Toward 3D printed microfluidic artificial lungs for respiratory support.

Microfluidic artificial lungs (µALs) are a new class of membrane oxygenators. Compared to traditional hollow-fiber oxygenators, µALs closely mimic the alveolar microenvironment due to their size-scale and promise improved gas exchange efficiency, hemocompatibility, biomimetic blood flow networks, and physiologically relevant blood vessel pressures and shear stresses. Clinical translation of µALs has been stalled by restrictive microfabrication techniques that limit potential artificial lung geometries, overall device size, and throughput. To address these limitations, a high-resolution Asiga MAX X27 UV digital light processing (DLP) 3D printer and custom photopolymerizable polydimethylsiloxane (PDMS) resin were used to rapidly manufacture small-scale µALs via vat photopolymerization (VPP). Devices were designed in SOLIDWORKS with 500 blood channels and 252 gas channels, where gas and blood flow channels were oriented orthogonally and separated by membranes on the top and bottom, permitting two-sided gas exchange. Successful devices were post-processed to remove uncured resin from microchannels and assembled with external tubing in preparation for gas exchange performance testing with ovine whole blood. 3D printed channel dimensions were 172 µm-tall × 320 µm-wide, with 62 µm-thick membranes and 124 µm-wide support columns. Measured outlet blood oxygen saturation (SO2) agreed with theoretical models and rated flow of the device was 1 mL min-1. Blood side pressure drop was 1.58 mmHg at rated flow. This work presents the highest density of 3D printed microchannels in a single device, one of the highest CO2 transfer efficiencies of any artificial lung to date, and a promising approach to translate µALs one step closer to the clinic.

The algorithm used for the calculation of gas exchange affects the estimation of O2 uptake kinetics at the onset of moderate-intensity exercise.

At the start of a moderate-intensity square-wave exercise, after a short delay, breath-by-breath O2 uptake at the mouth is approximated to a mono-exponential function, whose time constant is considered matched to that of the O2 uptake of the working muscles. We compared the kinetic parameters obtained from the breath-by-breath gas exchange data yielded by the 'Independent-breath' algorithm (IND), which accounts for the changes in lung gas stores, with those obtained with the classical 'Expiration-only' algorithm (EXP). The two algorithms were applied on the same flow and gas fraction traces acquired on 10 healthy volunteers, performing 10 times the same moderate-intensity exercise transition. Repeated O2 uptake responses were stacked together and the kinetic parameters of a mono-exponential function were estimated by non-linear regression, removing the data pertaining to 1-s progressively longer initial periods (ΔTr ). Independently of ΔTr , the mean response time (time constant + time delay) obtained for the IND data was faster compared to the EXP data (∼43 s vs. ∼47 s, P < 0.001), essentially because of shorter time delays. Between ΔTr  = 16 s and ΔTr  = 29s, the time constants of the IND data decreased (30.7 s vs. 28.0 s, P < 0.05; drop = 10%), but less than those of the EXP data (32.2 s vs. 26.2 s, P < 0.001; drop = 23%); with the same ΔTr , the time constants of the two algorithms' data were not different (P > 0.07). The different decrease in the time constant, together with the different mean response time, suggests that the data yielded by the two algorithms provide a different picture of the phenomena occurring at the beginning of the exercise.

Signal Variability Comparative Analysis of Healthy Early- and Late-Pubertal Children during Cardiopulmonary Exercise Testing.

