Journal of Applied Physiology Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 104: 482-489, 2008. First published November 29, 2007; doi:10.1152/japplphysiol.00553.2007
8750-7587/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
104/2/482    most recent
00553.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steinback, C. D.
Right arrow Articles by Poulin, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steinback, C. D.
Right arrow Articles by Poulin, M. J.

Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans

Craig D. Steinback and Marc J. Poulin

Departments of Physiology and Biophysics and Clinical Neurosciences, Hotchkiss Brain Institute and the Libin Cardiovascular Institute, Faculty of Medicine and Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada

Submitted 22 May 2007 ; accepted in final form 19 November 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 ± 4.2 yr, mean ± SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (VP) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH (P < 0.01) and PH (P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, VP was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of ~0.34 cm·s–1·%desaturation–1 (P < 0.05). The VP response to PH was biphasic with an initial decrease from baseline occurring at 79 ± 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of –0.24 cm·s–1·%desaturation–1. When expressed in relation to end-tidal PCO2, a sensitivity of –1.08 cm·s–1·Torr–1 was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.

cerebral blood flow; blood pressure; heart rate; hypocapnia

THERE IS SUBSTANTIAL INTERACTION between the cardiovascular and respiratory systems to ensure adequate oxygen delivery to organs and tissues. On a systemic scale, the oxygen transport cascade can be affected critically by alterations in respiration and or convective transport via the circulation. However, in the face of such perturbations, O2 transport is optimized by cardiorespiratory reflex interactions and adaptations. For instance, inputs from cardiovascular (e.g., baroreceptors) and respiratory (e.g., chemoreceptors) sensors share common neural pathways, inputting into common areas within the brain stem (9). Further, these afferent inputs have been shown to interact, modulating the differential control of both systems (18, 44). In addition, regulation of blood flow in the brain impacts importantly on tissue pH, affecting central chemoreception and in turn respiration (51). Equally, changes in respiration can affect arterial PCO2 (PaCO2) and in turn cerebral blood flow (CBF).

The hypoxia of altitude, concomitant with a systemic alkalosis, places a unique stress on the cardiorespiratory system. At the onset of exposure, a rise in cardiac output is observed that is driven by increases in heart rate (HR). With longer exposure (days to weeks), cardiac output then falls in conjunction with stroke volume while HR remains elevated (6, 10, 29, 50). Under these conditions, inadequate adaptations may result in exercise fatigue or, worse, deteriorate into life-threatening conditions such as acute mountain sickness or pulmonary or cerebral edema. Further, in other pathological situations where respiratory and or cardiovascular function is compromised (e.g., sleep apnea or pulmonary hypertension), secondary ailments may also evolve due to cardiorespiratory linkages. Thus an understanding of cardiorespiratory interactions is important from basic and applied physiology and clinical perspectives.

Previous investigations of the cardiovascular responses to acute hypoxia have typically focused on discreet "steady-state" time points many minutes into a hypoxic exposure. Additionally, experiments designed to investigate the cardiovascular response to specific carotid body stimulation have generally been carried out with isocapnia, thereby avoiding the concomitant hypocapnia that is typically associated with hypoxia at altitude. Since carbon dioxide is a known, potent regulator of blood flow (37), the influence of changes in PaCO2 need to be accounted for when studying the effects of hypoxia where concomitant hypocapnia may influence the local vasculature, the chemical regulation of cardiovascular responses, and integrated cardiorespiratory control.

The early work of Shapiro et al. (43) attempted to address the influence of eucapnic vs. isocapnic hypoxia on CBF in humans. This work elegantly illustrated a blunting of CBF due to alkalosis in the face of ongoing hypoxia. However, technical limitations precluded a comprehensive comparison between similar levels of hypoxia, nor was an investigation of other cardiovascular factors carried out. In a previous investigation from our laboratory, the cardiovascular and cerebrovascular responses to hypoxia were assessed using a multistep hypoxic design (4). In that study, hypocapnic hypoxia was shown to blunt cerebrovascular and cardiovascular sensitivities to hypoxia. However, the multistep approach did not allow the investigation of the time course of cerebrovascular and cardiovascular adaptation to hypoxia. Taken together, these data indicate a key role of arterial hypocapnia but highlight the need to further investigate the dynamic cardiovascular effects of hypoxia in the presence of hypocapnia.

The present investigation was part of a larger, multifaceted study comparing the dynamic cardiorespiratory responses to isocapnic vs. poikilocapnic hypoxia in humans. In a previous study, we showed that controlling PaCO2 critically affected dynamic respiratory responses during systemic hypoxia (45). In this context, it appears that the concomitant alkalosis associated with poikilocapnic hypoxia blunts the overall ventilatory response and influences ventilatory components but does not play a role in the pattern of ventilatory adaptation to hypoxia. It remains unclear whether alkalosis affects the dynamic nature of the cardiovascular response to hypoxia similarly.

Thus the present study investigates dynamic cardiovascular and cerebrovascular responses to hypoxia, as influenced by changes in PaCO2 in the hypocapnic range. Furthermore, we examined the influence of respiration on cardiovascular control by combining the novel data and analyses on cardiorespiratory interaction presented in the present study with those previously published respiratory observations (45).

