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Given that there are both sex-based structural differences in the respiratory system and age-associated declines in pulmonary function, the purpose of this study was to assess the effects of age and sex on the metabolic cost of breathing (V̇ o 2RM) for exercise ventilations in healthy younger and older males and females. Forty healthy participants (10 young males 24 ± 3 yr; 10 young females 24 ± 3 yr; 10 older males 63 ± 3 yr, 10 older females 63 ± 6 yr) mimicked their exercise breathing patterns (voluntary hyperpnea) in the absence of exercise across a range of exercise intensities. At peak exercise, V̇ o 2RM represented a significantly greater fraction of peak oxygen consumption (V̇ o 2peak) in young females, 12.7 ± 4.0%, compared with young males, 10.7 ± 3.0% (P = 0.027), whereas V̇ o 2RM represented 13.5 ± 2.3% of V̇ o 2peak in older females and 13.2 ± 3.3% in older males. At relative ventilations, there was a main effect of age, with older males consuming a significantly greater fraction of V̇ o 2RM (6.6 ± 1.9%) than the younger males (4.4 ± 1.3%; P = 0.012), and older females consuming a significantly greater fraction of V̇ o 2RM (6.9 ± 2.5%) than the younger females (5.1 ± 1.4%; P = 0.004) at 65% V̇ e max. Furthermore, both younger and older males had significantly better respiratory muscle efficiency than their female counterparts at peak exercise (P = 0.011; P = 0.015). Similarly, younger participants were significantly more efficient than older participants (6.5 ± 1.5% vs. 5.5 ± 2.0%; P = 0.001). Normal age-related changes in respiratory function, in addition to sex-based differences in airway anatomy, appear to influence the ventilatory responses and the cost incurred to breathe during exercise. NEW & NOTEWORTHY: Here we show that at moderate and high-intensity exercise, older individuals incur a higher cost to breathe than their younger counterparts. However, as individuals age, the sex difference in the cost of breathing narrows. Collectively, our findings suggest that the normative age-related changes in respiratory structure and function, and sex differences in airway anatomy, appear to influence the ventilatory responses to exercise and the oxygen cost to breathe. [ABSTRACT FROM AUTHOR]

Tracheomalacia is an airway condition in which the trachea excessively collapses during breathing. Neonates diagnosed with tracheomalacia require more energy to breathe, and the effect of tracheomalacia can be quantified by assessing flow-resistive work of breathing (WOB) in the trachea using computational fluid dynamics (CFD) modeling of the airway. However, CFD simulations are computationally expensive; the ability to instead predict WOB based on more straightforward measures would provide a clinically useful estimate of tracheal disease severity. The objective of this study is to quantify the WOB in the trachea using CFD and identify simple airway and/or clinical parameters that directly relate to WOB. This study included 30 neonatal intensive care unit subjects (15 with tracheomalacia and 15 without tracheomalacia). All subjects were imaged using ultrashort echo time (UTE) MRI. CFD simulations were performed using patient-specific data obtained from MRI (airway anatomy, dynamic motion, and airflow rates) to calculate the WOB in the trachea. Several airway and clinical measurements were obtained and compared with the tracheal resistive WOB. The maximum percent change in the tracheal cross-sectional area (ρ = 0.560, P = 0.001), average glottis cross-sectional area (ρ = −0.488, P = 0.006), minute ventilation (ρ = 0.613, P < 0.001), and lung tidal volume (ρ = 0.599, P < 0.001) had significant correlations with WOB. A multivariable regression model with three independent variables (minute ventilation, average glottis cross-sectional area, and minimum of the eccentricity index of the trachea) can be used to estimate WOB more accurately (R² = 0.726). This statistical model may allow clinicians to estimate tracheal resistive WOB based on airway images and clinical data. NEW & NOTEWORTHY The work of breathing due to resistance in the trachea is an important metric for quantifying the effect of tracheal abnormalities such as tracheomalacia, but currently requires complex dynamic imaging and computational fluid dynamics simulation to calculate it. This study produces a method to predict the tracheal work of breathing based on readily available imaging and clinical metrics. [ABSTRACT FROM AUTHOR]

This study examined the impact of aging on the elastic and resistive components of the work of breathing (Wb) during locomotor exercise at a given 1) ventilatory rate, 2) metabolic rate, and 3) operating lung volume. Eight healthy younger (25 ± 4 yr) and 8 older (72 ± 6 yr) participants performed incremental bicycle exercise, from which retrospective analyses identified similar ventilatory rates (approximately 40, 70, and 100 L·min-1), similar metabolic rates (VO2: approximately 1.2, 1.6, and 1.9 L·min-1), and similar lung volumes [inspiratory and expiratory reserve volumes (IRV/ERV: approximately 25/34%, 16/33%, and 13-34% of vital capacity]. Wb at each level was quantified by integrating the averaged esophageal pressure-volume loop, which was then partitioned into elastic and resistive components of inspiratory and expiratory work using the modified Campbell diagram. IRV was smaller in the older participants during exercise at ventilations of 70 and 100 L·min-1 and during exercise at the three metabolic rates (P < 0.05). Mainly because of a greater inspiratory elastic and resistive Wb in the older group (P < 0.05), total Wb was augmented by 40%-50% during exercise at matched ventilatory and matched metabolic rates. When examined during exercise evoking similar lung volumes, total Wb was not different between the groups (P = 0.86). Taken together, although aging exaggerates total Wb during locomotor exercise at a given ventilatory or a given metabolic rate, this difference is abolished during exercise at a given operating lung volume. These findings highlight the significance of operating lung volume in determining the age-related difference in Wb during locomotor exercise. [ABSTRACT FROM AUTHOR]

