Descending motor drive does not interact with muscle metaboreflex for ventilation regulation during rhythmic exercise in healthy humans.

The muscle metaboreflex effect on pulmonary ventilation (V̇E) regulation is more apparent during rhythmic exercise than rest, possibly because this reflex interacts with other mechanisms regulating V̇E during voluntary contractions, such as central command. Therefore, we tested whether one part of central command, the descending component of motor execution (i.e., descending motor drive), and the muscle metaboreflex interact synergistically to regulate V̇E. Thirteen healthy adults (9 men) completed four experiments in random order under isocapnia. The muscle metaboreflex was activated by rhythmic handgrip exercise at 60% maximal voluntary contraction (MVC) force with the dominant hand. Then, the muscle metaboreflex remained active during a 4-minute recovery period via post-exercise circulatory occlusion (PECO), or it was inactivated, maintaining free blood flow to the dominant upper limb. During the last 2-minutes of the handgrip exercise recovery, participants either performed rhythmic voluntary plantar flexion with the dominant leg at 30% MVC torque to generate descending motor drive or the dominant leg's calf muscles were involuntarily activated by electrical stimulation at a similar torque level (i.e., without descending motor drive). V̇E increased to a similar level during handgrip exercise in all conditions (≈22 L/min, P = 0.364). PECO maintained V̇E elevated above recovery with free blood flow (≈17 L/min vs. ≈13 L/min, P = 0.009). However, voluntary and involuntary plantar flexion with or without PECO evoked similar V̇E responses (∆ ≈ 4 L/min, P = 0.311). Therefore, an interaction between descending motor drive and muscle metaboreflex is not ubiquitous for V̇E regulation during rhythmic exercise.

Assessment of Ventilatory Heterogeneity in Chronic Obstructive Pulmonary Disease Using the Inspired Sinewave Test.

BACKGROUND: There is marked variability in the symptoms and outcomes of patients with chronic obstructive pulmonary disease (COPD) which are poorly predicted by spirometry/FEV1%pred. Furthermore, as spirometry requires the performance of potentially distressing respiratory manoeuvres which are to some extent user-effort dependent, there is need for non-invasive and simple-to-perform techniques to identify subtypes of COPD which are more closely related to clinically relevant outcomes. MATERIALS AND METHODS: The inspired sinewave test (IST) sinusoidally modulates the inspired concentration of a tracer gas (N2O) over successive tidal breaths. A single-compartment tidal-ventilation lung model processes the amplitude/phase of the expired N2O sinewave and estimates cardiopulmonary variables including: effective lung volume and indices of ventilatory heterogeneity (VH; ELV180/FRCpleth and ELV180/ELVpred). 83 COPD patients and 53 healthy controls performed the IST test, standard pulmonary function tests (Spirometry, body plethysmography and the single breath test of carbon monoxide uptake), and symptom severity questionnaires (COPD assessment test, CAT; mMRC dyspnoea-scale, mMRC-DS; Cough+Mucus score; C+M score). RESULTS: ELV180/FRCpleth and ELV180/ELVpred were significantly lower in patients with COPD vs healthy participants (0.34±0.11 vs 0.68±0.14 and 0.7±0.27 vs 0.98±0.15, respectively; P<0.05). Multivariable regression analysis demonstrated that ELV180/FRCpleth was a stronger and independent predictor of CAT, mMRC-DS and C+M score vs FEV1%pred. ELV180/ELVpred was a stronger and independent and better predictor of C+M score vs FEV1%pred. Phenotyping patients, based upon ELV180/ELVpred and FRC%pred, uncovered significant symptomatic differences between groups. CONCLUSION: The IST indices of VH were superior and independent predictors of symptom severity vs FEV1%pred and has potential as a non-invasive and simple-to-perform method to stratify patients into subgroups related to clinically relevant features of COPD.

Control of exercise hyperpnoea: Contributions from thin-fibre skeletal muscle afferents.

NEW FINDINGS: What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease. ABSTRACT: The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO2 /H+ ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients.

Muscle metaboreflex activation increases ventilation and heart rate during dynamic exercise in humans.

