Transcutaneous PCO2 for Exercise Gas Exchange Efficiency in Chronic Obstructive Pulmonary Disease.

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (VD/VT). Noninvasive methods for accurate VD/VT assessment during exercise in patients are lacking. The current study sought to compare transcutaneous PCO2 (TcPCO2) with the gold standard-arterial PCO2 (PaCO2)-and other available methods (end tidal CO2 and the Jones equation) for estimating VD/VT during incremental exercise in COPD. Ten COPD patients completed a symptom limited incremental cycle exercise. TcPCO2 was measured by a heated electrode on the ear-lobe. Radial artery blood was collected at rest, during unloaded cycling (UL) and every minute during exercise and recovery. Ventilation and gas exchange were measured breath-by-breath. Bland-Altman analysis examined agreement of PCO2 and VD/VT calculated using PaCO2, TcPCO2, end-tidal PCO2 (PETCO2) and estimated PaCO2 by the Jones equation (PaCO2-Jones). Lin's Concordance Correlation Coefficient (CCC) was assessed. 114 measurements were obtained from the 10 COPD subjects. The bias between TcPCO2 and PaCO2 was 0.86 mmHg with upper and lower limit of agreement ranging -2.28 mmHg to 3.99 mmHg. Correlation between TcPCO2 and PaCO2 during rest and exercise was r2=0.907 (p < 0.001; CCC = 0.941) and VD/VT using TcPCO2 vs. PaCO2 was r2=0.958 (p < 0.0001; CCC = 0.967). Correlation between PaCO2-Jones and PETCO2 vs. PaCO2 were r2=0.755, 0.755, (p < 0.001; CCC = 0.832, 0.718) and for VD/VT calculation (r2=0.793, 0.610; p < 0.0001; CCC = 0.760, 0.448), respectively. The results support the accuracy of TcPCO2 to reflect PaCO2 and calculate VD/VT during rest and exercise, but not in recovery, in COPD patients, enabling improved accuracy of noninvasive assessment of gas exchange inefficiency during incremental exercise testing.

Effect of tiotropium on spontaneous expiratory flow-volume curves during exercise in GOLD 1-2 COPD.

This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 µg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end-expiratory flow. Seven patients exhibited SEFV curve concavity with RAR ≤ 0.5 (RARlow) in ≥1 test without tiotropium; (mean ±â€¯SD FEV1: 1.60 ±â€¯0.59 L; 63.4 ±â€¯14.0%predicted). In RARlow patients, tiotropium increased end-exercise inspiratory capacity (IC, 2.10 ±â€¯0.05 vs. 1.89 ±â€¯0.05 L, tiotropium vs. placebo; p = 0.045) and RAR (0.57 ±â€¯0.02 vs. 0.53 ±â€¯0.02; p < 0.001). Patients without SEFV curve concavity with RAR > 0.5 (n = 13; RARhigh), had higher screening FEV1 (2.15 ±â€¯0.47 L; 79.6 ±â€¯10.1%predicted) versus RARlow patients and no difference in end-exercise IC and RAR between tiotropium and placebo (IC: 2.24 ±â€¯0.03 vs. 2.17 ±â€¯0.03 L; RAR: 0.63 ±â€¯0.005 vs. 0.62 ±â€¯0.005). RAR and%predicted IC at peak exercise were positively correlated in RARlow patients (R2 = 0.43, p = 0.0002). Tiotropium increased exercise RAR in GOLD 1-2 patients with SEFV curve concavity.

Reproducibility of NIRS assessment of muscle oxidative capacity in smokers with and without COPD.

Low muscle oxidative capacity contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). Near-infrared spectroscopy (NIRS) allows non-invasive determination of the muscle oxygen consumption (mV̇O2) recovery rate constant (k), which is proportional to oxidative capacity assuming two conditions are met: 1) exercise intensity is sufficient to fully-activate mitochondrial oxidative enzymes; 2) sufficient O2 availability. We aimed to determine reproducibility (coefficient of variation, CV; intraclass correlation coefficient, ICC) of NIRS k assessment in the gastrocnemius of 64 participants with (FEV1 64±23%predicted) or without COPD (FEV1 98±14%predicted). 10-15s dynamic contractions preceded 6min of intermittent arterial occlusions (5-10s each, ∼250mmHg) for k measurement. k was lower (P<0.05) in COPD (1.43±0.4min-1; CV=9.8±5.9%, ICC=0.88) than controls (1.74±0.69min-1; CV=9.9±8.4%; ICC=0.93). Poor k reproducibility was more common when post-contraction mV̇O2 and deoxygenation were low, suggesting insufficient exercise intensity for mitochondrial activation and/or the NIRS signal contained little light reflected from active muscle. The NIRS assessment was well tolerated and reproducible for muscle dysfunction evaluation in COPD.

Skeletal muscle power and fatigue at the tolerable limit of ramp-incremental exercise in COPD.