We utilized single-step hypoxic exposures with and without controlled PCO2 to separate the effects of predominant hypoxia from those of concomitant hypocapnia. Further, hypoxia was maintained during both conditions for a duration of 20 min such that the temporal aspects of the cardiovascular responses could be investigated. Although previous studies have investigated the affects of alkalosis on cardiovascular function during hypoxia, to our knowledge a rigorous comparison of the dynamic characteristics of the cardiovascular and cerebrovascular responses to poikilocapnic and isocapnic hypoxia has not been conducted in humans.

We hypothesized that the hypoxic stimulus would influence the shape of the dynamic pattern of cardiovascular and cerebrovascular responses, while hypocapnic alkalosis would act to suppress these patterns. Additionally, we predicted that the profiles of the cardiovascular and cerebrovascular responses undergo adaptation over time such that as hypoxia progresses a gradual fall in HR, mean arterial pressure (MAP), and CBF ensues. We speculate that this adaptation to hypoxia might be mediated by a cardioventilatory interaction, associated with the phenomenon of hypoxic ventilatory decline (HVD).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Ten healthy men (25.7 ± 4.2 yr, mean ± SD) participated in this study. All subjects provided informed written consent after receiving verbal and written instructions outlining the experimental procedures. Participants were not taking any medications, all were nonsmokers, and none had any history of cardiovascular or respiratory disease. This study was approved by the Conjoint Health Research Ethics Board at the University of Calgary (Grant ID no. 15671) and conforms to the standards set by the Declaration of Helsinki.

Protocol.   Experiments were conducted at an elevation of 1,103 m and a barometric pressure of 665 ± 5 Torr. Subjects abstained from caffeine, alcohol, and strenuous exercise for 12 h before testing. During experimentation, subjects took part in two randomized protocols separated by a 40-min rest period.

Before each protocol, subjects' resting end-tidal PO2 (PETO2) and PCO2 (PETCO2) were measured for ~10 min with the subject in a comfortable semisupine position. Respired gas was sampled continuously (20 ml/min) via a small-bore catheter (0.3-mm internal diameter) and analyzed for PO2 and PCO2 by mass spectrometer (AMIS 2000, Innovision, Odense, Denmark). Values for PO2 and PCO2 were sampled by computer every 10 ms, and PETO2 and PETCO2 were identified and recorded for each breath using a computer and dedicated software (Chamber v2.10, University Laboratory of Physiology, Oxford, UK).

Each protocol began with a 10-min baseline period during which the subject breathed normally through a facemask, which allowed for natural mouth and/or nasal breathing (model 16709, ResMed, Poway, CA). Accurate control of end-tidal gases was achieved using the technique of dynamic end-tidal forcing (4, 38, 39) and dedicated software (BreatheM v2.35, University Laboratory of Physiology).

After 10 min of euoxia (PETO2 ~ 88 Torr), PETO2 was decreased within 2–3 breaths to 45 Torr. During an isocapnic hypoxic protocol (IH), PETCO2 was held constant at +1 Torr above resting (45). During a poikilocapnic hypoxic protocol (PH), PETCO2 was allowed to vary naturally. Hypoxia was maintained for 20 min, after which period PETO2 was returned to 88 Torr for 10 min.

Cardiovascular measurements.   Backscatter Doppler signals from the right middle cerebral artery (MCA) were measured continuously using a 2-MHz pulsed Doppler ultrasound system (PCDOP 842, SciMed) using previously published methods and criteria (1, 32, 34). Briefly, the MCA was insonated through the right temporal window superior to the zygomatic arch. Focal depth and probe angle were varied to maximize the peak Doppler frequency shift. Instrumentation was carried out by the same investigator for all subjects. Our index of flow (VP) was calculated as the mean of the peak flow velocity envelope on a beat-by-beat basis. The total power spectrum signal was also collected as a representation of vessel cross-sectional area (5, 7). MAP, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were calculated from the blood pressure waveform on a beat-by-beat basis using finger photoplethysmography (Portapres, TPD Biomedical Instrumentation, Delft, The Netherlands). MAP was calculated as the area under the blood pressure waveform with the peak and the nadir representing SBP and DBP, respectively. HR was calculated from a standard three-lead ECG (Micromon 7142B, Kontron Medical, Milton Keynes, UK).

Data analysis.   One-minute averages were calculated for all variables immediately before the onset of hypoxia (time = –1 min), every 5 min during hypoxia (time = +5, +10, +15, and +20 min), and 5 min posthypoxia (time = +25 min). A 1-min average was also determined at the time point corresponding to the subject-specific nadir of the VP response during PH. This time point was also identified during the IH protocol for comparison between conditions. An index of cerebral vascular resistance was calculated from VP and MAP data.

To express cardiovascular gains as linear functions of the hypoxic stimulus, PETO2 was converted to a calculation of O2 saturation (ScO2) (42). Use of ScFormula avoided methodological limitations associated with pulse oximetry during conditions where changes finger blood flow may influence the accuracy of measurement (49). The gains of the acute cardiovascular response to hypoxia were calculated for VP (AHRVP), MAP (AHRMAP), and HR (AHRHR) using the following indexes:

Formula 1(1)

Formula 2(2)

Formula 3(3)

All delta ({Delta}) values were calculated in relation to the time point immediately before the onset of hypoxia (time = –1 min).

