End-tidal PO2 Research Articles

The effect of exercise on the ventilatory response to hypercapnia in humans

This study sought to investigate the effects of exercise on the dynamics of the ventilatory response to hypercapnia. Nine volunteers took part. Their ventilatory responses to hypercapnia were measured at rest and during a constant level of moderate (30% of maximal) exercise. End-tidal PCO2 was alternated between 1.5 and 10 Torr above the normal air-breathing value at rest or during exercise, as appropriate, in a manner designed to distinguish the effects of hypercapnia on the peripheral and central chemoreflexes. End-tidal PO2 was kept constant at 100 Torr. A two-compartment respiratory model of the peripheral and central chemoreflexes was fit to the ventilation data in order to estimate the gains and time constants of these chemoreflexes. Although no significant change in either peripheral or total chemoreflex sensitivity was detected with exercise, central chemoreflex sensitivity was nevertheless significantly (p<0.05) augmented from 2.2±0.9 to 2.7±1.4 l/min/Torr. Both chemoreflex responses were faster during exercise, with a marginally significant (p=0.05) decrease in peripheral time constant from 10±3 to 5±4 s, and a large significant decrease in the central time constant from 80±35 to 26±9 s (p<0.01). These results suggest that, rather than just being a product of their physiochemical environments, the time constants of the chemoreflexes may undergo active regulation. [Wellcome Trust]

Iron chelation does not potentiate early acclimatisation to sustained hypoxia in humans

The transcription factor hypoxia-inducible factor-1 (HIF-1) is believed to regulate a range of cardio-respiratory responses to sustained hypoxia. The iron chelator desferrioxamine (DFO) has been shown to stabilise HIF-1 in cell culture, and to mimic some effects of sustained hypoxia in healthy humans. This study was designed to determine whether iron chelation (8 h DFO infusion) would potentiate the early acclimatisation that occurs in response to 8 h of isocapnic hypoxia (end-tidal PO2 = 50 mmHg). Eight volunteers each undertook 4 protocols: 8 h euoxia with saline infusion (control); 8 h isocapnic hypoxia with saline infusion; 8 h euoxia with DFO infusion; 8 h isocapnic hypoxia with DFO infusion. Before and after each protocol, indices of ventilatory sensitivity to hypoxia (Gp), pulmonary vascular tone (ΔPmax) and venous plasma EPO concentration were measured. Hypoxia and DFO both independently increased Gp, ΔPmax and EPO, compared with the control protocol (p<0.05, paired t-tests). However, there was no interaction between the effects of hypoxia and DFO on any of these variables (p>0.05, ANOVA). Our hypothesis that iron chelation might potentiate the early acclimatisation responses observed to an 8-h period of hypoxia, therefore appears to be incorrect. Supported by the Wellcome Trust.

Intravenous iron loading inhibits the pulmonary vascular response to hypoxia in humans

Aim: To manipulate the hypoxia-inducible factor (HIF) transcription factors pharmacologically and thereby confirm that HIF regulates human pulmonary vascular responses to hypoxia. Background: HIF controls intracellular responses to hypoxia, and our recent work strongly implicates HIF in regulating human heart/lung physiology (Smith et al. PLoS Med 2006; 3: ). Iron is an obligate co-factor in the degradation pathway through which HIF is primarily regulated, and iron supplementation potentiates HIF degradation in vitro. Hypothesis: Supraphysiological levels of iron similarly augment HIF degradation in vivo and thus inhibit acclimatisation to hypoxia. Methods: Six normal subjects were each studied on two days. Day 1 (control) began with an infusion of saline while on Day 2 it was 200 mg iron sucrose. On each day subjects then underwent: a 40-min acute isocapnic hypoxia protocol (end-tidal PO2 50 mmHg), with pulmonary vascular tone assessed echocardiographically; 8 h of isocapnic hypoxia in a chamber; repeat of the acute hypoxia protocol. Results: Iron loading prevented the rise in pulmonary arterial pressure normally present after sustained hypoxia and blunted acclimatisation of the acute hypoxic pulmonary vasoconstrictive response (p < 0.01; Fig 1). Conclusions: HIF degradation is limited by physiological levels of iron, and HIF appears to control human pulmonary vascular responses to hypoxia. Funded by the Wellcome Trust. TGS is supported by a Rhodes Scholarship.

