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J Appl Physiol 104: 490-498, 2008. First published November 29, 2007; doi:10.1152/japplphysiol.00778.2007
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Differential effects of acute hypoxia and high altitude on cerebral blood flow velocity and dynamic cerebral autoregulation: alterations with hyperoxia

Philip N. Ainslie,1 Shigehiko Ogoh,2 Katie Burgess,3 Leo Celi,4 Ken McGrattan,4 Karen Peebles,1 Carissa Murrell,1 Prajan Subedi,5 and Keith R. Burgess3,6

1Department of Physiology, University of Otago, Dunedin, New Zealand; 2Department of Integrative Physiology, University of North Texas Health Science Center, Fort Texas, Texas; 3Peninsula Private Sleep Laboratory, Sydney, New South Wales, Australia; 4Department of Medicine, University of Otago, Dunedin, New Zealand; 5Institute of Medicine and Patan Hospital, Katmandu, Nepal; and 6Department of Medicine, University of Sydney, Sydney, New South Wales, Australia

Submitted 17 July 2007 ; accepted in final form 20 November 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We hypothesized that 1) acute severe hypoxia, but not hyperoxia, at sea level would impair dynamic cerebral autoregulation (CA); 2) impairment in CA at high altitude (HA) would be partly restored with hyperoxia; and 3) hyperoxia at HA and would have more influence on blood pressure (BP) and less influence on middle cerebral artery blood flow velocity (MCAv). In healthy volunteers, BP and MCAv were measured continuously during normoxia and in acute hypoxia (inspired O2 fraction = 0.12 and 0.10, respectively; n = 10) or hyperoxia (inspired O2 fraction, 1.0; n = 12). Dynamic CA was assessed using transfer-function gain, phase, and coherence between mean BP and MCAv. Arterial blood gases were also obtained. In matched volunteers, the same variables were measured during air breathing and hyperoxia at low altitude (LA; 1,400 m) and after 1–2 days after arrival at HA (~5,400 m, n = 10). In acute hypoxia and hyperoxia, BP was unchanged whereas it was decreased during hyperoxia at HA (–11 ± 4%; P < 0.05 vs. LA). MCAv was unchanged during acute hypoxia and at HA; however, acute hyperoxia caused MCAv to fall to a greater extent than at HA (–12 ± 3 vs. –5 ± 4%, respectively; P < 0.05). Whereas CA was unchanged in hyperoxia, gain in the low-frequency range was reduced during acute hypoxia, indicating improvement in CA. In contrast, HA was associated with elevations in transfer-function gain in the very low- and low-frequency range, indicating CA impairment; hyperoxia lowered these elevations by ~50% (P < 0.05). Findings indicate that hyperoxia at HA can partially improve CA and lower BP, with little effect on MCAv.

CEREBRAL AUTOREGULATION (CA) adjusts cerebral arteriolar caliber, or cerebrovascular resistance, to ensure that cerebral blood flow levels are matched to metabolic needs, and it is comprises two main components: static and dynamic. Static CA keeps cerebral blood flow constant, over gradual and progressive changes in cerebral perfusion (33). Dynamic CA refers to the rapid regulation of cerebral blood flow in response to changes in arterial blood pressure (BP) that occurs in a few seconds (43). Dynamic CA may have different control mechanisms than static CA (6), and data indicate that neural control of cerebral circulation may be more effective under dynamic than under steady-state conditions (43). Both static (16) and dynamic CA (3, 25) are impaired in newcomers to high altitude, especially in the presence of acute mountain sickness (40). A recent report also indicates that static CA is impaired in permanent high-altitude residents who live above 4,000 m, whereas it is intact in residents residing at lower elevations (17). Early animal studies show impairment in static CA at severe (nonphysiological) levels of acute hypoxia (11, 20), but this dynamic CA is maintained during "moderate" (6% O2) hypoxia (21). Collectively, both animal and human studies indicate that both static and dynamic CA are differentially affected by the duration or intensity, or both, of the hypoxic insult and the degree of previous adaptation (i.e., lifelong residency at high altitude).