Nasal high flow (NHF) is an efficient oxygenation tool for the treatment of respiratory failure. The study investigated the effect of breathing pattern on positive airway pressure and dead-space clearance by NHF. The breathing cycle during NHF was characterized in 26 patients with acute respiratory failure (ARF) and stable COPD and after mechanical ventilation (post-MV) via tracheostomy where also pressure was measured in the trachea. Dead-space clearance was measured in airway models during different breathing patterns. NHF reduced the respiratory rate (RR) and TI /TE through prolonging the TE; the TI/TE ranged between ≤0.5 observed in the COPD patients and ~1.0 in the ARF patients. NHF via a standard medium-sized cannula interface generated a low-level expiratory pressure proportional to NHF rate and breathing flow; the median generated positive end-expiratory pressure was only 1.71 cmH2O at NHF 45 L/min. The dilution and purging of expired gas from a nasal cavity model were observed to occur at the end of expiration as expiratory flow slowed and the dynamic pressure decreased. The higher RR with shorter end-expiratory period resulted in reduced dead-space clearance by NHF; 20 L/min cleared 43 ± 2 mL at RR 15 min-1 vs. 9 ± 5 mL at RR 45 min-1, P < 0.001, which was increased at higher NHF rate. At lower RR, the clearance was similar between NHF rates 20 and 60 L/min. Higher NHF rates elevate positive airway pressure, and at the increased RR can improve the clearance. This may enhance gas exchange and lead to a reduction in the work of breathing. [ABSTRACT FROM AUTHOR]

Intense inspiratory muscle work can evoke a metabolite-stimulated pressor reflex, commonly referred to as the respiratory muscle metaboreflex. When completing similar relative and absolute levels of inspiratory work, females have an attenuated blood pressure response. We sought to test the hypothesis that the lower blood pressure response to the respiratory muscle metaboreflex in females is associated with a reduced sympathetic response. Healthy young (26 ± 4 yr) males ( n = 9) and females ( n = 7) completed two experimental days. On day 1 , participants completed pulmonary function testing and became familiarized with an inspiratory pressure-threshold loading (PTL) task. On the second day, balloon-tipped catheters were placed in the esophagus and stomach to measure pleural and gastric pressures, and transdiaphragmatic pressure was calculated. A microelectrode was inserted into the fibular nerve to quantify muscle sympathetic nerve activity (MSNA), and participants then completed isocapnic PTL to task failure. There was a significant sex-by-time interaction in the mean arterial pressure (MAP, P = 0.015) and burst frequency ( P = 0.039) response to PTL. Males had a greater rise in MAP (Δ21 ± 9 mmHg) than females (Δ13 ± 5 mmHg, P = 0.026). Males also demonstrated a greater rise in MSNA burst frequency (Δ18 ± 7 bursts/min) than females (Δ10 ± 5 bursts/min, P = 0.015). The effect of sex was observed despite females and males completing the same magnitude of diaphragm work throughout the task ( P = 0.755). Our findings provide novel evidence that the lower blood pressure response to similar relative and absolute inspiratory muscle work in females is associated with lower sympathetic activation. NEW & NOTEWORTHY The blood pressure response to high levels of inspiratory muscle work is lower in females and occurs alongside a reduced sympathetic response. The reduced blood pressure and sympathetic response occur despite males and females performing similar levels of absolute inspiratory work. Our findings provide evidence that sex differences in the respiratory muscle metaboreflex are, in part, sympathetically mediated.

The mechanical work of breathing (Wb) is an insightful tool used to assess respiratory mechanics during exercise. There are several different methods used to calculate the Wb, however, each approach having its own distinct advantages/disadvantages. To date, a comprehensive assessment of the differences in the components of Wb between these methods is lacking. We therefore sought to compare the values of Wb during graded exercise as determined via the four most popular methods: 1) pressure-volume integration; 2) the Hedstrand diagram; 3) the Otis diagram; and the 4) modified Campbell diagram. Forty-two participants (30 ± 15 yr; 16 women) performed graded cycling to volitional exhaustion. Esophageal pressure-volume loops were obtained throughout exercise. These data were used to calculate the total Wb and, where possible, its subcomponents of inspiratory and expiratory, resistive and elastic Wb, using each of the four methods. Our results demonstrate that the components of Wb were indeed different between methods across the minute ventilations engendered by graded exercise. Importantly, however, no systematic pattern in these differences could be observed. Our findings indicate that the values of Wb obtained during exercise are uniquely determined by the specific method chosen to compute its value--no two methods yield identical results. Because there is currently no "gold-standard" for measuring the Wb, it is emphasized that future investigators be cognizant of the limitations incurred by their chosen method, such that observations made by others may be interpreted with greater context, and transparency. [ABSTRACT FROM AUTHOR]

