Intravenous L-carnitine increases plasma carnitine, reduces fatigue, and may preserve exercise capacity in hemodialysis patients.

Exercise capacity in patients with end-stage renal disease (ESRD) remains impaired despite correction of anemia. Carnitine insufficiency may contribute to impaired exercise and functional capacities in patients with ESRD. Two randomized placebo-controlled trials were conducted to test whether intravenous L-carnitine improves exercise capacity (assessed by maximal rate of oxygen consumption [VO(2max)]) and quality of life (measured by the Kidney Disease Questionnaire [KDQ]) in patients with ESRD. In study A, patients were administered L-carnitine, 20 mg/kg (n = 28), or placebo (n = 28) intravenously at the conclusion of each thrice-weekly dialysis session for 24 weeks. In study B, a dose-ranging study, patients were administered intravenous L-carnitine, 10 mg/kg (n = 32), 20 mg/kg (n = 30), or 40 mg/kg (n = 32), or placebo (n = 33) as in study A. The prospective primary statistical analysis evaluated changes in VO(2max) in each study and specified that changes in the KDQ were assessed only in the combined populations. L-Carnitine supplementation increased plasma carnitine concentrations, but did not affect VO(2max) in either study. Because change in VO(2max) showed significant heterogeneity, a secondary analysis using a mixture of linear models approach on the combined study populations was performed. L-Carnitine therapy (combined all doses) was associated with a statistically significant smaller deterioration in VO(2max) (-0.88 +/- 0.26 versus -0.05 +/- 0.19 mL/kg/min, placebo versus L-carnitine, respectively; P = 0.009). L-Carnitine significantly improved the fatigue domain of the KDQ after 12 (P = 0.01) and 24 weeks (P = 0.03) of treatment compared with placebo using the primary analysis but did not significantly affect the total score (P = 0.10) or other domains of the instrument (P > 0.11). Carnitine was well tolerated, and no drug-related adverse effects were identified. Intravenous L-carnitine treatment increased plasma carnitine concentrations, improved patient-assessed fatigue, and may prevent the decline in peak exercise capacity in hemodialysis patients. VO(2max) in the primary analysis and other assessed end points were unaffected by carnitine therapy.

Exercise-induced changes in circulating growth factors with cyclic variation in plasma estradiol in women.

The effect of 10 min of high-intensity cycling exercise on circulating growth hormone (GH), insulin-like growth factors I and II (IGF-I and -II), and insulin-like growth factor binding protein 3 (IGF BP-3) was studied in nine eumenorrheic women (age 19-48 yr) at two different phases of the menstrual cycle. Tests were performed on separate mornings corresponding to the follicular phase and to the periovulatory phase of the menstrual cycle, during which plasma levels of endogenous estradiol (E2) were relatively low (272 +/- 59 pmol/l) and high (1,112 +/- 407 pmol/l), respectively. GH increased significantly in response to exercise under both E2 conditions. Plasma GH before exercise (2.73 +/- 2.48 vs. 1.71 +/- 2.09 micrograms/l) and total GH over 10 min of exercise and 1-h recovery (324 +/- 199 vs. 197 +/- 163 ng) were both significantly greater for periovulatory phase than for follicular phase studies. IGF-I, but not IGF-II, increased acutely after exercise. IGF BP-3, assayed by radioimmunoassay, was not significantly different at preexercise, and exercise, or at 30-min recovery time points and was not different between the two study days. When assayed by Western blot, however, there was a significant increase in IGF BP-3 30 min after exercise for the periovulatory study. These findings indicate that the modulation of GH secretion associated with menstrual cycle variations in circulating E2 affects GH measured after exercise, at least in part, by an increase in baseline levels. The acute increase in IGF-I induced by exercise appears to be independent of the GH response and is not affected by menstrual cycle timing.

Inaccuracy of noninvasive estimates of VD/VT in clinical exercise testing.

