Preserved peak exercise capacity in Andean highlanders with excessive erythrocytosis both before and after isovolumic hemodilution.

In chronic mountain sickness (CMS), increased blood oxygen (O2)-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (Q̇t) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak V̇o2 despite increased blood O2-carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, V̇o2, Q̇t, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, Q̇t, and blood-muscle mitochondria diffusion). Participants with EE had similar peak V̇o2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower Q̇t and higher arterial [O2]. After IVHD, peak V̇o2 was preserved (but not enhanced), with lower O2 delivery (despite higher Q̇t) balanced by greater O2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O2 diffusional conductances and not by any differences in ventilation, [Hb], nor Q̇t. In conclusion, EE does not result in lower peak V̇o2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity.NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak V̇o2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (Q̇t), thus maintaining similar O2 delivery. Peak V̇o2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased Q̇t and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak V̇o2.

Ventilation-perfusion heterogeneity measured by the multiple inert gas elimination technique is minimally affected by intermittent breathing of 100% O2.

Proton magnetic resonance (MR) imaging to quantify regional ventilation-perfusion ( V˙A/Q˙ ) ratios combines specific ventilation imaging (SVI) and separate proton density and perfusion measures into a composite map. Specific ventilation imaging exploits the paramagnetic properties of O2 , which alters the local MR signal intensity, in an FI O2 -dependent manner. Specific ventilation imaging data are acquired during five wash-in/wash-out cycles of breathing 21% O2 alternating with 100% O2 over ~20 min. This technique assumes that alternating FI O2 does not affect V˙A/Q˙ heterogeneity, but this is unproven. We tested the hypothesis that alternating FI O2 exposure increases V˙A/Q˙ mismatch in nine patients with abnormal pulmonary gas exchange and increased V˙A/Q˙ mismatch using the multiple inert gas elimination technique (MIGET).The following data were acquired (a) breathing air (baseline), (b) breathing alternating air/100% O2 during an emulated-SVI protocol (eSVI), and (c) 20 min after ambient air breathing (recovery). MIGET heterogeneity indices of shunt, deadspace, ventilation versus V˙A/Q˙ ratio, LogSD V˙ , and perfusion versus V˙A/Q˙ ratio, LogSD Q˙ were calculated. LogSD V˙ was not different between eSVI and baseline (1.04 ± 0.39 baseline, 1.05 ± 0.38 eSVI, p = .84); but was reduced compared to baseline during recovery (0.97 ± 0.39, p = .04). There was no significant difference in LogSD Q˙ across conditions (0.81 ± 0.30 baseline, 0.79 ± 0.15 eSVI, 0.79 ± 0.20 recovery; p = .54); Deadspace was not significantly different (p = .54) but shunt showed a borderline increase during eSVI (1.0% ± 1.0 baseline, 2.6% ± 2.9 eSVI; p = .052) likely from altered hypoxic pulmonary vasoconstriction and/or absorption atelectasis. Intermittent breathing of 100% O2 does not substantially alter V˙A/Q˙ matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized.

Precapillary pulmonary gas exchange is similar for oxygen and inert gases.

