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Effects of different levels of end-tidal PO2 on ventilation during isocapnia in humans.
The purpose of this investigation was to examine how the ventilatory decline observed during sustained, eucapnic hypoxia (HVD) is affected by different levels of hypoxia. Six subjects were each studied 3-6 times at each of 5 different levels of isocapnic hypoxia (end-tidal PO2 equal to 45, 50, 55, 65 and 75 Torr) in random order. The following variables were linearly related to saturation: (1) the rapid increase in ventilation at the onset of hypoxia; (2) the decline in ventilation over the period of hypoxia; and (3) the undershoot in ventilation below the pre-hypoxic control values at the relief of hypoxia. The rapid decrease in ventilation at the relief of hypoxia, however, was not linearly related to saturation. The mean time to peak ventilation was 2.13 +/- 0.07 min (+/- SE) at the onset of hypoxia, which was significantly longer (P less than 0.05) than the time to minimum ventilation at the relief of hypoxia of 1.23 +/- 0.18 min. The recovery from the undershoot in ventilation was 95% +/- 3% complete after 5 min, whereas the recovery in sensitivity to hypoxia was only 35% +/- 13% complete after 5 min of euoxia.
Ventilation and gas exchange during sustained exercise at normal and raised CO2 in man.
Five subjects underwent each of three protocols for 43 min: (A) at rest; end-tidal PCO2 was held constant at 2-5 Torr above resting values; (B) during 70 Watt bicycle exercise; PETCO2 was uncontrolled; (C) during 70 Watt exercise; PETCO2 was held 2-5 Torr above exercising values. During all protocols, end-tidal PO2 (PETO2) was held at 100 Torr. The first 5 min of each protocol were excluded from data analysis to approach a steady state, and the remaining 38 min analysed to determine whether any trends were present. At rest, ventilation did not change over the 38 min period. However, during hypercapnic exercise (protocol C), ventilation rose significantly by a mean +/- SE of 4.9 +/- 0.8 L/min (P less than 0.01) over the 38 min period. In protocol B, ventilation was lower than in protocol C, but did not change over the 38 min period. However, PETCO2 fell significantly by a mean of 0.65 +/- 0.05 Torr (P less than 0.01). This change in PETCO2 was due to a significant fall in the respiratory quotient (mean = -0.05 +/- 0.01, P less than 0.01) and metabolic CO2 production (mean = -0.06 +/- 0.01 L/min, P less than 0.01). The fall in respiratory quotient implies a change in metabolic substrate during exercise. Furthermore, the results suggest that ventilation is not always matched closely to metabolic CO2 production during exercise.
Ventilatory chemoreflexes at rest following a brief period of heavy exercise in man.
1. Ventilatory chemoreflex responses have been studied at rest during the recovery from a brief period of heavy exercise. 2. Six young, healthy male subjects each undertook four experimental studies. In each study measurements were made at rest during recovery from an exhaustive 1-2 min sprint on a bicycle ergometer with a workload of 400 W. Three levels of end-tidal O2 pressure (Po2) were employed. Continuous ventilatory measurements were made during euoxia (end-tidal Po2, 100 Torr), hypoxia (end-tidal Po2, 50 Torr) and hyperoxia (end-tidal Po2, 300 Torr). Arterialized venous blood samples were drawn during each of the measurement periods for the estimation of arterial pH. In two of the studies, end-tidal CO2 pressure (Pco2) was maintained throughout at 1-2 Torr above the eucapnic level that existed prior to exercise (isocapnic post-exercise protocol, IPE). In the other two studies, end-tidal Pco2 was allowed to vary (poikilocapnic post-exercise protocol, PPE). Data from a previously published study on the same subjects involving an infusion of hydrochloric acid were used to provide control data with a varying level of metabolic acidosis, but with no prior exercise. 3. Ventilation-pH slopes in the IPE protocol were no different from control. Ventilation-pH slopes in the PPE protocol were significantly lower than in the IPE and control protocols (P < 0.05, ANOVA). This difference may be due to the progressive change in end-tidal Pco2 in the PPE protocol compared with the constant end-tidal Pco2 in the IPE and control protocols. 4. An arterial pH value of 7.35 was attained 30.4 +/- 2.7 min (mean +/- S.E.M.) after the end of exercise in the IPE protocol and 17.1 +/- 1.4 min after the end of exercise in the PPE protocol. 5. Hypoxic sensitivities at an arterial pH of 7.35 were not significantly different between the IPE, PPE and control protocols (ANOVA). 6. Euoxic ventilation at an arterial pH 7.35 was significantly greater than control for the IPE protocol (P < 0.001, Student's paired t test) and no different from control for the PPE protocol. 7. The results suggest that 30 min after heavy exercise, ventilation remains stimulated by processes other than the post-exercise metabolic acidosis, and that changes in peripheral chemoreflex sensitivity to hypoxia and acid are not implicated in this.