To evaluate the accuracy of noninvasive estimates of VD/VT in clinical exercise testing, we compared measurements of standard VD/VT with estimates based either on end-tidal CO2 (VD/VTET) or a published estimate of arterial PCO2 (VD/VTest) at peak exercise in 68 patients. Using regression analysis, we identified highly significant differences (p < 0.001) between each method and VD/VTstand across a broad range of observed VD/VT. Assuming a normal exercise VD/VT < or = 0.30, estimate methods were specific but were insensitive (50 percent for VD/VTET and 57 percent for VD/VTest) for identifying patients with abnormal gas exchange during exercise. Separate analysis of subgroups based on resting pulmonary function did not identify any group for which either method was acceptable. Our analysis showed that errors in estimating PaCO2, which are amplified by the Bohr equation when calculating VD/VT, are responsible for the inaccuracies of each noninvasive method. We conclude that noninvasive estimates of PaCO2 cannot replace measured arterial PCO2 for calculation of VD/VT during exercise.

Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heart failure.

STUDY DESIGN AND OBJECTIVES: Attainment of a steady state for oxygen uptake (VO2) during constant work rate exercise has been reported to take longer for patients with chronic heart failure (CHF) compared with normal. The steady state is also delayed in normal subjects during high-intensity exercise compared with moderate exercise, however, and the delay correlates with the degree of associated lactic acidosis. To determine whether prolonged kinetics of VO2 are attributable solely to the reduction of exercise capacity in CHF, VO2 kinetics were compared for patients with CHF and normal subjects, both for exercise of matched absolute work rate and for matched relative work intensity. SUBJECTS: Eighteen men with CHF and 10 normal men. METHODS AND RESULTS: Subjects performed 6 min of constant work rate cycle ergometry with breath-by-breath measurement of VO2. Patients were studied using 25 W, and a work rate midway between the lactic acidosis threshold and maximal capacity (50 percent delta). Normal subjects were tested similarly, and also at a work rate matched to the patients' average 50 percent delta work rate. The VO2 kinetics were characterized by the mean response time (MRT) to attain the 6 min VO2 value. Rates of recovery of VO2 were analyzed for 2 min following exercise. For the same absolute work rate, VO2 MRTs were significantly longer for patients than controls (25 W, 67 +/- 26 vs 37 +/- 25 s; approximately 60 W, 87 +/- 20 vs 54 +/- 27 s), but there was no significant difference in VO2 MRT between the two groups at a matched intensity of 50 percent delta (87 +/- 20 vs 81 +/- 18 s). However, the decrease in VO2 during 2 min of recovery was slower for the patients on all comparisons, even for matched exercise intensity. CONCLUSION: The VO2 dynamics for submaximal exercise are slowed in CHF. The slower dynamics are not entirely accounted for by the relatively higher intensity of a given work rate, since delayed recovery is evident even at a matched relative work intensity. Exercise intolerance in CHF is characterized not only by decreased maximal exercise capacity, but also by slower adaptations to and from submaximal levels of exercise.

A method for estimating bicarbonate buffering of lactic acid during constant work rate exercise.

A method to estimate the CO2 derived from buffering lactic acid by HCO3- during constant work rate exercise is described. It utilizes the simultaneous continuous measurement of O2 uptake (VO2) and CO2 output (VCO2), and the muscle respiratory quotient (RQm). The CO2 generated from aerobic metabolism of the contracting skeletal muscles was estimated from the product of the exercise-induced increase in VO2 and RQm calculated from gas exchange. By starting exercise from unloaded cycling, the increase in CO2 stores, not accompanied by a simultaneous decrease in O2 stores, was minimized. The total CO2 and aerobic CO2 outputs and, by difference, the millimoles (mmol) of lactate buffered by HCO3- (corrected for hyperventilation) were estimated. To test this method, ten normal subjects performed cycling exercise at each of two work rates for 6 min, one below the lactic acidosis threshold (LAT) (50 W for all subjects), and the other above the LAT, midway between LAT and peak VO2 [mean (SD), 144 (48) W]. Hyperventilation had a small effect on the calculation of mmol lactate buffered by HCO3- [6.5 (2.3)% at 6 min in four subjects who hyperventilated]. The mmol of buffer CO2 at 6 min of exercise was highly correlated (r = 0.925, P < 0.001) with the increase in venous blood lactate sampled 2 min into recovery (coefficient of variation = +/- 0.9 mmol.l-1). The reproducibility between tests done on different days was good. We conclude that the rate of release of CO2 from HCO3- can be estimated from the continuous analysis of simultaneously measured VCO2, VO2, and an estimate of muscle substrate.

