| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of 1Physiology and Biophysics and 2Clinical Neurosciences, Faculty of Medicine, and 3Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada T2N 4N1
Submitted 22 December 2003 ; accepted in final form 1 March 2004
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
p), and mean arterial blood pressure (MAP) responses to acute hypoxia. Nine healthy subjects undertook, in random order, three hypoxic protocols (end-tidal PO2 was held at eight steps between 300 and 45 Torr) in conditions of hypercapnia, isocapnia, or poikilocapnia (PETCO2 +7.5 Torr, +1.0 Torr, or uncontrolled, respectively). Transcranial Doppler ultrasound was used to measure p in the middle cerebral artery. The slopes of the linear regressions of ventilation, p, and MAP with arterial O2 saturation were significantly greater in hypercapnia than in both isocapnia and poikilocapnia (P < 0.05). Strong, significant correlations were observed between ventilation, p, and MAP with each PETCO2 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 PETCO2 and hypoxia. In summary, the between-individual variability in AHVR is shown to be firmly linked to the variability in p and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high p and MAP responses to hypoxia. cerebral blood flow; ventilation; hypercapnia; isocapnia; poikilocapnia
Acute hypoxia leads not only to changes in ventilation but also to changes in heart rate (HR), mean arterial blood pressure (MAP) (10, 11), and cerebral blood flow (CBF) (16, 30, 39). However, we have discovered no published evidence to suggest that the magnitude of the AHVR may also be reflected in similar changes in CBF and/or MAP during periods of acute hypoxia. Similarly, there seem to be no available data concerning the combined ventilatory, cerebrovascular, and cardiovascular responses to acute hypoxia in humans.
The aims of the present study, therefore, were 1) to examine the effect of high, normal, and uncontrolled end-tidal PCO2 (PETCO2) levels on the ventilatory, peak cerebral blood flow velocity (p) and MAP responses to acute hypoxia and 2) to examine the interrelationships between these responses to acute hypoxia during each different condition of PETCO2. We tested the hypothesis that changes in ventilatory sensitivities to hypoxia caused by changes in the background PETCO2 would also be reflected in, and potentially related to, subsequent changes in p and cardiovascular sensitivities. Previously, it has been shown that the ventilatory responses to acute hypoxia were not different when the hypoxic stimulus was given in either a descending order or ascending order (20). Such data are not available regarding the effect of hypoxic stimulus on the cerebrovascular and cardiovascular responses. Therefore, a secondary objective of this study was to investigate whether the p and cardiovascular responses to alterations in end-tidal PO2 (PETO2) are different when PETO2 is decremented from hyperoxia (PETO2 = 300 Torr) to hypoxia (PETO2 = 45 Torr) than when PETO2 is incremented from hypoxia (PETO2 = 45 Torr) to hyperoxia (PETO2 = 300 Torr).
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Nine healthy male subjects [24.21 ± 3.54 (SD) yr] participated in this study. All subjects were given both verbal and written instructions outlining the experimental procedure, and written, informed consent was obtained. Participants were not taking any medication, all were nonsmokers, and none had any history of cardiovascular, cerebrovascular, or respiratory disease. The research study was approved by the Conjoint Health Research Ethics Board at the University of Calgary.
Protocol
The experiments were conducted in our laboratory located 1,103 m above sea level, and the average barometric pressure for the study days was 663 ± 12 Torr. Each subject was studied on three occasions. Subjects were requested not to eat or drink caffeine-containing beverages within 4 h before their scheduled testing sessions in the laboratory. During the initial visit, resting end-tidal gases and estimates of hypoxic and hypercapnic ventilatory responses were measured, and the subjects became familiarized with the apparatus and experimental testing procedures. For the next two visits, subjects reported to the laboratory at the same time of day, with each visit separated by at least 3 days. During each of these visits, in a randomized design, subjects conducted three separate protocols. Each protocol was separated by a 45-min rest period.