Differential sensitivities of cerebral and brachial blood flow to hypercapnia in humans

Although it is known that the vasculatures of the brain and the forearm are sensitive to changes in arterial Pco(2), previous investigations have not made direct comparisons of the sensitivities of cerebral blood flow (CBF) (middle cerebral artery blood velocity associated with maximum frequency of Doppler shift; Vp) and brachial blood flow (BBF) to hypercapnia. We compared the sensitivities of Vp and BBF to hypercapnia in humans. On the basis of the critical importance of the brain for the survival of the organism, we hypothesized that Vp would be more sensitive than BBF to hypercapnia. Nine healthy males (30.1 +/- 5.2 yr, mean +/- SD) participated. Euoxic hypercapnia (end-tidal Po(2) = 88 Torr, end-tidal Pco(2) = 9 Torr above resting) was achieved by using the technique of dynamic end-tidal forcing. Vp was measured by transcranial Doppler ultrasound as an index of CBF, whereas BBF was measured in the brachial artery by echo Doppler. Vp and BBF were measured during two 60-min trials of hypercapnia, each trial separated by 60 min. Since no differences in the responses were found between trials, data from both trials were averaged to make comparisons between Vp and BBF. During hypercapnia, Vp and BBF increased by 34 +/- 8 and 14 +/- 8%, respectively. Vp remained elevated throughout the hypercapnic period, but BBF returned to baseline levels by 60 min. The Vp CO(2) sensitivity was greater than BBF (4 +/- 1 vs. 2 +/- 1%/Torr; P < 0.05). Our findings confirm that Vp has a greater sensitivity than BBF in response to hypercapnia and show an adaptive response of BBF that is not evident in Vp.

Long-term facilitation of breathing is absent after episodes of hypercapnic hypoxia in awake humans

Despite the failure by many previous investigators to demonstrate a long-term facilitation of breathing following episodes of hypoxia in awake humans, we attempted to produce it using a pattern of hypercapnic hypoxic episodes similar to that experienced by obstructive sleep apnoea patients, reasoning that if long-term facilitation was relevant to these patients then it is appropriate to test the effectiveness of such episodes. Ten subjects drawn from the University student population were instrumented to measure ventilation, heart rate and end-tidal PCO2 and PO2 breath-by-breath while seated in a comfortable reclining chair. After an initial resting period breathing room air they experienced fifteen, 30-s episodes breathing 6% O2 and 5% CO2 separated by 90 s of breathing air. We examined the measured variables for an hour after the episodes but found no trends toward an increase in ventilation or decrease in end-tidal PCO2 that would indicate the presence of a long-term facilitation. We therefore concluded that long-term facilitation of ventilation was not demonstrated in awake humans using this pattern of stimuli.

Influence of Hyperoxia on Pulmonary O2 Uptake On-Kinetics During Moderate, Heavy and Supra-Maximal Intensity Exercise in Humans

PURPOSE: To examine the influence of hyperoxic gas (50 % O in N) inspiration on pulmonary VO2 kinetics during step transitions to moderate, heavy and supra-maximal intensity cycle exercise. METHODS: Seven healthy male subjects completed repeat transitions to moderate (90 % of the gas exchange threshold, GET), heavy (70 % of the difference between the GET and VO peak) and supra-maximal (105 % VO peak) intensity work rates while breathing either normoxic (N) or hyperoxic (H) gas before and during exercise. RESULTS: As anticipated, hyperoxia resulted in a significant increase in end-tidal PO2 (N: ∼97 ± 4 vs. H: ∼267 ± 3 mmHg during baseline cycling). However, hyperoxia had no significant effect on the Phase II VO2 time constant during moderate (N: 28 ± 3 vs. H: 31 ± 7 s), heavy (N: 32 ± 9 vs. H: 33 ± 6 s) or supra-maximal (N: 37 ± 9 vs. H: 37 ± 9 s) exercise. Hyperoxia resulted in a 45 % reduction in the amplitude of the VO2 slow component during heavy exercise (N: 0.60 ± 0.21 vs. H: 0.33 ±0.17 L−1min-1; p <0.05) and a 15% extension of time to exhaustion during supra-maximal exercise (N: 173 ± 28 vs. H: 198 ± 41 s; p <0.05). CONCLUSION: The Phase II VO2 kinetics are not normally constrained by (diffusional) O2 transport limitations during moderate, heavy or supra-maximal intensity exercise in young healthy subjects performing upright cycle exercise.