Oxygen uptake during exercise in patients with primary fibromyalgia syndrome.

OBJECTIVE: Muscle ischemia has been postulated as a causative factor in pain and disability in patients with primary fibromyalgia syndrome (PFS) and previous studies have demonstrated that patients with PFS have reduced maximum oxygen uptake (VO2). Our objective was to examine the level and pattern of VO2 in response to graded exercise and defined levels of constant work rate exercise in patients with PFS. METHODS: Unmedicated patients fulfilling modified Yunus' criteria for the diagnosis of PFS and healthy control subjects performed upright cycle ergometry exercise with measurements of respiratory gas exchange and grading of pain using visual analog scores. RESULTS: Patients, but not controls, had significantly higher levels of pain after graded exercise than before exercise. Although peak VO2 did not differ between the 2 groups, effort dependent variables of exercise function were more variable in the patients than in control subjects. The onset of muscle anaerobiosis as reflected in respiratory gas exchange, the relationship between VO2 and work rate throughout the range of exercise work rates, and the mean response time for the increase in VO2 to the exercise level in response to a constant work rate of exercise were not different for patients compared to controls. CONCLUSION: Despite the subjective reports of pain, our studies demonstrate no abnormality in the overall rate and pattern of utilization of oxygen during muscular exercise in patients with PFS.

O2 uptake kinetics in response to exercise. A measure of tissue anaerobiosis in heart failure.

Oxygen uptake (VO2) reflects the rate of aerobic regeneration of high-energy phosphate compounds (primarily adenosine triphosphate [ATP]). Since lactate increase is thought to result from an inadequate rate of aerobic ATP regeneration, it might be expected that lactate increase would be associated with a delayed attainment of steady state for VO2 in response to constant load exercise. Similarly if mitochondrial ATP regeneration during exercise is inadequately supported by O2 transport mechanisms, adenosine diphosphate (ADP) and purine nucleotide by-products, such as hypoxanthine, should increase. This study investigated the relationship between VO2 kinetics during exercise and accompanying changes in blood lactate and hypoxanthine values in heart failure patients, as a model of compromised O2 transport. Twenty-five patients with chronic heart failure performed cycle ergometry for 6 min at 25 W and at a work rate midway (50 percent delta) between their lactic acidosis threshold (LAT) and peak VO2. Ventilation and gas exchange were measured breath by breath, and venous lactate, hypoxanthine, norepinephrine, and epinephrine were determined at rest and 2 min after each test. The slow component of VO2 kinetics was quantified as the rise in VO2 from the third to the sixth minute of exercise (delta VO2 [6-3]). Ten age- and size-matched normal subjects served as control subjects. delta VO2 (6-3) was correlated with the increase in lactate (r = 0.71, p < 0.001), hypoxanthine (r = 0.61, p < 0.001), and norepinephrine (r = 0.41, p < 0.01) but not epinephrine in response to exercise in the heart failure patients. The delta VO2 (6-3) and delta lactate were both greater in the patients than in the control subjects at similar absolute work rates (54 +/- 20 and 60 W, respectively). However, the slope of the relationship between delta La and delta VO2 (6-3) for the patient and normal groups was indistinguishable. The lactate increase was correlated with hypoxanthine increase (r = 0.66, p < 0.001), but not norepinephrine or epinephrine. In summary, VO2 kinetics in response to exercise reflects delayed attainment of the steady state in heart failure patients, which is correlated with increases in lactate and hypoxanthine, markers of increased anaerobic metabolism.