During each visit, the subject's normal PETCO2 and PETO2 were measured before the experiment, while the subject was sitting quietly and comfortably for 
10 min. The respired gas was sampled continuously (20 ml/min) via a fine catheter at the opening of one nostril by an adapted nasal O2 therapy kit and analyzed for PO2 and PCO2 by mass spectrometer (AMIS 2000, Innovision, Odense, Denmark). Values for PO2 and PCO2 were sampled by a computer every 10 ms. PETO2 and PETCO2 were identified and recorded for each breath by using a computer and dedicated software (Chamber version 1.00, University Laboratory of Physiology, Oxford, UK).
Incremental Step Hypoxic Protocol
Each experimental protocol began with an 8-min period during which the subject breathed normally through a mouthpiece with the nose occluded by a nose clip. Respiratory volumes were measured with a turbine device and volume transducer (VMM-400, Interface Associates). Respiratory flow direction and timing information were obtained with a pneumotachograph and differential pressure transducer (RSS100-HR, Hans Rudolf, Kansas City, MO). Accurate control of the end-tidal gases was achieved by using the technique of dynamic end-tidal forcing and dedicated software (BreatheM version 2.07, University Laboratory of Physiology, Oxford, UK). A controlling computer generated the inspired partial pressure of O2 and CO2 predicted to give the desired end-tidal partial pressures by using a fast gas-mixing system (33). The controlling computer received feedback of the measured end-tidal partial pressures on a breath-by-breath basis as the experiment progressed. These measured end-tidal values were then compared with the desired values, and the computer adjusted the initial predicted inspired gas mixture by using an integral proportional feedback algorithm based on the deviations of the measured end-tidal values from the desired end-tidal values (32). Using the same hypoxic ramp protocol, each subject conducted three protocols: 1) hypercapnic hypoxia (PETCO2 held at 7.5 Torr above resting value), 2) isocapnic hypoxia (PETCO2 held at 1.0 Torr above resting value), and 3) poikilocapnic hypoxia (PETCO2 uncontrolled).
After an 8-min lead-in period of euoxia (PETO2 = 88 Torr), the PETO2 was increased to 300 Torr for 5 min. The hypoxic stimulus was then varied by holding the PETO2 at eight different predetermined levels over the range of 300–45 Torr. These levels of hypoxia were calculated to provide equal steps in oxygen saturation of the arterial blood (SaO2), by using the relationship described by Severinghaus in 1979 (37). Each protocol was undertaken with the same steps of hypoxia, either in an ascending (PETO2 = 45.0, 48.2, 52.0, 57.0, 64.0, 75.2, 88.0, and 300.0 Torr) or descending order (PETO2 = 300.0, 88.0, 75.2, 64.0, 57.0, 52.0, 48.2, and 45.0 Torr), with each step lasting 90 s, as illustrated in Fig. 1.
|
Backscattered Doppler signals from the right middle cerebral artery (MCA) were measured continuously during the protocol by using a 2-MHz pulsed Doppler Ultrasound system (TC22, SciMed, Bristol, UK). The MCA was identified by an insonation pathway through the right temporal window just above the zygomatic arch by using search techniques described previously (28). The Doppler probe was secured with a headband device (Müller and Moll Fixation, Nicolet Instruments, Madison, WI) to maintain optimal insonation position and angle throughout the protocol. In this study, the peak blood velocity was acquired every 10 ms and averaged over each heartbeat (p), and this was used as the primary index of CBF (29). During each test, MAP and HR were measured continuously by using finger photoplethysmography (Portapress, TPD Biomedical Instrumentation) and a three-lead ECG arrangement (Micromon 7142B monitor, Kontron Medical), respectively.