In newborns, it is unclear how nasal high flow (NHF) generates positive airway pressure. In addition, the reported benefits of NHF such as reduction in work of breathing may be independent of airway pressure. The authors hypothesized that during NHF the area of leak and the flow determine airway pressure and that NHF can reduce the required minute ventilation to maintain gas exchange. In response to NHF, pressure was measured in the upper airways of 9 newborns and ventilation was measured in another group of 17 newborns. In a bench model, airway pressures were measured during NHF with different prong sizes, nare sizes, and flows. The airway pressures during 8 L/min NHF were greater when a larger cannula versus a smaller cannula was used (P < 0.05). NHF reduced minute ventilation in 16 of 17 neonates, with a mean decrease of 24% from a baseline of 0.66 L/min (SD 0.21) (P < 0.001), and was unrelated to changes in airway pressure; arterial oxygen saturation by pulse oximetry (SpO2) and tissue CO2 were unchanged. In the bench model, the airway pressure remained <2 cmH2O when <50% of the “nare” was occluded by the prongs. As the leak area decreased, because of a smaller nare or a larger cannula, the airway pressure increased exponentially and was dependent on flow. In newborns NHF using room air substantially reduced minute ventilation without affecting gas exchange irrespective of a decrease or an increase of respiratory rate. NHF generates low positive airway pressure that exponentially increases with flow and occlusion of the nares. NEW & NOTEWORTHY In healthy newborns, nasal high flow (NHF) with room air reduced minute ventilation by one-fourth without affecting gas exchange but, in contrast to adults, produced variable response in respiratory rate during sleep. During NHF, pressure in the upper airways did not exceed 2 cmH2O at 8 L/min (3.4 L·min−1·kg−1) and was unaffected by opening of the mouth. NHF can generate higher pressure with larger prongs that decrease the leak around the cannula or by increasing the flow rate. [ABSTRACT FROM AUTHOR]

Sympathetically induced vasoconstrictor modulation of local vasodilation occurs in contracting skeletal muscle during exercise to ensure appropriate perfusion of a large active muscle mass and to maintain also arterial blood pressure. In this synthesis, we discuss the contribution of group III-IV muscle afferents to the sympathetic modulation of blood flow distribution to locomotor and respiratory muscles during exercise. This is followed by an examination of the conditions under which diaphragm and locomotor muscle fatigue occur. Emphasis is given to those studies in humans and animal models that experimentally changed respiratory muscle work to evaluate blood flow redistribution and its effects on locomotor muscle fatigue, and conversely, those that evaluated the influence of coincident limb muscle contraction on respiratory muscle blood flow and fatigue. We propose the concept of a "two-way street of sympathetic vasoconstrictor activity" emanating from both limb and respiratory muscle metaboreceptors during exercise, which constrains blood flow and O2 transport thereby promoting fatigue of both sets of muscles. We end with considerations of a hierarchy of blood flow distribution during exercise between respiratory versus locomotor musculatures and the clinical implications of muscle afferent feedback influences on muscle perfusion, fatigue, and exercise tolerance. [ABSTRACT FROM AUTHOR]

Airway luminal area is the major determinant of resistance to airflow in the tracheobronchial tree. Women may have smaller central conducting airways than men; however, previous evidence is confounded by an indirect assessment of airway geometry and by subjects with prior smoking history. The purpose of this study was to examine the effect of sex on airway size in healthy nonsmokers. Using low-dose high-resolution computed tomography, we retrospectively assessed airway luminal area in healthy men (n = 51) and women (n = 73) of varying ages (19 – 86 yr). Subjects with a positive smoking history, cardiopulmonary disease, or a body mass index 40 kg/m2 were excluded. Luminal areas of the trachea, right and left main bronchus, bronchus intermediate, left and right upper lobes, and the left lower lobe were analyzed at three discrete points. The luminal areas of the conducting airways were ~26%–35% smaller in women. The trachea had the largest differences in luminal area between men and women (298 ± 47 vs. 195 ± 28 mm2 or 35% smaller for men and women, respectively), whereas the left lower lobe had the smallest differences (57 ± 15 vs. 42 ± 9 mm2 or 26% smaller for men and women, respectively). When a subset of subjects was matched for height, the sex differences in airway luminal area persisted, with women being ~20%–30% smaller. With all subjects, there were modest relationships between height and airway luminal area (r = 0.73– 0.53, P < 0.05). Although there was considerable overlap between sexes, the luminal areas of the large conducting airways were smaller in healthy women than in men. NEW & NOTEWORTHY Previous evidence for sex differences in airway size has been confounded by indirect measures and/or cohorts with significant smoking histories or pathologies. We found that central airways in healthy women were significantly smaller (~26%– 35%) than men. The significant sex-difference in airway size was attenuated (20%–30% smaller) but preserved in a subset of subjects matched for height. Over a range of ages, healthy women have smaller central airways than men. [ABSTRACT FROM AUTHOR]

