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 (NIRS), 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 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 (FEV1:51{plus minus}6%predicted) at rest and during cycling at 25%, 50%, 75% and 100% of 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{plus minus}0.3 to 4.5{plus minus}0.7nM/s) and cycling load (from 1.0{plus minus}0.2 to 12.8{plus minus}1.9nM/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

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-1β 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-1β 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-1β or CRP

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

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 ((Formula presented.)) 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 FIO2-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 FIO2 does not affect (Formula presented.) heterogeneity, but this is unproven. We tested the hypothesis that alternating FIO2 exposure increases (Formula presented.) mismatch in nine patients with abnormal pulmonary gas exchange and increased (Formula presented.) 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 (Formula presented.) ratio, LogSD (Formula presented.), and perfusion versus (Formula presented.) ratio, LogSD (Formula presented.) were calculated. LogSD (Formula presented.) 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 (Formula presented.) 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 (Formula presented.) matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized

Improvement in respiratory muscle O2 delivery is associated with less dyspnoea during exercise in COPD

An expansion upon work presented in 'Blood flow does not redistribute from respiratory to leg muscles during exercise breathing heliox or oxygen in COPD' (http://jap.physiology.org/content/jap/117/3/267.full.pdf

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: CO IC ) and by the indocyanine green dye dilution method (CO DD ) in patients with COPD. Methods: Fifty paired CO measurements were concurrently obtained using the two methods from 10 patients (FEV 1 : 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 CO IC and CO DD were strongly correlated (r = 0.986, P < 0.001). The mean absolute and percentage differences between CO IC and CO DD 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 (VO 2 ) and CO DD were linearly related: r = 0.893 (P < 0.001), CO DD = 5.94 × VO 2 + 2.27 L/min. Similar results were obtained for VO 2 and CO IC (r = 0.885, P < 0.001, CO IC = 6.00 × VO 2 + 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

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.

BackgroundThere 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.MethodsArterial and femoral venous concentration and skeletal muscle expression of TNFα, IL-6, IL-1β 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).ResultsCirculating 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 &lt; 0.05), but lower in AATD compared to non-AATD-COPD patients (6.1 ± 2.6 mg/dL, p &lt; 0.05). TNFα, IL-6 and IL-1β were significantly increased by 1.7-, 1.7-, and 4.7-fold, respectively, in non-AATD COPD compared to AATD COPD (p &lt; 0.05), and 1.3-, 1.7-, and 2.2-fold, respectively, compared to healthy subjects (p &lt; 0.05). Skeletal muscle TNFα was on average 3-4 fold greater in AATD-AUG compared to the other groups (p &lt; 0.05). Exercise showed no effect on these cytokines in any of our patient groups.ConclusionThese 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-1β or CRP