It is not known whether more severe acute levels of hypoxia cause a related impairment in dynamic CA. Moreover, although hyperoxia has been shown to reverse some of the impairment in static CA in high-altitude residents (17), it is not known whether dynamic CA is altered with hyperoxia, either acutely (i.e., at sea level) or in newcomers at high altitude. Such a possibility is attractive given that O2 is a well-established means to alleviate hypoxia and associated altitude illness (35). Conversely, at least at sea level, hyperoxia (>60 s) is a respiratory stimulant in adults (4), which results in subsequent reduction in end-tidal PCO2 and accompanying vasoconstriction in the arterioles reducing cerebral blood flow (9, 41). Because exposure to high altitude augments sympathetic activity and systemic BP (12), and alters cerebrovascular CO2 reactivity to hypocapnia (3), it seems plausible that acute hyperoxia administration might have more of a influence on BP and less of an influence on blood flow velocity in the middle cerebral artery (MCAv), compared with administration at sea-level. Surprisingly, no data are available which have examined the effect of severe levels of hypoxia or hyperoxia on dynamic CA, MCAv, and BP in otherwise unacclimatized humans at sea level and following ascent to high altitude. Therefore, the aims of this investigation were 1) to examine the effects of acute hypoxia or hyperoxia at sea level on dynamic CA and to verify whether dynamic CA is impaired in newcomers at high altitude and, if so, to what extent can it be altered with hyperoxia; and 2) to compare the effects of acute hyperoxia administration on BP and MCAv at sea level (in the absence of changes sympathetic activity and cerebral CO2 reactivity) and at high altitude. Based on the aforementioned observations, we tested three original hypotheses: first, acute severe hypoxia, but not hyperoxia, at sea level would impair dynamic CA; 2) hyperoxia would alleviate impairment in dynamic CA at high altitude; and 3) in contrast to administration at sea level, hyperoxia will have more of influence on BP and less of an influence on MCAv at high altitude.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects

Thirty-two healthy subjects participated in this cross-sectional study. Subjects were used in three main independent investigations to form the basis of this report: 1) acute hypoxic group; 2) acute hyperoxic group; and 3) high altitude, with and without, hyperoxia group. As shown in Table 1, there were no between-group differences in any of the subject demographics. 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. In all studies, subjects were instructed to refrain from exercise and alcohol for 12 h before the investigation and to refrain from caffeine 4 h before experimental testing. The research study was approved by the Conjoint Health Research Ethics Board at the University of Calgary, The Regional Ethics Committee of Otago, the Human Research Ethics Committee of Northern Sydney Health, and the Nepalese Research Council.


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  		Table 1. Subject demographics

 
Experimental Studies and Design

Study 1: acute hypoxia.   The effects of acute hypoxia (12% and 10%) on dynamic CA were examined in 10 volunteers who had resided at sea level >12 mo. Following instrumentation (described below), 15 min of normoxic baseline data were collected before two incremental steps of hypoxia with the inspired O2 fraction (FIO2) was rapidly reduced from 0.21 to 0.12 and then 0.10 for 4–5 min at each level. During both air breathing and administration of hypoxia, subjects breathed through a tight-fitting facemask, with their nose occluded. The hypoxic steps were induced by switching the inspired gas from room air to precalibrated hypoxic mixes (12% O2 and 10% O2), which were contained in 200-liter Douglas bags and connected to the inspiratory part of the breathing apparatus with a Y valve, with one end connected to the Douglas bag and the other end open to room air. The two hypoxic steps were used as a safety precaution and to allow subjects to gradually get used to changes in FIO2. Arterial blood gases were sampled during the last minute of each level; and beat-to-beat BP, MCAv, O2 saturation, and respiratory gas exchange were monitored continuously.