PURPOSE: The kinetics of physiological responses to exercise have traditionally been characterized by estimating exponential equation parameters using iterative best-fit techniques of heart rate (HR) and gas exchange (respiratory rate, oxygen uptake (V̇O 2 ), carbon dioxide output, and ventilation). In this study, we present a novel approach to characterizing the maturation of physiological responses to exercise in children by accounting for response uncertainty and variability. METHODS: Thirty-seven early-pubertal (17 females, 20 males) and 44 late-pubertal (25 females, 19 males) participants performed three multiple brief exercise bouts (MBEB). MBEB consisted of ten 2-min bouts of cycle ergometry at constant work rate interspersed by 1-min rest. Exercise intensity was categorized as low, moderate, or high, corresponding to 40%, 60%, and 80% of peak work rate, and performed in random order on 3 separate days. We evaluated sample entropy (SampEn), approximate entropy, detrended fluctuation analysis, and average absolute local variability of HR and gas exchange. RESULTS: SampEn of HR and gas-exchange responses to MBEB was greater in early- compared with late-pubertal participants (e.g., V̇O 2 early-pubertal vs late-pubertal, 1.70 ± 0.023 vs 1.41 ± 0.027; P = 2.97 × 10 -14 ), and decreased as MBEB intensity increased (e.g., 0.37 ± 0.01 HR for low-intensity compared with 0.21 ± 0.014 for high intensity, P = 3.56 × 10 -17 ). Females tended to have higher SampEn than males (e.g., 1.61 ± 0.025 V̇O 2 for females vs 1.46 ± 0.031 for males, P = 1.28 × 10 -4 ). Average absolute local variability was higher in younger participants for both gas exchange and HR (e.g., early-pubertal vs late-pubertal V̇O 2 , 17.48 % ± 0.56% vs 10.24 % ± 0.34%; P = 1.18 × 10 -21 ). CONCLUSIONS: The greater entropy in signal response to a known, quantifiable exercise perturbation in the younger children might represent maturation-dependent, enhanced competition among physiological controlling mechanisms that originate at the autonomic, subconscious, and cognitive levels.

EFFECT OF INHALED OXYGEN CONCENTRATION ON PULMONARY GAS EXCHANGE DURING OFF-PUMP CORONARY BYPASS GRAFTING.

Aim of study - supra-physiologic level of PaO2, securing oxygen reserves and preventing perioperative hypoxia, may offset the reduced oxygen delivery during cardiac surgery. However, high FiO2 will speed up gas absorption in low V/Q regions, promote atelectasis formation and increase pulmonary shunt fraction. PaO2/FiO2, P(a-Et)CO2 and PEtCO2/PaCO2 are the variables linked to CO2 and O2 exchange impairment. The aim of our study was to assess pulmonary gas exchange performance while ventilating patients with different FiO2 during OPCABG. The seventy patients were randomly equally distributed in two groups: H (High) and L (Low). The patients in the group H were ventilated with FiO2 0.8 and the patients in the group L _ with FiO2 0.5. PaO2/FiO2 ratio, P(a-Et)CO2 gradient and PEtCO2/PaCO2 ratio were checked at the start and the end points of operations. PaO2/FiO2 decreased, P(a-Et)CO2 increased and PaCO2/PEtCO2 decreased at the end of operations compared with the start values in both groups. PaO2/FiO2, P(a-Et)CO2 and PaCO2/PEtCO2 ware different between H and L groups. The difference became statistically significant at the end of operations. (PaO2/FiO2 326±65 vs 290±63 p=0.020; P(a-Et)CO2 5.7±2.3 mmHg vs 7.5±2.4 mmHg p=0.003; PaCO2/PEtCO2 0.84±0.05 vs 0.80±0.06 p=0.001). The groups were comparable according to the outcomes such as hemodynamic and laboratory data, duration of postoperative mechanical ventilation and ICU length of stay. FiO2 0.8 was associated with more derangements of pulmonary gas exchange compared with FiO2 0.5. Although FiO2 did not have an impact on the outcomes we studied, using FiO2 0.5 seems to be safer in patients undergoing OPCABG.

Improved oxygenation in prone positioning of mechanically ventilated patients with COVID-19 acute respiratory distress syndrome is associated with decreased pulmonary shunt fraction: a prospective multicenter study.

