Biomedical subjects
B J Whipp
Publications and source records attributed to B J Whipp.
Effect of dopamine on ventilatory response to incremental exercise in man.
We investigated whether dopamine, an inhibitory neuromodulator in the carotid body, would alter the ventilatory response typically associated with metabolic (lactic) acidosis during exercise. Six subjects performed incremental cycle ergometer exercise to exhaustion during infusions of dopamine (3 micrograms.kg-1.min-1) or saline. Ventilation and pulmonary gas exchange were computed breath-by-breath; arterialized venous blood was collected every 90 sec for measurement of lactate, potassium and blood gases. The resting ventilatory response to an isocapnic step decrease in end-tidal PO2 to 50 Torr was used as an index of carotid body drive. Dopamine diminished the hypoxic ventilatory response but had no effect on the ventilatory response during exercise. Peak lactate, potassium, and ventilation were unaffected by dopamine, and the degree of respiratory compensation for the metabolic acidosis was the same as in control experiments. Therefore, either the carotid bodies respond differently to hypoxia than to acute metabolic acidosis and/or hyperkalemia during heavy exercise, or the carotid bodies are not the sole mediators of hyperventilation above the lactate threshold.
Physiologic changes following bilateral carotid-body resection in patients with chronic obstructive pulmonary disease.
In an attempt to establish the characteristic pattern of change in (1) indices of pulmonary function, (2) arterial blood gas, and (3) arterial acid-base status which result from bilateral carotid body resection (BCBR), we analyzed the results of 146 consecutive patients with severe chronic obstructive pulmonary disease who had undergone BCBR at a single hospital site. In addition, we analyzed the results of incremental exercise testing in 21 similar patients, performed at a separate hospital. On average, TLC, FRC, and RV all decreased after surgery, whereas FEV1 increased. Although the data were highly variable, PaO2 decreased on average in proportion to the increase in PaCO2. The smaller group exercised to a higher metabolic rate after surgery; maximum ventilation, however, was unchanged. This led to a further fall in PaO2 and increase in PaCO2. We conclude that individual patient responses to BCBR are highly variable, but the procedure typically results in a small further hypoxemia and hypercapnia with no further impairment to pulmonary function.
Pulmonary gas exchange dynamics and the tolerance to muscular exercise: effects of fitness and training.
Oxygen uptake (VO2) kinetics are generally agreed to be first-order for moderate work rates with a time constant (tau VO2) that is thought to reflect the kinetics of intramuscular creatine phosphate depletion. However, when there is a concomitant lactic acidosis, tau VO2 is appreciably longer, reflecting an additional, delayed and slowed component that leads to VO2S greater than the aerobic equivalent of that work rate and which therefore invalidates current techniques for O2 deficit estimation. This "excess" VO2 is no more than approximately 250-300 ml/min at work rates for which [lactate] and [H+]a can be stabilized. At higher work rates which demand sustained and progressive increases in [lactate] and [H+]a, however, VO2 also continues to increase progressively, yielding excess VO2S greater than 11/min at exhaustion. The trajectory of excess VO2 therefore is to the maximum VO2: the resulting exercise limitation becomes progressively more pronounced the higher the work rate, which accounts for the hyperbolic character of the power-duration curve. Factors which speed VO2 kinetics in this domain reduce the excess VO2 mechanism and lead to improved exercise performance. We have demonstrated that, in addition to appropriately-designed training regimens, induction of a metabolic acidosis prior to exercise speeds VO2 kinetics at high work rates, reducing the increase in both [lactate] and [H+]a and reducing the CO2 load to ventilation during the transient phase of the work. The optimum procedure for inducing these improved pulmonary gas-exchange kinetics, however, remains to be determined.
Asymmetries of oxygen uptake transients at the on- and offset of heavy exercise in humans.