Study 2: acute hyperoxia.   In another group (n = 12) of matched volunteers, the effects of acute hyperoxia (FIO2 = 1.0) was monitored. Following instrumentation, 15 min of normoxic baseline data were collected during normoxia before one step of hyperoxia (FIO2, 1.0) was rapidly introduced (as detailed for study 1) and maintained for 10 min. Arterial blood gases were sampled in the last minute of each level; and beat-to-beat BP, MCAv, O2 saturation and respiratory gas exchange were monitored continuously.

Study 3: high altitude and hyperoxia.   In the same individuals, these studies were carried out at low altitude in Kathmandu (1,400 m) and 1–2 days after arrival in the base camp of Mt. Everest (~5,400 m; n = 10). With the exception of testing at low altitude, following the 15-min of baseline, hyperoxia (FIO2, 1.0) was administered for a further 10 min. At altitude, arterial blood gases were procured during the baseline conditions but not during administration of hyperoxia. Because of the relatively nonsterile environment at base camp, it was deemed unethical to risk the placement of an arterial line for repetitive sampling. Beat-to-beat BP and MCAv were monitored continuously and neurological symptoms typically associated with acute mountain sickness were collected, as described below.

Measurements of MCAv and arterial BP.   MCAv was estimated by the continuous measurement of backscattered Doppler signals from the right middle cerebral artery using a 2-MHz pulse Doppler ultrasound system (Power M-Mode Doppler 100, Spencer Technologies). Following previously described search techniques (2), the Doppler probe was secured with a headband device (Spencer Technologies, Nicolet Instruments, Madison, WI) to maintain optimal insonation position and angle throughout the protocol. Arterial BP and heart rate were measured continuously using finger photoplethysmography (Portapress, TPD Biomedical Instrumentation, Amsterdam, The Netherlands). Great care was taken to ensure that identical settings of Doppler ultrasound system were used each time during low altitude and high altitude (study 3). This procedure was very reproducible due to 1) the combination of M-mode and Doppler spectral analysis techniques (28); 2) all Doppler measurements were performed by the same experienced investigator; 3) a detailed tracing of each subject's facial features and probe placement was performed at low altitude and used as a guide for identical placement at high altitude; 4) use of the same Doppler settings (i.e., signal depth, gain, and same probe). Although photoplethysmographic measurements correlate well with intra-arterial measurements during experimental manipulations of BP (32), the absolute values can sometimes be inaccurate; therefore, all BP data are normalized to the 5-min baseline proceeding any intervention and expressed as percentage change from this baseline. Similarly, as used in other studies, MCAv was also expressed as the percent change from this baseline to enable the same relative comparison to the changes in BP and to reduce interindividual variability that is unrelated to the experimental manipulation (3, 27). Cerebrovascular resistance index was calculated from mean BP/MCAv. The BP and the transcranial Doppler waveforms were sampled continuously at 200 Hz using an analog-to-digital converter (Powerlab/16SP ML795, ADInstruments, Colorado Springs, CO) and stored on a personal computer for offline computations.

Administration of hyperoxia.   All experiments were conducted in the awake state and at similar times of the day in an attempt to standardize the effect of the diurnal variability of cerebral vasomotor reactivity. Subjects wore eyeshades or closed their eyes and listened to relaxing music of their choice, to minimize distraction during quiet breathing. During both air breathing and administration of hyperoxia, subjects breathed through a mouthpiece, with a nose clip. With exception of the testing at low altitude (1,400 m), following the 15 min of baseline, hyperoxia was administrated (~10 l/min; FIO2 = 1.0) to the inspired air for a further 10 min.

