduce the ventilatory profile of Con. An ∼3 min period with respiratory resistance or pressure cuff was introduced ∼4 min after exercise onset. NIR spectroscopy data for reduced haemoglobin‐myoglobin (Δ[Hb]) were extracted from the continuous display at specific times prior to, during and after removal of the resistance or pressure cuff. While the Δ[Hb] increased during moderate‐ and heavy‐intensity exercise, there was no additional increase in Δ[Hb] with Resist Br. In contrast, Δ[Hb] increased further with Leg Occl, reflecting increased muscle O2 extraction during the period of reduced muscle blood flow. In conclusion, increasing the work of breathing did not increase leg muscle deoxygenation during heavy exercise. Assuming that leg muscle O2 consumption did not decrease, this implies that leg blood flow was not reduced consequent to a redistribution of flow away from the working leg muscle.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Dynamic heterogeneity of exercising muscle blood flow and O2 utilization.

Resolving the bases for different physiological functioning or exercise performance within a population is dependent on our understanding of control mechanisms. For example, when most young healthy individuals run or cycle at moderate intensities, oxygen uptake (VO2) kinetics are rapid and the amplitude of the VO2 response is not constrained by O2 delivery. For this to occur, muscle O2 delivery (i.e., blood flow × arterial O2 concentration) must be coordinated superbly with muscle O2 requirements (VO2), the efficacy of which may differ among muscles and distinct fiber types. When the O2 transport system succumbs to the predations of aging or disease (emphysema, heart failure, and type 2 diabetes), muscle O2 delivery and O2 delivery-VO2 matching and, therefore, muscle contractile function become impaired. This forces greater influence of the upstream O2 transport pathway on muscle aerobic energy production, and the O2 delivery-VO2 relationship(s) assumes increased importance. This review is the first of its kind to bring a broad range of available techniques, mostly state of the art, including computer modeling, radiolabeled microspheres, positron emission tomography, magnetic resonance imaging, near-infrared spectroscopy, and phosphorescence quenching to resolve the O2 delivery-VO2 relationships and inherent heterogeneities at the whole body, interorgan, muscular, intramuscular, and microvascular/myocyte levels. Emphasis is placed on the following: 1) intact humans and animals as these provide the platform essential for framing and interpreting subsequent investigations, 2) contemporary findings using novel technological approaches to elucidate O2 delivery-VO2 heterogeneities in humans, and 3) future directions for investigating how normal physiological responses can be explained by O2 delivery-VO2 heterogeneities and the impact of aging/disease on these processes.

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