Data and Statistical Analyses
The AHVR, the acute hypoxic CBF response (AHRCBF), the acute hypoxic HR response (AHRHR), and the acute hypoxic MAP response (AHRMAP) were determined by linear regression between the mean ventilation (
E), p, HR, and MAP with SaO2 (100 – SaO2) during the final 15 s of each incremental step of hypoxia. Sensitivity of these dependent variables was calculated from the slopes of the linear regressions between ventilation, CBF, and MAP with SaO2 (100 – SaO2) (see Table 2 and Figs. 4A, 5A, and 6A). To calculate the percent (%) change from baseline, data were averaged over the 5-min period of euoxia immediately preceding any changes in PETO2. Because there were no discernable differences between the ascending and descending conditions, data from the two conditions were combined for further statistical analysis. Data were initially tested for normality, before being analyzed by repeated-measures analysis of variance, where appropriate. Post hoc tests (Tukey) were performed to isolate any significant differences. Resting end-tidal gases, E, p, HR, MAP, and the E, p, HR, and MAP sensitivities to hypoxia and hypercapnia between each day were compared statistically by using a Student’s paired t-test. Nonparametric equivalents included Wilcoxon matched pairs signed ranks and Kruskal-Wallis tests. The relationship between selected dependent variables was assessed by using a Pearson product-moment correlation (Figs. 4–6). Significance for all two-tailed tests was established at an 
-level of P < 0.05, and data are expressed as means ± SD. The between-day intersubject variability in all of the dependent variables was assessed by determining the coefficients of variation (standard deviation of the difference/grand mean x 100).
|
|
|
|
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
All subjects completed each test in both the descending and ascending protocols. Four of the nine subjects reported subjective discomfort during the first step of the hypercapnic hypoxic protocol; these were more marked during the ascending protocol, compared with those reported during the descending protocol. These four subjects had the highest AHVR and acute hypercapnic ventilatory response sensitivities. Despite the reported discomfort, all data from the nine subjects were included in the final analysis.
General Observations
Resting p, ventilation, HR, MAP, and the ventilatory and CBF sensitivities to CO2 were not different between the descending and ascending protocols and showed a low between-day variability (Table 1). Similarly, the ventilatory, CBF, HR, and MAP sensitivities to CO2 (calculated from the slope of the isocapnic-to-hypercapnic PETCO2 relationship) were not different between trials (Table 1). The order of the hypoxic stimulus did not elicit any differences in the AHRCBF, AHVR, AHRHR, or AHRMAP (Table 2). Therefore, data from the ascending and descending conditions were combined.
|
p, MAP, and PETCO2 responses during each condition are illustrated in Fig. 2. During the poikilocapnic condition, both p and MAP remained relatively unchanged. Although the responses were variable within subjects, ventilation tended to increase during the hypoxic conditions, which was reflected in the subsequent decreases in PETCO2. In each condition, baseline changes in p and MAP responses were similar. As shown, the PETCO2 was well controlled at the desired levels during the isocapnic and hypercapnic conditions (Figs. 2 and 3; Table 3). During the poikilocapnic hypoxic conditions, PETCO2 was decreased by 4.9 ± 2.0 Torr at the lowest level of hypoxia (PETO2 = 45 Torr). The combined effects of both hypercapnia and hypoxia on ventilation were clearly evident during the hypercapnic condition (Fig. 2). Representative sample results from one subject (identification no. 0037) during the descending and ascending experimental protocols are illustrated in Fig. 3, which highlights the main dependent outcome variables measured during each experiment from one typical subject.
|
|
|
Ventilatory data.
On average, compared with the isocapnic conditions, the AHVR was increased by 1.07 l·min–1·%–1 (47%; P < 0.05) in the hypercapnic conditions and decreased by 1.75 l·min–1·%–1 (77%; P < 0.05) in the poikilocapnic conditions. As mentioned, the order of the hypoxic stimulus did not elicit any differences in the AHVR responses, although a trend was present in the isocapnic condition (P = 0.09) (see Table 2). Compared with the hyperoxic control baseline, E at the lowest level of hypoxia (PETO2 = 45 Torr) was increased by 9.1, 41.1, and 57.4 l/min in the poikilocapnic, isocapnic, and hypercapnic conditions, respectively (Table 3). Compared with the isocapnic hyperoxic baseline at the lowest level of hypoxia, E was increased by 6.2 and 95.3 l/min in the poikilocapnic and hypercapnic conditions, respectively (Table 3). Furthermore, when expressed as the change from the relative hyperoxic control, increases in ventilation of 9.1 l/min (86%; P < 0.05) and 57.4 l/min (112%; P < 0.05) were evident at the lowest level of hypoxia during the poikilocapnic and hypercapnic conditions, respectively.