KEY POINTS: Precapillary gas exchange for oxygen has been documented in both humans and animals. It has been suggested that, if precapillary gas exchange occurs to a greater extent for inert gases than for oxygen, shunt and its effects on arterial oxygenation may be underestimated by the multiple inert gas elimination technique (MIGET). We evaluated fractional precapillary gas exchange in canines for O2 and two inert gases, sulphur hexafluoride and ethane, by measuring these gases in the proximal pulmonary artery, distal pulmonary artery (1 cm proximal to the wedge position) and systemic artery. Some 12-19% of pulmonary gas exchange occurred within small (1.7 mm in diameter or larger) pulmonary arteries and this was quantitatively similar for oxygen, sulphur hexafluoride and ethane. Under these experimental conditions, this suggests only minor effects of precapillary gas exchange on the magnitude of calculated shunt and the associated effect on pulmonary gas exchange estimated by MIGET. ABSTRACT: Some pulmonary gas exchange is known to occur proximal to the pulmonary capillary, although the magnitude of this gas exchange is uncertain, and it is unclear whether oxygen and inert gases are similarly affected. This has implications for measuring shunt and associated gas exchange consequences. By measuring respiratory and inert gas levels in the proximal pulmonary artery (P), a distal pulmonary artery 1 cm proximal to the wedge position (using a 5-F catheter) (D) and a systemic artery (A), we evaluated precapillary gas exchange in 27 paired samples from seven anaesthetized, ventilated canines. Fractional precapillary gas exchange (F) was quantified for each gas as F = (P - D)/(P - A). The lowest solubility inert gases, sulphur hexafluoride (SF6 ) and ethane were used because, with higher solubility gases, the P-A difference is sufficiently small that experimental error prevents accurate assessment of F. Distal samples (n = 12) with oxygen (O2 ) saturation values that were (within experimental error) equal to or above systemic arterial values, suggestive of retrograde capillary blood aspiration, were discarded, leaving 15 for analysis. D was significantly lower than P for SF6 (D/P = 88.6 ± 18.1%; P = 0.03) and ethane (D/P = 90.6 ± 16.0%; P = 0.04), indicating partial excretion of inert gas across small pulmonary arteries. Distal pulmonary arterial O2 saturation was significantly higher than proximal (74.1 ± 6.8% vs. 69.0 ± 4.9%; P = 0.03). Fractional precapillary gas exchange was similar for SF6 , ethane and O2 (0.12 ± 0.19, 0.12 ± 0.20 and 0.19 ± 0.26, respectively; P = 0.54). Under these experimental conditions, 12-19% of pulmonary gas exchange occurs within the small pulmonary arteries and the extent is similar between oxygen and inert gases.

Intra-pulmonary arteriovenous anastomoses and pulmonary gas exchange: evaluation by microspheres, contrast echocardiography and inert gas elimination.

KEY POINTS: Imaging techniques such as contrast echocardiography suggest that anatomical intra-pulmonary arteriovenous anastomoses (IPAVAs) are present at rest and are recruited to a greater extent in conditions such as exercise. IPAVAs have the potential to act as a shunt, although gas exchange methods have not demonstrated significant shunt in the normal lung. To evaluate this discrepancy, we compared anatomical shunt with 25-µm microspheres to contrast echocardiography, and gas exchange shunt measured by the multiple inert gas elimination technique (MIGET). Intra-pulmonary shunt measured by 25-µm microspheres was not significantly different from gas exchange shunt determined by MIGET, suggesting that MIGET does not underestimate the gas exchange consequences of anatomical shunt. A positive agitated saline contrast echocardiography score was associated with anatomical shunt measured by microspheres. Agitated saline contrast echocardiography had high sensitivity but low specificity to detect a ≥1% anatomical shunt, frequently detecting small shunts inconsequential for gas exchange. ABSTRACT: The echocardiographic visualization of transpulmonary agitated saline microbubbles suggests that anatomical intra-pulmonary arteriovenous anastomoses are recruited during exercise, in hypoxia, and when cardiac output is increased pharmacologically. However, the multiple inert gas elimination technique (MIGET) shows insignificant right-to-left gas exchange shunt in normal humans and canines. To evaluate this discrepancy, we measured anatomical shunt with 25-µm microspheres and compared the results to contrast echocardiography and MIGET-determined gas exchange shunt in nine anaesthetized, ventilated canines. Data were acquired under the following conditions: (1) at baseline, (2) 2 µg kg-1  min-1 i.v. dopamine, (3) 10 µg kg-1  min-1 i.v. dobutamine, and (4) following creation of an intra-atrial shunt (in four animals). Right to left anatomical shunt was quantified by the number of 25-µm microspheres recovered in systemic arterial blood. Ventilation-perfusion mismatch and gas exchange shunt were quantified by MIGET and cardiac output by direct Fick. Left ventricular contrast scores were assessed by agitated saline bubble counts, and separately by appearance of 25-µm microspheres. Across all conditions, anatomical shunt measured by 25-µm microspheres was not different from gas exchange shunt measured by MIGET (microspheres: 2.3 ± 7.4%; MIGET: 2.6 ± 6.1%, P = 0.64). Saline contrast bubble score was associated with microsphere shunt (ρ = 0.60, P < 0.001). Agitated saline contrast score had high sensitivity (100%) to detect a ≥1% shunt, but low specificity (22-48%). Gas exchange shunt by MIGET does not underestimate anatomical shunt measured using 25-µm microspheres. Contrast echocardiography is extremely sensitive, but not specific, often detecting small anatomical shunts which are inconsequential for gas exchange.