1. At work rates which do not result in a sustained increase in blood lactate ([L-]), oxygen uptake (VO2) approaches the steady state with first-order kinetics. However, when [L-] is increased, at least two kinetic components are required to characterize the VO2 response dynamics. The purpose of the present investigation was to determine whether these more-complex kinetics are best represented as: (a) two components which operate throughout the exercise or (b) a delayed slow component which is consequent to the lactic acidaemia and which does not influence the early development of the O2 deficit. 2. Six healthy subjects underwent an incremental ramp test on a cycle ergometer, to the limit of tolerance, for determination of the maximum VO2 (micro VO2) and and estimation [symbol: see text] of the threshold for lactic acidaemia (theta L) non-invasively. Subjects then performed, on different days, two to four repetitions of square-wave exercise from a baseline of unloaded pedalling ('O' Watts (W)) to work rates (WR) less than theta L (90% theta L) and greater than theta L (half-way between theta L and micro VO2). Ventilatory and pulmonary gas exchange variables were determined breath-by-breath. For each subject, the VO2 transitions were averaged prior to fitting a least-squares algorithm to the on- and off-transient responses. 3. The less than theta L test resulted in a mono-exponential VO2 response, with a time constant of 31.3 and 31.5 s for the on- and off-transients, respectively. 4. The VO2 responses to the greater than theta L test were fitted to three competing models: (a) a single exponential for the entire period; (b) a double exponential for the entire period; and (c) an initial single exponential with a subsequent phase of delayed onset. Model (c) yielded a significantly lower residual mean-squares error than methods (a) and (b), with a time constant for the initial component of 40.2 s for the on-transient and 32.9 s for the off-transient and a subsequent phase of VO2 increase for the on-transient which averaged 230 ml min-1. The delta VO2/delta WR for the early kinetics of the greater than theta L test were not different from the less than theta L test (9.6 and 9.5 ml min-1 W-1, respectively). 5. These data suggest that the slow phase of the greater than theta L VO2 kinetics is a delayed-onset process. This being the case, the O2 deficit during heavy exercise, as conventionally estimated, would be overestimated.
Role of the carotid bodies in the respiratory compensation for the metabolic acidosis of exercise in humans.
1. In response to an acute exercise-induced metabolic acidosis, the fall of arterial pH is constrained by the magnitude of the compensatory hyperventilation. To determine the role of the carotid bodies in this regulatory process, subjects performed prolonged (24 min) square-wave cycle ergometry from a background of unloaded cycling at inspired oxygen fractions (FI,O2) of 0.12 O2 (high carotid body gain), 0.21 O2 (normal carotid body gain) and 0.80 O2 (low carotid body gain). The work rates were selected to provide the same exercise intensity, despite the different inspirates; i.e. resulting in a constant increase in arterial blood [lactate] (delta [L-] approximately 4 mequiv l-1. 2. Ventilatory and pulmonary gas exchange variables were computed breath-by-breath and arterial blood was sampled at intervals throughout the tests and analysed subsequently for [lactate], [pyruvate], arterial partial pressures of oxygen and carbon dioxide (PO2, PCO2), pH, [bicarbonate] and [potassium]. 3. Hypoxia markedly reduced, and hyperoxia magnified, the transient decrease in arterial pH following exercise onset. However, there was a slow acid-base compensatory component, even when carotid chemosensitivity was suppressed by hyperoxia. We therefore conclude that, in humans, carotid body chemosensitivity plays a dominant role in constraining variations of arterial pH in response to the acute metabolic acidosis of heavy exercise, but that secondary-presumably central chemosensory-mechanisms subserve a slower compensatory role.
Effects of chronic acid-base changes on the rebreathing hypercapnic ventilatory response in man.