Blood gases.   During the acute hypoxic and hyperoxia experiments at sea level (studies 1 and 2), the radial artery was cannulated under local anesthesia (0.01% lidocaine). Following a 10- to 20-min rest period in the semirecumbent position, arterial blood gases were sampled and immediately analyzed at baseline and during each change in hypoxia or hyperoxia. During the high-altitude studies (study 3), arterial blood gases from the radial artery were obtained at rest using a 25-gauge needle into a preheparinized syringe with the subject in the seated position after 10-min of rest. Following standardized calibration, all blood samples were analyzed using a battery-powered arterial blood gas analyzing system (i-STAT system, I-STAT, East Windsor, NJ). Although arterial blood gases could not be sampled during administration of hyperoxia at high altitude, the approximate PaO2 was estimated [assuming a gradient of –10 Torr from the alveolar PO2 (PAO2)] using the alveolar gas equation: PAO2 = PIO2 – PaCO2/R, where PIO2 is the partial pressure of inspired O2; arterial PCO2 (PaCO2) was assumed to be equal the resting baseline PaCO2 – 3.9 Torr (i.e., the same degree of hyperoxic-induced hypocapnia experienced during hyperoxic administration at sea level); and R was assumed to = 0.9 at 5,400 m (Ainslie PN, unpublished data).

Acute mountain sickness.   Neurological symptoms typically ascribed at high altitude were examined using the Lake Louise Questionnaire (34). Acute mountain sickness was defined if a subject presented with a total Lake Louise score (self-assessment + clinical scores) of ≥5 points.

Dynamic cerebral autoregulation.   Three-minute steady-state data segments were used for transfer function analysis to identify an index of dynamic cerebral autoregulation. The beat-to-beat data of mean BP and MCAv were then linearly interpolated and resampled at 2 Hz for spectral analysis. The spectra of mean BP and MCAv were calculated with a fast Fourier transformation algorithm, and the transfer function between these two variables was calculated with a cross-spectral method to assess dynamic CBF autoregulation, as described in detailed elsewhere (3, 31, 42, 43). For these calculations, 3 min of steady-state mean BP and MCAv were used during the last 3 min of baseline and the last 3 min of each level of hypoxia or hyperoxia. Mean value of transfer function gain, phase, and coherence function were calculated in the very low-frequency (0.02 to 0.07 Hz), low-frequency (0.07 to 0.20 Hz), and high-frequency (0.20 to 0.35 Hz) ranges to reflect different patterns of the dynamic pressure-flow relationship (42). Rapid BP fluctuations in the high-frequency range, such as those induced by respiratory frequency, are transferred to MCAv, whereas BP fluctuations in the low-frequency range are independent of the respiratory frequency and dampened by autoregulatory mechanisms (7). Furthermore, the very low-frequency range of both flow and pressure variability appear to reflect multiple physiological mechanisms (42). Coherence function, between BP and MCAv, is used to assess the linear relation and reliability of the transfer function gain and phase. Transfer function gain estimates are used as an "index" of the ability of the cerebrovascular bed to buffer changes in MCAv induced by transient changes in BP in the different frequencies (14). Reductions in gain are interpreted to mean that larger changes in BP lead only to small changes in MCAv, indicating effective autoregulation. Conversely, elevations in gain are interpreted to mean that larger changes in BP lead to similarly larger changes in MCAv, indicating impaired autoregulation. The phase was used to estimate the temporal relationship between BP and MCAv (42).

Statistical Analysis

All data were analyzed using the SPSS social statistics package (Version 9, Surrey, UK). A Shapiro-Wilks test was applied to each dependent variable to mathematically assess distribution normality. Parametric and nonparametric equivalents of a two-factor trial [low altitude vs. high altitude and exposure time: baseline vs. hyperoxia, repeated-measures ANOVA] and two-way mixed ANOVA with one between (state: low altitude vs. high altitude) and one within (exposure time) factor were incorporated to examine the effects of trial, time, and state on selected variables. Independent or dependant t-tests were also used in the acute hypoxia and hyperoxia studies for comparison within and between the different experiments. Relationships between selected variables were identified using Pearson product-moment Correlation or Spearman's rank correlation coefficient. Significance for all two tailed tests were established at an alpha level of P < 0.05, and data are expressed as means ± SD.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Changes in Arterial Blood Gases (Table 2)

During acute hypoxia, there was a progressive decrease in PaO2 and related modest hypocapnia. In acute hyperoxia, PaO2 was elevated and significant hypocapnia ensued. During exposure to high altitude, the expected changes in arterial blood gases were evident (i.e., respiratory alkalosis with concomitant hypocapnia). The estimated absolute increase in PaO2 during administration of hyperoxia at high altitude was lower than the absolute increase that incurred during acute hyperoxic administration at sea level (325 ± 34 vs. 580 ± 21 Torr; P < 0.05).