A second, objective mathematical approach was also used to analyze Formula 3P data. The mathematical model described by Poulin et al. (34) was applied to the isocapnic data to corroborate our manually derived indexes. Because of a brief gap in data collection (~10 s), data for one subject could not be analyzed using this approach. As such, modeling data represent 9 of 10 subjects. This anomaly did not influence the mean values reported elsewhere.

Statistical analysis.   All cardiovascular data were analyzed using a multivariate repeated-measures design, with two parallel conditions compared using preplanned contrasts. To account for multiple comparisons (c), P values were corrected using the chosen comparisonwise error rate ({alpha}, 0.05) and the calculated experimentwise error rate ({alpha}e) (19):

Formula 4(4)

Formula 5(5)

Formula 6(6)
where P0 and P1 represent the original and corrected P values, respectively, and {alpha}1 represents the adjustment factor based on the chosen level of significance. The number of multiple comparisons differed with the variable analyzed.

Relationships between variables were investigated using Pearson correlation analysis. All statistical analyses were performed using SPPS (v13.0, SPSS). Significance was set at P1 < 0.05. Data are expressed as means ± SD.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Mean traces of PETO2 and PETCO2, indicating gas control, during both protocols and the temporal profiles of ventilation (Formula 6E) and for all cardiovascular variables, expressed as percentages relative to baseline, are illustrated in Fig. 1; absolute values for cardiovascular variables at relevant time points are shown in Table 1.


Figure 1
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 1. Mean values (n = 10) of end-tidal gases, ventilation, and cardiovascular variables during isocapnic hypoxia (solid lines) and poikilocapnic hypoxia (dashed lines). Cardiovascular variables are expressed as a percentage of baselines. A: end-tidal PO2 (PETO2). B: end-tidal PCO2 (PETCO2). C: ventilation (Formula 6E). D: heart rate (HR). E: mean arterial blood pressure (MAP). F: middle cerebral artery peak velocity (Formula 6P).

 

View this table:
[in this window]
[in a new window]

  		Table 1. Absolute values for end-tidal gases, ventilation, and cardiovascular variables during isocapnic and poikilocapnic hypoxia

 
HR.   HR was increased from 64.4 ± 10.7 to 84.3 ± 10.3 beats/min during IH (+32.5 ± 15.5%, P < 0.001) and from 62.2 ± 11.7 to 80.1 ± 15.4 beats/min(+29.2 ± 10.6%, P < 0.001) during PH, at the nadir time point, but diminished to 76.4 ± 12.0 beats/min (P < 0.05) and 72.5 ± 12.5 beats/min (P < 0.001), respectively, by time = +20 min. This is shown as a decline in AHRHR over time during both IH and PH, with initial values of 1.32 ± 0.47 and 1.07 ± 0.41 beats·min–1·%desaturation–1 at the nadir time point, respectively, declining to 0.75 ± 0.24 beats·min–1·% desaturation–1 (P < 0.05) during IH and 0.64 ± 0.23 beats·min–1·% desaturation–1 (P < 0.01) during PH at time = +20 min. HR gains across time during IH and PH are shown in Table 2. The HR response to hypoxia exhibited a strikingly similar pattern to that of Formula 6E. Correlation analysis of the relationship between Formula 6E and HR indicated a modest but significant relationship during both IH (r = 0.62, P < 0.001) and PH (r = 0.31, P < 0.01).


View this table:
[in this window]
[in a new window]

  		Table 2. Cardiovascular sensitivities during isocapnic and poikilocapnic hypoxia

 
Blood pressure.   There was a modest increase in MAP during both protocols. However, while the increase in MAP occurred immediately following the initiation of IH, the response during PH was delayed. During IH, MAP rose from 68.7 ± 11.7 to 74.9 ± 11.9 mmHg at the nadir time point but was not elevated until time = +5 min during PH (67.7 ± 7.6 to 72.5 ± 9.2 mmHg). Subsequently, the increase in MAP was maintained throughout hypoxia during both conditions. At the offset of hypoxia, MAP returned toward baseline during IH. However, during PH, MAP remained elevated with respect to baseline at time = +25 min (76.7 ± 13.1 mmHg, P < 0.05). Calculation of AHRMAP indicated a consistent gain across all time points during IH (~0.37 mmHg/%desaturation). During PH, AHRMAP was significantly lower than during IH at the nadir time point (0.05 ± 0.29 vs. 0.39 ± 0.48 mmHg/%desaturation, P < 0.05), rising to a similar level as IH by time = +5 min. No further differences were observed between conditions.

CBF.   Our index of MCA cross sectional area (power) was unchanged from baseline during both conditions. Therefore, Formula 6P was used as our index of CBF. During IH, Formula 6P was significantly elevated throughout the hypoxic exposure and remained modestly elevated at time = +25 min (102.5 ± 2.8%; +1.9 ± 1.4 cm/s, P < 0.01). Alternatively, the response during PH was biphasic, with an initial decrease in Formula 6P (94.0 ± 5.3%, –3.1 ± 2.7 cm/s, P < 0.01), reaching its nadir at 79 ± 26 s. This was followed by a subsequent rise in Formula 6P, becoming significantly elevated above baseline by time = +5 min (103.2 ± 5.0%, +2.0 ± 2.4 cm/s, P < 0.01). As in IH, Formula 6P following PH remained modestly increased above baseline (102.4 ± 6.2%, +1.8 ± 2.8 cm/s, P < 0.05).