NEW FINDINGS: What is the central question of this study? Classically, the stimulation of thin-fibre skeletal muscle afferents, via the application of postexercise circulatory occlusion (PECO) at rest, fails to generate ventilatory responses. We used a new experimental protocol to examine whether the involvement of these metabosensitive afferents in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. What is the main finding and its importance? We found that PECO of one leg augmented the ventilatory and heart rate responses to single-legged exercise of the contralateral leg, suggesting that metaboreceptive muscle afferents contribute to the control of the exercise hyperpnoea. ABSTRACT: Inhibition of thin-fibre skeletal muscle afferent neurotransmission attenuates ventilatory and cardiovascular responses to exercise. However, stimulation of muscle metaboreceptive afferents at rest, via postexercise circulatory occlusion (PECO), classically fails to generate increases in ventilation or heart rate. It is possible that the involvement of muscle afferent feedback in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. Therefore, we assessed the cardiorespiratory responses to single-legged cycling exercise with or without PECO of the contralateral leg. Thirteen healthy participants performed left-legged cycling exercise (40 or 60 W) followed by either: (i) no PECO (Con trial); or (ii) PECO (PECO trial) of the left leg for 3 min. During this 3 min period, right-legged cycling exercise was performed at the same workload as the preceding left-legged exercise (40 or 60 W). During 60 W right-legged cycling, ventilation relative to baseline was significantly higher in the PECO versus Con trial (22.9 ± 2 versus 18.7 ± 1.8 l min-1 ; P < 0.05), but there was no difference between the trials performed at 40 W. The change in heart rate was significantly greater during right-legged cycling in the PECO versus Con trial in the 40 (41.2 ± 4 versus 34.1 ± 3.1 beats min-1 ; P < 0.05) and 60 W trials (49.7 ± 2.7 versus 43.4 ± 3.7 beats min-1 ; P < 0.05). There were no differences in oxygen uptake, carbon dioxide production and ratings of perceived exertion between trials. These findings suggest that stimulation of muscle metaboreceptive afferents can drive increases in ventilation and heart rate during dynamic exercise.

Noninvasive cardiac output monitoring in a porcine model using the inspired sinewave technique: a proof-of-concept study.

BACKGROUND: Cardiac output (Q˙) monitoring can support the management of high-risk surgical patients, but the pulmonary artery catheterisation required by the current 'gold standard'-bolus thermodilution (Q˙T)-has the potential to cause life-threatening complications. We present a novel noninvasive and fully automated method that uses the inspired sinewave technique to continuously monitor cardiac output (Q˙IST). METHODS: Over successive breaths the inspired nitrous oxide (N2O) concentration was forced to oscillate sinusoidally with a fixed mean (4%), amplitude (3%), and period (60 s). Q˙IST was determined in a single-compartment tidal ventilation lung model that used the resulting amplitude/phase of the expired N2O sinewave. The agreement and trending ability of Q˙IST were compared with Q˙T during pharmacologically induced haemodynamic changes, before and after repeated lung lavages, in eight anaesthetised pigs. RESULTS: Before lung lavage, changes in Q˙IST and Q˙T from baseline had a mean bias of -0.52 L min-1 (95% confidence interval [CI], -0.41 to -0.63). The concordance between Q˙IST and Q˙T was 92.5% as assessed by four-quadrant analysis, and polar plot analysis revealed a mean angular bias of 5.98° (95% CI, -24.4°-36.3°). After lung lavage, concordance was slightly reduced (89.4%), and the mean angular bias widened to 21.8° (-4.2°, 47.6°). Impaired trending ability correlated with shunt fraction (r=0.79, P<0.05). CONCLUSIONS: The inspired sinewave technique provides continuous and noninvasive monitoring of cardiac output, with a 'marginal-good' trending ability compared with cardiac output based on thermodilution. However, the trending ability can be reduced with increasing shunt fraction, such as in acute lung injury.

The inspired sine-wave technique: A novel method to measure lung volume and ventilatory heterogeneity.