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  		Table 2. Alterations in arterial blood gases, cardiovascular function, and cerebrovascular function during acute hypoxia and hyperoxia and following ascent to high altitude

 
Changes in Cardiorespiratory and Cerebrovascular Hemodynamics (Table 2, Fig. 1)

In both acute hypoxia and at high altitude, but not hyperoxia, there was an elevation in resting heart rate. Conversely, whereas BP was unchanged during acute hypoxia and hyperoxia, it was increased at high altitude (P < 0.05 vs. low altitude). Whereas MCAv was unchanged at high altitude, there was an increase in cerebral vascular resistance (P < 0.05). During acute hyperoxia, MCAv was decreased, and cerebral vascular resistance was elevated. There was no change in MCAv at high altitude during hyperoxia, whereas BP was lowered. During acute hypoxia, there was a trend for MCAv to increase (P = 0.07), and a related lowering of cerebral vascular resistance was apparent. Ventilation was elevated during both acute hypoxia (10%) and hyperoxia (Table 2). Consistent with previous studies (5), these ventilatory changes were mediated by changes in tidal volume rather than frequency (Table 1). Because of equipment failure, it was not possible to monitor these ventilatory parameters at high altitude.


Figure 1
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  		Fig. 1. Percent changes in blood flow velocity in the middle cerebral artery (MCAv; A) and mean arterial blood pressure (MAP; B) during 10 min of hyperoxia at sea level ({circ}) and at high altitude (bullet). Hyperoxia caused a greater decrease in MAP and lesser of a change in MCAv at high altitude compared with sea level. (*P < 0.05). Both MAPand MCAv data were normalized to the 5-min baseline proceeding hyperoxia and expressed as percent change from this baseline. Values are means ± SD.

 
Changes in Dynamic Cerebral Autoregulation (Table 3, Figs. 2–5)

Acute hypoxia (10%) was associated with decrease in transfer function gain in low-frequency range, indicating improvement in dynamic CA. There were no other changes in transfer function indexes in the very low-frequency or high-frequency range, or in any frequency range for the MAP and MCAv variability. Conversely, at high altitude, transfer function gain in both the very low-frequency or low-frequency range was elevated, indicating impairment in dynamic cerebral autoregulation. Whereas MCAv variability was unchanged at high altitude, MAP variability in the very low-frequency range was elevated. This impairment in dynamic CA (i.e., elevation in very low-frequency or low-frequency gain) at high altitude (5,400 m) was modestly related (R2 = 0.29 and R2 = 0.43, respectively; both P < 0.05) to an elevation in the reported symptoms of acute mountain sickness (low altitude, 0.9 ± 0.7 points vs. 5.4 ± 1.7 points; P < 0.05). Whereas there was no change in any transfer function indexes in three frequency ranges during acute hyperoxia, hyperoxia at high altitude resulted in a significant lowering of the elevated gain in the low-frequency range and MAP variability (P < 0.05 vs. high altitude); however, these changes did not fully return to baseline values. Although there was a tendency for gain in the very low frequency to be lower with hyperoxia at high altitude, this did not reach statistical significance (P = 0.07). During all studies, there were no evident changes in phase or coherence in any frequency range.