The nadir of the Formula 6P response during PH was found to correspond closely with the timing of the peak ventilatory response during PH (80 ± 42 s). When correlation analyses of the change in Formula 6P vs. changes in Formula 6E or PETCO2 were performed, no significant relationships were found [r = –0.08, not significant (NS), and r = –0.09, NS]. However, on removing one subject who exhibited no change in Formula 6P at the onset of PH, the relationship between Formula 6P and Formula 6E became significant (r = –0.68, P < 0.05), although the relationship with PETCO2 remained nonsignificant (r = –0.2, NS). Further analysis of the relationships between the change in Formula 6P and Formula 6E and PETCO2 could not explain the subsequent rise in Formula 6P during PH.

No differences in middle cerebral artery resistance (or conductance) were observed during IH. However, during PH an increase in resistance (a decrease in conductance) was observed early in hypoxia, corresponding to the nadir of the Formula 6P response (P = 0.031 compared with baseline). This increase in resistance was subsequently normalized by time = +5 min as Formula 6P continued to rise, becoming equivalent to that observed during IH by time = +10 min.

The AHRVP during IH was 0.29 ± 0.25 cm·s–1· % desaturation–1 at the nadir time point and remained unchanged throughout the hypoxic exposure. Alternatively, the AHRVP during PH exhibited an increase across time with an initial nadir sensitivity of –0.25 ± 0.19 cm·s–1·% desaturation–1 increasing to 0.08 ± 0.16 cm·s–1·% desaturation–1 at time = +5 min (P < 0.001 with respect to nadir) and further rose to 0.28 ± 0.22 cm·s–1·%desaturation–1 at time = +20 min (P < 0.001 with respect to nadir). The relationships of AHRVP between conditions and across time are shown in Table 2.

Modeled response to IH.   Formula 6P data were modeled for 9 of 10 subjects to provide a secondary, objective verification of our derived sensitivities. The steady-state Formula 6P gain in response to hypoxia (gh) was 0.32 ± 012 cm·s–1·%desaturation–1 with a time delay (Td) and time constant ({tau}on) of 9.1 ± 8.7 s and 81.2 ± 86.2 s, respectively. Correlation analysis of the relationship between gh and AHRVP at time = +20 min (n = 9) showed a strong relationship (R = 0.90, P = 0.001) between the two measures of hypoxic gain, corroborating our manually derived calculations.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Main findings.   To our knowledge this is the first study to investigate the dynamic temporal cardiovascular responses to both isocapnic and poikilocapnic hypoxia in humans. The investigation of adaptation to poikilocapnic hypoxia is important, as this represents the in vivo conditions associated with altitude. While the HR response was the same between IH and PH, significant differences in the dynamic profiles of the MAP and Formula 6P responses were observed. MAP was increased during both conditions, with the response developing later in hypoxia during PH. The Formula 6P response during IH exhibited a typical increase, occurring rapidly after the onset of hypoxia, which was then maintained for the duration of the exposure. Alternatively, the response during PH was biphasic, with an initial decrease in CBF followed by a subsequent recovery, which then became significantly elevated with respect to baseline, and equivalent to the IH condition by time = +10 min.

HR response.   HR was shown to increase substantially at the initiation of both IH and PH, with a subsequent progressive decline with time. This response pattern has been shown previously during isocapnic protocols (46, 47), with steady-state gains (at ~20 min) very similar to our own (30). Studies of isolated carotid body stimulation in animals document a reflex bradycardia when ventilation is constrained (31), and no change (47) or a decrease (11) in HR is observed during hypoxia in humans when breathing is controlled. The tachycardia exhibited by the systemic response to hypoxia is therefore related to the stimulation of lung mechanoreceptors, which cause HR to increase via parasympathetic withdrawal (30). This study confirms the relationship between Formula 6E and HR. In this way, the progressive decline in HR with time, despite a maintained level of hypoxia, may be linked to the development of hypoxic ventilatory decline, wherein a decline in ventilation results in a gradual decrease in HR as we have documented. Indeed, in a study of longer duration, the secondary rise in ventilation associated with the onset of hypoxic acclimatization was mirrored by similar changes in HR (46). Further, during sustained hypercapnia, ventilation is elevated with no evidence of ventilatory decline as seen during prolonged hypoxic exposures (33). The increase in HR is similar, remaining consistently elevated throughout sustained hypercapnic exposures (27).

These direct linkages between ventilation and HR are not surprising in light of respiratory sinus arrhythmia, where ventilation "gates" HR (13). However, in the present study, no significant difference in HR was observed between IH and PH, whereas ventilation was significantly higher during IH. While this disparity may tend to contradict a major role of lung stretch receptors, two factors may explain these results. First, a recent paper by Rutherford et al. (40) proposes an additional tachycardic effect due to hypocapnic coronary vasoconstriction. Second, blunting of the chemosensory response to hypoxia during hypocapnia could be expected to result in a decreased reflex bradycardia; therefore a smaller Formula 6E may act to withdraw parasympathetic tone and cause HR to rise to the same extent as during isocapnia. This may help explain the equivalency in HR responses during IH and PH, despite differing ventilatory responses (45). Interestingly, the above relationship is strongest with respect to changes in total ventilation, not changes tidal volume. This would tend to indicate that rate of lung stretch, not just volume, also plays a role in the tachycardic response to hypoxia.