CBF velocity data.
As shown in Table 2, unremarkable changes in AHRCBF sensitivity were evident during conditions of poikilocapnic hypoxia. Compared with isocapnic conditions, AHRCBF sensitivity was decreased by 0.59 cm·s–1·%–1 (83%; P < 0.05) during the poikilocapnic conditions. Conversely, during the hypercapnic conditions, there was a increase of 0.67 cm·s–1·%–1 (93%; P < 0.05), compared with the isocapnic condition; this represents an 11-fold increase (1.26 cm·s–1·%–1; P < 0.001) in the hypercapnic conditions, compared with the poikilocapnic conditions (Table 2). Table 3 shows the p data expressed as change from the hyperoxic baseline in each condition and also as the change from the isocapnic hyperoxic baseline. During the hypercapnic condition, at the lowest level of hypoxia, p was increased by 25.1 cm/s (34%; P < 0.05) from the hypercapnic hyperoxic baseline; however, when expressed as the change from the isocapnic hyperoxic baseline, this increase in p was significantly higher (43.3 cm/s; 79%; P < 0.05; Table 3).
Cardiovascular data. No significant differences between the AHRHR were apparent in the poikilocapnic and isocapnic conditions; however, the increase in AHRHR was significant when the poikilocapnic and hypercapnic conditions are compared (0.88 vs. 1.48 beats·min–1·%–1; P < 0.05; Table 2). The changes in the AHRMAP sensitivities were remarkably similar to those of the change in the AHRCBF. Compared with the isocapnic condition, the AHRMAP was increased by 0.70 l·min–1·%–1 (97%; P < 0.05 ) in the hypercapnic conditions and decreased by 0.44 l·min–1·%–1 (61%; P < 0.05) in the poikilocapnic conditions. When compared with the isocapnic hyperoxic baseline at the lowest level of hypoxia, MAP was increased by 32 mmHg (41%; P < 0.05) and 5 mmHg [6%; not significant (NS)] in the poikilocapnic and hypercapnic conditions, respectively. Similarly, when expressed as the change from the relative hyperoxic control, increases in MAP of 3.5 (4%; NS) and 26 mmHg (30%; P < 0.05) were evident at the lowest level of hypoxia during the poikilocapnic and hypercapnic conditions, respectively.
Relationships Between Variables
p and MAP.
The similar changes in MAP and p during each condition were reflected in significant correlations between the AHRMAP and AHRCBF in both hypercapnic (r = 0.92; P < 0.01) and isocapnic (r = 0.69; P < 0.01) conditions but not in the poikilocapnic (r = 0.08; NS) condition. These relationships are illustrated in Fig. 4A. These relationships were further comparable when all of the p and MAP data from each hypoxic step are included into a regression graph, as shown in Fig. 4B, which includes averaged data from the last 15 s of the seven steps of PETO2 from each subject. Comparable to the AHRCBF and AHRMAP relationships, significant relationships were apparent between p and MAP in both hypercapnic (r = 0.85; P < 0.01) and isocapnic (r = 0.67; P < 0.01) conditions but not in the poikilocapnic (r = –0.22; NS) condition.
p and AHVR.