We examined the effects of age, sex, and their interaction on mechanical ventilatory constraint and dyspnea during exercise in 22 older (age = 68 ± 1 yr; n = 12 women) and 22 younger (age = 25 ± 1 y, n = 11 women) subjects. During submaximal exercise, older subjects had higher end-inspiratory (EILV) and end-expiratory (EELV) lung volumes than younger subjects (both P < 0.05). During maximal exercise, older subjects had similar EILV ( P > 0.05) but higher EELV than younger subjects ( P < 0.05). No sex differences in EILV or EELV were observed. We noted that women had a higher work of breathing (Wb) for a given minute ventilation (V̇e) ≥65 l/min than men ( P < 0.05) and older subjects had a higher Wb for a given V̇e ≥60 l/min ( P < 0.05). No sex or age differences in Wb were present at any submaximal relative V̇e. At absolute exercise intensities, older women experienced expiratory flow limitation (EFL) more frequently than older men ( P < 0.05), and older subjects were more likely to experience EFL than younger subjects ( P < 0.05). At relative exercise intensities, women and older individuals experienced EFL more frequently than men and younger individuals, respectively (both P < 0.05). There were significant effects of age, sex, and their interaction on dyspnea intensity during exercise at absolute, but not relative, intensities (all P < 0.05). Across subjects, dyspnea at 80 W was significantly correlated with indexes of mechanical ventilatory constraint (all P < 0.05). Collectively, our findings suggest age and sex have significant impacts on Wb, operating lung volumes, EFL, and dyspnea during exercise. Moreover, it appears that mechanical ventilatory constraint may partially explain sex differences in exertional dyspnea in older individuals. NEW & NOTEWORTHY We found that age and sex have a significant effect on mechanical ventilatory constraint and the perception of dyspnea during exercise. We also observed that the perception of exertional dyspnea is associated with indexes of mechanical ventilatory constraint. Collectively, our results suggest that the combined influences of age and biological sex on mechanical ventilatory constraint during exercise contributes, in part, to the increased perception of dyspnea during exercise in older women. [ABSTRACT FROM AUTHOR]

There is evidence suggesting diaphragmatic fatigue (DF) occurs relatively early during high-intensity exercise; however, studies investigating the temporal characteristics of exercise-induced DF are limited by incongruent methodology. Eight healthy adult males (25 ± 5 yr) performed a maximal incremental exercise test on a cycle ergometer on day 1. A constant-load time-to-exhaustion (TTE) exercise test was conducted on day 2 at 60% delta between the calculated gas exchange threshold and peak work rate. Two additional constant-load exercise tests were performed at the same intensity on days 3 and 4 in a random order to either 50 or 75% TTE. DF was assessed on days 2, 3 and 4 by measuring transdiaphragmatic twitch pressure (Pdi,tw) in response to cervical magnetic stimulation. DF was present after 75 and 100% TTE (⩾20% decrease in Pdi,tw). The magnitude of fatigue was 15.5 ± 5.7%, 23.6 ± 6.4%, and 35.0 ± 12.1% at 50, 75, and 100% TTE, respectively. Significant differences were found between 100 to 75 and 50% TTE (both P < 0.01) and 75 to 50% TTE (P < 0.01). There was a significant relationship between the magnitude of fatigue and cumulative diaphragm force output (r = 0.785; P < 0.001). Ventilation, the mechanical work of breathing (WOB) and pressuretime products were not different between trials (P > 0.05). Our data indicate that exercise-induced DF presents a relatively late onset and is proportional to the cumulative WOB; thus the ability of the diaphragm to generate pressure progressively declines throughout exercise. NEW & NOTEWORTHY The notion that diaphragmatic fatigue (DF) occurs relatively early during exercise is equivocal. Our results indicate that DF occurs during high-intensity endurance exercise in healthy men and its magnitude is strongly related to the amount of pressure and work generated by respiratory muscles. Thus we conclude that the work of breathing is the major determinant of exerciseinduced DF. [ABSTRACT FROM AUTHOR]

Exercise-induced laryngeal obstruction (EILO), a phenomenon in which the larynx closes inappropriately during physical activity, is a prevalent cause of exertional dyspnea in young individuals. The physiological ventilatory impact of EILO and its relationship to dyspnea are poorly understood. The objective of this study was to evaluate exercise-related changes in laryngeal aperture on ventilation, pulmonary mechanics, and respiratory neural drive. We prospectively evaluated 12 subjects (6 with EILO and 6 healthy age- and gender-matched controls). Subjects underwent baseline spirometry and a symptom-limited incremental exercise test with simultaneous and synchronized recording of endoscopic video and gastric, esophageal, and transdiaphragmatic pressures, diaphragm electromyography, and respiratory airflow. The EILO and control groups had similar peak work rates and minute ventilation (*E) (work rate: 227 ± 35 vs. 237 ± 35 W; *E: 103 ± 20 vs. 98 ± 23 l/min; P > 0.05). At submaximal work rates (140-240 W), subjects with EILO demonstrated increased work of breathing (P < 0.05) and respiratory neural drive (P < 0.05), developing in close temporal association with onset of endoscopic evidence of laryngeal closure (P < 0.05). Unexpectedly, a ventilatory increase (P < 0.05), driven by augmented tidal volume (P < 0.05), was seen in subjects with EILO before the onset of laryngeal closure; there were however no differences in dyspnea intensity between groups. Using simultaneous measurements of respiratory mechanics and diaphragm electromyography with endoscopic video, we demonstrate, for the first time, increased work of breathing and respiratory neural drive in association with the development of EILO. Future detailed investigations are now needed to understand the role of upper airway closure in causing exertional dyspnea and exercise limitation. [ABSTRACT FROM AUTHOR]