Blood pressure response.   In the present study our subjects exhibited MAP of ~70 mmHg and SBP and DBP of ~110 mmHg and ~55 mmHg, respectively, at rest. These values are lower than the stereotypical norms of 93 mmHg, 120 mmHg, and 80 mmHg for mean, systolic, and diastolic pressures, respectively. There are a number of factors that may contribute to this apparent difference. First, the subjects taking part in the present investigation were all young healthy men who were regularly active in various cardiovascular exercises and may be expected to have slightly lower resting blood pressures. Second, the extensive research of Imholz et al. has assessed the accuracy of photoplethysmography during many interventions (for reviews see Refs. 21, 22). Their research indicates that various devices utilizing this technique, including the Portapres system used in the present study, may tend to underestimate both mean and diastolic pressures in a range of –1.6 ± 8 mmHg (22). However, this same research shows that these devices accurately track broad changes in arterial blood pressure compared with intra-arterial measures. In the context of the present study, our values for mean and diastolic blood pressure may be slightly below expected values, but we are confident that the temporal pattern of changes in blood pressure are an accurate representation of true blood pressure.

While the blood pressure response to isocapnic hypoxia is the result of a complex interaction between neural and local effects on vascular tone as well as the influence of cardiac output, a modest increase in MAP has been documented in response to systemic hypoxia in humans (16, 31). Similarly, in the present study, MAP was elevated during both IH and PH, but with the response developing earlier during the isocapnic condition. The disparity in the response dynamics during PH may be attributable to the concomitant hypocapnia. Both Richardson et al. (37) and Kontos et al. (28) have documented a biphasic blood pressure response during hyperventilation-induced hypocapnia, with a transient decrease within the first 1–5 min due to histamine-mediated decreases in vascular resistance (28) and subsequent rise to baseline levels over the next 5 min due to the local vasoconstrictor actions of alkalosis (12). Although hypoxia is also a vasodilating agent, it also causes a large increase in sympathetic vasoconstrictor nerve activity (52). In this way, the combined effects of hypocapnia and hypoxia may result in a blood pressure response that is suppressed early in hypoxia but becomes significantly elevated with longer exposure. The steady-state gains (time = +20 min) of the response were similar to that reported previously during IH (3) and PH (4) from our laboratory.

CBF response.   To accurately study CBF dynamics, PO2 and PCO2 must be finely controlled. The technique of end-tidal gas forcing has been shown to significantly reduce variability in middle cerebral artery flow (17), in part by controlling variations in PO2 and PCO2, which can have profound effects on the cerebral circulation (20). In the present study, the response to IH was characterized by an increase in CBF with a steady-state gain of ~0.3 cm/s per percent desaturation and a time constant of ~81 s, whereas the response to PH was biphasic. A recent study by Ainslie et al. (2) has also documented a initial decrease in Formula 6P at the onset of PH. However, while Formula 6P returned toward baseline with maintained exposure, they did not document a subsequent rise in Formula 6P as we have reported in the present investigation.

In our study, no changes in middle cerebral artery resistance (or conductance) were observed during IH. These data would suggest that the flow profile during IH is mediated via changes in perfusion, and not hypoxic vasodilation in the brain. This is counter to previous reports indicating a decrease in cerebral vascular resistance (8, 25, 43) during IH and data indicating that the level of hypoxia utilized in the present study exceeds the threshold for hypoxic cerebral vasodilation (15, 25). However, our hypoxic stimulus may have been potent enough to cause a significant rise in cardiac output greater than the vasodilation occurring in the brain, masking any changes in vascular resistance. However, without a measure of cardiac output in the present study, this remains unclear. During PH, the onset of hypoxia was characterized by an increase in cerebral vascular resistance, causing a decrease in blood flow. By 10 min, the change in resistance was normalized, and blood flow rose significantly. As blood pressure was not decreased at the onset of hypoxia during the PH condition, the initial increase in resistance may be mediated by a hypocapnia-induced constriction in the brain. However, we were unable to document any significant relationships between changes in Formula 6P and changes in PETCO2. That being said, our indirect measure of arterial CO2 may not accurately represent changes in brain tissue pH. The subsequent normalization of middle cerebral artery resistance, and an increase in blood flow equivalent to the IH condition by time = +10 min, would appear to indicate an elimination of any hypocapnic constriction and a dominance of perfusion-related mechanisms similar to that seen during IH.

Support for the role of decreased brain PCO2/pH at the onset of PH comes from the similarity of the Formula 6P profile compared with that reported during hyperventilation-induced hypocapnia (14, 35). The CBF response to euoxic hypocapnia is characterized by an initial decrease in Formula 6P, followed by a secondary slow rise over time similar to what we report during PH. If we express the percentage reduction in Formula 6P at the onset of PH as a function of PETCO2, a nadir sensitivity of –2.13%/Torr is calculated. This is very similar to previous investigations of the cerebrovascular responses to hypocapnia (14, 35). However, although Formula 6P exhibits a progressive rise during euoxic hypocapnia, it does not return to baseline levels (14, 35), whereas we document significantly elevated Formula 6P by time = +20 min. The near equivalency of Formula 6P during IH and PH at time = +20 min indicates that the hypoxic stimulus dominates late in the PH exposure. The resultant Formula 6P-time curve represents an interaction between these two competing variables.