Increased hypoxic ventilatory sensitivity during exercise in man: are neural afferents necessary?
1. The acute ventilatory response to 3 min periods of hypoxia (AHR) was examined in nine patients with clinically complete spinal cord transection (T4-T7) during (a) rest and (b) electrically induced leg exercise (EEL). 2. EEL was produced by surface electrode stimulation of the quadriceps muscles so as to cause the legs to extend at the knee against gravity. End-tidal PCO2 was held constant 1-2 mmHg above resting values throughout both protocols. 3. On exercise, the average increase in metabolic CO2 production (VCO2 +/- S.E.M.) was 41 +/- 5 ml min-1. Venous lactate levels did not rise with exercise. 4. Baseline euoxic ventilation did not increase significantly with EEL, but there was a consistent and highly significant increase in the ventilatory response to hypoxia during EEL (mean delta AHR +/- S.E.M. of 1.6 +/- 0.21 min-1). 5. We conclude that an increase in hypoxic sensitivity during exercise can occur in the absence of volitional control of exercise and in the absence of afferent neural input from the limbs.
Acute ventilatory responses to hypoxia during voluntary and electrically induced leg exercise in man.
1. The acute ventilatory response to a brief period of hypoxia (AHVR) was measured in six subjects (a) at rest, (b) during electrically induced leg exercise (EEL), (c) during voluntary leg exercise at an external work rate matched to electrical exercise (EV1) and (d) during voluntary leg exercise at an internal work rate (i.e. metabolic rate) matched to electrical exercise (EV2). The end-tidal PO2 during hypoxia was 50 mmHg and the end-tidal PCO2 was held constant at 1-2 mmHg above resting values throughout each of these four protocols. 2. EEL was produced by surface electrode stimulation of the quadriceps muscles so as to cause the legs to extend at the knee and lift a set of weights via a pulley system. During EV1, each subject lifted the same weight through the same height and at the same frequency as during his EEL protocol. During EV2, the weight, the height through which it was lifted and the frequency of voluntary contractions were altered to produce a similar O2 consumption and CO2 production as during EEL. 3. In each subject, end-tidal PCO2 values showed no change between the four protocols, and in three subjects in whom they were measured, arterial PCO2 values were also similar between the protocols. Venous lactate levels did not increase after EEL or EV2. 4. The AHVR during EEL (14.1 +/- 1.42 l min-1; mean +/- S.E.M) was significantly increased (Student's paired t test) compared with rest (7.55 +/- 1.10 l min-1; P < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)
The IUPS human Physiome Project.
The Physiome Project of the International Union of Physiological Sciences (IUPS) is attempting to provide a comprehensive framework for modelling the human body using computational methods which can incorporate the biochemistry, biophysics and anatomy of cells, tissues and organs. A major goal of the project is to use computational modelling to analyse integrative biological function in terms of underlying structure and molecular mechanisms. To support that goal the project is establishing web-accessible physiological databases dealing with model-related data, including bibliographic information, at the cell, tissue, organ and organ system levels. Here we discuss the background and goals of the project, the problems of modelling across multiple spatial and temporal scales, and the development of model ontologies and markup languages at all levels of biological function.