BACKGROUND: Prone position is used in acute respiratory distress syndrome and in coronavirus disease 2019 (Covid-19) acute respiratory distress syndrome (ARDS). However, physiological mechanisms remain unclear. The aim of this study was to determine whether improved oxygenation was related to pulmonary shunt fraction (Q's/Q't), alveolar dead space (Vd/Vtalv) and ventilation/perfusion mismatch (V'A/Q'). METHODS: This was an international, prospective, observational, multicenter, cohort study, including six intensive care units in Sweden and Poland and 71 mechanically ventilated adult patients. RESULTS: Prone position increased PaO2:FiO2 after 30 min, by 78% (83-148 mm Hg). The effect persisted 120 min after return to supine (p < 0.001). The oxygenation index decreased 30 min after prone positioning by 43% (21-12 units). Q's/Q't decreased already after 30 min in the prone position by 17% (0.41-0.34). The effect persisted 120 min after return to supine (p < 0.005). Q's/Q't and PaO2:FiO2 were correlated both in prone (Beta -137) (p < 0.001) and in the supine position (Beta -270) (p < 0.001). V'A/Q' was unaffected and did not correlate to PaO2:FiO2 (p = 0.8). Vd/Vtalv increased at 120 min by 11% (0.55-0.61) (p < 0.05) and did not correlate to PaO2:FiO2 (p = 0.3). The ventilatory ratio increased after 30 min in the prone position by 58% (1.9-3.0) (p < 0.001). PaO2:FiO2 at baseline predicted PaO2:FiO2 at 30 min after proning (Beta 1.3) (p < 0.001). CONCLUSIONS: Improved oxygenation by prone positioning in COVID-19 ARDS patients was primarily associated with a decrease in pulmonary shunt fraction. Dead space remained high and the global V'A/Q' measure could not explain the differences in gas exchange.

Factors associated with a nonresponse to prone positioning in patients with severe acute respiratory distress syndrome due to SARS-CoV-2.

OBJECTIVE: To identify risk factors for nonresponse to prone positioning in mechanically ventilated patients with COVID-19-associated severe acute respiratory distress syndrome and refractory hypoxemia in a tertiary care hospital in Colombia. METHODS: Observational study based on a retrospective cohort of mechanically ventilated patients with severe acute respiratory distress syndrome due to SARS-CoV-2 who underwent prone positioning due to refractory hypoxemia. The study considered an improvement ≥ 20% in the PaO2/FiO2 ratio after the first cycle of 16 hours in the prone position to be a 'response'. Nonresponding patients were considered cases, and responding patients were controls. We controlled for clinical, laboratory, and radiological variables. RESULTS: A total of 724 patients were included (58.67 ± 12.37 years, 67.7% males). Of those, 21.9% were nonresponders. Mortality was 54.1% for nonresponders and 31.3% for responders (p < 0.001). Variables associated with nonresponse were time from the start of mechanical ventilation to pronation (OR 1.23; 95%CI 1.10 - 1.41); preintubation PaO2/FiO2 ratio (OR 0.62; 95%CI 0.40 - 0.96); preprone PaO2/FiO2 ratio (OR 1.88. 95%CI 1.22 - 2.94); and radiologic multilobe consolidation (OR 2.12; 95%CI 1.33 - 3.33) or mixed pattern (OR 1.72; 95%CI 1.07 - 2.85) compared with a ground-glass pattern. CONCLUSION: This study identified factors associated with nonresponse to prone positioning in patients with refractory hypoxemia and acute respiratory distress syndrome due to SARS-CoV-2 receiving mechanical ventilation. Recognizing such factors helps identify candidates for other rescue strategies, including more extensive prone positioning or extracorporeal membrane oxygenation. Further studies are needed to assess the consistency of these findings in populations with acute respiratory distress syndrome of other etiologies.

Can the heart rate response at the respiratory compensation point be used to retrieve the maximal metabolic steady state?