The use of a secondary, objective mathematical model applied to the IH data served to verify our derivations of cerebrovascular sensitivities. The complexity of the response occurring during PH precludes the use of this model on these data. However, on the basis of the strong correlation between modeled gain (gh) and AHRVP during IH, we are confident that our calculation of AHRVP during PH is also accurate.

Methodological considerations.   The present study was conducted at an altitude of ~1,100 m. This must be taken into consideration when interpreting our results, particularly considering 7 of 10 subjects were native to altitudes lower than 500 m and/or returned to near sea level altitude multiple times yearly. As such, we could expect that our subjects may be representative of sojourners, but not natives, of mild altitude. Previous studies have shown that acclimatization to both mild (1,560 m) (2) and moderate (3,810 m) (23) altitude is characterized by augmented cardiovascular gains. As such, we may expect our cardiovascular gains to be slightly higher than those reported at near sea level.

The use of transcranial Doppler (TCD) ultrasound has been used extensively in clinical and research settings as a noninvasive method of measuring CBF. However, this is based on some basic assumptions that must be taken into consideration when interpreting results (26). First, here we have used VP as our index of flow while assuming that cross-sectional area of the MCA remains constant. We have based this assumption on previously published data indicating no appreciable change in MCA caliber during similar interventions as used in the present study (41). Further, the total power spectrum of the Doppler signal has been previously shown to be an accurate representation of vessel cross-sectional area (5, 7) and in keeping with the results of the present investigation does not change during the chosen level of hypoxia (36). Second, we have assumed that Formula 6P is the most accurate representation of flow velocity in the MCA. This is in keeping with previously published data (24) and the observation that the intensity-weighted mean velocity exhibited the same responses as Formula 6P (not shown). As such, we believe that Formula 6P represents an accurate index of MCA blood flow in the present study.

The present study sought to investigate the dynamic cardiovascular responses to both isocapnic and poikilocapnic hypoxia. This required a prolonged and finely controlled stimulus. The use of dynamic end-tidal forcing allowed for precise control of end-tidal (~arterial) PO2 and PCO2 on a breath-by-breath basis. Recent work by Vantanajal from our laboratory (48) using similar methods has shown this particular technique to be precise to within ±0.6 Torr for PETCO2 and ±2.0 Torr for PETO2. In this way, we were certain that the delivered stimulus was consistent and accurate, avoiding oscillations that could interfere with analysis and interpretation. However, one limitation of our experimental approach is its use of one specific hypoxic stimulus. As such, data from this particular protocol may not be representative of the response at more extreme or less severe hypoxic levels.

Summary   The alterations in cardiovascular gains over time observed here may not be specific to hypoxia per se. From these data we provide evidence of the effect of ventilation and arterial or tissue PCO2/pH in the cardiovascular and cerebrovascular adaptation to sustained hypoxia. Furthermore, the local and neural mechanisms of hypoxia may also independently adapt. The cerebrovascular response to poikilocapnic (hypocapnic) hypoxia contains an early response, which appears to be mediated predominantly by the decrease in PCO2, followed by a secondary response, mediated predominantly by hypoxia. However, these effects appear to be due to an increase in cerebral perfusion, not a change in cerebral resistance. As such, the overall response likely involves multiple, possibly interacting, mechanisms. The protocols in the present study, specifically the inclusion of a poikilocapnic design, are more representative of in vivo environments and illustrate the dynamic nature by which hypocapnic alkalosis critically alters the cardiovascular and cerebrovascular responses to hypoxia.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This project was supported by the Alberta Heritage Foundation for Medical Research (AHFMR); Heart and Stroke Foundation of Alberta, NWT and Nunavut; the Canadian Institutes of Health Research; and the Canada Foundation for Innovation. M. J. Poulin is an AHFMR Senior Medical Scholar.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Dr. P. N. Ainslie and Dr. J. C. Kolb for input and feedback throughout the study, and we extend our gratitude to Professor P. A. Robbins for assistance in setting up the technique of dynamic end-tidal forcing in Calgary.

Present address for C. D. Steinback: School of Kinesiology, Faculty of Health Sciences, The University of Western Ontario, 1151 Richmond St., London, Ontario, Canada N6A 3K7 (e-mail: cdsteinb@uwo.ca).


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. J. Poulin, Dept. of Physiology and Biophysics, Faculty of Medicine, Univ. of Calgary, HMRB-212, 3330 Hospital Dr., NW, Calgary, Alberta, Canada T2N 4N1 (e-mail: poulin{at}ucalgary.ca)