Effects of Fasting and Carbohydrate Replenishment on Voluntary Apnea Duration in Resting Humans

PURPOSE: Voluntary breath-hol ding is normally ended by the urge to breathe, which is caused by the rising carbon dioxide in arterial blood. For a given energy output lipid metabolism causes less carbon dioxide to be produced than during carbohydrate metabolism. It has recently been shown that a combination of 18 h of carbohydrate free diet and prolonged exercise prior to breath-holding lowered Respiratory Exchange Ratio (RER) and PO2 at Maximal Breath-hold Break-Point (MBP). We hypothesized that fasting alone would result in longer breath-hold duration due to a delay in the Physiological Break-Point (PBP) and MBP. We also hypothesized that if subjects' diet were supplemented with carbohydrates the breath-hold durations would be shorter, and blood glucose and end-tidal PO higher, i.e. safer. METHODS: Ten male non-divers performed multiple resting breath-holds either to the first diaphragmal contraction (PBP), or alternating, to MBP. The breath-holds were performed during Control (uncontrolled diet, C), after 14 hours (F14h) and 18 hours of fasting (F1 8h) and followed immediately by Carbohydrate Supplementation (CS). Duration, RER, end-tidal PO and PCO, SaO and blood glucose were determined. RESULTS: RER and blood glucose increased after CS as compared with fasting and control conditions (p <0.001). Maximal breath-hold duration increased from C: 155±30 s to F18h: 177±31 s, and was reduced during CS to 144±27 s (p <0.001). End-tidal PO2 was higher at CS compared to F1 8h (8.5±1.5 vs. 7.4±1.7 kPa at MBP, p <0.05). Corresponding values for SaO2 at MBP, CS: were 88±5% vs F18h: 85±6%, p <0.05. Similar changes were seen in the breath-holds that were terminated at PBP. CONCLUSIONS: Dietary restriction alone can cause a change in energy metabolism and respiratory physiology during breath-holding. The lower oxygen level at breakpoint (fasting) suggests that breath-holding may be less safe during fasting and that this increased risk may be mitigated by ingestion of carbohydrates before breath-holding.

The effect of hydralazine on cardiorespiratory responses to hypoxia may not involve activation of the HIF pathway

Hypoxia-inducible factor 1(HIF-1) regulates the expression of many genes involved in cellular oxygen homeostasis. In mice, partial HIF-1 deficiency is associated with impaired pulmonary vascular and ventilatory responses to hypoxia. Hydralazine, a vasodilator and respiratory stimulant, has recently been found in vitro to stabilise HIF-1 and in mice to increase plasma vascular endothelial growth factor (VEGF) concentration. To examine whether this occurs in humans, we studied changes in VEGF and erythropoietin (EPO) together with cardiorespiratory responses following hydralazine administration. Ten volunteers participated in two 2-day protocols. Hydralazine or placebo was administered at 1 pm and 11 pm on the first day, and at 1 pm on the second day. In the mornings and afternoons of both days we measured plasma VEGF and EPO concentrations, systemic arterial blood pressure, and changes in heart rate (HR), cardiac output (CO), maximum systolic pressure difference across the tricuspid valve (Δ Pmax) and ventilation (VE) in response to 20 min of isocapnic hypoxia (end-tidal PO2=50 torr). Hydralazine had no significant effect on plasma VEGF and EPO concentrations at any time point, but did affect cardiorespiratory responses: recent hydralazine decreased diastolic blood pressure (P<0.05); hydralazine increased HR and CO in both euoxia and hypoxia (P<0.05) whilst having no effect on Δ Pmax; Recent hydralazine increased both VE in euoxia and the sensitivity of the ventilatory response to hypoxia (P<0.05). The human cardiorespiratory responses to hydralazine may not involve activation of the HIF pathway.