Strong correlations were evident between the AHVR and AHRCBF in both hypercapnic (r = 0.90; P < 0.01) and poikilocapnic (r = –0.85; P < 0.01) conditions, but not in the isocapnic (r = 0.46; P = 0.56) condition (Fig. 5A). When all of the individual data points are included in the regression analysis, significant relationships were evident between p and E in the hypercapnic (r = 0.70; P < 0.01), isocapnic (r = 0.69; P < 0.01), and poikilocapnic (r = –0.39; P < 0.05) conditions (Fig. 5B).
MAP and AHVR.
There were significant correlations between the AHRMAP and AHVR sensitivities in the hypercapnic (r = 0.76; P < 0.01) but not in the isocapnic (r = 0.32; NS) or the poikilocapnic (r = –0.27; NS) conditions (Fig. 6A). When all of the individual data points are included into regression analysis, significant relationships were evident between MAP and E in both the hypercapnic (r = 0.72; P < 0.01) and isocapnic (r = 0.71; P < 0.01) conditions, but not in the poikilocapnic (r = 0.03; NS) condition (Fig. 6B).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
This study reports three main findings. First, the integrative ventilatory, cerebrovascular, and cardiovascular responses to hypoxia are strongly influenced by PETCO2, regardless of whether or not the hypoxic stimulus was in a descending or ascending order. These findings imply that the order of the hypoxic stimulus to the level of 45 Torr (SaO2 80%) does not influence the pattern of the cerebrovascular or cardiovascular responses. Second, with poikilocapnia, a high AHVR blocks much of the hypoxic p response. Conversely, during periods of hypercapnic hypoxia, a high AHVR is associated with a high AHRCBF, demonstrating a linkage of individual sensitivities of ventilation and CBF to the interaction of PCO2 and hypoxia. Finally, the between-individual variability in AHVR is shown to be firmly linked to the variability in p and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high p and MAP responses to hypoxia. The following discussion details the evidence and assumptions that underlie these conclusions.
Ventilatory and p Responses to Hypoxia
CBF rises in proportion to the severity of isocapnic hypoxia in all mammals. However, during poikilocapnic hypoxia, considerable variability exists between individuals and species because of the wide variability in AHVR, which determines how far the PCO2 falls (36). A strong AHVR and a large fall in PCO2 in experimental subjects led to early reports that hypoxia-induced cerebral vasodilation was a threshold phenomenon, scarcely beginning until arterial PO2 (PaO2) had fallen to 30 Torr (39). Our results from the poikilocapnic protocol are not inconsistent with this "threshold phenomenon," i.e., the vasodilatory effects of the hypoxia appear to be balanced by the vasoconstrictive effects of hypocapnia throughout the range of hypoxia, resulting in little change in the CBF.
Using isocapnia in nine healthy male volunteers, Cohen et al. (5) showed that a step reduction of PaO2 to 34.6 ± 1.6 (SE) Torr (SaO2 66%) increased CBF by 70% (from 0.45 to 0.77 ml·g–1·min–1). This isocapnic rise in CBF was twice that reported at the same SaO2 by Kety and Schmidt (16) when arterial PCO2 was allowed to fall. In the sheep model, Yang et al. (45) reported that step reduction of PaO2 to 40 Torr increased CBF by 156% in isocapnia but only by 68% during poikilocapnic conditions (arterial PCO2 decreased from 36 to 28 Torr). These aforementioned studies would suggest that the effect of isocapnia is a doubling of the hypoxic increase in CBF compared with poikilocapnia. The present study, using transcranial Doppler ultrasound, would suggest that, at the lowest level of hypoxia (PETO2 = 45 Torr; SaO2 80%), isocapnia and hypercapnia caused a 24 and 34% increase in CBF compared with changes from baseline, respectively. The disparity in the results of the present study and those of the aforementioned earlier studies are likely due to the modest level of hypoxia (PETO2 = 45 Torr; SaO2 80%), methodological differences in the estimation of CBF, species differences, and a greater degree of control over the end-tidal gases using the technique of dynamic end-tidal forcing.
Cerebral autoregulation.