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
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 57: 769–774, 1982.[Web of Science][Medline]
  2. Ainslie PN, Barach A, Cummings KJ, Murrell C, Hamlin M, Hellemans J. Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans. J Appl Physiol 102: 1953–1961, 2007.[Abstract/Free Full Text]
  3. Ainslie PN, Kolb JC, Ide K, Poulin MJ. Effect of five nights of normobaric hypoxia on cardiovascular responses to acute isocapnic hypoxia in humans: relationship to ventilatory chemosensitivity. Ergonomics 48: 1523–1534, 2005.[Medline]
  4. Ainslie PN, Poulin MJ. Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide. J Appl Physiol 97: 149–159, 2004.[Abstract/Free Full Text]
  5. Arts MG, Roevros JM. On the instantaneous measurement of bloodflow by ultrasonic means. Med Biol Eng 10: 23–34, 1972.[CrossRef][Web of Science][Medline]
  6. Asmussen E, Consolazio FC. The circulation in rest and work on Mount Evans. Am J Physiol 132: 555–563, 1941.[Free Full Text]
  7. Burns PN. The physical principles of Doppler and spectral analysis. J Clin Ultrasound 15: 567–590, 1987.[Web of Science][Medline]
  8. Cohen PJ, Alexander SC, Smith TC, Reivich M, Wollman H. Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. J Appl Physiol 23: 183–189, 1967.[Free Full Text]
  9. Dampney RA, Horiuchi J. Functional organisation of central cardiovascular pathways: studies using c-fos gene expression. Prog Neurobiol 71: 359–384, 2003.[CrossRef][Web of Science][Medline]
  10. Davidson D, Stalcup SA, Mellins RB. Systemic hemodynamics affecting cardiac output during hypocapnic and hypercapnic hypoxia. J Appl Physiol 60: 1230–1236, 1986.[Abstract/Free Full Text]
  11. De Burgh Daly M. Carotid bodies: "primary" cardiovascular responses. In: Peripheral Arterial Chemoreceptors and Respiratory-Cardiovascular Integration. Oxford: Oxford Univ. Press, 1997, chapt. 9, p. 288–344.
  12. De Burgh Daly M. Interactions between respiration and circulation. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 2002, sect 3, pt. II, chapt. 16, p. 529–594.
  13. Eckberg DL. The human respiratory gate. J Physiol 548: 339–352, 2003.[Abstract/Free Full Text]
  14. Ellingsen I, Hauge A, Nicolaysen G, Thoresen M, Walloe L. Changes in human cerebral blood flow due to step changes in PaO2 and PaCO2. Acta Physiol Scand 129: 157–163, 1987.[Web of Science][Medline]
  15. Gupta AK, Menon DK, Czosnyka M, Smielewski P, Jones JG. Thresholds for hypoxic cerebral vasodilation in volunteers. Anesth Analg 85: 817–820, 1997.[Abstract]
  16. Halliwill JR, Morgan BJ, Charkoudian N. Peripheral chemoreflex and baroreflex interactions in cardiovascular regulation in humans. J Physiol 552: 295–302, 2003.[Abstract/Free Full Text]
  17. Harris AD, Ide K, Poulin MJ, Frayne R. Control of end-tidal PCO2 reduces middle cerebral artery blood velocity variability: implications for physiological neuroimaging. Neuroimage 29: 1272–1277, 2006.[CrossRef][Medline]
  18. Heistad D, Abboud FM, Mark AL, Schmid PG. Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation. J Appl Physiol 39: 411–416, 1975.[Abstract/Free Full Text]
  19. Hinkle DE, Wiersma W, Jurs SG. Multiple-comparison procedures. In: AppliedStatistics for the Behavioral Sciences. New York: Houghton-Mifflin, 2003, p. 370–399.
  20. Ide K, Eliasziw M, Poulin MJ. The relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans. J Appl Physiol 95: 129–137, 2003.[Abstract/Free Full Text]
  21. Imholz BP, Wieling W, Langewouters GJ, van Montfrans GA. Continuous finger arterial pressure: utility in the cardiovascular laboratory. Clin Auton Res 1: 43–53, 1991.[CrossRef][Medline]
  22. Imholz BP, Wieling W, van Montfrans GA, Wesseling KH. Fifteen years experience with finger arterial pressure monitoring: assessment of the technology. Cardiovasc Res 38: 605–616, 1998.[Abstract/Free Full Text]
  23. Jensen JB, Sperling B, Severinghaus JW, Lassen NA. Augmented hypoxic cerebral vasodilation in men during 5 days at 3,810 m altitude. J Appl Physiol 80: 1214–1218, 1996.[Abstract/Free Full Text]
  24. Kirkham FJ, Padayachee TS, Parsons S, Seargeant LS, House FR, Gosling RG. Transcranial measurement of blood velocities in the basal cerebral arteries using pulsed Doppler ultrasound: velocity as an index of flow. Ultrasound Med Biol 12: 15–21, 1986.[CrossRef][Web of Science][Medline]
  25. Kogure K, Scheinberg P, Reinmuth OM, Fujishima M, Busto R. Mechanisms of cerebral vasodilatation in hypoxia. J Appl Physiol 29: 223–229, 1970.[Free Full Text]
  26. Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 20: 1–3, 1989.[Free Full Text]
  27. Kontos HA, Richardson DW, Patterson JL Jr. Roles of hypercapnia and acidosis in the vasodilator response to hypercapnic acidosis. Am J Physiol 215: 1406–1408, 1968.[Free Full Text]
  28. Kontos HA, Richardson DW, Raper AJ, Zubair uH, Patterson JL Jr. Mechanisms of action of hypocapnic alkalosis on limb blood vessels in man and dog. Am J Physiol 223: 1296–1307, 1972.[Free Full Text]