Cardiac output measurement during exercise in COPD: A comparison of dye dilution and impedance cardiography.

INTRODUCTION: Impedance cardiography (IC) derived from morphological analysis of the thoracic impedance signal is now commonly used for noninvasive assessment of cardiac output (CO) at rest and during exercise. However, in Chronic Obstructive Pulmonary Disease (COPD), conflicting findings put its accuracy into question. OBJECTIVES: We therefore compared concurrent CO measurements captured by IC (PhysioFlow: COIC ) and by the indocyanine green dye dilution method (CODD ) in patients with COPD. METHODS: Fifty paired CO measurements were concurrently obtained using the two methods from 10 patients (FEV1 : 50.5 ± 17.5% predicted) at rest and during cycling at 25%, 50%, 75% and 100% peak work rate. RESULTS: From rest to peak exercise COIC and CODD were strongly correlated (r = 0.986, P < 0.001). The mean absolute and percentage differences between COIC and CODD were 1.08 L/min (limits of agreement (LoA): 0.05-2.11 L/min) and 18 ± 2%, respectively, with IC yielding systematically higher values. Bland-Altman analysis indicated that during exercise only 7 of the 50 paired measurements differed by more than 20%. When data were expressed as changes from rest, correlations and agreement between the two methods remained strong over the entire exercise range (r = 0.974, P < 0.001, with no significant difference: 0.19 L/min; LoA: -0.76 to 1.15 L/min). Oxygen uptake (VO2 ) and CODD were linearly related: r = 0.893 (P < 0.001), CODD = 5.94 × VO2 + 2.27 L/min. Similar results were obtained for VO2 and COIC (r = 0.885, P < 0.001, COIC = 6.00 × VO2 + 3.30 L/min). CONCLUSIONS: These findings suggest that IC provides an acceptable CO measurement from rest to peak cycling exercise in patients with COPD.

Near-infrared spectroscopy using indocyanine green dye for minimally invasive measurement of respiratory and leg muscle blood flow in patients with COPD.

Reliability of near-infrared spectroscopy, measuring indocyanine green (ICG) for minimally invasive assessment of relative muscle blood flow during exercise has been examined in fit young individuals but not in chronic obstructive pulmonary disease (COPD). Here we ask whether it could be used to evaluate respiratory and locomotor muscle perfusion in COPD patients. Vastus lateralis muscle blood flow (MBF, the reference method calculated from arterial and muscle ICG concentration curves) and a blood flow index [BFI, calculated using only the (same) muscle ICG concentration curves] were compared in 10 patients (forced expiratory volume in 1 s: 51 ± 6% predicted) at rest and during cycling at 25, 50, 75, and 100% of peak work rate (WRpeak). Intercostal muscle MBF and BFI were also compared during isocapnic hyperpnea at rest, reproducing ventilation levels up to those at WRpeak. Intercostal and vastus lateralis BFI increased with increasing ventilation during hyperpnea (from 2.5 ± 0.3 to 4.5 ± 0.7 nM/s) and cycling load (from 1.0 ± 0.2 to 12.8 ± 1.9 nM/s), respectively. There were strong correlations between BFI and MBF for both intercostal ( r = 0.993 group mean data, r = 0.872 individual data) and vastus lateralis ( r = 0.994 group mean data, r = 0.895 individual data). Fold changes from rest in BFI and MBF did not differ for either the intercostal muscles or the vastus lateralis. Group mean BFI data showed strong interrelationships with respiratory and cycling workload, and whole body metabolic demand ( r ranged from 0.913 to 0.989) simultaneously recorded during exercise. We conclude that BFI is a reliable and minimally invasive tool for evaluating relative changes in respiratory and locomotor muscle perfusion from rest to peak exercise in COPD patient groups. NEW & NOTEWORTHY We show that noninvasive near-infrared spectroscopic (NIRS) detection of indocyanine green dye (ICG) after peripheral venous injection adequately reflects intercostal and locomotor muscle perfusion during exercise and hyperpnea in patients with chronic obstructive pulmonary disease (COPD). Mean, individual, and fold change responses from rest to exercise or hyperpnea correlated closely with the reference method, which requires arterial sampling. NIRS-ICG is a reliable, robust, and essentially noninvasive tool for assessing relative changes in intercostal and locomotor muscle perfusion in COPD patient groups.

Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique.

We have developed a novel functional proton magnetic resonance imaging (MRI) technique to measure regional ventilation-perfusion (V̇A/Q̇) ratio in the lung. We conducted a comparison study of this technique in healthy subjects (n = 7, age = 42 ± 16 yr, Forced expiratory volume in 1 s = 94% predicted), by comparing data measured using MRI to that obtained from the multiple inert gas elimination technique (MIGET). Regional ventilation measured in a sagittal lung slice using Specific Ventilation Imaging was combined with proton density measured using a fast gradient-echo sequence to calculate regional alveolar ventilation, registered with perfusion images acquired using arterial spin labeling, and divided on a voxel-by-voxel basis to obtain regional V̇A/Q̇ ratio. LogSDV̇ and LogSDQ̇, measures of heterogeneity derived from the standard deviation (log scale) of the ventilation and perfusion vs. V̇A/Q̇ ratio histograms respectively, were calculated. On a separate day, subjects underwent study with MIGET and LogSDV̇ and LogSDQ̇ were calculated from MIGET data using the 50-compartment model. MIGET LogSDV̇ and LogSDQ̇ were normal in all subjects. LogSDQ̇ was highly correlated between MRI and MIGET (R = 0.89, P = 0.007); the intercept was not significantly different from zero (-0.062, P = 0.65) and the slope did not significantly differ from identity (1.29, P = 0.34). MIGET and MRI measures of LogSDV̇ were well correlated (R = 0.83, P = 0.02); the intercept differed from zero (0.20, P = 0.04) and the slope deviated from the line of identity (0.52, P = 0.01). We conclude that in normal subjects, there is a reasonable agreement between MIGET measures of heterogeneity and those from proton MRI measured in a single slice of lung.NEW & NOTEWORTHY We report a comparison of a new proton MRI technique to measure regional V̇A/Q̇ ratio against the multiple inert gas elimination technique (MIGET). The study reports good relationships between measures of heterogeneity derived from MIGET and those derived from MRI. Although currently limited to a single slice acquisition, these data suggest that single sagittal slice measures of V̇A/Q̇ ratio provide an adequate means to assess heterogeneity in the normal lung.

Heterogeneity of blood flow and metabolism during exercise in patients with chronic obstructive pulmonary disease.

The study investigated whether the capacity to regulate muscle blood flow (Q) relative to metabolic demand (VO2) is impaired in COPD. Using six NIRS optodes over the upper, middle and lower vastus lateralis in 6 patients, (FEV1:46±12%predicted) we recorded from each: a) Q by indocyanine green dye injection, b) VO2/Q ratios based on fractional tissue O2 saturation and c) VO2 as their product, during constant-load exercise (at 20%, 50% and 80% of peak capacity) in normoxia and hyperoxia (FIO2:1.0). At 50 and 80%, relative dispersion (RD) for Q, but not for VO2, was greater in normoxia (0.67±0.07 and 0.79±0.08, respectively) compared to hyperoxia (0.57±0.12 and 0.72±0.07, respectively). In both conditions, RD for VO2 and Q significantly increased throughout exercise; however, RD of VO2/Q ratio was minimal (normoxia: 0.12-0.08 vs hyperoxia: 0.13-0.09). Muscle Q and VO2 appear closely matched in COPD patients, indicating a minimal impact of heterogeneity on muscle oxygen availability at submaximal levels of exercise.

Selective Life-Long Skeletal Myofiber-Targeted VEGF Gene Ablation Impairs Exercise Capacity in Adult Mice.