Differences between middle cerebral artery blood velocity waveforms of young and postmenopausal women

We characterized middle cerebral artery (MCA) blood flow velocity waveforms measured by transcranial Doppler ultrasonography in premenopausal (26.6 +/- 6.1 years, mean +/- SD) and postmenopausal (54.0 +/- 3.6 years) women, of whom six were receiving hormone therapy (PM-HT) and seven were not (PM-non-HT). We hypothesized that feature points on MCA waveforms are altered in postmenopausal women compared with those in young women. A short protocol involved maintaining end-tidal PO2 at euoxia (88 mm Hg) and end-tidal PCO2 at 1.5 mm Hg above eucapnic values using a dynamic end-tidal forcing system. Doppler data for the velocity spectral outline (Vp) were collected every 10 ms, and velocity waveform analyses were done on a beat-by-beat basis. Waveform features were identified over each cardiac cycle, including the average Vp (VCYC), maximum acceleration (AMAX), and the ratio of the velocity at the reflected wave and the velocity at peak systole (VR:VMAX). VCYC was unchanged between premenopausal and postmenopausal women (69.4 +/- 9.6 and 67.5 +/- 11.1 cm/s, respectively). AMAX was significantly higher (P = 0.007) in premenopausal women (987.9 +/- 280.7 cm/s) compared with postmenopausal women (743.1 +/- 100.3). Conversely, VR:VMAX was significantly smaller (P < 0.001) in premenopausal women (0.90 +/- 0.09) compared with postmenopausal women (1.11 +/- 0.05). In postmenopausal women, the reflected wave is higher than the maximum velocity at peak systole, suggesting the presence of a shoulder in the MCA waveform. Further investigations are required to assess whether this waveform analysis can provide insight into pathophysiologic changes in cerebral hemodynamics with aging.

Time components of circulatory transport from the lungs to a peripheral artery in humans

Blood gas changes occurring in the lung undergo delay and damping on their way to a peripheral artery sampling site. Knowledge of the time components of circulatory transfer is important for the understanding of respiratory control and cardiovascular reflexes in response to blood gas transients. Providing steady state with regard to VA/Q distribution, cardiac output and peripheral blood flow, the relationship between the time courses of small end-tidal and peripheral PO2 changes is determined by the transfer function of the interposed vascular segment. This transfer function, expressed as delay time TD and mean transit time (MTT), was measured in six well-trained subjects, allowing the calculation of arterial time-courses from end-tidal to the reverse. They were studied at rest and during four different dynamic leg exercise intensities in the supine posture. TD and MTT amounted to 15.8 +/- 1.7 (mean +/- SEM) and 18.3 +/- 2.1 s at rest and were shortened to 7.7 +/- 0.6 and 11.5 +/- 1.8 s during exercise at 170 W. The shortening of TD and MTT did not appear to be simply an inverse function of cardiac output, suggesting that the shortening occurs in the central circulatory segment but not in the arm segment.

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (DeltaPmax), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6-24 h to measure spontaneous diurnal variations in DeltaPmax and cardiac output. Cardiac output varied by up to approximately 2.5 l/min; DeltaPmax varied little with cardiac output [0.61+/-0.74 (SD) mmHg min l(-1)]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal PO2 = 50 mmHg) for 8 h. In this group DeltaPmax rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in DeltaPmax during air breathing with changes in DeltaPmax during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in DeltaPmax during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of DeltaPmax to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.