Nonlinear modeling of the dynamic effects of arterial pressure and CO2 variations on cerebral blood flow in healthy humans.
The effect of spontaneous beat-to-beat mean arterial blood pressure fluctuations and breath-to-breath end-tidal CO2 fluctuations on beat-to-beat cerebral blood flow velocity variations is studied using the Laguerre-Volterra network methodology for multiple-input nonlinear systems. The observations made from experimental measurements from ten healthy human subjects reveal that, whereas pressure fluctuations explain most of the high-frequency blood flow velocity variations (above 0.04 Hz), end-tidal CO2 fluctuations as well as nonlinear interactions between pressure and CO2 have a considerable effect in the lower frequencies (below 0.04 Hz). They also indicate that cerebral autoregulation is strongly nonlinear and dynamic (frequency-dependent). Nonlinearities are mainly active in the low-frequency range (below 0.04 Hz) and are more prominent in the dynamics of the end-tidal CO2-blood flow velocity relationship. Significant nonstationarities are also revealed by the obtained models, with greater variability evident for the effects of CO2 on blood flow velocity dynamics.
Selected contribution: High-altitude natives living at sea level acclimatize to high altitude like sea-level natives
Sea-level (SL) natives acclimatizing to high altitude (HA) increase their acute ventilatory response to hypoxia (AHVR), but HA natives have values for AHVR below those for SL natives at SL (blunting). HA natives who live at SL retain some blunting of AHVR and have more marked blunting to sustained (20-min) hypoxia. This study addressed the question of what happens when HA natives resident at SL return to HA: do they acclimatize like SL natives or revert to the characteristics of HA natives? Fifteen HA natives resident at SL were studied, together with 15 SL natives as controls. Air-breathing end-tidal PCO2 and AHVR were determined at SL. Subjects were then transported to 4,300 m, where these measurements were repeated on each of the following 5 days. There were no significant differences in the magnitude or time course of the changes in end-tidal PCO2 and AHVR between the two groups. We conclude that HA natives normally resident at SL undergo ventilatory acclimatization to HA in the same manner as SL natives.
Selected contribution: Peripheral chemoreflex function in high-altitude natives and patients with chronic mountain sickness
Peripheral chemoreflex function was-studied in high-altitude (HA) natives at HA, in patients with chronic mountain sickness (CMS) at HA, and in sea-level (SL) natives at SL. Results were as follows. 1) Acute ventilatory responses to hypoxia (AHVR) in the HA and CMS groups were approximately one-third of those of the SL group. 2) In CMS patients, some indexes of AHVR were modestly, but significantly, lower than in healthy HA natives. 3) Prior oxygenation increased AHVR in all subject groups. 4) Neither low-dose dopamine nor somatostatin suppressed any component of ventilation that could not be suppressed by acute hyperoxia. 5) In all subject groups, the ventilatory response to hyperoxia was biphasic. Initially, ventilation fell but subsequently rose so that, by 20 min, ventilation was higher in hyperoxia than hypoxia for both HA and CMS subjects. 6) Peripheral chemoreflex stimulation of ventilation was modestly greater in HA and CMS subjects at an end-tidal PO2 = 52.5 Torr than in SL natives at an end-tidal PO2 = 100 Torr. 7) For the HA and CMS subjects combined, there was a strong correlation between end-tidal PCO2 and hematocrit, which persisted after controlling for AHVR.
Methods for averaging irregular respiratory flow profiles in awake humans.