The CO2 rebreathing method can be very useful to test the hypercapnic ventilatory response in patients, including those with chronic acid-base changes (e.g. chronic metabolic acidosis due to renal failure). The ventilatory response to hypercapnia (CO2-R) was measured in 4 normal men by the rebreathing method under control conditions (CaCO3: 0.1 g.kg-1.day-1) and with induced metabolic acidosis (NH4Cl: 0.3 g.kg-1.day-1) and alkalosis (NaHCO3: 0.7 g.kg-1.day-1). The slope of the CO2-R did not change as a result of the acid-base alterations, but was shifted to the left of normal by metabolic acidosis, and to the right by metabolic alkalosis. These results compare favorably with previous reports on the CO2-R as measured by the steady-state technique, and validate the rebreathing method as a reliable and useful technique for evaluating CO2-R in man with altered acid-base states.
The effects of training on the metabolic and respiratory profile of high-intensity cycle ergometer exercise.
The tolerable work duration (t) for high-intensity cycling is well described as a hyperbolic function of power (W): W = (W'.t-1) + Wa, where Wa is the upper limit for sustainable power (lying between maximum W and the threshold for sustained blood [lactate] increase, theta lac), and W' is a constant which defines the amount of work which can be performed greater than Wa. As training increases the tolerable duration of high-intensity cycling, we explored whether this reflected an alteration of Wa, W' or both. Before and after a 7-week regimen of intense interval cycle-training by healthy males, we estimated ( ) theta lac and determined maximum O2 uptake (mu VO2); Wa; W'; and the temporal profiles of pulmonary gas exchange, blood gas, acid-base and metabolic response to constant-load cycling at and above Wa. Although training increased theta lac (24%), mu VO2 (15%) and Wa (15%), W' was unaffected. For exercise at Wa, a steady state was attained for VO2, [lactate] and pH both pre- and post-training, despite blood [norepinephrine] and [epinephrine] ([NE], [E]) and rectal temperature continuing to rise. For exercise greater than Wa, there was a progressive increase in VO2 (resulting in mu VO2 at fatigue), [lactate], [NE], [E] and rectal temperature, and a progressive decrease for pH. We conclude that the increased endurance capacity for high-intensity exercise following training reflects an increased W asymptote of the W-t relationship with no effect on its curvature; consequently, there is no appreciable change in the amount of work which can be performed above Wa.(ABSTRACT TRUNCATED AT 250 WORDS)
Modulation of muscle and pulmonary O2 uptakes by circulatory dynamics during exercise.
The effect of cardiovascular adjustments on the coupling of cellular to pulmonary gas exchange during unsteady states of exercise remains controversial. Computer simulations were performed to assess these influences on O2 delivery and pulmonary O2 uptake (pVO2). Algorithms were developed representing muscle and "rest-of-body" compartments, connected in parallel by arterial and venous circulations to a pump-and-lungs compartment. Exercise-induced increases in VO2 and cardiac output went to the muscle compartment. Model parameters [e.g., time constants for blood flow and muscle O2 uptake (mVO2)] could be varied independently. Simulation results demonstrated that 1) the rise in pVO2 during exercise contains three phases; 2) the contribution of changes in venous O2 stores to pVO2 kinetics and the O2 deficit occur almost entirely in phase 1; 3) under a wide variety of manipulations, the kinetics of pVO2 in phase 2 were within a couple of seconds of that assigned to mVO2 (i.e., there is not an obligatory slowing of VO2 kinetics at the lungs relative to those at the muscles; 4) by use of available estimates of blood flow adjustment, O2 delivery would not limit mVO2 after exercise onset; and 5) blood flow could limit O2 delivery in recovery, if blood flow returned to base-line levels at rates similar to those during the on-transient phase.
Ventilatory control during exercise in calves with artificial hearts.
