Karlman Wasserman, William L Beaver, Xing-Guo Sun, William Stringer

Resting arterial H⁺ concentration ([H⁺]a) is in the nanomolar range (40+/-2 nm/L) while its production is in the millimolar range/min, with little variation from subject to subject. To determin the precision with which [H⁺]a is regulated during exercise, [H⁺]a, PaCO2 and ventilation (Ve) were measured during progressively increasing work rate exercise in 16 normal subjects. (Ve) increased with [H⁺]a, the latter attributable to PaCO2 increase below the lactic acidosis threshold (LAT) (DVe/D[H⁺]a ~15 L min^-1 nanomol^-1_). [H⁺]a and PaCO2 increased, simultaneously, as work rate was increased below LAT. PaCO2 reversed direction of change between LAT and ventilatory compensation point (VCP). Above LAT, [H⁺]a increase relative to (Ve) increase was greater than below LAT. PaCO2 decreased above the LAT, while [H⁺]a continued to increase. Thus the exercise acidosis was converted from respiratory, below, to a metabolic, above the LAT. We conclude that [H⁺]a is increased and regulated over the full range of exercise, but with less sensitivity above the LAT.

Respiratory Physiology & Neurobiology 178 (2011) 191-195

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Brian J. Whipp, Susan A. Ward, and Harry B. Rossiter
Med. Sci. Sports Exerc., Vol. 37, No. 9, pp. 1574-1585, 2005 
For moderate-intensity exercise (below lactate threshold, thetaL), muscle O(2) consumption (VO(2)) kinetics are expressed in a first-order phase 2 (or fundamental) pulmonary O(2) uptake (VO(2)) response: dVO(2)/dt . tau + DeltaVO(2)((t)) = DeltaVO(2)((ss)); where DeltaVO(2)(ss) is the steady-state VO(2) increment, and tau the VO(2) time constant (which is within approximately 10% of tauQVO(2)). A likely source of VO(2) control in this intensity domain is ADP-mediated, for which intramuscular phosphocreatine (PCr) may serve as a proxy variable. Whether, in reality, this behavior reflects the operation of a single homogeneous compartment is unclear, however; a multicompartment structure comprised of units having a similar DeltaVO(2)((ss)) but with widely varying tau can also yield a “well-fit” exponential response with an apparent single tau. In support of this is the inverse (although poorly predictive) correlation between tau and both theta(L) and VO(2max). Above theta(L), the fundamental VO(2) kinetics are supplemented with a delayed, slowly developing component that can set VO(2) on a trajectory towards VO(2max), and that has complex temporal- and intensity-related kinetics. This VO(2) slow component is also demonstrable in [PCr], suggesting that the decreased efficiency above theta(L) predominantly reflects a high phosphate cost of force production rather than a high O(2) cost of phosphate production. In addition, the oxygen deficit for the slow component is more likely to reflect a progressive shifting of DeltaVO(2)((ss)) rather than a single DeltaVO(2)((ss)) having a single tau.

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Hean-Yee Ong, Conor S. O’Dochartaigh, Sharon Lovell, Victor H. Patterson, Karlman Wasserman, D. Paul Nicholls, and Marshall S. Riley
Am J Respir Crit Care Med, Vol 169. pp 1238-1244, 2004 
During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle’s disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.