NEW FINDINGS: What is the central question of this study? We present a new non-invasive medical technology, the inspired sine-wave technique, which involves inhalation of sinusoidally fluctuating concentrations of a tracer gas. The technique requires only passive patient cooperation and can monitor different cardiorespiratory variables, such as end-expired lung volume, ventilatory heterogeneity and pulmonary blood flow. What is the main finding and its importance? In this article, we demonstrate that the measurements of end-expired lung volume are repeatable and accurate, in comparison to whole-body plethysmography, and the technique is sensitive to the changes in ventilatory heterogeneity associated with advancing age. As such, it has the potential to provide clinically valuable information. ABSTRACT: The inspired sine-wave technique (IST) is a new method that can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal breaths, the concentration of a tracer gas (i.e. nitrous oxide, N2 O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sine wave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV180 /FRCpleth , ELV180 /FRCpred and ELV60 /ELV180 ). This investigation aimed to determine the repeatability and agreement of ELV with FRCpleth and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent. Forty-eight healthy never-smoker participants (20-86 years) underwent traditional pulmonary function testing (e.g. spirometry, body plethysmography) and the IST test, which consisted of 4 min of quiet breathing through a face mask while inspired N2 O concentrations were oscillated in a sine-wave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 or 60 s. The ELV180 /FRCpleth and ELV180 /FRCpred were age dependent (average decreases of 0.58 and 0.48% year-1 ), suggesting an increase in VH with advancing age. The ELV showed a mean bias of -1.09 litres versus FRCpleth , but when normalized for the effects of age this bias reduced to -0.35 litres. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be taken into account in clinical investigations.

The control of ventilation during exercise: a lesson in critical thinking.

Learning the basic competencies of critical thinking are very important in the education of any young scientist, and teachers must be prepared to help students develop a valuable set of analytic tools. In my experience, this is best achieved by encouraging students to study areas with little scientific consensus, such as the control mechanisms of the exercise ventilatory response, as it can allow greater objectivity when evaluating evidence, while also giving students the freedom to think independently and problem solve. In this article, I discuss teaching strategies by which physiology, biomedical science, and sport science students can simultaneously develop their understanding of respiratory control mechanisms and learn to critically analyze evidence thoroughly. This can be best achieved by utilizing both teacher-led and student-led learning environments, the latter of which encourages the development of learner autonomy and independent problem solving. In this article, I also aim to demonstrate a systematic approach of critical assessment that students can be taught, adapt, and apply independently. Among other things, this strategy involves: 1) defining the precise phenomenon in question; 2) understanding what investigations must demonstrate to explain the phenomenon and its underlying mechanisms; 3) evaluating the explanations/mechanisms of the phenomenon and the evidence for them; and 4) forming strategies to produce strong evidence, if none exists.

Ventilatory responses to muscle metaboreflex activation in chronic obstructive pulmonary disease.

KEY POINTS: Recent evidence indicates a role for group III/IV muscle afferents in reflex control of the human ventilatory response to exercise. Dyspnoea in chronic obstructive pulmonary disease (COPD) may be linked to this reflex response. This study shows that activation of the muscle metaboreflex causes a ventilatory response in COPD patients but not in healthy controls. This indicates abnormal involvement of muscle afferents in the control of ventilation in COPD which may be a contributing factor to exercise dyspnoea. ABSTRACT: Blockade of thin fibre muscle afferent feedback during dynamic exercise reduces exercise hyperpnoea in health and chronic obstructive pulmonary disease (COPD). Therefore, we hypothesised that activation of the muscle metaboreflex at rest would cause hyperpnoea. We evaluated the effect of muscle metaboreflex activation on ventilation, in resting COPD patients and healthy participants. Following a bout of rhythmic hand grip exercise, post exercise circulatory occlusion (PECO) was applied to the resting forearm to sustain activation of the muscle metaboreflex, in 18 COPD patients (FEV1 /FVC ratio < 70%), 9 also classified as chronically hypercapnic, and 9 age- and gender-matched controls. The cardiovascular response to exercise and the sustained blood pressure elevation during PECO was similar in patients and controls. During exercise ventilation increased by 6.64 ± 0.84 in controls and significantly (P < 0.05) more, 8.38 ± 0.81 l min-1 , in patients. During PECO it fell to baseline levels in controls but remained significantly (P < 0.05) elevated by 2.78 ± 0.51 l min-1 in patients until release of circulatory occlusion, with no significant difference in responses between patient groups. Muscle metaboreflex activation causes increased ventilation in COPD patients but not in healthy participants. Chronic hypercapnia in COPD patients does not exaggerate this response. The muscle metaboreflex appears to be abnormally involved in the control of ventilation in COPD and may be a contributing factor to exercise dyspnoea.

The ventilatory response to muscle afferent activation during concurrent hypercapnia in humans: central and peripheral mechanisms.