To determine the role of cardiac reflexes in mediating exercise hyperpnea, we investigated ventilatory responses to treadmill exercise in seven calves with artificial hearts and seven controls. In both groups, the ventilatory responses were adequate for the metabolic demands of the exercise; this resulted in regulation of arterial PCO2 and pH despite the absence of cardiac output increase in the implanted group. In this group, there was a small but significant reduction of arterial PO2 by 4 +/- 3 Torr and a rise of blood lactate by 1.1 +/- 1 mmol/l. When cardiac output was experimentally increased in the implanted calves to a level commensurate with that spontaneously occurring in the control calves, ventilation was not affected. However, experimental reductions of cardiac output led to an immediate augmentation of exercise hyperpnea by 4.56 +/- 4.3 l/min and a further significant lactate increase of 1.2 +/- 1.22 mmol/l that was associated with a significant decrease in the exercise O2 consumption (0.32 +/- 0.13 l/min). These observations indicate that neither cardiac nor hemodynamic effects of increased cardiac output constitute an obligatory cause of exercise hyperpnea in the calf.
A respiratory gas exchange simulator for routine calibration in metabolic studies.
We have developed a method for simulating respiratory gas exchange for on-line calibration of metabolic measurement systems. It utilizes a pump which intakes a mixture of atmospheric air and a known flow of precision-analysed calibration gas (21% CO2, 79% N2). It expels the resulting mixture with flow wave form and profiles of gas concentration which closely resemble those of normal expiration. Control of the calibration mixture's inflow allows the investigator to set any desired metabolic rate regardless of the minute ventilatory rate. This separation of metabolic from ventilatory rates provides a stringent test of the computational performance of the respiratory gas exchange measurement systems. The apparatus can reproduce any range of respiratory and metabolic performance (currently ranging from 0.2-5 l.min-1 O2 uptake and CO2 output) with accuracy +/- 2%.
Gas exchange theory and the lactic acidosis (anaerobic) threshold.
The physiological requirements of performing exercise above the anaerobic threshold are considerably more demanding than for lower work rates. Lactic acidosis develops at a metabolic rate that is specific to the individual and the task being performed. Although numerous pyruvate-dependent mechanisms can lead to an elevated blood lactate, the increase in lactate during muscular exercise is accompanied by an increase in lactate/pyruvate ratio (i.e., increased NADH/NAD ratio). This is typically caused by an inadequate O2 supply to the mitochondria. Thus, the anaerobic threshold can be considered to be an important assessment of the ability of the cardiovascular system to supply O2 at a rate adequate to prevent muscle anaerobiosis during exercise testing. In this paper, we demonstrate, with statistical justification, that the pattern of arterial lactate and lactate/pyruvate ratio increase during exercise evidences threshold dynamics rather than the continuous exponential increase proposed by some investigators. The pattern of change in arterial bicarbonate (HCO3-) and pulmonary gas exchange supports this threshold concept. To estimate the anaerobic threshold by gas exchange methods, we measure CO2 output (VCO2) as a continuous function of O2 uptake (VO2) (V-slope analysis) as work rate is increased. The break-point in this plot reflects the obligate buffering of increasing lactic acid production by HCO3-. The anaerobic threshold measured by the V-slope analysis appears to be a sensitive index of the development of metabolic acidosis even in subjects in whom other gas exchange indexes are insensitive, owing to irregular breathing, reduced chemoreceptor sensitivity, impaired respiratory mechanics, or all of these occurrences.
Physiological determinants of pulmonary gas exchange kinetics during exercise.
We consider how the optimal selection of the profile of imposed work rate, coupled with rigorous, statistically justified analysis of the pattern of the pulmonary gas exchange response, makes it possible to assemble a control model incorporating the proportional role of the muscle, circulation, and gas stores. Gains, time constants, and delays may be assigned to the components of the response and its linearity assessed. These techniques also allow the investigator to examine the features of poorly understood and even unexpected response patterns. Recent interest in the analysis of the non-steady state of exercise-in normal subjects and in patients with gas exchange defects-has led to an improved understanding of the sub-threshold dynamics. At work rates above the lactate threshold, the more complex kinetics are to date poorly described, and hence poorly understood, remaining a fertile area for the application of control-systems techniques to exercise.
Breathing-valve encumbrance and arterial blood gas and acid-base status in exercise in man.