Exercise is dependent on adequate oxygen supply for mitochondrial respiration in both cardiac and locomotor muscle. To determine whether skeletal myofiber VEGF is critical for regulating exercise capacity, independent of VEGF function in the heart, ablation of the VEGF gene was targeted to skeletal myofibers (skmVEGF-/-) during embryogenesis (∼ E9.5), leaving intact VEGF expression by all other cells in muscle. In adult mice, VEGF levels were decreased in the soleus (by 65%), plantaris (94%), gastrocnemius (74%), EDL (99%) and diaphragm (64%) (P < 0.0001, each muscle). VEGF levels were unchanged in the heart. Treadmill speed (WT 86 ± 4 cm/sec, skmVEGF-/- 70 ± 5 cm/sec, P = 0.006) and endurance (WT 78 ± 24 min, skmVEGF-/- 18 ± 4 min, P = 0.0004) were severely limited in skmVEGF-/- mice in contrast to minor effect of conditional skmVEGF gene deletion in the adult. Body weight was also reduced (WT 22.8 ± 1.6 g, skmVEGF-/-, 21.1 ± 1.5, P = 0.02), but the muscle mass/body weight ratio was unchanged. The capillary/fiber ratio was lower in skmVEGF-/- plantaris (WT 1.51 ± 0.12, skmVEGF-/- 1.16 ± 0.20, P = 0.01), gastrocnemius (WT 1.61 ± 0.08, skmVEGF-/- 1.39 ± 0.08, P = 0.01), EDL (WT 1.36 ± 0.07, skmVEGF-/- 1.14 ± 0.13, P = 0.03) and diaphragm (WT 1.39 ± 0.18, skmVEGF-/- 0.79 ± 0.16, P = 0.0001) but, not in soleus. Cardiac function (heart rate, maximal pressure, maximal dP/dt, minimal dP/dt,) in response to dobutamine was not impaired in anesthetized skmVEGF-/- mice. Isolated soleus and EDL fatigue times were 16% and 20% (P < 0.02) longer, respectively, in skmVEGF-/- mice than the WT group. These data suggest that skeletal myofiber VEGF expressed during development is necessary to establish capillary networks that allow maximal exercise capacity.

A method for assessing heterogeneity of blood flow and metabolism in exercising normal human muscle by near-infrared spectroscopy.

Heterogeneity in the distribution of both blood flow (Q̇) and O2 consumption (V̇O2) has not been assessed by near-infrared spectroscopy in exercising normal human muscle. We used near-infrared spectroscopy to measure the regional distribution of Q̇ and V̇O2 in six trained cyclists at rest and during constant-load exercise (unloaded pedaling, 20%, 50%, and 80% of peak Watts) in both normoxia and hypoxia (inspired O2 fraction = 0.12). Over six optodes over the upper, middle, and lower vastus lateralis, we recorded 1) indocyanine green dye inflow after intravenous injection to measure Q̇; and 2) fractional tissue O2 saturation (StiO2) to estimate local V̇O2-to-Q̇ ratios (V̇o2/Q̇). Varying both exercise intensity and inspired O2 fraction provided a (directly measured) femoral venous O2 saturation range from about 10 to 70%, and a correspondingly wide range in StiO2. Mean Q̇-weighted StiO2 over the six optodes related linearly to femoral venous O2 saturation in each subject. We used this relationship to compute local muscle venous blood O2 saturation from StiO2 recorded at each optode, from which local V̇O2/Q̇ could be calculated by the Fick principle. Multiplying regional V̇O2/Q̇ by Q̇ yielded the corresponding local V̇O2. While six optodes along only in one muscle may not fully capture the extent of heterogeneity, relative dispersion of both Q̇ and V̇O2 was ∼0.4 under all conditions, while that for V̇O2/Q̇ was minimal (only ∼0.1), indicating in fit young subjects 1) a strong capacity to regulate Q̇ according to regional metabolic need; and 2) a likely minimal impact of heterogeneity on muscle O2 availability.

Inflammatory cytokine response to exercise in alpha-1-antitrypsin deficient COPD patients 'on' or 'off' augmentation therapy.