Respiratory flow profiles have been of interest as an output of the respiratory controller. In determining average flow profiles, however, previous methods that align individual breaths in the time domain are susceptible to distortions caused by the great variability, both between breaths and within breaths. We aimed to develop a method for determining typical flow profiles that circumvents such distortions. Our method aligns different breaths by phase of respiratory cycle, which is defined as the angle associated with the point on the normalized flow-volume diagram (a phase-plane plot). Over a number of breaths, median values for flow, volume, and elapsed time from the start of the breath at each phase angle are determined. Because these estimates are mutually semi-independent and in general violate the laws of mass balance, an adjustment was performed such that the volume was precisely the time integral of the flow. The method produced typical flow profiles with characteristics that were significantly closer to the mean values obtained from the individual cycles than those obtained by the technique of Benchetrit and co-workers (Benchetrit G, Shea SA, Dinh TP, Bodocco S, Baconnier P, and Guz A, Respir Physiol 75: 199-210, 1989), which reconstructs the typical flow profile from Fourier coefficients.
Effect of heart failure and physical training on the acute ventilatory response to hypoxia at rest and during exercise.
We studied the acute ventilatory response to hypoxia (AHVR) in 10 patients with chronic heart failure (CHF) and in 10 subjects with normal left ventricular function (NLVF) before and after 8 weeks of home-based physical training. Subjects were studied at rest and during constant cycle exercise at a work rate equivalent to 40% of their maximum oxygen consumption. The AHVR was not significantly different between the patients with CHF and those with NLVF either at rest (1.32 +/- 0.19 vs. 1.63 +/- 0.20 litres/min/% arterial desaturation; mean +/- SE) or during constant light exercise (2.37 +/- 0.48 vs. 2.86 +/- 0.55 litres/min/% arterial desaturation). Both groups showed evidence of improved physical fitness after training with increases in maximum oxygen consumption of 11 +/- 2.7% (p < 0.01) for the group with NLVF and of 8 +/- 3.2% (p < 0.05) for the group with CHF. Values for the AHVR in the trained state were not significantly different between the patients with CHF and those with NLVF either at rest (1.23 +/- 0.24 vs. 1.63 +/- 0.22 litres/min/% arterial desaturation) or during constant light exercise (2.52 +/- 0.69 vs. 2.24 +/- 0.37 litres/min/% arterial desaturation). Moreover, these responses did not differ from those in the untrained state (see above). The AHVR increased during exercise compared with rest in both groups (p < 0.05). The AHVR is not substantially altered in patients with CHF compared to subjects with NLVF. Physical training may reduce ventilation during exercise, but it has relatively little or no effect on the AHVR. However, exercise increases the AHVR in patients with CHF, as it does in normals.
Fitting curves to human respiratory data
Records of gas flow during breathing are cyclical, with the cycles varying in duration. The shape of these cycles may change with the intensity of respiratory stimulation or the development of respiratory disease, but currently research is hampered by the lack of a fully satisfactory technique for determining the shape of a typical cycle. The approach adopted here is to replace the time series by a 'phase diagram', plotting the time integral of flow against flow itself. Principal curves are then fitted. These are curves 'through the middle of the data' which were introduced by Hastie and Stuetzle. The shapes of these curves are compared, either directly or after reconstructing an average cycle corresponding to each fitted curve. This has the advantage that the shape of the waveform is separated from the amplitude, and from the duration of the breath. A disadvantage is that periods of zero flow are lost, and the reconstructed average cycle may show irregularities at points near zero flow as a result. In practice, the methodology showed clear differences in shape between the protocols, gave reasonable average cycles and ordered the waveform shapes according to the hardness of breathing induced by the protocols.
The pattern of breathing in man in response to sine waves of alveolar carbon dioxide and hypoxia.