It has been suggested that the mouth-piece-breathing valve assemblies commonly used in laboratory investigations of ventilatory control may influence regulation of arterial blood gas and acid-base status during exercise. To examine this hypothesis, 10 healthy males each underwent two incremental cycle-ergometer tests (15 W min-1) to the limit of tolerance: one was conducted free of breathing apparatus; the other utilized a mouth-piece (with noseclip) connected to a low-resistance turbine volume sensor. The order was randomly assigned and tests were separated by a 2 h recovery. Blood sampled from an indwelling brachial artery catheter at rest and every 30 W during exercise was analyzed for PCO2, PO2, pH and HCO-3. Maximum power was not different between the two tests. Furthermore, no systematic effect of the assembly could be discerned on PaCO2, PaO2 or pHa over the entire range of power. We therefore conclude that although ventilation and its pattern may be affected by laboratory breathing apparatus, such encumbrance (if of low resistance and dead space) does not influence blood gas and acid-base regulation during exercise.
Fitness as a determinant of oxygen uptake response to constant-load exercise.
Exercise performed above the lactate threshold (OLa) produces a slowly-developing phase of oxygen uptake (VO2) kinetics which elevates VO2 above that predicted from the sub-OLa VO2-work rate relationship. This phenomenon has only been demonstrated, to date, in subjects who were relatively homogeneous with respect to fitness. This investigation therefore examined whether this behaviour occurred at a given absolute VO2 or whether it was a characteristic of supra-OLa exercise in a group of subjects with over a threefold range of OLa (990-3000 ml O2.min-1) and peak VO2 (1600-5260 ml O2.min-1). Twelve healthy subjects performed: 1) exhausting incremental cycle ergometer exercise for estimation of OLa (OLa) and peak VO2, and 11) a series of constant-load tests above and below OLa for determination of the VO2 profile and efficiency of work. During all tests expired ventilation, VO2 and carbon dioxide production were monitored breath-by-breath. The efficiency of work determined during incremental exercise (28.1 +/- 0.7%, means +/- SE, n = 12) did not differ from that determined during sub-OLa constant-load exercise (27.4 +/- 0.5%, p greater than 0.05). For constant-load exercise, VO2 rose above that predicted, from the sub-OLa VO2-work rate relationship, for all supra-OLa work rates. This was evident above 990 ml O2.min-1 in the least fit subject but only above 3000 ml O2.min-1 in the fittest subject. As a consequence the efficiency of work was reduced from 27.4 +/- 0.5% for sub-OLa exercise to 22.6 +/- 0.4% (p less than 0.05) at the lowest supra-OLa work rate (i.e. OLa + 20 W, on average).(ABSTRACT TRUNCATED AT 250 WORDS)
Ventilatory control of the 'isocapnic buffering' region in rapidly-incremental exercise.
During incremental exercise PCO2 does not fall for several work rates ('isocapnic buffering') above the anaerobic threshold (theta an). We explored this apparent lack of compensatory hyperventilation in 24 normal subjects who underwent incremental cycling (15 W/min) to exhaustion. Ventilation, pulmonary gas exchange, and end-tidal gas tensions were computed breath-by-breath. In 10 subjects, arterial blood was sampled every 2 min throughout the test. Our findings confirmed the 'isocapnic' supra-theta an region, but it consistently followed a progressive increase of PETCO2 in the sub-theta an region. A similar pattern was evident for PaCO2. The leveling-out of PETCO2 and PaCO2 was a result of breathing frequency increasing at theta an, thereby shortening expiratory time, i.e., progressively truncating the continued increase in the alveolar PCO2 slope. Consequently 'isocapnic buffering' during incremental exercise does not reflect PCO2 which continues to be regulated at a constant sub-theta an value. Rather it reflects a ventilatory response to the metabolic acidosis which levels a systematically-rising phase of PETCO2 and PaCO2, largely through a change in breathing pattern. Respiratory compensation, as reflected by a declining PETCO2 and PaCO2, does not occur typically for a subsequent 2 or more minutes.