BACKGROUND: There is still limited information on systemic inflammation in alpha-1-antitrypsin-deficient (AATD) COPD patients and what effect alpha-1-antitrypsin augmentation therapy and/or exercise might have on circulating inflammatory cytokines. We hypothesized that AATD COPD patients on augmentation therapy (AATD + AUG) would have lower circulating and skeletal muscle inflammatory cytokines compared to AATD COPD patients not receiving augmentation therapy (AATD-AUG) and/or the typical non-AATD (COPD) patient. We also hypothesized that cytokine response to exercise would be lower in AATD + AUG compared to AATD-AUG or COPD subjects. METHODS: Arterial and femoral venous concentration and skeletal muscle expression of TNFα, IL-6, IL-1ß and CRP were measured at rest, during and up to 4-hours after 50% maximal 1-hour knee extensor exercise in all COPD patient groups, including 2 additional groups (i.e. AATD with normal lung function, and healthy age-/activity-matched controls). RESULTS: Circulating CRP was higher in AATD + AUG (4.7 ± 1.6 mg/dL) and AATD-AUG (3.3 ± 1.2 mg/dL) compared to healthy controls (1.5 ± 0.3 mg/dL, p < 0.05), but lower in AATD compared to non-AATD-COPD patients (6.1 ± 2.6 mg/dL, p < 0.05). TNFα, IL-6 and IL-1ß were significantly increased by 1.7-, 1.7-, and 4.7-fold, respectively, in non-AATD COPD compared to AATD COPD (p < 0.05), and 1.3-, 1.7-, and 2.2-fold, respectively, compared to healthy subjects (p < 0.05). Skeletal muscle TNFα was on average 3-4 fold greater in AATD-AUG compared to the other groups (p < 0.05). Exercise showed no effect on these cytokines in any of our patient groups. CONCLUSION: These data show that AATD COPD patients do not experience the same chronic systemic inflammation and exhibit reduced inflammation compared to non-AATD COPD patients. Augmentation therapy may help to improve muscle efflux of TNFα and reduce muscle TNFα concentration, but showed no effect on IL-6, IL-1ß or CRP.

Blood flow does not redistribute from respiratory to leg muscles during exercise breathing heliox or oxygen in COPD.

In patients with chronic obstructive pulmonary disease (COPD), one of the proposed mechanisms for improving exercise tolerance, when work of breathing is experimentally reduced, is redistribution of blood flow from the respiratory to locomotor muscles. Accordingly, we investigated whether exercise capacity is improved on the basis of blood flow redistribution during exercise while subjects are breathing heliox (designed to primarily reduce the mechanical work of breathing) and during exercise with oxygen supplementation (designed to primarily enhance systemic oxygen delivery but also to reduce mechanical work of breathing). Intercostal, abdominal, and vastus lateralis muscle perfusion were simultaneously measured in 10 patients with COPD (forced expiratory volume in 1 s: 46 ± 12% predicted) by near-infrared spectroscopy using indocyanine green dye. Measurements were performed during constant-load exercise at 75% of peak capacity to exhaustion while subjects breathed room air and, then at the same workload, breathed either normoxic heliox (helium 79% and oxygen 21%) or 100% oxygen, the latter two in balanced order. Times to exhaustion while breathing heliox and oxygen did not differ (659 ± 42 s with heliox and 696 ± 48 s with 100% O2), but both exceeded that on room air (406 ± 36 s, P < 0.001). At exhaustion, intercostal and abdominal muscle blood flow during heliox (9.5 ± 0.6 and 8.0 ± 0.7 ml · min(-1)·100 g(-1), respectively) was greater compared with room air (6.8 ± 0.5 and 6.0 ± 0.5 ml·min(-1)·100 g·, respectively; P < 0.05), whereas neither intercostal nor abdominal muscle blood flow differed between oxygen and air breathing. Quadriceps muscle blood flow was also greater with heliox compared with room air (30.2 ± 4.1 vs. 25.4 ± 2.9 ml·min(-1)·100 g(-1); P < 0.01) but did not differ between air and oxygen breathing. Although our findings confirm that reducing the burden on respiration by heliox or oxygen breathing prolongs time to exhaustion (at 75% of maximal capacity) in patients with COPD, they do not support the hypothesis that redistribution of blood flow from the respiratory to locomotor muscles is the explanation.

Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation.

Pulmonary TNFα has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/dt) was not altered by TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen.

Cerebral cortex oxygen delivery and exercise limitation in patients with COPD.