Muscle fatigue (a reduced power for a given activation) is common following exercise in chronic obstructive pulmonary disease (COPD). Whether muscle fatigue, and reduced maximal voluntary locomotor power, are sufficient to limit whole body exercise in COPD is unknown. We hypothesized in COPD: 1) exercise is terminated with a locomotor muscle power reserve; 2) reduction in maximal locomotor power is related to ventilatory limitation; and 3) muscle fatigue at intolerance is less than age-matched controls. We used a rapid switch from hyperbolic to isokinetic cycling to measure the decline in peak isokinetic power at the limit of incremental exercise ("performance fatigue") in 13 COPD patients (FEV1 49 ± 17%pred) and 12 controls. By establishing the baseline relationship between muscle activity and isokinetic power, we apportioned performance fatigue into the reduction in muscle activation and muscle fatigue. Peak isokinetic power at intolerance was ~130% of peak incremental power in controls (274 ± 73 vs. 212 ± 84 W, P < 0.05), but ~260% in COPD patients (187 ± 141 vs. 72 ± 34 W, P < 0.05), greater than controls (P < 0.05). Muscle fatigue as a fraction of baseline peak isokinetic power was not different in COPD patients vs. controls (0.11 ± 0.20 vs. 0.19 ± 0.11). Baseline to intolerance, the median frequency of maximal isokinetic muscle activity, was unchanged in COPD patients but reduced in controls (+4.3 ± 11.6 vs. -5.5 ± 7.6%, P < 0.05). Performance fatigue as a fraction of peak incremental power was greater in COPD vs. controls and related to resting (FEV1/FVC) and peak exercise (V̇E/maximal voluntary ventilation) pulmonary function (r2 = 0.47 and 0.55, P < 0.05). COPD patients are more fatigable than controls, but this fatigue is insufficient to constrain locomotor power and define exercise intolerance.

Biological quality control for cardiopulmonary exercise testing in multicenter clinical trials.

BACKGROUND: Precision and accuracy assurance in cardiopulmonary exercise testing (CPET) facilitates multicenter clinical trials by maximizing statistical power and minimizing participant risk. Current guidelines recommend quality control that is largely based on precision at individual testing centers (minimizing test-retest variability). The aim of this study was to establish a multicenter biological quality control (BioQC) method that considers both precision and accuracy in CPET. METHODS: BioQC testing was 6-min treadmill walking at 20 W and 70 W (below the lactate threshold) with healthy non-smoking laboratory staff (15 centers; ~16 months). Measurements were made twice within the initial 4 weeks and quarterly thereafter. Quality control was based on: 1) within-center precision (coefficient of variation [CV] for oxygen uptake [V̇O2], carbon dioxide output [V̇CO2], and minute ventilation [V̇E] within ±10%); and 2) a criterion that V̇O2 at 20 W and 70 W, and ∆V̇O2/∆WR were each within ±10 % predicted. "Failed" BioQC tests (i.e., those outside the predetermined criterion) prompted troubleshooting and repeated measurements. An additional retrospective analysis, using a composite z-score combining both BioQC precision and accuracy of V̇O2 at 70 W and ∆V̇O2/∆WR, was compared with the other methods. RESULTS: Of 129 tests (5 to 8 per center), 98 (76%) were accepted by within-center precision alone. Within-center CV was <9%, but between-center CV remained high (9.6 to 12.5%). Only 43 (33%) tests had all V̇O2 measurements within the ±10% predicted criterion. However, a composite z-score of 0.67 identified 67 (52%) non-normal outlying tests, exclusion of which coincided with the minimum CV for CPET variables. CONCLUSIONS: Study-wide BioQC using a composite z-score can increase study-wide precision and accuracy, and optimize the design and conduct of multicenter clinical trials involving CPET. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01072396; February 19, 2010.

Physiologic effects of an ambulatory ventilation system in chronic obstructive pulmonary disease.

RATIONALE: Exercise intolerance limits the ability of patients with chronic obstructive pulmonary disease (COPD) to perform daily living activities. Noninvasive ventilation reduces dyspnea and improves exercise performance, but current systems are unsuitable for ambulatory use. OBJECTIVES: In patients with COPD experiencing exercise-induced desaturation, we evaluated improvements in exercise tolerance facilitated by a wearable, 1-lb, noninvasive open ventilation (NIOV) system featuring a nasal pillow interface during constant work rate (CWR) cycle ergometer exercise and associated effects on dyspnea, respiratory muscle activation, and pulmonary gas exchange efficiency. METHODS: Fifteen men with COPD (FEV1 = 32.2 ± 12.0% predicted; FEV1/FVC = 31.6 ± 7.1%; exercise oxygen saturation as measured by pulse oximetry [Spo2] = 86.5 ± 2.9%) participated. After incremental testing establishing peak work rate, subjects completed three visits in which they performed CWR exercise to tolerance at 80% peak work rate: (1) unencumbered breathing room air, (2) using NIOV+compressed air, (3) using NIOV+compressed O2, or (4) using O2 via nasal cannula. Assessments included exercise duration, surface inspiratory muscle EMG, Spo2, transcutaneous Pco2, and Borg dyspnea scores. MEASUREMENTS AND MAIN RESULTS: Exercise endurance was 17.6 ± 5.7 minutes using NIOV+O2, greatly prolonged compared with unencumbered (5.6 ± 1.9 min), nasal O2 (11.4 ± 6.8 min), and NIOV+Air (6.3 ± 4.1 min). Isotime Spo2 was higher and intercostal, scalene, and diaphragmatic EMG activity was reduced using NIOV+O2 compared with unencumbered, nasal O2, and NIOV+Air, signifying respiratory muscle unloading. Isotime dyspnea reduction correlated with isotime EMG reduction (r = 0.42, P = 0.0053). There were no significant differences in isotime VD/VT or transcutaneous Pco2 among treatments. CONCLUSIONS: NIOV+O2 yielded substantial exercise endurance improvements accompanied by respiratory muscle unloading and dyspnea reductions in patients with severe hypoxemic COPD.

Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV(smm) subtypes cocirculate, with the vast majority of animals infected with SIV(smm) subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV(smm)-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV(smm) subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV(smm) subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV(smm) infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV(smm) infection.