The metabolic rate (VO2) at the maximal metabolic steady state (MMSS) is generally not different from the VO2 at the respiratory compensation point (RCP). Based on this, it is often assumed that the heart rate (HR) at RCP would also be similar to that at MMSS. The study aims to compare the HR at RCP with that at MMSS. Seventeen individuals completed a ramp-incremental test, a series of severe-intensity trials to estimate critical power and two-to-three 30-min trials to confirm MMSS. The HR at RCP was retrieved by linear interpolation of the ramp-VO2/HR relationship and compared to the HR at MMSS recorded at 10, 15, 20, 25 and 30 min. The HR at RCP was 166 ± 12 bpm. The HR during MMSS at the timepoints of interest was 168 ± 8, 171 ± 8, 175 ± 9, 177 ± 9 and 178 ± 10 bpm. The HR at RCP was not different from the HR at MMSS at 10 min (P > 0.05) but lower at subsequent timepoints (P < 0.05) with this difference becoming progressively larger. For all timepoints, limits of agreement were large (~30 bpm). Given these differences and the variability at the individual level, the HR at RCP cannot be used to control the metabolic stimulus of endurance exercise.

Current definitions of the breathing cycle in alveolar breath-by-breath gas exchange analysis.

Identification of the breathing cycle forms the basis of any breath-by-breath gas exchange analysis. Classically, the breathing cycle is defined as the time interval between the beginning of two consecutive inspiration phases. Based on this definition, several research groups have developed algorithms designed to estimate the volume and rate of gas transferred across the alveolar membrane ("alveolar gas exchange"); however, most algorithms require measurement of lung volume at the beginning of the ith breath (VLi-1; i.e., the end-expiratory lung volume of the preceding ith breath). The main limitation of these algorithms is that direct measurement of VLi-1 is challenging and often unavailable. Two solutions avoid the requirement to measure VLi-1 by redefining the breathing cycle. One method defines the breathing cycle as the time between two equal fractional concentrations of lung expired oxygen (Fo2) (or carbon dioxide; Fco2), typically in the alveolar phase, whereas the other uses the time between equal values of the Fo2/Fn2 (or Fco2/Fn2) ratios [i.e., the ratio of fractional concentrations of lung expired O2 (or CO2) and nitrogen (N2)]. Thus, these methods identify the breathing cycle by analyzing the gas fraction traces rather than the gas flow signal. In this review, we define the traditional approach and two alternative definitions of the human breathing cycle and present the rationale for redefining this term. We also explore the strengths and limitations of the available approaches and provide implications for future studies.

The effect of increasing work rate amplitudes from a common metabolic baseline on the kinetic response of V̇o2p, blood flow, and muscle deoxygenation.

A step-transition in external work rate (WR) increases pulmonary O2 uptake (V̇o2p) in a monoexponential fashion. Although the rate of this increase, quantified by the time constant (τ), has frequently been shown to be similar between multiple different WR amplitudes (ΔWR), the adjustment of O2 delivery to the muscle (via blood flow; BF), a potential regulator of V̇o2p kinetics, has not been extensively studied. To investigate the role of BF on V̇o2p kinetics, 10 participants performed step-transitions on a knee-extension ergometer from a common baseline WR (3 W) to: 24, 33, 45, 54, and 66 W. Each transition lasted 8 min and was repeated four to six times. Volume turbinometry and mass spectrometry, Doppler ultrasound, and near-infrared spectroscopy were used to measure V̇o2p, BF, and muscle deoxygenation (deoxy[Hb + Mb]), respectively. Similar transitions were ensemble-averaged, and phase II V̇o2p, BF, and deoxy[Hb + Mb] were fit with a monoexponential nonlinear least squares regression equation. With increasing ΔWR, τV̇o2p became larger at the higher ΔWRs (P < 0.05), while τBF did not change significantly, and the mean response time (MRT) of deoxy[Hb + Mb] became smaller. These findings that V̇o2p kinetics become slower with increasing ΔWR, while BF kinetics are not influenced by ΔWR, suggest that O2 delivery could not limit V̇o2p in this situation. However, the speeding of deoxy[Hb + Mb] kinetics with increasing ΔWR does imply that the O2 delivery-to-O2 utilization of the microvasculature decreases at higher ΔWRs. This suggests that the contribution of O2 delivery and O2 extraction to V̇O2 in the muscle changes with increasing ΔWR.NEW & NOTEWORTHY A step increase in work rate produces a monoexponential increase in V̇o2p and blood flow to a new steady-state. We found that step transitions from a common metabolic baseline to increasing work rate amplitudes produced a slowing of V̇o2p kinetics, no change in blood flow kinetics, and a speeding of muscle deoxygenation kinetics. As work rate amplitude increased, the ratio of blood flow to V̇o2p became smaller, while the amplitude of muscle deoxygenation became greater. The gain in vascular conductance became smaller, while kinetics tended to become slower at higher work rate amplitudes.