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Chuang, M. L. Ting, H. Otsuka, T. et al
J Appl Physiol 87:1087-1097; 1999
Previous studies have shown that a metabolic alkalosis develops in the muscle during early exercise. This has been linked to phosphocreatine hydrolysis. Over a similar time frame, the femoral vein blood pH and plasma K(+) and HCO(-)(3) concentrations increase without an increase in PCO(2). Thus CO(2) from aerobic metabolism is converted to HCO(-)(3) rather than being eliminated by the lungs. The purpose of this study was to quantify the increase in early CO(2) stores and the component due to the exercise-induced metabolic alkalosis (E-I Alk). To avoid masking the increase in CO(2) stores by CO(2) released as HCO(-)(3) buffers lactic acid, the transient increase in CO(2) stores was measured only for work rates (WRs) below the lactic acidosis threshold (LAT). The increase in CO(2) stores was evident at the airway starting at approximately 15 s; the increase reached a peak at approximately 60 s and was complete by approximately 3 min of exercise. The increase in CO(2) stores was greater, but the kinetics were unaffected at the higher WR. Three components of the change in aerobically generated CO(2) stores were considered relevant: the carbamate component of the Haldane effect, the increase in CO(2) stores due to increase in tissue PCO(2), and the E-I Alk. The Haldane effect was calculated to be approximately 5%. Physically dissolved CO(2) in the tissues was approximately 30% of the store increase. The remaining E-I Alk CO(2) stores averaged 61 and 68% for 60 and 80% LAT WRs, respectively. The kinetics of O(2) uptake correlated with the time course of the increase in CO(2) stores; the size of the O(2) deficit correlated with the size of the E-I Alk component of the CO(2) stores. We conclude that a major component of the aerobically generated increase in CO(2) stores is the new HCO(-)(3) generated as phosphocreatine is converted to creatine.

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Karlman Wasserman, MD, PhD, FCCP
Chest 1997; 112: 1091-1101
No abstract available. A classic paper describing diagnosis of cardio-pulmonary pathophysiology from CPET.

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Paolo Palange, Gabriele Valli, Paolo Onorati, Rosa Antonucci, Patrizia Paoletti, Alessia Rosato, Felice Manfredi, and Pietro Serra
J Appl Physiol 97: 1637–1642, 2004.
We tested the hypothesis that heliox breathing, by reducing lung dynamic hyperinflation (DH) and dyspnea (Dys) sensation, may significantly improve exercise endurance capacity in patients with chronic obstructive pulmonary disease [n = 12, forced expiratory volume in 1 s = 1.15 (SD 0.32) liters]. Each subject underwent two cycle ergometer high-intensity constant work rate exercises to exhaustion, one on room air and one on heliox (79% He-21% O2). Minute ventilation (VE), carbon dioxide output, heart rate, inspiratory capacity (IC), Dys, and arterial partial pressure of CO2 were measured. Exercise endurance time increased significantly with heliox [9.0 (SD 4.5) vs. 4.2 (SD 2.0) min; P < 0.001]. This was associated with a significant reduction in lung DH at isotime (Iso), as reflected by the increase in IC [1.97 (SD 0.40) vs. 1.77 (SD 0.41) liters; P < 0.001] and a decrease in Dys [6 (SD 1) vs. 8 (SD 1) score; P < 0.001]. Heliox induced a state of relative hyperventilation, as reflected by the increase in VE [38.3 (SD 7.7) vs. 35.5 (SD 8.8) l/min; P < 0.01] and VE/carbon dioxide output [36.3 (SD 6.0) vs. 33.9 (SD 5.6); P < 0.01] at peak exercise and by the reduction in arterial partial pressure of CO2 at Iso [44 (SD 6) vs. 48 (SD 6) Torr; P < 0.05] and at peak exercise [46 (SD 6) vs. 48 (SD 6) Torr; P < 0.05]. The reduction in Dys at Iso correlated significantly (R = -0.75; P < 0.01) with the increase in IC induced by heliox. The increment induced by heliox in exercise endurance time correlated significantly with resting increment in resting forced expiratory in 1 s (R = 0.88; P < 0.01), increase in IC at Iso (R = 0.70; P < 0.02), and reduction in Dys at Iso (R = -0.71; P < 0.01). In chronic obstructive pulmonary disease, heliox breathing improves high-intensity exercise endurance capacity by increasing maximal ventilatory capacity and by reducing lung DH and Dys.

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Janos Porszasz, Richard Casaburi, Attila Somfay, Linda J. Woodhouse, and Brian J. Whipp
Med. Sci. Sports Exerc., Vol. 35, No. 9, pp. 1596-1602, 2003
INTRODUCTION: A treadmill exercise test requiring a low initial metabolic rate that then increments the work rate linearly to reach the subject’s limit of tolerance in approximately 10 min would have significant advantages for exercise testing and rehabilitation of subjects with impaired exercise tolerance. METHODS: We developed such a treadmill protocol that uses a linear increase in walking speed coupled with a curvilinear increase in treadmill grade to yield a linear increase in work rate. RESULTS: Twenty-two healthy, sedentary subjects performed both this new treadmill protocol and a standard cycle ergometry ramp protocol eliciting similar work rate profiles. The low initial treadmill speed and grade resulted in a low initial metabolic rate, commensurate with unloaded pedaling on a cycle ergometer (average [OV0312]O2 = 0.54 +/- 0.16 vs 46 +/- 0.12 l x min(-1)). This combination of simultaneous increase in speed and grade yielded a linear work rate and its oxygen uptake response (R2 = 0.96 +/- 0.03) with a slope of 11.4 +/- 2.4 ml x min(-1) x W(-1)-slightly, but significantly, higher than on the cycle (9.6 +/- 2.0 ml x min(-1) x W(-1)). This difference was attributed to unmeasured work associated, for example, with additional limb movements and frictional losses. As previously demonstrated, both the peak oxygen uptake and the estimated lactate threshold were higher on the treadmill than for cycle ergometry (averaging 23% and 27%, respectively, in these subjects). CONCLUSION: This treadmill protocol provides a linear profile of work rate as is currently standard for cycle ergometry and is appropriate for testing of subjects with low exercise tolerance.

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Frits M.E. Franssen, Roelinka Broekhuizen, Paul P. Janssen, Emiel F.M. Wouters, Annemie M.W. Schols
Chest 2004; 125:2021-2028
BACKGROUND: Skeletal muscle wasting is related to muscle dysfunction, exercise intolerance, and increased mortality risk in patients with COPD. STUDY OBJECTIVES: The aims of this study were to investigate the effects of whole-body exercise training on body composition in normal-weight patients with COPD, and to study the relationship between changes in body composition and functional capacity. SETTING AND PARTICIPANTS: Fifty patients with COPD (FEV(1), 39% of predicted [SD, 16]) admitted to the pulmonary rehabilitation center at Hornerheide, and 36 healthy age-matched control subjects (for baseline comparison) were included. INTERVENTIONS: Patients participated in a standardized inpatient exercise training program consisting of daily submaximal cycle ergometry, treadmill walking, weight training, and gymnastics during 8 weeks. MEASUREMENTS: Fat-free mass (FFM) was measured by bioelectrical impedance analysis. None of the patients met the criteria for nutritional supplementation (body mass index </= 21, or FFM index </= 15 kg/m(2) in women and </= 16 kg/m(2) in men). Exercise capacity was measured using incremental cycle ergometry. Isokinetic quadriceps strength was measured with a Biodex dynamometer (Biodex Medical Corporation; Shirley, NY). RESULTS: At baseline, patients were characterized by a significantly lower FFM than the control subjects. Age and FFM were independent predictors of skeletal muscle function and exercise capacity in patients. After rehabilitation, weight (72.4 +/- 9.8 to 73.0 +/- 9.4 kg, p < 0.05) significantly increased, as a result of increased FFM (52.4 +/- 7.3 to 53.4 +/- 7.7 kg, p < 0.05), while fat mass (20.0 +/- 6.1 to 19.6 +/- 5.7 kg) tended to decrease. Peak work rate (63 +/- 29 to 84 +/- 42 W, p < 0.001), maximal oxygen consumption (O(2)max) [1,028 +/- 307 to 1,229 +/- 421 mL/min, p < 0.001], and isokinetic quadriceps strength (82.5 +/- 36.4 to 90.3 +/- 34.9 Newton-meters, p < 0.05) all improved. Changes in FFM were proportionally smaller than functional improvements, and were related to changes in O(2)max (r = 0.361, p < 0.05), but not to other changes in functional capacity. CONCLUSIONS: Intensive exercise training per se is able to induce an anabolic response in normal-weight patients with COPD classified into Global Initiative for Chronic Obstructive Lung Disease stages III-IV. Improvements in exercise performance and muscle function are proportionally larger than increases in FFM.

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Romualdo Belardinelli, Francesca Lacalaprice, Flavia Carle, Adelaide Minnucci, Giovanni Cianci, GianPiero Perna, Giuseppe D’Eusanio
European Heart Journal (2003) 24, 1304-1313
BACKGROUND: The objective of the study was to identify the parameter(s) of cardiopulmonary exercise testing (CPET) that can detect exercise-induced myocardial ischaemia (EIMI), and to determine its diagnostic accuracy for identifying patients with coronary artery disease (CAD). METHODS AND RESULTS: We prospectively studied 202 consecutive patients (173 men, 29 women, mean age 55.7+/-10.8 years) with documented CAD. All patients underwent an incremental exercise stress testing (ECG-St) with breath-by-breath gas exchange analysis, followed by a 2-day stress/rest gated SPECT myocardial scintigraphy (GSMS) as the gold standard for ischaemia detection. ROC analysis selected a two-variable model-O(2)pulse flattening duration, calculated from the onset of myocardial ischaemia to peak exercise, and deltaVO(2)/deltawork rate slope-to predict EIMI by CPET. GSMS identified 140 patients with reversible myocardial defects, with a Summed Difference Score (SDS) of 9.7+/-2.8, and excluded EIMI in 62 (SDS 1.3+/-1.6). ECG-St had low sensitivity (46%) and specificity (66%) to diagnose EIMI as compared with CPET (87% and 74%, respectively). CONCLUSIONS: The addition of gas exchange analysis improves the diagnostic accuracy of standard ECG stress testing in identifying EIMI. A two-variable model based on O(2)pulse flattening duration and deltaVO(2)/deltawork rate slope had the highest predictive ability to identify EIMI.

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Piergiuseppe Agostoni, Michele Bianchia, Andrea Moraschia, Pietro Palermoa, Gaia Cattadoria, Rocco La Gioiab, Maurizio Bussottia, Karlman Wasserman
Europ J of Heart Failure 2005; 7: 498-504
AIMS: Cardiopulmonary exercise test (CPET) is used to evaluate patients with chronic heart failure (HF) usually by means of a personalized ramp exercise protocol. Our aim was to evaluate if exercise duration or ramp rate influences the results. METHODS AND RESULTS: Ninety HF patients were studied (peak V (O(2)): >20 ml/min/kg, n=28, 15-20 ml/min/kg, n=39 and <15 ml/min/kg, n=23). Each patient did four CPET studies. The initial study was used to separate the subjects into three groups, according to their exercise capacity. In the remaining studies, work-rate was increased at three different rates designed to have the subjects reach peak exercise in 5, 10 and 15 min from the start of the ramp increase in work-rate, respectively. The order was randomized. The work-rate applied for the total population averaged 22.7+/-8.0, 11.6+/-3.7, 7.5+/-2.9 W/min with effective loaded exercise duration of 5 min and 16 s+/-29 s, 9 min and 43 s+/-49 s and 14 min and 32 s+/-1 min and 12 s for the 5-, 10- and 15-min tests, respectively. Peak V (O(2)) averaged 16.9+/-4.3*, 18.0+/-4.4 and 18.0+/-5.4 ml/min/kg for the 5-, 10- and 15-min tests, (*=p<0.001 vs. 10 min). The shortest test had the lowest peak heart rate and ventilation and highest peak work-rate. Peak V (O(2)) and heart rate were lowest in 5-min tests regardless of HF severity. The DeltaV (O(2))/Deltawork-rate was lowest in 5-min tests and highest in 15-min tests. At all ramp rates, DeltaV (O(2))/Deltawork-rate was lower for the subjects with the lower peak V (O(2)). The V (e)/V (CO(2)) slope and V (O(2)) at anaerobic threshold were not affected by the protocol for any grade of HF. CONCLUSIONS: In chronic HF, exercise protocol has a small effect on peak V (O(2)) and DeltaV (O(2))/Deltawork but does not affect V (O(2)) at anaerobic threshold and V (e)/V (CO(2)) slope.

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