The impact of hypercapnia on retinal capillary blood flow assessed by scanning laser Doppler flowmetry

Aim: To determine the effect of hypercapnia on retinal capillary blood flow using scanning laser Doppler flowmetry (SLDF). Methods: One randomly selected eye of each of 10 normal healthy subjects (mean age 25 years, SD 2.3) was studied. Subjects breathed unrestricted air for 15 min before (baseline) and after raising fractional (percent) end-tidal concentration of CO 2 (F ETCO 2) for 15 min by adding low flows of CO 2 to air entering a sequential gas delivery circuit attached to a nasal mask. Five good quality baseline SLDF images were acquired both of the optic nerve head (ONH) and of the macula. Subsequently, a minimum of 7 sequential images were acquired during hypercapnia. Five further images were acquired of the ONH, or of the macula, after returning to unlimited air breathing. The respiratory parameters of subjects were continually monitored. Results: The group mean increase in end-tidal CO 2 was 14.13% (SD 4.10) relative to baseline. The nasal macula ( P = 0.028) and foveal ( P = 0.042) areas showed a significant increase in retinal capillary blood flow in response to hypercapnia while no significant change was noted in the ONH or temporal macula areas. Change in blood flow significantly correlated with change of F ETCO 2 and/or end-tidal PO 2 for 3 of the 4 locations. Conclusions: Hypercapnia provoked a significant increase in retinal capillary blood flow in 2 of 4 retinal locations. Hypercapnia also induced a change in respiratory parameters that significantly correlated with change in retinal capillary blood flow in 3 of the 4 locations.

Effects of human pregnancy on the ventilatory chemoreflex response to carbon dioxide

This study examined the effects of human pregnancy on the central chemoreflex control of breathing. Subjects were two groups (n=11) of pregnant subjects (PG, gestational age, 36.5+/-0.4 wk) and nonpregnant control subjects (CG), equated for mean age, body height, prepregnant body mass, parity, and aerobic fitness. All subjects performed a hyperoxic CO2 rebreathing procedure, which includes prior hyperventilation and maintenance of iso-oxia. Resting blood gases and plasma progesterone and estradiol concentrations were measured. During rebreathing trials, end-tidal Pco2 increased, whereas end-tidal Po2 was maintained at a constant hyperoxic level. The point at which ventilation (Ve) began to rise as end-tidal Pco2 increased was identified as the central chemoreflex ventilatory recruitment threshold for CO2 (VRTco2). Ve levels below (basal Ve) and above (central chemoreflex sensitivity) the VRTco2 were determined. The VRTco2 was significantly lower in the PG vs. CG (40.5+/-0.8 vs. 45.8+/-1.6 Torr), and both basal Ve (14.8+/-1.1 vs. 9.3+/-1.6 l/min) and central chemoreflex sensitivity (5.07+/-0.74 vs. 3.16+/-0.29 l.min-1.Torr-1) were significantly higher in the PG vs. CG. Pooled data from the two groups showed significant correlations for resting arterial Pco2 with basal Ve, central chemoreflex sensitivity, and the VRTco2. The VRTco2 was also correlated with progesterone and estradiol concentrations. These data support the hypothesis that pregnancy decreases the threshold and increases the sensitivity of the central chemoreflex response to CO2. These changes may be due to the effects of gestational hormones on chemoreflex and/or nonchemoreflex drives to breathe.

Ventilatory acclimatization in response to very small changes in Po2 in humans

Ventilatory acclimatization to hypoxia (VAH) consists of a progressive increase in ventilation and decrease in end-tidal Pco(2) (Pet(CO(2))). Underlying VAH, there are also increases in the acute ventilatory sensitivities to hypoxia and hypercapnia. To investigate whether these changes could be induced with very mild alterations in end-tidal Po(2) (Pet(O(2))), two 5-day exposures were compared: 1) mild hypoxia, with Pet(O(2)) held at 10 Torr below the subject's normal value; and 2) mild hyperoxia, with Pet(O(2)) held at 10 Torr above the subject's normal value. During both exposures, Pet(CO(2)) was uncontrolled. For each exposure, the entire protocol required measurements on 13 consecutive mornings: 3 mornings before the hypoxic or hyperoxic exposure, 5 mornings during the exposure, and 5 mornings postexposure. After the subjects breathed room air for at least 30 min, measurements were made of Pet(CO(2)), Pet(O(2)), and the acute ventilatory sensitivities to hypoxia and hypercapnia. Ten subjects completed both protocols. There was a significant increase in the acute ventilatory sensitivity to hypoxia (Gp) after exposure to mild hypoxia, and a significant decrease in Gp after exposure to mild hyperoxia (P < 0.05, repeated-measures ANOVA). No other variables were affected by mild hypoxia or hyperoxia. The results, when combined with those from other studies, suggest that Gp varies linearly with Pet(O(2)), with a sensitivity of 3.5%/Torr (SE 1.0). This sensitivity is sufficient to suggest that Gp is continuously varying in response to normal physiological fluctuations in Pet(O(2)). We conclude that at least some of the mechanisms underlying VAH may have a physiological role at sea level.