NEW FINDINGS: What is the central question of this study? During hypercapnia but not normocapnia, activation of muscle afferents by postexercise circulatory occlusion increases ventilation, possibly due to additional activation of metabolite-stimulated muscle afferents. Alternatively, chemoreflex activation caused by hypercapnia may have a synergistic interaction with muscle afferent feedback, so stimulating breathing. What is the main finding and its importance? Muscle afferent activation during muscle hypercapnia with concurrent systemic normocapnia did not increase breathing. With systemic hypercapnia, there was a response that did not change with hyperoxic hypercapnia. A synergistic interaction between central chemoreception and muscle afferent feedback is therefore indicated. During hypercapnia, activation of thin-fibre muscle afferents using postexercise circulatory occlusion (PECO) provokes a ventilatory response not seen in normocapnia. We investigated the ventilatory responses to PECO when hypercapnia was restricted to the active muscle ('Local' trial) or during systemic hypercapnia ('Systemic' trial). In the Local trial, a hypercapnic gas mixture (5% CO2 in air) was inhaled for 5 min when circulation to the active calf muscle was open, then rapidly closed by thigh-cuff inflation (200 mmHg), immediately before a return to breathing room air and performance of isometric exercise and PECO. In the Systemic trial, circulation through the muscle was closed throughout the exercise and PECO phases, performed during the hypercapnic gas inhalation. In a third trial, in Systemic conditions a hyperoxic hypercapnic gas mixture (95% O2 and 5% CO2 ) was breathed for 1 min during PECO ('Hyperoxia' trial). The increase in ventilation during calf muscle exercise was not different between trials. In the Local trial, ventilation fell to pre-exercise levels during PECO, but in the Systemic trial it remained at end-exercise levels (4.9 ± 0.8 l min(-1) ) and was equally well maintained throughout the Hyperoxia trial (4.3 ± 1 l min(-1) ). Cardiovascular responses during PECO were not different in the three trials, indicating similar activation of muscle afferents. Sustained elevation of ventilation during PECO in the Systemic but not the Local trial suggests that ventilation is stimulated via an interaction between muscle afferent feedback and hypercapnia-induced chemoreceptor activation. The similar ventilatory responses in Systemic and Hyperoxia conditions further suggest that in this respect, central rather than peripheral chemoreceptors play the major role.

Muscle afferent activation causes ventilatory and cardiovascular responses during concurrent hypercapnia in humans.

Respiratory and cardiovascular responses to muscle mechanoreflex (passive calf stretch) and metaboreflex activation (local circulatory occlusion) were examined during inhalation of a hypercapnic gas mixture in four trials. These controlled for the effects of central command, metabolite sensitization of muscle afferents and hypercapnia-induced elevation of central respiratory drive. In an isokinetic dynamometer, with circulation through the right leg occluded by inflation of a thigh cuff, 13 participants either rested (control trial; CON) or plantarflexed their ankle at 50% maximal force for 1.5 min (voluntary exercise trial; EX). Thereafter, circulatory occlusion was maintained and the calf passively stretched before return to the resting position. Both trials were performed while breathing air, as well as while breathing a normoxic, hypercapnic (5% CO(2)) gas mixture (CO(2) trial and CO(2)+EX trial). Hypercapnic gas inhalation increased baseline minute ventilation (V), heart rate and mean arterial pressure (+27.67 ± 1.74 l min(-1), +7 ± 0.85 beats min(-1) and +13 ± 3.41 mmHg, respectively; means ± SEM) above control values (9.78 ± 0.86 l min(-1), 62 ± 2.3 beats min(-1) and 88 ± 2.6 mmHg, respectively). Voluntary exercise further increased these variables from baseline during both trials (P < 0.05). During the continued circulatory occlusion after voluntary exercise, mean arterial pressure remained significantly elevated (P < 0.05). Minute ventilation returned to baseline during circulatory occlusion following exercise in the EX trial, but in the CO(2)+EX trial the V remained elevated at end-exercise levels during this period (+7.12 ± 1.13 l min(-1)). Passive stretch caused further increases in V during CO(2)+EX and CO(2) trials but not in CON and EX. These results indicate that in the absence of central command, either muscle metaboreflex and/or mechanoreflex activation stimulates ventilation during concurrent hypercapnia.