Patients with chronic obstructive pulmonary disease (COPD) endure excessive resistive and elastic loads leading to chronic respiratory failure. Oxygen supplementation corrects hypoxemia but is not expected to reduce mechanical loads. Nasal high-flow (NHF) therapy supports breathing by reducing dead space, but it is unclear how it affects mechanical loads of patients with COPD. The objective of this study was to compare the effects of low-flow oxygen and NHF therapy on ventilation and work of breathing (WOB) in patients with COPD and controls during sleep. Patients with COPD (n = 12) and controls (n = 6) were recruited and submitted to polysomnography to measure sleep parameters and ventilation in response to administration of oxygen and NHF. A subset of six patients also had an esophageal catheter inserted for the purpose of measuring WOB. Patients with COPD had similar minute ventilation (VE) but lower tidal volumes than matched controls. With oxygen, SaO2 was increased and VE was reduced in both controls and patients with COPD, but there was an increase in transcutaneous CO2 levels. NHF produced a greater reduction in VE and was associated with a reduction in CO2 levels. Although NHF halved WOB, oxygen produced only a minor reduction in this parameter. We conclude that oxygen produced little change in WOB, which was associated with CO2 elevations. On the other hand, NHF produced a large reduction in VE and WOB with a concomitant decrease in CO2 levels. Our data indicate that NHF improves alveolar ventilation during sleep compared with oxygen and room air in patients with COPD and therefore can decrease their cost of breathing. [ABSTRACT FROM AUTHOR]

Extraordinary advances in respiratory physiology occurred between 1941 and 1956 in the Department of Physiology, University of Rochester. These were principally the result of a collaboration between Wallace Fenn, Hermann Rahn, and Arthur Otis. Remarkably, all three scientists had worked in very dissimilar areas of physiology before and, by their own admission, were largely ignorant of respiratory physiology. However, because of the exigencies of war they were brought together to study the physiology of pressure breathing. The result was that they laid much of the foundations of pulmonary gas exchange and pulmonary mechanics and some of their work is still cited today. In pulmonary gas exchange they exploited the new oxygen-carbon dioxide diagram; clarified the effects of changes of altitude, hyperventilation, and pressure breathing; and pioneered the analysis of ventilation-perfusion relationships. In respiratory mechanics, they carried out groundbreaking work on the pressure-volume behavior of the lung and chest wall and went on to analyze aspects of gas flow and work of breathing. This explosion of ideas from what initially appeared to be a poorly prepared group has lessons for us today. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that, besides dyspnea relief, an improvement in locomotor muscle oxygen delivery may also contribute to enhanced exercise tolerance following normoxic heliox (replacement of inspired nitrogen by helium) administration in patients with chronic obstructive pulmonary disease (COPD). Whether blood flow redistribution from intercostal to locomotor muscles contributes to this improvement currently remains unknown. Accordingly, the objective of this study was to investigate whether such redistribution plays a role in improving locomotor muscle oxygen delivery while breathing heliox at near-maximal [75% peak work rate (WRpeak)], maximal (100%WRpeak), and supramaximal (115%WRpeak) exercise in COPD. Intercostal and vastus lateralis muscle perfusion was measured in 10 COPD patients (FEV1 = 50.5 ± 5.5% predicted) by near-infrared spectroscopy using indocyanine green dye. Patients undertook exercise tests at 75 and 100%WRpeak breathing either air or heliox and at 115%WRpeak breathing heliox only. Patients did not exhibit exercise-induced hyperinflation. Normoxic heliox reduced respiratory muscle work and relieved dyspnea across all exercise intensities. During near-maximal exercise, quadriceps and intercostal muscle blood flows were greater, while breathing normoxic heliox compared with air (35.8 ± 7.0 vs. 29.0 ± 6.5 and 6.0 ± 1.3 vs. 4.9 ± 1.2 ml∙min-1∙100 g-1, respectively; P < 0.05; mean ± SE). In addition, compared with air, normoxic heliox administration increased arterial oxygen content, as well as oxygen delivery to quadriceps and intercostal muscles (from 47 ± 9 to 60 ± 12, and from 8 ± 1 to 13 ± 3 mlO2∙min-1∙100 g-1, respectively; P < 0.05). In contrast, normoxic heliox had neither an effect on systemic nor an effect on quadriceps or intercostal muscle blood flow and oxygen delivery during maximal or supramaximal exercise. Since intercostal muscle blood flow did not decrease by normoxic heliox administration, blood flow redistribution from intercostal to locomotor muscles does not represent a likely mechanism of improvement in locomotor muscle oxygen delivery. Our findings might not be applicable to patients who hyperinflate during exercise. [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS in relation to the [ICG] in arterial blood as measured using photodensitometry. This method is invasive since it requires arterial cannulation, repeated blood withdrawals, and reinfusions. A less invasive alternative is to calculate a relative measure of blood flow known as the blood flow index (BFI), which is based solely on the NIRS ICG curve, thus negating the need for arterial cannulation. Accordingly, the purpose of this study was to determine whether BFI can be used to measure RMBF at rest and during voluntary isocapnic hyperpnea at 25, 40, 55, and 70% of maximal voluntary ventilation in seven healthy humans. BFI was calculated as the change in maximal [ICG] divided by the rise time of the NIRS-derived ICG curve. Intercostal and sternocleidomastoid muscle BFI were correlated with simultaneously measured work of breathing and electromyography (EMG) data from the same muscles. BFI showed strong relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R²) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P < 0.001) and 0.863 (P < 0.001), respectively, whereas the R² for BFI vs. EMG for the intercostal and sternocleidomastoid muscles were 0.879 (P < 0.001) and 0.930 (P < 0.001), respectively. These data suggest that the BFI closely reflects RMBF in conscious humans across a wide range of ventilations and provides a less invasive and less technically demanding alternative to measuring RMBF. [ABSTRACT FROM AUTHOR]