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  		Table 3. Spectral analysis of MAP and MCAv during acute hypoxia and hyperoxia and following ascent to high altitude

 

Figure 2
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  		Fig. 2. Changes in transfer function gain between MAP and MCAv variables at low-frequency (LF, 0.07–0.20 Hz; A) and very low-frequency (VLF, 0.02 to 0.07 Hz; B) during acute hypoxia, acute hyperoxia, and ascent to high altitude with hyperoxia. Acute hypoxia (10%) was associated with decrease in transfer function gain in LF range, apparent in all of the 10 subjects, indicating improvement in cerebral autoregulation. Conversely, at high altitude, transfer function gain in the VLF (9 of the 10 subjects) and LF (in all subjects) ranges were elevated, indicating impairment in cerebral autoregulation. Whereas there was no change in VLF or LF transfer function gain during acute hyperoxia, hyperoxia at high altitude resulted in a reduction in the elevated transfer function gain in both VLF (in 8 of 10 subjects) and LF ranges (in all 10 subjects), indicating partial restoration of dynamic cerebral autoregulation. As shown, however, the reduction in the elevated gain was not restored fully back to low-altitude values. Each faint line represents an individual value. Horizontal lines in graphs represent the group mean. There were no differences in very-low or low-frequency phase or coherence in any condition (Table 3). *Significant difference, P < 0.05 compared with baseline.

 

Figure 3
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  		Fig. 3. Representative frequency-domain analysis of changes in MAP and MCAv for 1 subject whose results typified the overall findings before (21% O2, baseline; solid line) and during hypoxia (10% O2; dashed line). A: power spectral density of MAP variability. B: power spectral density of MCAv variability. C: coherence function. D: transfer function gain between MAP and MCAv oscillations. E: phase relationship between MAP and MCAv oscillations. HF, high-frequency range (0.20 to 0.35 Hz). Note: 1) reduction in transfer function gain in LF range during hypoxia, indicating improvement in dynamic CA; 2) whereas there were no overall significant differences in coherence and phase (Table 3), individual variability does exist throughout the frequency ranges; 3) axis break on all x-axes (0.35–0.45 Hz).

 

Figure 4
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  		Fig. 4. Representative frequency-domain analysis of changes in MAP and MCAv for 1 subject whose results typified the overall findings before (21% O2, baseline; solid line) and during hyperoxia (100% O2; dashed line). A: power spectral density of MAP variability. B: power spectral density of MCAv variability. C: coherence function. D: transfer function gain between MAP and MCAv oscillations. E: phase relationship between MAP and MCAv oscillations. Note: 1) no apparent differences in any variable; 2) whereas there were no overall significant differences in coherence and phase (Table 3), individual variability does exist throughout the frequency ranges; and 3) axis break on all x-axes (0.35–0.45 Hz).

 

Figure 5
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  		Fig. 5. Representative frequency-domain analysis of changes in MAP and MCAv for 1 subject whose results typified the overall findings before hypoxia (low altitude; solid line), at high altitude (dashed line), and during hyperoxia administration at high altitude (100% O2; gray line). A: power spectral density of MAP variability. B: power spectral density of MCAv variability. C: coherence function. D: transfer function gain between MAP and MCAv oscillations. E: phase relationship between MAP and MCAv oscillations. Note: 1) elevation in MAP variability in the VLF range at high altitude; 2) elevation in transfer function gain in the VLF and LF range at high altitude, indicating impairment in dynamic cerebral autoregulation; and the effect of hyperoxia in reducing these elevations in gain, indicating partial restoration of dynamic CA; 3) whereas there were no overall significant differences in coherence and phase (Table 3), individual variability does exist throughout the frequency ranges; and 4) axis break on all x-axes (0.35–0.45 Hz).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The three novel findings of this study are that 1) at sea level, acute hypoxia improved dynamic CA, as reflected in reductions in gain in the low-frequency range, whereas it was unchanged in hyperoxia; 2) impairment in dynamic CA, reflected in elevations in gain in the very low-frequency and low-frequency range, at high altitude can be partly restored with hyperoxia; and 3) hyperoxia caused a greater decrease in BP and less of a change in MCAv at high altitude compared with low altitude.