Sine waves of alveolar CO2 at constant high alveolar O2, and sine waves of alveolar hypoxia (1/(PA, O2 -C) where C congruent to 32 torr) at constant alveolar CO2 have been administered to three subjects in each case. Six different periods of the sine waves were studied, ranging between 900 and 30 s for the CO2 sine waves and 300 and 20 s for the hypoxic sine waves. The sinusoidal variations in inspiratory and expiratory volumes (VT, I, VT, E), durations (TI, TE) and mean flows (vI, vE) produced by these manoeuvres were calculated, and the results analysed from the phase shifts of the responses. For the CO2 sine-wave results, the peak in the TI oscillation generally appeared after the minima for VT, I and vI, but before their maxima. The peak in the TE oscillation was variable. For the hypoxic sine-wave results, the peak in the TI oscillation showed no over-all tendency to lead or lag the peaks of VT, I and vI. The peak in the TE oscillation generally appeared after the maxima for VT, E and vE but before their minima. For the CO2 sine-wave results, expiratory mean flow led inspiratory mean flow, with the volumes showing no significant difference. For the hypoxic sine-wave results expiratory volumes and mean flows led inspiratory volumes and mean flows. The results are discussed in relation to the transient responses of the components of breathing pattern obtained from other perturbations of chemical drive.
The ventilatory response of the human respiratory system to sine waves of alveolar carbon dioxide and hypoxia.
Sine waves of alveolar CO2 at constant high alveolar O2, and sine waves of alveolar hypoxia (1/(PA, O2 -C), C congruent to 32 torr) at constant alveolar CO2 have been administered to three subjects in each case. Sine waves of six different periods were studied, ranging between 900 and 30 s for the CO2 sine waves and 300 and 20 s for the hypoxic sine waves. The sinusoidal variations in ventilation produced by these manoeuvres, expressed as amplitudes and phase shifts, were compared with values predicted from the dynamic responses to alveolar steps of gas tension already to be found in the literature. For the CO2 sine waves, the amplitudes of response agreed well with those predicted at the higher frequencies, but were less than predicted at the lower frequencies. For the hypoxic sine waves, the amplitude of response varied less with frequency than was predicted. For both the CO2 and the hypoxic sine waves, the phase shift of response was less than expected at the higher frequencies. An attempt was made to fit parameters to a simple model, based on the wash-in and wash-out of respiratory gases into and out of a tissue compartment, and used in the literature for describing the responses to step changes. No satisfactory fit was found. It is concluded that the simple model is unsatisfactory by itself for describing the responses to sinusoidal chemical stimulation; features additional to those included in the model are required to explain fully the responses seen. The possibilities for chemoreception at the higher frequencies are discussed in the light of the low phase shifts.
A fast gas-mixing system for breath-to-breath respiratory control studies.
A computer-controlled gas-mixing system that manipulates inspired CO2 and O2 on a breath-to-breath basis has been developed. The system uses pairs of solenoid valves, one pair for each gas. These valves can either be fully shut when a low voltage is applied, or fully open when a high voltage is applied. The valves cycle open and shut every 1/12 s. A circuit converts signals from the computer, which dictates the flows of the gases, into a special form for driving the valve pairs. These signals determine the percentage of time within the 1/12-s cycle each valve spends in a open state and the percentage of time it spends shut, which, in effect, set the average flows of the various gases to the mixing chamber. The delay for response of the system to commanded CO2 or O2 changes is less than 200 ms. The system has application for the manipulation of inspired gas fractions so as to achieve desired end-tidal forcing functions.
A prediction-correction scheme for forcing alveolar gases along certain time courses.
A computerized prediction-correction scheme has been devised for the control of alveolar gases. First, a model is run off-line to predict the inspiratory gas tensions at each second that should yield the desired alveolar patterns. Second, during the experiment, there is feedback correction based on the deviation of the actual alveolar values from the desired alveolar values. The actual alveolar values are found by a second computer and passed to the controlling computer using interrupts. The controlling computer has four digital-toi-analog outputs for controlling CO2, O2, N2, and air flows so as to achieve the commanded inspiratory PCO2 and PO2 (CO2 and O2 partial pressures, respectively). The scheme is illustrated for the generation of sinusoidal alveolar PCO2 with alveolar PO2 held constant and for steps of alveolar PCO2 at constant alveolar PO2.