We examined the effects of respiratory muscle work [inspiratory (Wr-insp); expiratory (Wr-exp)] and arterial oxygenation (SpO2) on exercise-induced locomotor muscle fatigue in patients with chronic obstructive pulmonary disease (COPD). Eight patients (FEV, 48 ± 4%) performed constant-load cycling to exhaustion (Ctrl; 9.8 ± 1.2 min). In subsequent trials, the identical exercise was repeated with 1) proportional assist ventilation + heliox (PAV); 2) heliox (He:21% O2); 3) 60% O2 inspirate (hyperoxia); or 4) hyperoxic heliox mixture (He:40% O2). Five age-matched healthy control subjects performed Ctrl exercise at the same relative workload but for 14.7 min (≈best COPD performance). Exercise-induced quadriceps fatigue was assessed via changes in quadriceps twitch force (Qtw,pot) from before to 10 min after exercise in response to supramaximal femoral nerve stimulation. During Ctrl, absolute workload (124 ± 6 vs. 62 ± 7 W), Wr-insp (207 ± 18 vs. 301 ± 37 cmH2O·s·min-1), Wr-exp (172 ± 15 vs. 635 ± 58 cmH2O·s·min-1), and SpO2 (96 ± 1% vs. 87 ± 3%) differed between control subjects and patients. Various interventions altered Wr-insp, Wr-exp, and SpO2 from Ctrl (PAV: -55 ± 5%, -21 ± 7%, +6 ± 2%; He:21% O2: -16 ± 2%, -25 ± 5%, +4 ± 1%; hyperoxia: -11 ± 2%, -17 ± 4%, +16 ± 4%; He:40% O2: -22 ± 2%, -27 ± 6%, +15 ± 4%). Ten minutes after Ctrl exercise, Qtw,pot was reduced by 25 ± 2% (P < 0.01) in all COPD and 2 ± 1% (P = 0.07) in healthy control subjects. In COPD, ΔQtw,pot was attenuated by one-third after each interventional trial; however, most of the exercise-induced reductions in Qtw,pot remained. Our findings suggest that the high susceptibility to locomotor muscle fatigue in patients with COPD is in part attributable to insufficient O2 transport as a consequence of exaggerated arterial hypoxemia and/or excessive respiratory muscle work but also support a critical role for the well-known altered intrinsic muscle characteristics in these patients. [ABSTRACT FROM AUTHOR]

It is problematic to withhold therapy in a patient with chronic obstructive pulmonary disease (COPD) who presents with acute respiratory failure so that detailed physiological measurements can be obtained. Accordingly, most information on respiratory muscle activity in patients experiencing acute respiratory failure has been acquired by studying patients who fail a trial of weaning after a period of mechanical ventilation. Such patients experience marked increases in inspiratory muscle load consequent to increases in resistance, elastance, and intrinsic positive end-expiratory pressure. Inspiratory muscle strength is reduced secondary to hyperinflation and possibly direct muscle damage and the release of inflammatory mediators. Most patients recruit both their sternomastoid and expiratory muscles, even though airflow limitation prevents the expiratory muscles from lowering lung volume. Even when acute hypercapnia is present, patients do not exhibit respiratory center depression; indeed, voluntary activation of the diaphragm, in absolute terms, is greater in hypercapnic patients than in normocapnic patients. Instead, the major mechanism of acute hypercapnia is the development of rapid shallow breathing. Despite the marked increase in mechanical load and decreased force-generating capacity of the inspiratory muscles, patients do not develop long-lasting muscle fatigue, at least over the period of a failed weaning trial. Although the disease originates within the lung parenchyma, much of the distress faced by patients with COPD, especially during acute respiratory failure, is caused by the burdens imposed on the respiratory muscles. [ABSTRACT FROM AUTHOR]

Measurement of respiratory muscle blood flow (RMBF) in humans has important implica- tions for understanding patterns of blood flow distribution during exercise in healthy individuals and those with chronic disease. Previous studies examining RMBF in humans have required invasive methods on anesthetized subjects. To assess RMBF in awake subjects, we applied an indicator-dilution method using near-infrared spectroscopy (NTRS) and the light-absorbing tracer indocyanine green dye (ICG). NIRS optodes were placed on the left seventh intercostal space at the apposition of the costal diaphragm and on an inactive control muscle (vastus lateralis). The primary respiratory muscles within view of the NIRS optodes include the internal and external intercostals. Intravenous bolus injection of ICG allowed for cardiac output (by the conventional dye-dilution method with arterial sampling), RMBF, and vastus lateralis blood flow to be quantified simultaneously. Esophageal and gastric pressures were also measured to calculate the work of breath- ing and transdiaphragmatic pressure. Measurements were obtained in five conscious humans during both resting breathing and three sepa- rate 5-tmn bouts of constant isocapnic hyperpnea at 27.1 ± 3.2, 56.0 ± 6.1, and 75.9 ± 5.7% of maximum minute ventilation as determined on a previous maximal exercise test. RIvIBF progressively increased (9.9 ± 0.6, 14.8 ± 2.7, 29.9 ± 5.8, and 50.1 ± 12.5 m1 100 ml-1 min-1, respectively) with increasing levels of ventilation while blood flow to the inactive control muscle remained constant (10.4 ± 1.4, 8.7 ± 0.7, 12.9 ± 1.7, and 12.2 ± 1.8 ml.100 ml-1min-1, respectively). As ventilation rose, RMBF was closely and signifi- cantly correlated with 1) cardiac output (r = 0.994, P = 0.006), 2) the work of breathing (r = 0.995, P = 0.005), and 3) transdiaphragmatic pressure (r = 0.998, P = 0.002). These data suggest that the NIRS-ICG technique provides a feasible and sensitive index of RMBF at different levels of ventilation in humans. [ABSTRACT FROM AUTHOR]