Two temporal components within the human pulmonary vascular response to ∼2 h of isocapnic hypoxia

The time course of the pulmonary vascular response to hypoxia in humans has not been fully defined. In this investigation, study A was designed to assess the form of the increase in pulmonary vascular tone at the onset of hypoxia and to determine whether a steady plateau ensues over the following approximately 20 min. Twelve volunteers were exposed twice to 5 min of isocapnic euoxia (end-tidal Po(2) = 100 Torr), 25 min of isocapnic hypoxia (end-tidal Po(2) = 50 Torr), and finally 5 min of isocapnic euoxia. Study B was designed to look for the onset of a slower pulmonary vascular response, and, if possible, to determine a latency for this process. Seven volunteers were exposed to 5 min of isocapnic euoxia, 105 min of isocapnic hypoxia, and finally 10 min of isocapnic euoxia. For both studies, control protocols consisting of isocapnic euoxia were undertaken. Doppler echocardiography was used to measure cardiac output and the maximum tricuspid pressure gradient during systole, and estimates of pulmonary vascular resistance were calculated. For study A, the initial response was well described by a monoexponential process with a time constant of 2.4 +/- 0.7 min (mean +/- SE). After this, there was a plateau phase lasting at least 20 min. In study B, a second slower phase was identified, with vascular tone beginning to rise again after a latency of 43 +/- 5 min. These findings demonstrate the presence of two distinct phases of hypoxic pulmonary vasoconstriction, which may result from two distinct underlying processes.

Reproducibility of Cardiopulmonary Exercise Measurements in Patients With Pulmonary Arterial Hypertension

As part of a recent study, cardiopulmonary exercise tests (CPETs) were used to evaluate and follow up patients with pulmonary arterial hypertension (PAH). These patients were more impaired than those in other published series evaluating CPET reproducibility. We used these patient tests to assess patient performance variability and evaluate reading variability. To achieve this end, six independent evaluators graded key CPET measurements in patients with PAH who underwent duplicate CPETs within 3 days of each other. Over a 15-month period at two tertiary-care teaching hospitals, 42 patients with PAH underwent repeated, paired CPETs using cycle ergometry. Each patient underwent one to six pairs of cycle ergometry tests to maximal tolerance. Each pair of tests was separated by 3 months, with each test in the pair separated by 1 to 3 days. Specific guidelines were given to the independent evaluators for the key measurements assessed from each CPET study: peak O(2) uptake (Vo(2)), peak heart rate, peak O(2) pulse, anaerobic threshold (AT), and end-tidal Po(2), end-tidal Pco(2), and the ventilatory equivalent for CO(2) at the AT (Ve/Vco(2)@AT). There were no fatalities or complications occurring among the 242 tests performed on 42 patients. The mean peak Vo(2) was 722 mL/min or 41% of predicted; 34 patients were Weber class C or D. Using the specific guidelines to measure the variability of measurements made by the six independent evaluators, the coefficients of variation were < 2.2% for peak Vo(2), peak heart rate, peak O(2) pulse, end-tidal values at the AT, and Ve/Vco(2)@AT, while for the AT, it was 8.5%. There were no significant differences in these measurements between the first and second tests of any pair or between the earlier and later sets of pairs. Using specific guidelines, key CPET measurements can be safely, reliably, and reproducibly assessed even in patients with severe exercise intolerance.

Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide.

This study examined the effect of high, normal, and uncontrolled end-tidal Pco(2) (Pet(CO(2))) on the ventilatory, peak cerebral blood flow velocity (V(p)), and mean arterial blood pressure (MAP) responses to acute hypoxia. Nine healthy subjects undertook, in random order, three hypoxic protocols (end-tidal Po(2) was held at eight steps between 300 and 45 Torr) in conditions of hypercapnia, isocapnia, or poikilocapnia (Pet(CO(2)) +7.5 Torr, +1.0 Torr, or uncontrolled, respectively). Transcranial Doppler ultrasound was used to measure V(p) in the middle cerebral artery. The slopes of the linear regressions of ventilation, V(p), and MAP with arterial O(2) saturation were significantly greater in hypercapnia than in both isocapnia and poikilocapnia (P < 0.05). Strong, significant correlations were observed between ventilation, V(p), and MAP with each Pet(CO(2)) condition. These data suggest that 1). a high acute hypoxic ventilatory response (AHVR) decreases the acute hypoxic cerebral blood flow responses during poikilocapnia hypoxia, due to hypocapnic-induced cerebral vasoconstriction; and 2). in hypercapnic hypoxia, a high AHVR is associated with a high acute hypoxic cerebral blood flow response, demonstrating a linkage of individual sensitivities of ventilation and cerebral blood flow to the interaction of Pet(CO(2)) and hypoxia. In summary, the between-individual variability in AHVR is shown to be firmly linked to the variability in V(p) and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high V(p) and MAP responses to hypoxia.

Relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans

This study examined the relationship between cerebral blood flow (CBF) and end-tidal PCO2 (PETCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PETCO2 in a range of 22 to 50 Torr with a constant end-tidal PO2 (100 Torr) in eight subjects. PETCO2 and end-tidal PO2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PETCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia (protocol I) and vice-versa (protocol D). Over the range of PETCO2 studied, the sensitivity of peak blood velocity to changes in PETCO2 (CBF-PETCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PETCO2 sensitivity; for a given PETCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PETCO2 sensitivity varies depending on the level of PETCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.

Changes in respiratory control after three hours of isocapnic hypoxia in humans

Despite the obvious role of hypoxia in eliciting respiratory acclimatisation in humans, the function of the peripheral chemoreflex is uncertain. We investigated this uncertainty using 3 h of isocapnic hypoxia as a stimulus (end-tidal PCO2, 0.5–1.0 mmHg above eucapnia; end-tidal PO2, 50 mmHg), hypothesising that this stimulus would induce an enhancement of the peripheral chemoreflex ventilatory response to hypoxia. Current evidence conflicts as to whether this enhancement is mediated by an increase in the sensitivity or a decrease in the threshold of the peripheral chemoreflex ventilatory response to carbon dioxide. Employing a modified rebreathing technique to assess chemoreflex function, we found evidence of the latter in nine healthy volunteers (six male, three female). Testing consisted of pairs of isoxic rebreathing tests at high and low levels of oxygen, performed before, immediately after and 1 h after a 3 h isocapnic hypoxic exposure. No parameters changed significantly in the high-oxygen rebreathing tests. In the low-oxygen rebreathing tests there were no changes in non-chemoreflex ventilatory drives, or in the sensitivity to carbon dioxide, but the carbon dioxide response threshold decreased (≈1.5 mmHg) immediately after exposure, and the decrease persisted for 1 h (one-way repeated-measures ANOVA; P < 0.05). We repeated the protocol in five of the original nine volunteers, but this time exposing them to isocapnic normoxia. No trends or significant changes were observed in any of the rebreathing test parameters. These findings demonstrate that in the earliest stages of acclimatisation, there is a decrease in the threshold of the peripheral chemoreflex response to carbon dioxide, which persists for at least 1 h after the return to normoxia. We suggest that ventilatory acclimatisation to hypoxia results from this decreased threshold, reflecting an increase in the activity of the peripheral chemoreflex.