Improvement of Dynamic Cerebral Autoregulation in Acute Hypoxia

An unexpected finding was that, at sea level, acute hypoxia improved dynamic CA, whereas it was unchanged in hyperoxia. This improvement was reflected in a decrease in the gain between BP and MCAv variability at low-frequencies during acute severe hypoxia (10%), indicating that there was smaller oscillations in MCAv for given changes in BP. In contrast to our findings, a recent report showed that, during acute exposure to 15% O2, very low-frequency power of MAP and MCAv variability increased by 185 and 292%, respectively, compared with normoxia. Moreover, in that study, there were significant increases in coherence and gain in the very low-frequency range during the mild hypoxia at 15% (15). Because we did not examine changes at 15% O2, and because more severe levels of hypoxia were not induced in that study (15), it is difficult to compare related results; nevertheless, our finding is consistent with a early report in animals of an unaltered static CA in acute hypoxia [6% O2; (20)]. The mechanisms by which acute hypoxia may alter dynamic CA are not known. Relative hypocapnia is known to improve static CA (1), with variable effects on dynamic CA (8, 29); however, because both acute hypoxia and hyperoxia induced comparable levels of hypocapnia (–4.1 and –3.9 Torr, respectively) and all indexes of dynamic CA was unaltered with hyperoxia, the influence of hypocapnia alone would seem not to be the sole cause of improved dynamic CA in hypoxia. During acute hypoxia, our results indicate smaller oscillations in MCAv for given changes in BP; therefore, one possible mechanism is that acute hypoxia may increase the responsiveness of cerebrovascular smooth muscle to changes in transmural pressure (i.e., a myogenic response). Unfortunately, our results do not provide any additional insight into potential mechanisms that may underlie the apparent changes dynamic CA.

Impairment in Dynamic CA at High Altitude is Partly Restored With Hyperoxia; Implications for the Pathophysiology of Altitude Illness

At high altitude (5,400 m), symptoms of acute mountain sickness were elevated and were related to the impairment in dynamic CA (i.e., elevations in gain in the very low-frequency and low-frequency range). Acute mountain sickness may represent an early stage of high-altitude cerebral edema (35). Impairment in CA, leading to overperfusion and vasogenic edema subsequent to mechanical disruption of the blood-brain barrier, has been implicated (35), although not measured, in the selective accumulation of intracellular cytotoxic and extracellular vasogenic edema recently observed in acute mountain sickness (18). The alleviation of some of the impairment in dynamic CA with hyperoxia at high altitude is consistent with the treatment of high-altitude illness (35). This finding, in sea-level residents at high altitude, is also broadly comparable to a recent report of a hyperoxic-induced partial restoration of static autoregulation in high altitude residents living above 4000 m (17). The mechanism by which hyperoxia may lead to improvement in dynamic or static CA is unknown, but it is tempting to speculate that it may be related to subtle changes in vasogenic edema, potentially caused by the marked reduction in arterial BP.

Differential Effects of Hyperoxia on BP and MCAv at High Altitude

Hyperoxia caused a greater decrease in BP and lesser of a change in MCAv at high altitude compared with sea level. Our data are consistent with previous reports that exposure to high altitude provoked increases in BP (12), potentially mediated by augmented sympathetic activity. It seems reasonable to suggest that, during sympathoexcitation at high altitude (12), hyperoxia transiently attenuated the transduction of sympathetic activity into vascular resistance (37), potentially mediated via peripheral chemoreceptor deactivation (23), thus lowering BP. At sea level, compared with high altitude, sympathetic nerve activity is low (12); thus the effect of hyperoxic-induced withdrawal of sympathetic nerve activity on BP is small at sea level.