In healthy humans, cerebral oxygen desaturation during exercise affects motor unit recruitment, while oxygen supplementation enhances cerebral oxygenation and work capacity. It remains unknown whether in patients with chronic obstructive pulmonary disease (COPD), the well-documented improvement in exercise tolerance with oxygen supplementation may also be partly due to the increase in cerebral oxygenation. Using near infrared spectroscopy, we measured both frontal cerebral cortex blood flow (CBF) using indocyanine green dye and cerebrovascular oxygen saturation (S(t,O(2))) in 12 COPD patients during constant-load exercise to exhaustion at 75% of peak capacity. Subjects exercised while breathing air, 100% oxygen or normoxic heliox, the latter two in balanced order. Time to exhaustion while breathing air was less than for either oxygen or heliox (mean±sem 394±35 versus 670±43 and 637±46 s, respectively). Under each condition, CBF increased from rest to exhaustion. At exhaustion, CBF was higher while breathing air and heliox than oxygen (30.9±2.3 and 31.3±3.5 versus 26.6±3.2 mL·min(-1) per 100 g, respectively), compensating for the lower arterial oxygen content (C(a,O(2))) in air and heliox, and leading to similar cerebral cortex oxygen delivery (CQ(O(2)) for air was 5.3±0.4, for oxygen was 5.5±0.6 and for heliox was 5.6±1.0 mL O(2) per min per 100 g). In contrast, end-exercise S(t,O(2)) was greater while breathing oxygen compared with air or heliox (67±4 versus 57±3 and 53±3%, respectively), reflecting C(a,O(2)) rather than CQ(O(2)). Prolonged time to exhaustion by breathing oxygen and heliox, despite these having a similar CQ(O(2)) to air, a lower S(t,O(2)) with heliox than oxygen, and yet similar endurance time and similar S(t,O(2)) in air and heliox despite greater endurance with heliox, do not support the hypothesis that an improvement in cerebral cortex oxygen availability plays a contributing role in increasing exercise capacity with oxygen or heliox in patients with COPD.

Heliox increases quadriceps muscle oxygen delivery during exercise in COPD patients with and without dynamic hyperinflation.

Some reports suggest that heliox breathing during exercise may improve peripheral muscle oxygen availability in patients with chronic obstructive pulmonary disease (COPD). Besides COPD patients who dynamically hyperinflate during exercise (hyperinflators), there are patients who do not hyperinflate (non-hyperinflators). As heliox breathing may differently affect cardiac output in hyperinflators (by increasing preload and decreasing afterload of both ventricles) and non-hyperinflators (by increasing venous return) during exercise, it was reasoned that heliox administration would improve peripheral muscle oxygen delivery possibly by different mechanisms in those two COPD categories. Chest wall volume and respiratory muscle activity were determined during constant-load exercise at 75% peak capacity to exhaustion, while breathing room air or normoxic heliox in 17 COPD patients: 9 hyperinflators (forced expiratory volume in 1 s = 39 ± 5% predicted), and 8 non-hyperinflators (forced expiratory volume in 1 s = 48 ± 5% predicted). Quadriceps muscle blood flow was measured by near-infrared spectroscopy using indocyanine green dye. Hyperinflators and non-hyperinflators demonstrated comparable improvements in endurance time during heliox (231 ± 23 and 257 ± 28 s, respectively). At exhaustion in room air, expiratory muscle activity (expressed by peak-expiratory gastric pressure) was lower in hyperinflators than in non-hyperinflators. In hyperinflators, heliox reduced end-expiratory chest wall volume and diaphragmatic activity, and increased arterial oxygen content (by 17.8 ± 2.5 ml/l), whereas, in non-hyperinflators, heliox reduced peak-expiratory gastric pressure and increased systemic vascular conductance (by 11.0 ± 2.8 ml·min(-1)·mmHg(-1)). Quadriceps muscle blood flow and oxygen delivery significantly improved during heliox compared with room air by a comparable magnitude (in hyperinflators by 6.1 ± 1.3 ml·min(-1)·100 g(-1) and 1.3 ± 0.3 ml O(2)·min(-1)·100 g(-1), and in non-hyperinflators by 7.2 ± 1.6 ml·min(-1)·100 g(-1) and 1.6 ± 0.3 ml O(2)·min(-1)·100 g(-1), respectively). Despite similar increase in locomotor muscle oxygen delivery with heliox in both groups, the mechanisms of such improvements were different: 1) in hyperinflators, heliox increased arterial oxygen content and quadriceps blood flow at similar cardiac output, whereas 2) in non-hyperinflators, heliox improved central hemodynamics and increased systemic vascular conductance and quadriceps blood flow at similar arterial oxygen content.

Frontal cerebral cortex blood flow, oxygen delivery and oxygenation during normoxic and hypoxic exercise in athletes.