An undergraduate laboratory to study exercise thresholds.

In exercise physiology, laboratory components help students connect theoretical concepts to their own exercise experiences and introduce them to data collection, analysis, and interpretation using classic techniques. Most courses include a lab protocol that involves exhaustive incremental exercise during which expired gas volumes and concentrations of oxygen and carbon dioxide are measured. During these protocols, there are characteristic alterations in gas exchange and ventilatory profiles that give rise to two exercise thresholds: the gas exchange threshold (GET) and the respiratory compensation point (RCP). The ability to explain why these thresholds occur and how they are identified is fundamental to learning in exercise physiology and requisite to the understanding of core concepts including exercise intensity, prescription, and performance. Proper identification of GET and RCP requires the assembly of eight data plots. In the past, the burden of time and expertise required to process and prepare data for interpretation has been a source of frustration. In addition, students often express a desire for more opportunities to practice/refine their skills. The objective of this article is to share a blended laboratory model that features the "Exercise Thresholds App," a free online resource that eliminates postprocessing of data and provides a bank of profiles on which end-users can practice threshold identification skills with immediate feedback. In addition to including prelaboratory and postlaboratory recommendations, we present student accounts of understanding, engagement, and satisfaction following completion of the laboratory experience and introduce a new quiz feature of the app to assist instructors with evaluating student learning.NEW & NOTEWORTHY We present a laboratory to study exercise thresholds from gas exchange and ventilatory measures that features the "Exercise Thresholds App," a free online resource that eliminates postprocessing of data and provides a bank of profiles on which end-users can practice threshold identification skills. In addition to including prelaboratory and postlaboratory recommendations, we present student accounts of understanding, engagement, and satisfaction and introduce a new quiz feature of the app to assist instructors with evaluating learning.

Effects of greater erythroid Cl-/HCO3- transporter (band 3) expression on ventilation and gas exchange during exhaustive exercise.

Band 3 protein is a Cl-/[Formula: see text] transporter on the red blood cell (RBC) surface with an important role in CO2 excretion. Greater band 3 expression by roughly 20% is found in people with the GP.Mur blood type. Intriguingly, a disproportional percentage of those with GP.Mur excel in field-and-track sports. Could higher band 3 activity benefit an individual's physical performance? This study explored the impact of GP.Mur/higher band 3 expression on ventilation and gas exchange during exhaustive exercise. We recruited 36 nonsmoking, elite male athletes (36.1% GP.Mur) from top sports universities to perform incremental exhaustive treadmill cardiopulmonary exercise testing (CPET). We analyzed CPET data with respect to absolute running time and to individual's %running time and %maximal O2 uptake. We found persistently higher respiratory frequencies and slightly lower tidal volume in GP.Mur athletes, resulting in a slightly larger increase of ventilation as the workload intensified. The expiratory duty cycle (Te/Ttot) was persistently longer and inspiratory duty cycle (Ti/Ttot) was persistently shorter for GP.Mur subjects throughout the run. Consequently, end-tidal pressure of carbon dioxide ([Formula: see text], a surrogate marker for alveolar and arterial CO2 tension-[Formula: see text] and [Formula: see text]) was lower in the GP.Mur athletes during the early stages of exercise. In conclusion, athletes with GP.Mur and higher band 3 expression hyperventilate more during exercise in a pattern that uses a greater fraction of time for expiration than inspiration to increase the rate of CO2 excretion than increased tidal volume. This greater ventilation response reduced Pco2 and may help to extend exercise capacity in high-level sports.NEW & NOTEWORTHY Higher expression of the Cl-/[Formula: see text] transporter band 3 anion exchanger-1 (AE1) on the red blood cell membrane, as in people with the GP.Mur blood type, increases the rate of CO2 excretion during exercise.