Changes in respiratory control during and after 48 h of isocapnic and poikilocapnic hypoxia in humans.
Ventilatory acclimatization to hypoxia is associated with an increase in ventilation under conditions of acute hyperoxia (VEhyperoxia) and an increase in acute hypoxic ventilatory response (AHVR). This study compares 48-h exposures to isocapnic hypoxia (protocol I) with 48-h exposures to poikilocapnic hypoxia (protocol P) in 10 subjects to assess the importance of hypocapnic alkalosis in generating the changes observed in ventilatory acclimatization to hypoxia. During both hypoxic exposures, end-tidal PO2 was maintained at 60 Torr, with end-tidal PCO2 held at the subject's prehypoxic level (protocol I) or uncontrolled (protocol P). VEhyperoxia and AHVR were assessed regularly throughout the exposures. VEhyperoxia (P < 0.001, ANOVA) and AHVR (P < 0.001) increased during the hypoxic exposures, with no significant differences between protocols I and P. The increase in VEhyperoxia was associated with an increase in slope of the ventilation-end-tidal PCO2 response (P < 0.001) with no significant change in intercept. These results suggest that changes in respiratory control early in ventilatory acclimatization to hypoxia result from the effects of hypoxia per se and not the alkalosis normally accompanying hypoxia.
Indexes of flow and cross-sectional area of the middle cerebral artery using doppler ultrasound during hypoxia and hypercapnia in humans.
BACKGROUND AND PURPOSE: This study examined changes in cross-sectional area of the middle cerebral artery as assessed by changes in Doppler signal power during hypoxia and hypercapnia. In addition, it examined the degree of consistency among three indexes of cerebral blood flow and velocity: the velocity spectral outline (VP), the intensity-weighted mean velocity (VIWM), and an index of middle cerebral artery flow (P. VIWM). P. VIWM was calculated as the product of VIWM multiplied by the total power signal. Power is proportional to cross-sectional area of the vessel; this calculation therefore allows for any changes in this variable. METHODS: Four protocols were used, each repeated six times for six healthy adults aged 20.8 +/- 1.7 years (mean +/- SD). The first was a control protocol (A) with end-tidal PO2 (ETPO2) maintained at 100 mm Hg and ETPCO2 at 1 to 2 mm Hg above eucapnia throughout. The second was a hypoxic step protocol (B) with ETPO2 lowered from control values to 50 mm Hg for 20 minutes. The third was a hypercapnic step protocol (C) with ETPCO2 elevated from control by 7.5 mm Hg for 20 minutes. The fourth was a combined hypoxic and hypercapnic step protocol (D) lasting 20 minutes. A dynamic end-tidal forcing system was used to control ETPCO2 and ETPO2. Doppler data were collected and stored every 10 milliseconds, and mean values were determined later on a beat-by-beat basis. VP, VIWM, power, and P.VIWM were expressed as a percentage of the average value over a 3-minute period before the step. RESULTS: In protocols A and B, there were no changes in power and there were no differences between VP, VIWM, and P.VIWM. In C, at the relief from hypercapnia, there was a transient nonsignificant increase in power and a transient nonsignificant decrease in both VP and VIWM compared with P.VIWM. In D, during the stimulus period, VP was significantly higher than VIWM (paired t test, P < .05), but both indexes were not different from P.VIWM. In the period that followed relief from hypoxia and hypercapnia, the Doppler power signal was significantly increased by 3.8%. During this period, VP and VIWM were significantly lower than P.VIWM. CONCLUSIONS: At the levels of either hypoxia or hypercapnia used in this study, there were no changes in cross-sectional area of the middle cerebral artery, and changes in both VP and VIWM accurately reflect changes in P.VIWM. With combined hypoxia and hypercapnia, however, at the relief from the stimuli when there is a very large and rapid decrease in P.VIWM, power is increased, suggesting an increase in the cross-sectional area. During this period, changes in VP and VIWM underestimate the changes in P.VIWM.