Abnormal oxygen uptake responses to exercise in patients with mild pulmonary sarcoidosis.

Exercise intolerance and exertional dyspnea are common complaints in patients with sarcoidosis. Although in many cases these complaints are attributable to restrictive or obstructive lung mechanics or inefficiency of pulmonary gas exchange, other processes also may contribute to impairment in exercise function and may not be readily detected or distinguished from problems of lung mechanics on the basis of symptoms or routine laboratory testing. To identify the frequency and etiology of impaired exercise capacity in sarcoidosis patients with mild lung disease, integrative cardiopulmonary exercise testing was performed in 23 patients. Breath-by-breath measurements were made of gas exchange, ventilation, and heart rate. In 9 of 20 evaluable patients, the oxygen uptake (VO2) at the anaerobic threshold was low, and/or the rate of increase of VO2 was abnormal relative to work rate or heart rate, suggesting a defect in cardiocirculatory function. Resting and exercise echocardiography revealed normal left ventricular ejection fractions and wall motion in all nine of these patients, but findings suggestive of right ventricular hypertrophy and/or right ventricular dysfunction were present in five. Abnormal responses of VO2 during exercise are common in patients with sarcoidosis and may be due to subclinical impairment of right-sided cardiac function.

Oxygen uptake kinetics in response to exercise in patients with pulmonary vascular disease.

The increase in muscular oxygen consumption that accompanies the onset of exercise is accomplished by increases in blood flow and arterial-venous O2 difference. These processes are reflected in a similar increase in pulmonary oxygen uptake (VO2), which rises in a dynamic pattern having two components and with an overall time course that may be characterized as an exponential. Because the immediate determinants of VO2 are the blood flow and respiratory gas composition in the pulmonary circulation, it was hypothesized that VO2 kinetics at exercise onset would be abnormal in patients with pulmonary vascular disease. To test this, 10 patients with pulmonary hypertension and two with pulmonary hypoperfusion caused by congenital heart disease performed constant work rate (15 +/- 16 SD watt) exercise on an upright cycle ergometer, with breath-by-breath measurement of respiratory gas exchange for determination of VO2 kinetics. The phase I increase in VO2, comprising approximately the first 30 s of exercise, was small (18 +/- 15 SD % above resting VO2). The time constant for the phase II increase in VO2 averaged 74 +/- 16 s, and the mean response time for attainment of the exercise steady state (75 +/- 17 SD s) was prolonged compared with normal values for the same work rate exercise (approximately 100 to 130% increase in phase I, and mean response time less than 25 s). In two patients who underwent surgical procedures substantially improving pulmonary hemodynamics, VO2 kinetics also improved. These findings are consistent with the concept that VO2 kinetics may be limited by pulmonary hemodynamics in the presence of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that circulatory oscillations accompany ventilatory oscillations during exercise in patients with heart failure.

Periodic breathing (PB) during exercise in patients with congestive heart failure (CHF) is associated with prominent oscillations (OSC) of O2 uptake (VO2). We hypothesized that the VO2 OSC represent OSC in true O2 exchange, resulting from concomitant cardiac output fluctuations and are not merely due to OSC of lung O2 stores. We compared the amplitude of the OSC of VO2, ventilation (VE), and end-expiratory lung volume (EELV) in 17 patients with CHF and PB and in seven healthy control subjects who volitionally simulated PB. Subjects underwent an incremental and/or a constant work-rate exercise test. VE and VO2 were measured breath by breath. EELV change was estimated by summing the difference between inspiratory and expiratory tidal volumes for each breath. The amplitude of the OSC, delta, is expressed as the ratio of the difference between the peak and nadir of the oscillating variable divided by its mean [delta = (peak - nadir)/mean]. In CHF, during incremental testing, the amplitude of the VE OSC was smaller than that of the VO2 OSC (delta VE = 49 +/- 15% [SD], delta VO2 = 63 +/- 25%, p less than 0.01). In contrast, during volitional PB in the control subjects, VE OSC were larger than VO2 OSC (delta VE = 48 +/- 12%, delta VO2 = 25 +/- 11%, p less than 0.01). This suggests that changing VE itself cannot account for the marked VO2 OSC seen in CHF. In the patients, EELV showed no systematic OSC, did not correlate with delta VO2, and was not significantly different from zero.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyanotic congenital heart disease: dynamics of oxygen uptake and ventilation during exercise.