Single-FiO2 lung modelling with machine learning: a computer simulation incorporating volumetric capnography.

We investigated whether machine learning (ML) analysis of ICU monitoring data incorporating volumetric capnography measurements of mean alveolar PCO2 can partition venous admixture (VenAd) into its shunt and low V/Q components without manipulating the inspired oxygen fraction (FiO2). From a 21-compartment ventilation / perfusion (V/Q) model of pulmonary blood flow we generated blood gas and mean alveolar PCO2 data in simulated scenarios with shunt values from 7.3% to 36.5% and a range of FiO2 settings, indirect calorimetry and cardiac output measurements and acid- base and hemoglobin oxygen affinity conditions. A 'deep learning' ML application, trained and validated solely on single FiO2 bedside monitoring data from 14,736 scenarios, then recovered shunt values in 500 test scenarios with true shunt values 'held back'. ML shunt estimates versus true values (n = 500) produced a linear regression model with slope = 0.987, intercept = -0.001 and R2 = 0.999. Kernel density estimate and error plots confirmed close agreement. With corresponding VenAd values calculated from the same bedside data, low V/Q flow can be reported as VenAd-shunt. ML analysis of blood gas, indirect calorimetry, volumetric capnography and cardiac output measurements can quantify pulmonary oxygenation deficits as percentage shunt flow (V/Q = 0) versus percentage low V/Q flow (V/Q > 0). High fidelity reports are possible from analysis of data collected solely at the operating FiO2.

Acute ventilatory responses to swimming at increasing intensities.

Background: Physical exercise is a source of stress to the human body, triggering different ventilatory responses through different regulatory mechanisms and the aquatic environment imposes several restrictions to the swimmer, particularly regarding the restricted ventilation. Thus, we aimed to assess the acute ventilatory responses and to characterize the adopted breathing patterns when swimming front crawl at increasing intensity domains. Methods: Eighteen well-trained swimmers performed 7 × 200 m front crawl (0.05 m∙s-1 velocity increments) and a maximal 100 m (30 s rest intervals). Pulmonary gas exchange and ventilation were continuously measured (breath-by-breath) and capillary blood samples for lactate concentration ([La-]) analysis were collected at rest, during intervals and at the end of the protocol, allowing the identification of the low, moderate, heavy, severe and extreme intensity domains. Results: With the swimming velocity rise, respiratory frequency (f R), [La-] and stroke rate (SR) increased ([29.1-49.7] breaths∙min-1, [2.7-11.4] mmol∙L-1, [26.23-40.85] cycles; respectively) and stroke length (SL) decreased ([2.43-2.04] m∙min-1; respectively). Oxygen uptake (VO2), minute ventilation (VE), carbon dioxide production (VCO2) and heart rate (HR) increased until severe ([37.5-53.5] mL∙kg-1∙min-1, [55.8-96.3] L∙min-1, [32.2-51.5] mL∙kg-1∙min-1 and [152-182] bpm; respectively) and stabilized from severe to extreme (53.1 ± 8.4, mL∙kg-1∙min-1, 99.5 ± 19.1 L∙min-1, 49.7 ± 8.3 mL∙kg-1∙min-1 and 186 ± 11 bpm; respectively) while tidal volume (VT) was similar from low to severe ([2.02-2.18] L) and decreased at extreme intensities (2.08 ± 0.56 L). Lastly, the f R/SR ratio increased from low to heavy and decreased from severe to the extreme intensity domains (1.12 ± 0.24, 1.19 ± 0.25, 1.26 ± 0.26, 1.32 ± 0.26 and 1.23 ± 0.26). Conclusions: Our findings confirm a different ventilatory response pattern at extreme intensities when compared to the usually evaluated exertions. This novel insight helps to understand and characterize the maximal efforts in swimming and reinforces the importance to include extreme efforts in future swimming evaluations.