Blood pressure sensitivity was elevated during both the isocapnic and hypercapnic hypoxia protocols, indicating a greater degree of sympathetic-mediated cardiovascular stress. It has been shown that blood pressure elevation itself increases cerebral perfusion pressure that can affect MCA blood flow velocity (40). In healthy people with intact cerebral autoregulatory mechanisms, however, the change in CBF as well as MCA flow velocity induced by blood pressure change usually lasts for only a few seconds (1, 23). In other words, effective cerebral autoregulation acts to hold CBF constant when blood pressure varies and, hence, acts to reduce any correlation between these quantities (26). Because cerebral autoregulation is known to be attenuated during hypoxic and hypercapnic conditions (2, 26), the strong relationship between p and MAP during the isocapnic- and hypercapnic-hypoxic conditions is consistent with the view that increases in MAP would lead to parallel increases in cerebral perfusion pressure and, therefore, p.
AHVR and MAP. It is of interest that there were significant correlations between ventilatory chemosensitivity and increases in MAP. We speculate on two possible, potentially related explanations for this relationship. The first explanation is related to the effect of an enhanced cardiovascular response on peripheral chemosensitivity. Both acute hypoxia (44) and acclimatization to altitude (3, 12) have been shown to elicit large increases in sympathetic overactivity. The effect of such an enhanced sympathetic activation on respiration might be mediated through sympathetic efferents innervating the carotid bodies (24). An alternative explanation for the relationship is a modulatory effect of afferent nerve traffic from pulmonary stretch receptors on sympathetic neurons in the brain stem mediated through central connections between respiratory and sympathetic neurons (4). The second explanation for the significant correlations between ventilatory chemosensitivity and the MAP explores the opposite possibility: the effect of enhanced chemosensitivity on maintenance of MAP during hypoxic stimulation. It is accepted that systemic arterial blood pressure is maintained primarily by the carotid chemoreceptor reflex during hypoxic stimulation, that is, pressor responses, which are caused by vasoconstriction in the peripheral vascular beds and by enhanced cardiac output (6). Because there was a significant increase in carotid chemoreceptor reflex sensitivities during the isocapnic- and hypercapnic-hypoxic conditions, it is conceivable that this is an important mediator of the enhanced MAP sensitivity.
p and AHVR.
During the poikilocapnic condition, a strong negative relationship was found between the AHVR and the AHRCBF sensitivities. This relationship is perhaps not surprising because a higher AHVR will block much of the CBF response due to hypocapnic-induced cerebral vasoconstriction secondary to the increased ventilation (36). In the present study, there were significant correlations between the ventilatory and p responses and their sensitivities during the hypoxic-hypercapnic condition. The effect of hypoxia and hypercapnia is known to attenuate normal cerebral autoregulatory mechanisms, and, therefore, increases in MAP are likely to cause increases in cerebral perfusion pressure and p (2, 26). Activation of the sympathetic nervous system explains the correlation between ventilatory and p responses to hypoxia during hypercapnia only under the assumption that p passively follows MAP. Our data clearly show a strong, positive relationship between the increases in MAP and p. Such a relationship raises the possibility that, when normal cerebral autoregulatory mechanisms are attenuated, p passively follows blood pressure; however, this has yet to be confirmed in humans, and a number of other explanations should be considered. For example, increased tidal volume will make pleural pressures more negative and, in turn, will reduce venous and cerebral spinal fluid pressures, thus increasing the perfusion pressure (26). Therefore, the strong correlations between p and AHVR may be explained, at least in part, by the mechanical effects of hyperventilation.