The presence of intracardiac shunts dissociates the right and left circulations, making dynamic coupling of cellular and pulmonary gas exchange inefficient or impossible. As a result, patients may have profound changes in arterial blood gases and prolongation of adaptation and recovery even with low levels of physical activity. Because the exercise-induced symptoms in patients with cyanotic congenital heart disease have bases apart from heart failure, assignment of a New York Heart Association functional class may be misleading if not erroneous. Dr. Jane Somerville recommends the "Ability Index" shown in Table 1.

O2 uptake in hyperthyroidism during constant work rate and incremental exercise.

To investigate the effect of hyperthyroidism on the pattern and time course of O2 uptake (VO2) following the transition from rest to exercise, six patients and six healthy subjects performed cycle exercise at an average work rate (WR) of 18 and 20 W respectively. Cardiorespiratory variables were measured breath-by-breath. The patients also performed a progressively increasing WR test (1-min increments) to the limit of tolerance. Two patients repeated the studies when euthyroid. Resting and exercise steady-state (SS) VO2 (ml.kg-1.min-1) were higher in the patients than control (5.8, SD 0.9 vs 4.0, SD 0.3 and 12.1, SD 1.5 vs 10.2, SD 1.0 respectively). The increase in VO2 during the first 20 s exercise (phase I) was lower in the patients (mean 89 ml.min-1, SD 30) compared to the control (265 ml.min-1, SD 90), while the difference in half time of the subsequent (phase II) increase to the SS VO2 (patient 26 s, SD 8; controls 17 s, SD 8) were not significant (P = 0.06). The O2 cost per WR increment (delta VO2/delta WR) in ml.min-1.w-1, measured during the incremental period (mean 10.9; range 8.3-12.2), was always within two standard deviations of the normal value (10.3, SD 1). In the two patients who repeated the tests, both the increment of VO2 from rest to SS during constant WR exercise and the delta VO2/delta WRs during the progressive exercise were higher in the hyperthyroid state than during the euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)

Early dynamics of O2 uptake and heart rate as affected by exercise work rate.

The kinetics of O2 uptake (Vo2) and heart rate (HR) in response to constant work rate exercise have been characterized as two phases, an immediate response as the result largely of abrupt hemodynamic changes and a slower response as the result of increases in both blood flow and arteriovenous O2 difference (avDo2). There are few data reported concerning Vo2 and HR during phase I or the relationship between their kinetics and work rate or intensity. Because phase I responses depend on abrupt cardiovascular adjustments, it was hypothesized that phase I increases in Vo2 and HR would be greater the more "fit" the subject and would be relatively independent of work rate. To test this, 10 normal subjects exercised from rest to each of five work rates ranging from unloaded cycling to 150 W. The phase I increases of Vo2, HR, and Vo2/HR had small but significant correlations with work rate but not with fitness. At very low work rates (unloaded cycling and 25 W), Vo2 and HR often exceeded their steady-state levels in phase I. There was therefore no phase II increase for Vo2 or HR at these work rates, the entire O2 requirement having been met by phase I circulatory adjustments. For all other work rates, mean response times for Vo2 and HR were related to fitness and were slower than those for Vo2/HR, suggesting that avDo2 reached a steady state before cardiac output did.

Control of ventilation during exercise in patients with central venous-to-systemic arterial shunts.

The diversion of systemic venous blood into the arterial circulation in patients with intracardiac right-to-left shunts represents a pathophysiological condition in which there are alterations in some of the potential stimuli for the exercise hyperpnea. We therefore studied 18 adult patients with congenital (16) or noncongenital (2) right-to-left shunts and a group of normal control subjects during constant work rate and progressive work rate exercise to assess the effects of these alterations on the dynamics of exercise ventilation and gas exchange. Minute ventilation (VE) was significantly higher in the patients than in the controls, both at rest (10.7 +/- 2.4 vs. 7.5 +/- 1.2 l/min, respectively) and during constant-load exercise (24.9 +/- 4.8 vs. 12.7 +/- 2.61 l/min, respectively). When beginning constant work rate exercise from rest, the ventilatory response of the patients followed a pattern that was distinct from that of the normal subjects. At the onset of exercise, the patients' end-tidal PCO2 decreased, end-tidal PO2 increased, and gas exchange ratio increased, indicating that pulmonary blood was hyperventilated relative to the resting state. However, arterial blood gases, in six patients in which they were measured, revealed that despite the large VE response to exercise, arterial pH and PCO2 were not significantly different from resting values when sampled during the first 2 min of moderate-intensity exercise. Arterial PCO2 changed by an average of only 1.4 Torr after 4.5-6 min of exercise. Thus the exercise-induced alveolar and pulmonary capillary hypocapnia was of an appropriate degree to compensate for the shunting of CO2-rich venous blood into the systemic arterial circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessing cardiac function by gas exchange.

Exercise stresses the primary function of the cardiovascular system, which is the supply of O2 and removal of CO2 from the cells of the body. Even ordinary walking requires an increase in O2 consumption and CO2 production by the exercising muscles of 20 times the resting level. While pulmonary dysfunction may affect arterial blood gas tensions, the dynamics of O2 uptake and CO2 output by the lungs depend on the circulatory responses to exercise. Thus, measurement of the dynamics of O2 uptake in response to exercise has been shown to reflect cardiovascular function. Inability of the circulatory responses to meet an increased O2 requirement may be reflected in abnormalities in O2 uptake dynamics, and an early increase in CO2 output relative to O2 uptake consequent to bicarbonate buffering of lactic acid. Application of currently available technology for the continuous measurement and analysis of pulmonary gas exchange can afford the practicing or investigative cardiologist with a noninvasive and inexpensive means for assessing cardiovascular function.

Dynamics of oxygen uptake during exercise in adults with cyanotic congenital heart disease.

The dynamic increase in oxygen uptake (VO2) at the start of exercise reflects the circulatory adjustments to metabolic changes induced by the exercise. Because VO2 measured at the lungs is the product of pulmonary blood flow and arteriovenous oxygen difference, pathologic conditions affecting the capacity of these factors to change would be expected to alter VO2 kinetics. To determine whether measurement of VO2 kinetics can detect conditions in which the pulmonary blood flow response to exercise is abnormal, VO2 was measured, breath-by-breath, during the transition from rest to exercise in 13 adults with cyanotic congenital heart disease (central venoarterial shunting) and in nine normal subjects. The increase in VO2 above baseline during the first 20 sec of exercise (phase I), reflecting the immediate increase in pulmonary blood flow, was diminished in the patients compared with that in normal subjects (14.8 +/- 10.9 vs. 49.8 +/- 19.2 ml of oxygen) (p less than .001). The patients' phase I responses correlated with their reported physical activity tolerance (p less than .01). In addition, the second phase of the VO2 response kinetics was prolonged in patients compared with normal subjects (half-time = 63 +/- 13 vs 15 +/- 13 sec) (p less than .001). We conclude that striking disturbances in VO2 kinetics occur in patients with cyanotic congenital heart disease and that these measurements provide a useful noninvasive means of evaluating the degree to which the increase in pulmonary blood flow is constrained in response to exercise.