Pulmonary ventilation and gas exchange during prolonged exercise in humans: Influence of dehydration, hyperthermia and sympathoadrenal activity.

NEW FINDINGS: What is the central question of the study? Ventilation increases during prolonged intense exercise, but the impact of dehydration and hyperthermia, with associated blunting of pulmonary circulation, and independent influences of dehydration, hyperthermia and sympathoadrenal discharge on ventilatory and pulmonary gas exchange responses remain unclear. What is the main finding and its importance? Dehydration and hyperthermia led to hyperventilation and compensatory adjustments in pulmonary CO2 and O2 exchange, such that CO2 output increased and O2 uptake remained unchanged despite the blunted circulation. Isolated hyperthermia and adrenaline infusion, but not isolated dehydration, increased ventilation to levels similar to combined dehydration and hyperthermia. Hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise, partly via sympathoadrenal activation. ABSTRACT: The mechanisms driving hyperthermic hyperventilation during exercise are unclear. In a series of retrospective analyses, we evaluated the impact of combined versus isolated dehydration and hyperthermia and the effects of sympathoadrenal discharge on ventilation and pulmonary gas exchange during prolonged intense exercise. In the first study, endurance-trained males performed two submaximal cycling exercise trials in the heat. On day 1, participants cycled until volitional exhaustion (135 ± 11 min) while experiencing progressive dehydration and hyperthermia. On day 2, participants maintained euhydration and core temperature (Tc ) during a time-matched exercise (control). At rest and during the first 20 min of exercise, pulmonary ventilation ( V ̇ E ${\skew2\dot V_{\rm{E}}}$ ), arterial blood gases, CO2 output and O2 uptake were similar in both trials. At 135 ± 11 min, however, V ̇ E ${\skew2\dot V_{\rm{E}}}$ was elevated with dehydration and hyperthermia, and this was accompanied by lower arterial partial pressure of CO2 , higher breathing frequency, arterial partial pressure of O2 , arteriovenous CO2 and O2 differences, and elevated CO2 output and unchanged O2 uptake despite a reduced pulmonary circulation. The increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ was closely related to the rise in Tc and circulating catecholamines (R2  ≥ 0.818, P ≤ 0.034). In three additional studies in different participants, hyperthermia independently increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ to an extent similar to combined dehydration and hyperthermia, whereas prevention of hyperthermia in dehydrated individuals restored V ̇ E ${\skew2\dot V_{\rm{E}}}$ to control levels. Furthermore, adrenaline infusion during exercise elevated both Tc and V ̇ E ${\skew2\dot V_{\rm{E}}}$ . These findings indicate that: (1) adjustments in pulmonary gas exchange limit homeostatic disturbances in the face of a blunted pulmonary circulation; (2) hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise; and (3) sympathoadrenal activation might partly mediate the hyperthermic hyperventilation.

Neurophysiological mechanisms of exertional dyspnea in post-pulmonary embolism syndrome.