Effects of peripheral and central chemoreflex activation on the isopnoeic rating of breathing in exercising humans.
1. Respiratory sensation during exercise is generally considered to be related to respiratory mechanical factors which may be manifest as an abnormal relationship between the force applied to the lungs and chest wall and the resulting motion (if any); that is, a 'length-tension' inappropriateness (Campbell & Howell, 1963). This suggests that there should be a direct correlation between ventilation (VE) and the associated intensity of the perceived sensation, such that the sensation associated with a particular level of VE should remain essentially constant regardless of the source of respiratory stimulation. 2. In order to establish whether certain respiratory stimuli might be 'dyspnoeagenic' (i.e. capable of evoking an intensity of respiratory sensation out of proportion to their influence on VE), we investigated the influence of both peripheral chemoreflex activation (induced by isocapnic hypoxia) and central chemoreflex activation (induced by hypercapnic hyperoxia) on the intensity of respiratory sensation in seven healthy adults during moderate cycle ergometer exercise (i.e. below the lactate threshold, theta 1ac). 3. In each test, an 'isopnoea' was established for which a particular level of VE was sustained over a prolonged period (approximately 30 min) while the proportional contributions to the ventilatory drive from either exercise and the peripheral chemoreflex or from exercise and the central chemoreflex were slowly altered to new stable levels, without the subject's knowledge, VE, tidal volume, inspiratory and expiratory durations, mean inspiratory flow, and end-tidal PCO2 and PO2 (PET,CO2, PET,O2) were monitored breath-by-breath. The intensity of respiratory sensation was rated with a visual analogue scale. 4. Isopnoeic ratings of respiratory sensation were systematically greater for peripheral chemoreflex activation by isocapnic hypoxia during exercise at 50% theta 1ac (for which the degree of peripheral chemoreflex activation, estimated by hyperoxic transition or 'Dejours' testing, averaged approximately 23% of the total VE), compared to 90% theta 1ac during isocapnic hyperoxia. Ratings during exercise at 50% theta 1ac for central chemoreflex activation by hypercapnic hyperoxia were not systematically different from 90% theta 1ac during isocapnic hyperoxia, however. 5. As VE was stable throughout each isopnoea and the MVV (maximum voluntary ventilation) was uninfluenced by the test condition, the dyspnoea index (VE x 100/MVV) was not affected. Breathing pattern was also unaffected. 6. We conclude that in normal subjects exercising moderately, activation of the peripheral chemoreceptors by isocapnic hypoxia evokes an intensity of respiratory sensation which is out of proportion to that evoked by an isopnoeic stimulation of the central chemoreceptors with hypercapnic hyperoxia at the same level of exercise.(ABSTRACT TRUNCATED AT 400 WORDS)
Model implications of gas exchange dynamics on blood gases in incremental exercise.
In humans, arterial PCO2 (PaCO2) has been demonstrated to be regulated at or near resting levels in the steady state of moderate exercise (i.e., for work rates not associated with a sustained lactic acidosis). To determine how PaCO2 might be expected to behave under the nonsteady-state conditions of incremental exercise testing, the influence of the dynamic characteristics of the primary variables that determine PaCO2 was explored by means of computer modeling. We constructed a dynamic model that utilized previously reported experimental estimates for the kinetic response parameters of ventilation (VE) and CO2 output (VCO2). In response to incremental work rate forcings, the model yielded an increase in PaCO2, which reflected the disparity between the VE and VCO2 time constants; this hypercapnic condition was maintained despite VE and VCO2 both increasing linearly with respect to the input work rate profile. The degree of hypercapnia increased with the rate of the incremental forcing, reaching 9 Torr for a 50-W/min forcing. In conclusion, therefore, sustained increases in PaCO2 during nonsteady-state incremental exercise should be interpreted with caution, because this is the predicted response even in subjects with normal ventilatory control and lung function.