We previously found that, following surgical resection of -58% of lung units by right pneumonectomy (PNX) in adult canines, oxygen- diffusing capacity (DLo2) fell sufficiently to become a major factor limiting exercise capacity, although the decline was mitigated by recruitment, remodeling, and growth of the remaining lung units. To determine whether an upper limit of compensation is reached follow- ing the loss of even more lung units, we measured pulmonary gas exchange, hemodynamics, and ventilatory power requirements in adult canines during treadmill exercise following two-stage resection of ~70% of lung units in the presence or absence of mediastinal distortion. Results were compared with that in control animals following right PNX or thoracotomy without resection (Sham). Following 70% lung resection, peak 02 uptake was 45% below normal. Ventilation-perfusion mismatch developed, and pulmonary arterial pressure and ventilatory power requirements became markedly elevated. In contrast, the relationship of DLo2 to cardiac output remained normal, indicating preservation of DLo2-to-cardiac output ratio and alveolar-capillary recruitment up to peak exercise. The impairment in airway and vascular function exceeded the impairment in gas exchange and imposed the major limitation to exercise following 70% resection. Mediastinal distortion further reduced air and blood flow conductance, resulting in CO2 retention. Results suggest that adaptation of extra-acinar airways and blood vessels lagged behind that of acinar tissue. As more lung units were lost, functional compensation became limited by the disproportionately reduced convective conductance rather than by alveolar diffusion disequilibrium. [ABSTRACT FROM AUTHOR]

Our aim was to isolate the independent effects of 1) inspiratory muscle work (Wb) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [Inspired O2 fraction (FIO2) = 0.15, arterial hemoglobin saturation (SaO2) = 81 ± 1%; 8.6 ± 0.5 mm, 273 ± 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (SaO2 = 95 ± 1%; Normoxia-Ctrl). These trials were repeated, but with a 35- 80% reduction in Wb achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 mm after exercise. The isolated effects of Wb in hypoxia on quadriceps fatigue, independent of reductions in SaO2, were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAY at equal levels of Sao2 (P = 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Qtw.pot) decreased by 30 ± 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAY exercise (21 ± 4%; P = 0.0007). This effect of Wb on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing Wb had no significant effect on fatigue. The isolated effects of reduced SaO2 on quadriceps fatigue, independent of changes in Wb, were revealed by comparing Hypoxia-PAY and Normoxia-PAY at equal levels of Wb. Qtw.pot decreased by 15 ± 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAY (-22 ± 3%; P = 0.034). We conclude that both arterial hypoxemia and Wb, contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, Wb has no effect on peripheral fatigue. [ABSTRACT FROM AUTHOR]

We investigated the effects of aging on the elastic properties of lung tissue and the chest wall, simultaneously quantifying the contribution of each component to static inspiratory muscle work in resting and exercising adults. We further evaluated the interaction of aging and habitual physical activity on respiratory mechanics. Static lung volumes and elastic properties of the lung and chest wall (pressure-volume relaxation maneuvers) in 29 chronically sedentary and 29 habitually active subjects, grouped by age, were investigated: young (Y, 20-30 years), middle-aged (M, 40-50 years), and older (O, >60 years). Using static pressure-volume data, we computed the elastic work of breathing (joules per liter, J·I-1), including inspiratory muscle work, over resting and exercising tidal volume excursions. Elastic work of the lung (Y = 0.79 ± 0.05; M = 0.47 ± 0.05; O = 0.43 ± 0.05 J·I-1) and chest wall (Y = -0.49 ± 0.06; M = -0.12 ± 0.07; O = 0.04 ± 0.05 J·I-1) changed significantly with age (P < 0.05). With aging, a parallel displacement of the chest wall pressure-volume curve resulted in a shift from energy being stored primarily during expiration to energy storage during inspiration, and driving expiration, both at rest and during exercise. Although deviating significantly from young adults, this did not significantly elevate static inspiratory muscle work but resulted in a redistribution of the tissues on which this work was performed and the phase of the respiratory cycle in which it occurred. Nevertheless, static inspiratory muscle work remained similar across age groups, at rest and during exercise, and habitual physical activity failed to influence these changes. [ABSTRACT FROM AUTHOR]

We examined the relationship between the work of breathing (W b ) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive W b during exercise in females. Healthy participants ( n = 11 females and n = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where W b was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm 2 vs. females: 27.5 ± 7.4 mm 2 ) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm 2 vs. females: 1,594 ± 389 mm 2 ) were significantly larger in males (both P = 0.003). When minute ventilation was greater than ∼60 L·min -1 , the resistive W b was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size ( r = 0.524, P = 0.012) and Weibel area ( r = 0.525, P = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive W b during exercise in females compared with males. NEW & NOTEWORTHY We hypothesized that the higher resistive work of breathing in females compared with males during high-intensity exercise is due to smaller airways. In vivo measures of the fourth to eighth airway generations made using optical coherence tomography show that females tend to have smaller airway luminal areas of the fourth to sixth airway generations. Sex differences in airway luminal area result in a greater resistive work of breathing during exercise in females compared with males.