Following pulmonary embolism (PE), a third of patients develop persistent dyspnea, which is commonly termed the post-PE syndrome. The neurophysiological underpinnings of exertional dyspnea in patients with post-PE syndrome without pulmonary hypertension (PH) are unclear. Thus, the current study determined if abnormally high inspiratory neural drive (IND) due, in part, to residual pulmonary gas-exchange abnormalities, was linked to heightened exertional dyspnea and exercise limitation, in such patients. Fourteen participants with post-PE syndrome (without resting PH) and 14 age-, sex-, and body mass index-matched healthy controls undertook pulmonary function testing and a symptom-limited cycle cardiopulmonary exercise test with measurements of IND (diaphragmatic electromyography), ventilatory requirements for CO2 (V̇e/V̇co2), and perceived dyspnea intensity (modified Borg 0-10 scale). Post-PE (vs. control) had a reduced resting transfer coefficient for carbon monoxide (KCO: 84 ± 15 vs. 104 ± 14%pred, P < 0.001) and peak oxygen uptake (V̇o2peak) (76 ± 14 vs. 124 ± 28%pred, P < 0.001). IND and V̇e/V̇co2 were higher in post-PE than controls at standardized submaximal work rates (P < 0.05). Dyspnea increased similarly in both groups as a function of increasing IND but was higher in post-PE at standardized submaximal work rates (P < 0.05). High IND was associated with low KCO (r = -0.484, P < 0.001), high V̇e/V̇co2 nadir (r = 0.453, P < 0.001), and low V̇o2peak (r = -0.523, P < 0.001). In patients with post-PE syndrome, exercise IND was higher than controls and was associated with greater dyspnea intensity. The heightened IND and dyspnea in post-PE, in turn, were strongly associated with low resting KCO and high exercise V̇e/V̇co2, which suggest important pulmonary gas-exchange abnormalities in this patient population.NEW & NOTEWORTHY This study is the first to show that increased exertional dyspnea in patients with post-pulmonary embolism (PE) syndrome, without overt pulmonary hypertension, was strongly associated with elevated inspiratory neural drive (IND) to the diaphragm during exercise, compared with healthy controls. The greater IND was associated with impairments in pulmonary gas exchange and significant deconditioning. Our results help to explain why many patients with post-PE syndrome report significant dyspnea at relatively low levels of physical activity.

Variability in exercise tolerance and physiological responses to exercise prescribed relative to physiological thresholds and to maximum oxygen uptake.

NEW FINDINGS: What is the central question of this study? Does prescribing exercise intensity using physiological thresholds create a more homogeneous exercise stimulus than using traditional intensity anchors? What is the main finding and its importance? Prescribing exercise using physiological thresholds, notably critical power, reduced the variability in exercise tolerance and acute metabolic responses. At higher intensities, approaching or exceeding the transition from heavy to severe intensity exercise, the imprecision of using fixed % V ̇ O 2 max ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$  as an intensity anchor becomes amplified. ABSTRACT: The objective of this study was to determine whether the variability in exercise tolerance and physiological responses is lower when exercise is prescribed relative to physiological thresholds (THR) compared to traditional intensity anchors (TRAD). Ten individuals completed a series of maximal exercise tests and a series of moderate (MOD), heavy (HVY) and severe intensity (HIIT) exercise bouts prescribed using THR intensity anchors (critical power and gas exchange threshold) and TRAD intensity anchors (maximum oxygen uptake; V ̇ O 2 max ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ). There were no differences in exercise tolerance or acute response variability between MODTHR and MODTRAD . All individuals completed HVYTHR but only 30% completed HVYTRAD . Compared to HVYTHR , where work rates were all below critical power, work rates in HVYTRAD exceeded critical power in 70% of individuals. There was, however, no difference in acute response variability between HVYTHR and HVYTRAD . All individuals completed HIITTHR but only 20% completed HIITTRAD . The variability in peak (F = 0.274) and average (F = 0.318) blood lactate responses was lower in HIITTHR compared to HIITTRAD . The variability in W' depletion (the finite work capacity above critical power) after the final interval bout was lower in HIITTHR compared to HIITTRAD (F = 0.305). Using physiological thresholds to prescribe exercise intensity reduced the heterogeneity in exercise tolerance and physiological responses to exercise spanning the boundary between the heavy and severe intensity domains. To increase the precision of exercise intensity prescription, it is recommended that, where possible, physiological thresholds are used in place of V ̇ O 2 max ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ .