Ammonium ion and the anaerobic threshold in man.

To determine if ammonium ion plays a role in the lactate and ventilatory thresholds of incremental exercise, we investigated the effects on blood lactate and ventilation of NH(4+)-buffering by monosodium glutamate. Six normal volunteers underwent intravenous loading with MSG, 9 g, in a randomized, double-blind, saline placebo controlled crossover study. Four of the six subjects had a greater than 10 percent fall in peak (NH4+) following MSG (37 +/- 2.0 vs 25 +/- 4.3 micrograms/dl p = 0.003, PLB vs MSG). When MSG blunted the rise in venous (NH4+) during exercise, uncoupling of the LT and VT was observed. Specifically, with suppression of peak exercise (NH4+) by MSG, the LT was delayed (r = -0.84, p = 0.03), the VT was earlier (r = 0.86, p = 0.02), and the VO2 difference between the LT and VT widened (r = -0.90, p = 0.02). We conclude that NH4+ plays a role in determining the LT and VT of incremental exercise and that the VT may not be exclusively dependent on blood lactate.

Improvement in exercise capacity after nocturnal positive pressure ventilation and tracheostomy in a postpoliomyelitis patient.

Progressive neuromuscular symptoms years after recovery from acute paralytic poliomyelitis have been termed the PPS. We describe a 52-year-old man who contracted poliomyelitis at age 9 years who fully recovered and 33 years later developed progressive dyspnea. Neurologic evaluation revealed bilateral paralysis of the vocal cords, generalized weakness, and accentuated mouth occlusion pressure and ventilatory responses to hypercapnic, hyperoxic breathing. An EMG and muscle biopsy showed changes consistent with acute and chronic denervation. Cardiopulmonary exercise evaluation demonstrated a pulmonary mechanical limit with excessive ventilation relative to CO2 output. Tracheostomy and nocturnal positive pressure ventilation resulted in increased respiratory muscle strength, normalization of ventilatory drive and marked improvement in exercise capacity.

Maximum cardiac output during incremental exercise by first-pass radionuclide ventriculography.

STUDY OBJECTIVE: To validate a noninvasive first-pass radionuclide ventriculographic (FPRV) measurement of maximum cardiac output (Qv) during exercise. DESIGN: Comparison of Qv to that measured by the Fick principle (Qf) at peak exercise. SETTING: Academic cardiopulmonary exercise laboratory. PATIENTS: Seventy-eight consecutive patients without a history of septal defect undergoing clinically indicated maximum incremental cardiopulmonary exercise testing with pulmonary arterial catheterization and FPRV. MEASUREMENTS AND RESULTS: Ventilation and gas exchange were measured breath-by-breath or by a mixing chamber/mass spectrometer system. Arterial and mixed venous O2 content were measured each minute during exercise. When patients without left-to-right ventricular stroke count ratio evidence for left-sided regurgitation were isolated, peak Qv was linearly related to Qf (r=0.75, p=0.0001). To account for a small systematic overestimation (bias) of Qf by Qv, the linear equation for the Qv/Qf relation was derived for patients studied between 1990 and 1993 and applied to those studied subsequently. The resulting corrected peak Qv was tightly related to peak Qf (r=0.90, p<0.001) with confidence intervals for slope and intercept overlapping identity. CONCLUSION: FPRV can reasonably estimate maximum cardiac output during incremental exercise in patients for whom the technique has ruled out left-sided cardiac regurgitant lesions.

Breathing reserve at the lactate threshold to differentiate a pulmonary mechanical from cardiovascular limit to exercise.

STUDY OBJECTIVES: Criteria used to define the respective roles of pulmonary mechanics and cardiovascular disease in limiting exercise performance are usually obtained at peak exercise, but are dependent on maximal patient effort. To differentiate heart from lung disease during a less effort-dependent domain of exercise, the predictive value of the breathing reserve index (BRI=minute ventilation [VE]/maximal voluntary ventilation [MVV]) at the lactate threshold (LT) was evaluated. DESIGN: Thirty-two patients with COPD and a pulmonary mechanical limit (PML) to exercise defined by classic criteria at maximum oxygen uptake (VO2max) were compared with 29 patients with a cardiovascular limit (CVL) and 12 normal control subjects. Expired gases and VE were measured breath by breath using a commercially available metabolic cart (Model 2001; MedGraphics Corp; St. Paul, Minn). Arterial blood gases, pH, and lactate were sampled each minute during exercise, and cardiac output (Q) was measured by first-pass radionuclide ventriculography (System 77; Baird Corp; Bedford, Mass) at rest and peak exercise. RESULTS: For all patients, the BRI at lactate threshold (BRILT) correlated with the BRI at VO2max (BRIMAX) (r=0.85, p<0.0001). The BRILT was higher for PML (0.73+/-0.03, mean+/-SEM) vs CVL (0.27+/-0.02, p<0.0001), and vs control subjects (0.24+/-0.03, p<0.0001). A BRILT > or = 0.42 predicted a PML at maximum exercise, with a sensitivity of 96.9%, a specificity of 95.1%, a positive predictive value of 93.9%, and a negative predictive value of 97.5%. CONCLUSIONS: The BRILT, a variable measured during the submaximal realm of exercise, can distinguish a PML from CVL.

Determinants of abnormal maximum oxygen uptake after lung transplantation for chronic obstructive pulmonary disease.

BACKGROUND: Single lung transplantation for chronic obstructive pulmonary disease relieves a ventilatory limit to incremental exercise, but maximum oxygen uptake remains abnormal. The purpose of this study was to define the relative contributions of Fick principle variables to abnormal aerobic capacity after lung transplantation. METHODS: Twelve paired incremental cardiopulmonary exercise test results obtained before and 3 to 6 months after single lung transplantation for chronic obstructive pulmonary disease were compared. RESULTS: Maximum workload nearly doubled after operation (42.5+/-4.2 vs 25.5+/-4.7 watts, P < .05). Peak exercise minute ventilation increased (32.8+/-3.3 vs 21+/-2.4 L/min, n = 11, P < .05), but maximum oxygen uptake remained markedly abnormal after transplantation (46.6%+/-4.4% vs 32.1%+/-2.9% predicted, P < .05, n = 8). Peak exercise cardiac output was normal (11.0+/-1.4 L/min, 89% predicted), but arterial-mixed venous oxygen content difference at peak exercise was only half of normal (7.2+/-0.61 mL/dL), as a result in part of the failure of mixed venous oxygen saturation to fall normally (peak exercise SvO2 = 49.8%+/-2.8%). CONCLUSIONS: Lung transplantation for chronic obstructive pulmonary disease relieves a ventilatory limit to exercise, but maximum aerobic capacity remains abnormal, in part because of abnormal systemic O2 extraction.

Exercise performance in cystic fibrosis before and after bilateral lung transplantation.

BACKGROUND: Lung transplantation improves pulmonary function and quality of life for patients with end-stage cystic fibrosis; however, a systematic evaluation of exercise performance in lung transplant recipients with cystic fibrosis has not been reported. METHODS: Ten patients with end-stage cystic fibrosis performed incremental exercise testing before and after bilateral lung transplantation; their results were compared with those of 10 age-similar healthy volunteers. Breath-by-breath measurements of gas exchange and ventilation were obtained, arterial blood was sampled each minute, and cardiac output determined at rest and peak exercise by radionuclide ventriculography. The arterial-venous O2 content difference was derived by the Fick principle. RESULTS: After transplantation, peak O2 uptake improved (31% +/- 3% vs 45% +/- 4% predicted, P = .03) but was still reduced versus normal (100% +/- 8% predicted, p < .0001). Exercise was limited by pulmonary mechanics in all patients before transplantation but in only 2 after transplantation. Compared with control subjects, the lactate threshold occurred early, both before and after transplantation. Peak exercise cardiac output and arterial O2 content were not different from normal, either before or after transplantation. In contrast, the peak exercise arterial-venous O2 content difference was markedly reduced before and after transplantation versus normal (7.1 +/- 1.2 and 9.3 +/- 0.9 vs 17.1 +/- 1.2 mL/dL, p < or = .0001 for each) and without significant improvement. CONCLUSIONS: Exercise performance in patients with end-stage cystic fibrosis improves after lung transplantation but remains well below normal. Reduced systemic O2 extraction is an important factor limiting exercise in patients with cystic fibrosis after transplantation and may also contribute to the exercise limit before transplantation.

Central respiratory effects of glutamine synthesis inhibition in dogs.

Glutamic acid is an excitatory neurotransmitter that may have a significant role in the central chemical drive of ventilation. Therefore cardiorespiratory function was measured in pentobarbital sodium-anesthetized dogs before and after central inhibition of glutamate metabolism by means of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthase (GS) catalyzing amidation of glutamate to glutamine. GS was inhibited centrally by perfusing the ventriculocisternal space with artificial cerebrospinal fluid (CSF) containing 92.5 mmol MSO per liter at a fixed pH, perfusion rate, and pressure. After GS inhibition, CSF transfer rate of [13N]glutamine synthesized from 13NH4+ amidation of glutamate was reduced five-fold, and minute ventilation increased from 2.90 +/- 0.41 (SE) l/min (0.164 +/- 0.020 l.min-1.kg body wt-1) to 4.46 +/- 0.52 l/min (0.254 +/- 0.029 l.min-1.kg body wt-1). This increase in ventilation with endogenous glutamate and the increase in ventilation previously observed during ventriculocisternal perfusion of exogenous glutamate are compared quantitatively via a model of central neurotransmitter glutamate chemoreception. The results support the hypothesis that the endogenous brain glutamate is important in the central chemical drive of ventilation.

31P nuclear magnetic resonance spectroscopy study of the anaerobic threshold in humans.

The relationships among the lactate threshold (LT), ventilatory threshold (VT), and intracellular biochemical events in exercising muscle have not been well defined. Therefore 14 normal subjects performed incremental plantar flexion to exhaustion on 2 study days, the first for determination of LT and VT and the second for continuous 31P nuclear magnetic resonance spectroscopy of calf muscle. Exercising calf muscle pH fell precipitously at 66.4 +/- 3.4% (SE) of the maximum O2 uptake (VO2max) and was termed the intramuscular pH threshold. This did not occur at a significantly different metabolic rate from that at the LT (78.6 +/- 5.9% VO2max) or at the VT (75.0 +/- 4.1% VO2max, P = 0.15 by analysis of variance). Four subjects showed an intramuscular pH threshold and VT without a perceptible rise in forearm venous blood lactate. It is concluded that traditional markers of the "anaerobic threshold," the LT and VT, occur as intramuscular pH becomes acid for a group of normal subjects undergoing incremental exercise to exhaustion. It is speculated that neuronal pathways linking intramuscular biochemical events to the ventilatory control center may explain the intact VT in those subjects without an "intermediary" LT.

Dietary effects on exercising muscle metabolism and performance by 31P-MRS.

To determine how diet modulates short-term exercise capacity, skeletal muscle pH and bioenergetic state were examined by 31P-magnetic resonance spectroscopy in nine healthy volunteers. Subjects performed incremental quadriceps exercise to exhaustion after 5 days of high-carbohydrate (HCHO) or high-fat (HFAT) diet randomly assigned in crossover fashion and separated by a 2.5-day period of ad libitum mixed diet. Simultaneous measurements were made of pulmonary gas exchange, minute ventilation, and quadriceps muscle pH and phosphorylation potential. At rest and peak exercise, respiratory exchange ratio and minute ventilation were higher after HCHO than after HFAT (P < 0.05), reflecting greater CHO utilization. Peak O2 consumption (VO2) was not increased after HCHO (P > 0.05), but exercise duration was (339 +/- 34 s for HCHO vs. 308 +/- 25 s for HFAT; P < 0.05). HCHO was associated with a blunted early fall of phosphocreatine (PCr)/Pi vs. VO2 (-4.1 +/- 0.7 x 10(-2) min/ml for HCHO vs. -5.6 +/- 1.2 x 10(-2) min/ml for HFAT; P < 0.05). On both study days, the slope of PCr/Pi vs. VO2, before and after the PCr threshold, was correlated with exercise time. The results suggest that a diet rich in CHO improves exercise efficiency through beneficial effects on intracellular phosphorylation potential.

Skeletal muscle ECF pH error signal for exercise ventilatory control.

An autonomic reflex linking exercising skeletal muscle metabolism to central ventilatory control is thought to be mediated by neural afferents having free endings that terminate in the interstitial fluid of muscle. To determine whether changes in muscle extracellular fluid pH (pHe) can provide an error signal for exercise ventilatory control, pHe was measured during electrically induced contraction by 31P-magnetic resonance spectroscopy and the chemical shift of a phosphorylated, pH-sensitive marker that distributes to the extracellular fluid (phenylphosphonic acid). Seven lightly anesthetized rats underwent unilateral continuous 5-Hz sciatic nerve stimulation in an 8.45-T nuclear magnetic resonance magnet, which resulted in a mixed lactic acidosis and respiratory alkalosis, with no net change in arterial pH. Skeletal muscle intracellular pH fell from 7.30 +/- 0.03 units at rest to 6.72 +/- 0.05 units at 2.4 min of stimulation and then rose to 7.05 +/- 0.01 units (P < 0.05), despite ongoing stimulation and muscle contraction. Despite arterial hypocapnia, pHe showed an immediate drop from its resting baseline of 7.40 +/- 0.01 to 7.16 +/- 0.04 units (P < 0.05) and remained acidic throughout the stimulation protocol. During the on- and off-transients for 5-Hz stimulation, changes in the pH gradient between intracellular and extracellular compartments suggested time-dependent recruitment of sarcolemmal ion-transport mechanisms. pHe of exercising skeletal muscle meets temporal and qualitative criteria necessary for a ventilatory metaboreflex mediator in a setting where arterial pH does not.

Skeletal muscle chemoreflex and pHi in exercise ventilatory control.

To determine whether skeletal muscle hydrogen ion mediates ventilatory drive in humans during exercise, 12 healthy subjects performed three bouts of isotonic submaximal quadriceps exercise on each of 2 days in a 1.5-T magnet for 31P-magnetic resonance spectroscopy (31P-MRS). Bilateral lower extremity positive pressure cuffs were inflated to 45 Torr during exercise (BLPPex) or recovery (BLPPrec) in a randomized order to accentuate a muscle chemoreflex. Simultaneous measurements were made of breath-by-breath expired gases and minute ventilation, arterialized venous blood, and by 31P-MRS of the vastus medialis, acquired from the average of 12 radio-frequency pulses at a repetition time of 2.5 s. With BLPPex, end-exercise minute ventilation was higher (53.3 +/- 3.8 vs. 37.3 +/- 2.2 l/min; P < 0.0001), arterialized PCO2 lower (33 +/- 1 vs. 36 +/- 1 Torr; P = 0.0009), and quadriceps intracellular pH (pHi) more acid (6.44 +/- 0.07 vs. 6.62 +/- 0.07; P = 0.004), compared with BLPPrec. Blood lactate was modestly increased with BLPPex but without a change in arterialized pH. For each subject, pHi was linearly related to minute ventilation during exercise but not to arterialized pH. These data suggest that skeletal muscle hydrogen ion contributes to the exercise ventilatory response.

Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents.

BACKGROUND: Obesity is associated with poor fitness and adverse metabolic consequences in children. OBJECTIVE: To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. DESIGN AND SUBJECTS: Randomized controlled trial, 21 obese (body mass index ≥ 95% percentile) subjects, ages 10 to 17 years. METHODS: Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). MEASUREMENTS: Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. RESULTS: Subjects were 13.0 ± 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). CONCLUSIONS: Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.

Preoperative cardiopulmonary exercise testing: determining the limit to exercise and predicting outcome after thoracotomy.

Over the past 15 years evaluation of the patient with exertional complaints has changed from a simple qualitative estimate of overall fitness to a detailed assessment of cardiovascular and pulmonary pathophysiology. By quantifying exercise impairment and identifying the physiological limit to exercise, CPEx can help direct and evaluate the efficacy of medical and surgical interventions. Although no clear consensus has emerged, an objective determination of the etiology of exercise intolerance may also help identify the patient at increased risk for postthoracotomy complications.

Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity.

Breathlessness arises from increased medullary respiratory center activity projecting to the forebrain (respiratory corollary discharge hypothesis). Subjects with congenital central hypoventilation syndrome (CCHS) lack the normal hyperpnea and breathlessness during hypercapnia. The corollary discharge hypothesis predicts that if CCHS subjects have normal hyperpnea during exercise, they will experience normal breathlessness during exercise. To test this, we studied four CCHS subjects and six matched controls during an exhausting constant-load cycling test requiring substantial anaerobiosis. CCHS subjects rated significantly less breathlessness at the end of the test than controls, but ventilation (index of respiratory corollary discharge) was also somewhat lower in CCHS (not significant). In both groups, breathlessness increased disproportionately more than ventilation towards the end of exercise. These data failed to disprove the corollary discharge hypothesis of breathlessness, but do suggest that the relationship between ventilation and breathlessness is non-linear and/or that projections of chemoreceptor afferents to the forebrain (presumed lacking in CCHS) is one source of breathlessness in normals.

Ventilatory and cardiovascular responses to inspired He-O2 during exercise in chronic obstructive pulmonary disease.

Blunted maximum cardiac output and systemic O2 extraction could constitute primary limits to exercise in severe chronic obstructive pulmonary disease (COPD) or they could simply reflect cessation of exercise because of abnormal pulmonary mechanics. To determine which is the case, eight consecutive patients with severe COPD (FEV1 = 0. 56 +/- 0.04 L, mean +/- SEM), five of whom had alpha1-antiprotease deficiency, performed two incremental cycling tests while breathing N2-O2 or He-O2. Expired gases and V E were measured, and radial and pulmonary arterial blood was simultaneously sampled each minute. Peak exercise V E was higher with He-O2 than with N2-O2 (25.5 +/- 2. 2 versus 19.3 +/- 1.5 L/min, p = 0.002) and PaCO2 was lower (42 +/- 2 versus 46 +/- 2 mm Hg, p = 0.0003). V O2max improved only modestly (594 +/- 75 versus 514 +/- 54 ml/min, p = 0.04), and was accompanied by an increase in peak exercise CaO2 (18.7 +/- 0.9 versus 17.6 +/- 0. 9 ml/dl, p = 0.02). Peak Fick cardiac output was decreased (39 +/- 3% pred) and CvO2 was elevated (130 +/- 10% pred), and neither improved with He-O2 (p > 0.05 for each). Abnormal peak exercise cardiac output and systemic O2 extraction in severe COPD cannot be fully accounted for by limiting pulmonary mechanics and may contribute to exercise intolerance.

Systemic oxygen extraction during incremental exercise in patients with severe chronic obstructive pulmonary disease.

To determine if decreased systemic oxygen (O2) extraction contributes to the exercise limit in severe chronic obstructive pulmonary disease (COPD), 40 consecutive incremental cycle ergometer exercise tests performed by such patients, from which a "log-log" lactate threshold (LT) was identified, were compared to those of 8 patients with left ventricular failure (LVF) and 10 normal controls. Pulmonary gas exchange and minute ventilation were measured continuously and arterial blood gas tensions, pH, and lactate concentrations were sampled each minute. Cardiac output (Qc) was measured by first-pass radionuclide ventriculography. The systemic O2 extraction ratio (O2ER) was calculated as arterial - mixed venous O2 content difference (CaO2 - CvO2)/CaO2. Peak exercise O2 uptake (VO2peak) was markedly reduced in both COPD and LVF [41 (3) and 42 (3)% predicted, respectively], compared to controls [89 (2)% predicted, P < 0.0001 for each]. Similarly, the LT occurred at a low percentage of predicted maximal oxygen consumption in both COPD and LVF [25 (2) and 27 (3)%] compared to normals [46 (3)%, P < 0.0001 for each]. The systemic O2ER at peak exercise was severely reduced in COPD [0.36 (0.02)] compared to the other groups [P < 0.0001 for each], for whom it was nearly identical [0.58 (0.03) vs 0.63 (0.04), LVF vs control, P > 0.05]. In the COPD group, an early LT correlated with reduced systemic O2ER at peak exercise (r = 0.64, P < 0.0001), but not with any index of systemic O2 delivery. These data suggest that lactic acidemia during exercise in patients with severe COPD is better related to abnormal systemic O2 extraction than to its delivery and contributes to the exercise limit.

Abnormal skeletal muscle oxidative capacity after lung transplantation by 31P-MRS.

Although lung transplantation improves exercise capacity by removal of a ventilatory limitation, recipients' postoperative maximum oxygen uptake (VO2max) remains markedly abnormal. To determine if abnormal skeletal muscle oxidative capacity contributes to this impaired aerobic capacity, nine lung transplant recipients and eight healthy volunteers performed incremental quadriceps exercise to exhaustion with simultaneous measurements of pulmonary gas exchange, minute ventilation, blood lactate, and quadriceps muscle pH and phosphorylation potential by 31P-magnetic resonance spectroscopy (31P-MRS). Five to 38 mo after lung transplantation, peak VO2 was decreased compared with that of normal control subjects (6.7 +/- 0.4 versus 12.3 +/- 1.0 ml/min/kg, p < 0.001), even after accounting for differences in age and lean body weight. Neither ventilation, arterial O2 saturation nor mild anemia could account for the decrease in aerobic capacity. Quadriceps muscle intracellular pH (pH(i)) was more acidic at rest (7.07 +/- 0.01 versus 7.12 +/- 0.01 units, p < 0.05) and fell during exercise from baseline values at a lower metabolic rate (282 +/- 21 versus 577 +/- 52 ml/min, p < 0.001). Regressions for pH(i) versus VO2, phosphocreatine/inorganic phosphate ratio (PCr/Pi) versus VO2, and blood lactate versus pH(i) were not different. Among transplant recipients, the metabolic rate at which pH(i) fell correlated closely with VO2max (r = 0.87, p < 0.01). The persistent decrease in VO2max after lung transplantation may be related to abnormalities of skeletal muscle oxidative capacity.

Expiratory flow pattern following single-lung transplantation in emphysema.

In single lung transplantation (SLT) recipients, a "plateau" of the maximal expiratory flow volume curve (MEFV) and a "biphasic" MEFV have been reported to reflect anastomosis pathology. A plateau is defined as constant airflow over a large expired volume early in the MEFV. A biphasic MEFV has an initial period of high flow followed by a terminal low flow phase. Models of expiratory flow limitation by wave speed, however, predict that the MEFV of SLT recipients with emphysema should both be biphasic and demonstrate a plateau even without anastomosis pathology. Review of the spirometries and clinical courses of our first ten patients receiving SLT for emphysema demonstrated a biphasic MEFV, and a plateau of the MEFV in all patients. No patient showed evidence of anastomosis pathology. Independent lung spirometries, generated by a novel technique, revealed that the initial high flow phase of the MEFV came from the transplanted lung and the terminal low flow from the native emphysematous lung. The location of the flow limitation was demonstrated to be immediately downstream from the anastomosis. Therefore, the MEFV of SLT recipients with emphysema routinely demonstrates both a biphasic pattern and a plateau, neither of which necessarily reflect anastomosis pathology.