Work of breathing ([Formula: see text]) derived from a single lung volume and pleural pressure is limited and does not fully characterize the mechanical work done by the respiratory musculature. It has long been known that abdominal activation increases with increasing exercise intensity, yet the mechanical work done by these muscles is not reflected in [Formula: see text]. Using optoelectronic plethysmography (OEP), we sought to show first that the volumes obtained from OEP (V CW ) were comparable to volumes obtained from flow integration (V t ) during cycling and running, and second, to show that partitioned volume from OEP could be utilized to quantify the mechanical work done by the rib cage ([Formula: see text] RC ) and abdomen ([Formula: see text] AB ) during exercise. We fit 11 subjects (6 males/5 females) with reflective markers and balloon catheters. Subjects completed an incremental ramp cycling test to exhaustion and a series of submaximal running trials. We found good agreement between V CW versus V t during cycling (bias = 0.002; P > 0.05) and running (bias = 0.016; P > 0.05). From rest to maximal exercise,[Formula: see text] AB increased by 84% (range: 30%-99%; [Formula: see text] AB : 1 ± 1 J/min to 61 ± 52 J/min). The relative contribution of the abdomen increased from 17 ± 9% at rest to 26 ± 16% during maximal exercise. Our study highlights and provides a quantitative measure of the role of the abdominal muscles during exercise. Incorporating the work done by the abdomen allows for a greater understanding of the mechanical tasks required by the respiratory muscles and could provide further insight into how the respiratory system functions during disease and injury. NEW & NOTEWORTHY We demonstrated that optoelectronic plethysmography (OEP) is a reliable tool to determine ventilatory volume changes during cycling and running, without restricting natural upper arm movements. Second, using OEP volumes coupled with pressure-derived measures, we calculated the work done by the rib cage and abdomen, respectively, during exercise. Collectively, our findings indicate that pulmonary mechanics can be accurately quantified using OEP, and abdominal work performed during ventilation contributes substantially to the overall work of the respiratory musculature.

The modified Campbell diagram provides one of the most comprehensive assessments of the work of breathing (Wb) during exercise, wherein the resistive and elastic work of inspiration and expiration are quantified. Importantly, a necessary step in constructing the modified Campbell diagram is to obtain a value for chest wall compliance (C CW ). To date, it remains unknown whether estimating or directly measuring C CW impacts the Wb, as determined by the modified Campbell diagram. Therefore, the purpose of this study was to evaluate whether the components of the Wb differ when the modified Campbell diagram is constructed using an estimated versus measured value of C CW . Forty-two participants ( n = 26 men, 16 women) performed graded exercise to volitional exhaustion on a cycle ergometer. C CW was measured directly at rest via quasistatic relaxation. Estimated values of C CW were taken from prior literature. The measured value of C CW was greater than that obtained via estimation (214 ± 52 mL/cmH 2 O vs. 189 ± 18 mL/cmH 2 O; P < 0.05). At modest-to-high minute ventilations (i.e., 50-200 L/min), the inspiratory elastic Wb was greater and expiratory resistive Wb was lower, when modified Campbell diagrams were constructed using estimated compared with measured values of C CW ( P = 0.001). These differences were however small and never exceeded ±5%. Thus, although our findings demonstrate that estimating C CW has a measurable impact on the determination of the Wb, its effect appears relatively small within a cohort of healthy adults during graded exercise.

Smaller airways increase resistance and the propensity toward turbulent airflow, both of which are thought to be mechanisms behind greater resistive and total work of breathing (Wb) in females. Previous research examining the effect of airway size on the Wb between the sexes is limited by the inability to experimentally manipulate airway size. Heliox (21% oxygen, balance helium) is less dense than room air, which reduces turbulent airflow and airway resistance. The purpose of our study was to utilize heliox inspiration in women to provide a stimulus physiologically similar to increasing airway size. We hypothesized that when breathing heliox women would have a Wb similar to men breathing room air. Eighteen healthy young subjects ( n = 9 women, 9 men) completed two maximal exercise tests on a cycle ergometer over 2 days. Subjects breathed room air for one test and heliox for the other. Wb was assessed with an esophageal balloon catheter. During the room air trial, when ventilations were >65 L/min, women had a significantly greater Wb compared with men ( P < 0.05). The greater Wb in women was due to greater resistance to turbulent flow. For both sexes, breathing heliox resulted in increased expiratory flow (+132 ± 18% of room air), an elimination of expiratory flow limitation, and a reduction in Wb (69 ± 12% of room air) (all P < 0.05). When the women were breathing heliox, Wb was not different from that in the men breathing room air. Our findings support the idea that the smaller conducting airways in females are responsible for a greater total and resistive Wb. NEW & NOTEWORTHY When healthy young women breathe heliox gas during exercise, their work of breathing is not different from men breathing room air. Heliox inspiration reduces airway resistance and promotes laminar flow, which is a physiologically similar effect of increasing airway size. Our findings provide experimental evidence that smaller airways in women are responsible for the greater work of breathing during exercise.