Role of Increased Respiratory Effort
Both the isocapnic- and hypercapnic-hypoxic conditions stimulated large increases in ventilation and thus respiratory effort. Previously, it has been suggested that increases in respiratory effort per se can produce sympathoexcitation via a number of pathways (43). In addition, feedback pathways involving mechanoreflexes or metaboreflexes, arising from the respiratory muscles, might be activated during the hypercapnic-hypoxic-induced hyperventilation (41). An important question that arises is, to what extent are our results caused by the hypercapnic-hypoxic-induced peripheral and central chemoreflex stimulation per se to that of the secondary influence of the hyperpnea? From the data in the present study, we cannot address this question. However, an elegantly designed study by Halliwill et al. (10), using isocapnic hypoxia (SaO2 85%) and matched isocapnic hyperpnea, provides data to suggest that the increases in HR and sympathetic outflow observed at altitude or during exposure to hypoxia are indeed the result of peripheral activation per se and not secondary to the concomitant hyperpnea and hypocapnia. In contrast, very little has been reported on the role of isocapnic hyperpnea in the regulation of CBF. In the highly controlled, anesthetized cat model, Neubauer et al. (22) provided data to show that an increase in respiratory output, produced by either hindlimb stimulation or carotid sinus nerve (without any change in blood-gas composition), is associated with an increase in blood flow (19–22%) to the ventilatory medulla. The authors conclude that such increase in ventilatory medulla blood flow reflects an increase in the metabolism of the ventilatory medulla due to activation of respiratory neurons. As mentioned, the mechanical effects of hyperventilation may also play a role in producing increases in cerebral perfusion pressure and, therefore, CBF. To the best of our knowledge, we have not found any human studies that have investigated the effect of isocapnic hyperpnea or hyperventilation on inducing changes in CBF. However, we acknowledge the distinct possibility that isocapnic hyperpnea per se may play a significant role in increasing ventilatory medulla blood flow and, therefore, is important in the interpretation of our results. Although we measured the blood velocity in the MCA, and not in the basilar artery, which provides the blood supply to the brain stem, the important finding from the present study is the linkage of responses within each subject.
Limitations of Experimental Approach
Estimation of CBF. We used Doppler ultrasound to measure flow velocity, rather than blood flow, in the MCA. Nevertheless, we believe that velocity is a reasonable estimate of flow in our experiments because 1) the diameter of the MCA has been shown to vary by <4% during changes in arterial pressure and CO2 tension (9), and 2) velocity and flow through the MCA are highly correlated (9). Our estimates of cerebrovascular CO2 reactivity [2.68 cm·s–1·Torr–1 (4–5%/Torr) for hypercapnia] are consistent with previous reports based on measurements of tissue nitrous oxide uptake (16), functional magnetic resonance imaging (34), positron emission tomography (31), 133Xe washout (42), and other transcranial Doppler ultrasound studies (14, 28). In further support, previously studies by Poulin and Robbins (29, 30) have investigated the relative changes in MCA diameter by using the transcranial Doppler power signal. The authors demonstrated that MCA diameter remained relatively constant during conditions comparable to these in the present study (29, 30). In our study, over the course of each protocol and condition, Doppler power remained relatively unchanged, suggesting that there was little, if any, change in cross-sectional area of the MCA.
An important consideration is whether steady-state p was reached during the hypoxic steps of 90 s. Earlier studies in humans (7, 38) and in the anesthetized monkey (46) suggested that 6–7 min were required for the CBF response to hypoxia to reach its maximal response. More recent work incorporating transcranial Doppler ultrasound and dynamic end-tidal forcing, a system that can provide rapid changes in PETO2 within one or two breaths, has shown that the p responses to hypoxia are much faster than previously considered (28). Furthermore, the p responses to isocapnic hypoxia reported in this study are comparable with those of previous studies using shorter (i.e., 60 s) and longer (i.e., 20 min) (27, 28) hypoxic stimuli, compared with those used in this study, suggesting that the 90-s incremental steps at each level of hypoxia were sufficiently long for the p responses to unfold.