  29. Lenfant C, Sullivan K. Adaptation to high altitude. N Engl J Med 284: 1298–1309, 1971.[Web of Science][Medline]
  30. Lucy SD, Hughson RL, Kowalchuk JM, Paterson DH, Cunningham DA. Body position and cardiac dynamic and chronotropic responses to steady-state isocapnic hypoxaemia in humans. Exp Physiol 85: 227–237, 2000.[Abstract]
  31. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 74: 543–594, 1994.[Free Full Text]
  32. Padayachee TS, Gosling RG. Transcranial pulsed Doppler methods in assessing the cerebral circulation. In: Cardiovascular Applications of Doppler Ultrasound, edited by Salmasi AM and Nicolaides AN. Oxford: Churchill Livingstone, 1989, chapt. 19, p. 261–273.
  33. Pandit JJ, Manning-Fox J, Dorrington KL, Robbins PA. Effects of subanaesthetic sevoflurane on ventilation. 1: Response to acute and sustained hypercapnia in humans. Br J Anaesth 83: 204–209, 1999.[Abstract/Free Full Text]
  34. Poulin MJ, Liang PJ, Robbins PA. Dynamics of the cerebral blood flow response to step changes in end-tidal PCO2 and PO2 in humans. J Appl Physiol 81: 1084–1095, 1996.[Abstract/Free Full Text]
  35. Poulin MJ, Liang PJ, Robbins PA. Fast and slow components of cerebral blood flow response to step decreases in end-tidal PCO2 in humans. J Appl Physiol 85: 388–397, 1998.[Abstract/Free Full Text]
  36. Poulin MJ, Robbins PA. Indexes of flow and cross-sectional area of the middle cerebral artery using Doppler ultrasound during hypoxia and hypercapnia in humans. Stroke 27: 2244–2250, 1996.[Abstract/Free Full Text]
  37. Richardson DW, Kontos HA, Raper AJ, Patterson JL Jr. Systemic circulatory responses to hypocapnia in man. Am J Physiol 223: 1308–1312, 1972.[Free Full Text]
  38. Robbins PA, Swanson GD, Howson MG. A prediction-correction scheme for forcing alveolar gases along certain time courses. J Appl Physiol 52: 1353–1357, 1982.[Abstract/Free Full Text]
  39. Robbins PA, Swanson GD, Micco AJ, Schubert WP. A fast gas-mixing system for breath-to-breath respiratory control studies. J Appl Physiol 52: 1358–1362, 1982.[Abstract/Free Full Text]
  40. Rutherford JJ, Clutton-Brock TH, Parkes MJ. Hypocapnia reduces the T wave of the electrocardiogram in normal human subjects. Am J Physiol Regul Integr Comp Physiol 289: R148–R155, 2005.[Abstract/Free Full Text]
  41. Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke 31: 1672–1678, 2000.[Abstract/Free Full Text]
  42. Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol 46: 599–602, 1979.[Abstract/Free Full Text]
  43. Shapiro W, Wasserman AJ, Baker JP, Patterson JL Jr. Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man. J Clin Invest 49: 2362–2368, 1970.[Web of Science][Medline]
  44. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 87: 1953–1957, 1991.[Web of Science][Medline]
  45. Steinback CD, Poulin MJ. Ventilatory responses to isocapnic and poikilocapnic hypoxia in humans. Respir Physiol Neurobiol 155: 104–113, 2007.[CrossRef][Web of Science][Medline]
  46. Talbot NP, Balanos GM, Dorrington KL, Robbins PA. Two temporal components within the human pulmonary vascular response to ~2 h of isocapnic hypoxia. J Appl Physiol 98: 1125–1139, 2005.[Abstract/Free Full Text]
  47. Tanaka M, Takaishi S, Ohdaira T, Kobayashi T, Maruyama R, Ahn B, Masuda A, Masuyama S, Honda Y. Dependence of biphasic heart rate response to sustained hypoxia on magnitude of ventilation in man. Jpn J Physiol 42: 865–875, 1992.[CrossRef][Medline]
  48. Vantanajal JS. Cerebral Blood Flow Responses to Sustained Alterations in End-Tidal PO2 and PCO2 in Humans (MSc Dissertation). University of Calgary, 2004. [available at http://wwwlib.umi.com/dissertations/].
  49. Vegfors M, Lindberg LG, Lennmarken C. The influence of changes in blood flow on the accuracy of pulse oximetry in humans. Acta Anaesthesiol Scand 36: 346–349, 1992.[Web of Science][Medline]
  50. Vogel JA, Harris CW. Cardiopulmonary responses of resting man during early exposure to high altitude. J Appl Physiol 22: 1124–1128, 1967.[Free Full Text]
  51. Xie A, Skatrud JB, Morgan B, Chenuel B, Khayat R, Reichmuth K, Lin J, Dempsey JA. Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans. J Physiol 577: 319–329, 2006.[Abstract/Free Full Text]
  52. Xie A, Skatrud JB, Puleo DS, Morgan BJ. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 91: 1555–1562, 2001.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. D. Steinback, D. Salzer, P. J. Medeiros, J. Kowalchuk, and J. K. Shoemaker
Hypercapnic vs. hypoxic control of cardiovascular, cardiovagal, and sympathetic function
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2009; 296(2): R402 - R410.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
104/2/482    most recent
00553.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Steinback, C. D.
Right arrow Articles by Poulin, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Steinback, C. D.
Right arrow Articles by Poulin, M. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.