During maximal hypoxic exercise, a reduction in cerebral oxygen delivery may constitute a signal to the central nervous system to terminate exercise. We investigated whether the rate of increase in frontal cerebral cortex oxygen delivery is limited in hypoxic compared to normoxic exercise. We assessed frontal cerebral cortex blood flow using near-infrared spectroscopy and the light-absorbing tracer indocyanine green dye, as well as frontal cortex oxygen saturation (S(tO2)%) in 11 trained cyclists during graded incremental exercise to the limit of tolerance (maximal work rate, WRmax) in normoxia and acute hypoxia (inspired O2 fraction (F(IO2)), 0.12). In normoxia, frontal cortex blood flow and oxygen delivery increased (P < 0.05) from baseline to sub-maximal exercise, reaching peak values at near-maximal exercise (80% WRmax: 287 ± 9 W; 81 ± 23% and 75 ± 22% increase relative to baseline, respectively), both leveling off thereafter up to WRmax (382 ± 10 W). Frontal cortex S(tO2)% did not change from baseline (66 ± 3%) throughout graded exercise. During hypoxic exercise, frontal cortex blood flow increased (P = 0.016) from baseline to sub-maximal exercise, peaking at 80% WRmax (213 ± 6 W; 60 ± 15% relative increase) before declining towards baseline at WRmax (289 ± 5 W). Despite this, frontal cortex oxygen delivery remained unchanged from baseline throughout graded exercise, being at WRmax lower than at comparable loads (287 ± 9 W) in normoxia (by 58 ± 12%; P = 0.01). Frontal cortex S(tO2)% fell from baseline (58 ± 2%) on light and moderate exercise in parallel with arterial oxygen saturation, but then remained unchanged to exhaustion (47 ± 1%). Thus, during maximal, but not light to moderate, exercise frontal cortex oxygen delivery is limited in hypoxia compared to normoxia. This limitation could potentially constitute the signal to limit maximal exercise capacity in hypoxia.

Effect of helium breathing on intercostal and quadriceps muscle blood flow during exercise in COPD patients.

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 (WR(peak))], maximal (100%WR(peak)), and supramaximal (115%WR(peak)) exercise in COPD. Intercostal and vastus lateralis muscle perfusion was measured in 10 COPD patients (FEV(1) = 50.5 ± 5.5% predicted) by near-infrared spectroscopy using indocyanine green dye. Patients undertook exercise tests at 75 and 100%WR(peak) breathing either air or heliox and at 115%WR(peak) 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 mlO(2)·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.

Intercostal muscle blood flow limitation during exercise in chronic obstructive pulmonary disease.

RATIONALE: It has been hypothesized that, because of the high work of breathing sustained by patients with chronic obstructive pulmonary disease (COPD) during exercise, blood flow may increase in favor of the respiratory muscles, thereby compromising locomotor muscle blood flow. OBJECTIVES: To test this hypothesis by investigating whether, at the same work of breathing, intercostal muscle blood flow during exercise is as high as during resting isocapnic hyperpnea when respiratory and locomotor muscles do not compete for the available blood flow. METHODS: Intercostal and vastus lateralis muscle perfusion was measured simultaneously in 10 patients with COPD (FEV1 = 50.5 ± 5.5% predicted) by near-infrared spectroscopy using indocyanine green dye. MEASUREMENTS AND MAIN RESULTS: Measurements were made at several exercise intensities up to peak work rate (WRpeak) and subsequently during resting hyperpnea at minute ventilation levels up to those at WRpeak. During resting hyperpnea, intercostal muscle blood flow increased with the power of breathing to 11.4 ± 1.6 ml/min per 100 g at the same ventilation recorded at WRpeak. Conversely, during graded exercise, intercostal muscle blood flow remained unchanged from rest up to 50% WRpeak (6.8 ± 1.3 ml/min per 100 g) and then fell to 4.5 ± 0.8 ml/min per 100 g at WRpeak (P = 0.003). Cardiac output plateaued above 50% WRpeak (8.4 ± 0.1 l/min), whereas vastus lateralis muscle blood flow increased progressively, reaching 39.8 ± 7.1 ml/min per 100 g at WRpeak. CONCLUSIONS: During intense exercise in COPD, restriction of intercostal muscle perfusion but preservation of quadriceps muscle blood flow along with attainment of a plateau in cardiac output represents the inability of the circulatory system to satisfy the energy demands of locomotor and respiratory muscles.