Blood pressure measurements. We used photoplethysmography to measure finger arterial pressure at rest and during the acute hypoxic tests. Although photoplethysmographic measurements correlate well with intra-arterial measurements during experimental manipulations of arterial pressure (25), the absolute values can sometimes be inaccurate. Nonetheless, in our laboratory under carefully controlled conditions, the resting plethysmographic measurements compare closely with manual measurements from sphygmomanometer recordings (<4.6% difference between plesthysmographic and manual measurements, n = 37 measurements; unpublished observations). Furthermore, the relative change in MAP is the relevant variable for the calculated sensitivity measurements used in the present study.
Statistical power and correlational analyses. Due to the relatively small number of subjects studied, an important consideration is whether or not this study had adequate statistical power to support the conclusions reached. The repeated-measures design of the study, combined with a very strong within-subjects intraclass correlation and low coefficients of variation (Table 1) for the dependent variables of interest, largely offsets the potential lack of power risked by using a small number of subjects. This is evidenced by highly significant effects for many of the dependent variables. In addition, post hoc power calculations revealed an average power of >0.81 for the calculations involving the majority of the dependent variables. Another important consideration is the use of correlations and the subsequent proposals of physiological mechanisms for a link between such data. To avoid any spurious correlations, and hence false conclusions, we avoided investigating relationships between variables that have "common divisors." The use of such common divisors would result in probable spurious correlations (18) and hence wrongful interpretation of our results. Although we recognize the limitations of correlational analysis, we feel justified in the proposal of physiological mechanisms for a link between our data and are confident that the data are not spuriously related or as a result of a statistical artifact.
In summary, the results of the present study provide insight into the complex integration of the ventilatory, cardiovascular, and cerebrovascular control systems during periods of acute hypoxia in awake humans. The between-individual variability in AHVR is shown to be firmly linked to the variability in p and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high p and MAP responses to hypoxia.
|
GRANTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. D. Steinback and M. J. Poulin Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans J Appl Physiol, February 1, 2008; 104(2): 482 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bartsch and J. S. R. Gibbs Effect of Altitude on the Heart and the Lungs Circulation, November 6, 2007; 116(19): 2191 - 2202. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Duffin Measuring the ventilatory response to hypoxia J. Physiol., October 1, 2007; 584(1): 285 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Ainslie, A. Barach, K. J. Cummings, C. Murrell, M. Hamlin, and J. Hellemans Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans J Appl Physiol, May 1, 2007; 102(5): 1953 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Cummings, M. Swart, and P. N. Ainslie Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2 J Appl Physiol, May 1, 2007; 102(5): 1891 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Foster, P. J. Hanly, M. Ostrowski, and M. J. Poulin Effects of Continuous Positive Airway Pressure on Cerebral Vascular Response to Hypoxia in Patients with Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 720 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Ainslie, K. Burgess, P. Subedi, and K. R. Burgess Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep J Appl Physiol, February 1, 2007; 102(2): 658 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Teppema, G. M. Balanos, C. D. Steinback, A. D. Brown, G. E. Foster, H. J. Duff, R. Leigh, and M. J. Poulin Effects of Acetazolamide on Ventilatory, Cerebrovascular, and Pulmonary Vascular Responses to Hypoxia Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 277 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Foster, D. C. McKenzie, W. K. Milsom, and A. W. Sheel Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia J. Physiol., September 1, 2005; 567(2): 689 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. E. Imray, S. D. Myers, K. T. S. Pattinson, A. R. Bradwell, C. W. Chan, S. Harris, P. Collins, A. D. Wright, and the Birmingham Medical Research Expeditionary Soci Effect of exercise on cerebral perfusion in humans at high altitude J Appl Physiol, August 1, 2005; 99(2): 699 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N Ainslie, J. C Ashmead, K. Ide, B. J Morgan, and M. J Poulin Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans J. Physiol., July 15, 2005; 566(2): 613 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
, Hypercapnic protocol; 
, isocapnic protocol; 
, poikilocapnic protocol.
p, and MAP from isocapnic hyperoxic protocol and from within each hyperoxic control baseline at the lowest level of hypoxia (PETO2 = 45 Torr) during poikilocapnic, isocapnic, and hypercapnic conditions