Why should hyperoxia cause less of a decrease in MCAv at high altitude compared with sea level? We speculate on four possibilities. First, although the influence of elevation in sympathetic activity on the human cerebral circulation seems to play a minor role in the normal regulation of CBF, reports in animals (26) and humans indicate that the importance of sympathetically mediated vasoconstriction may be to protect the blood-brain barrier when limits of autoregulation are exceeded (24, 31). Thus some withdrawal of sympathetically mediated cerebral vasoconstriction at high altitude by hyperoxia may cause a smaller decrease in MCAv compared with acute administration at sea level where such vasoconstriction is absent. Second, because marked hypocapnia ensued at high altitude (~24 Torr), and a recent report highlights a reduction in the cerebrovascular reactivity to hypocapnia at high altitude (3), it seems possible that the hyperoxic-induced hyperventilation and resultant hypocapnia may have a reduced influence on cerebral vasoconstriction and a related reduction in MCAv. In other words, the profound hypocapnic may influence the MCAv response to hyperoxia at high altitude. Third, because of altitude-induced alterations in ventilatory control, hyperoxia may have a differential influence on ventilation (i.e., hyperoxia may cancel out some of the hypoxic-ventilatory drive) and therefore reduce the degree of hypocapnia compared with that provoked at sea level. Fourth, it should also be noted that, in addition to the hyperoxic-induced reduction in PaCO2 and accompanying vasoconstriction in the arterioles reducing cerebral blood flow (4, 9, 41), increases in PaO2 also have a direct vasoconstrictive effect independently of the PaCO2 response (9, 22). Importantly, because of the reduction in barometric pressure and related arterial hypoxemia, the relative hyperoxic-induced increase in PaO2 (and potentially hypocapnia) would likely be less at high altitude than at sea level (580 ± 21 vs. 325 ± 34 Torr); thus our results may be explained, in part, by lower degree of hyperoxemia inducing less of a decrease in MCAv at high altitude. A recent study (5) has demonstrated that reductions in regional cerebral blood flow can occur at relative low levels of acute hyperoxia (FIO2 = 0.4) and that more marked hyperoxia (FIO2 = 1.0) only reduced cerebral blood flow by a further ~3%; therefore, it remains possible that the level of hyperoxia at high altitude may be adequate to provoke related decreases in MCAv and that some of the other aforementioned factors are responsible for limited any change. Importantly, even at sea level, the exact means by which altered levels of CO2 and O2 in the blood, plasma, and tissues affect cerebral blood flow are not fully known (5); however, the possibility that hyperoxia, via either CO2- and/or O2-related mechanisms, has a differential effect on MCAv at high altitude, compared with sea-level, warrants future research.

Technological Considerations

The "classic" static CA curve highlights that cerebral blood flow remains constant despite changes in BP. These curves are based predominately from serial operating data points in animal studies. More recently, the use of "dynamic" responses to cerebral blood flow to changes in BP have been studied extensively during physiological (3, 30) and pathophysiological (13, 36) conditions. These data highlight that whereas autoregulation of cerebral blood flow operates reasonably well for slow fluctuations in perfusion pressure, more rapid changes in perfusion pressure may not be buffered as well and thus elicit pressure-dependant changes in cerebral blood flow. In other words, quantification of CA using "static" methods, obscures the fact that most of the challenges to cerebral perfusion originate from rapid shifts (i.e., within seconds) in cerebral perfusion. Loss of dynamic CA may therefore be a more sensitive index of a threatened cerebral circulation than the standard static measures of CA (6). The classic CA curves, based predominately from serial operating data points in animal studies, show the returning part of CBF, which is at 0 Hz for frequency domain analysis. Using transfer function analysis, however, it is impossible to show a classic CA curve, because the operating point of BP does not move at each condition; thus comparison between static and dynamic is difficult, especially because they may both reflect different physiological processes. Finally, whereas there were no significant differences in coherence and phase (Table 3) in any of the experiments, it should be acknowledged that individual variability does exist throughout the frequency ranges (Figs. 3–5). Subtle difference in experimental design, data sampling or analysis may explain the slight differences in the spectra of the transfer function analysis (42), although our overall values (Table 3) are consistent with other studies (15, 31). Another technological consideration is that we used Doppler ultrasound to measure flow velocity, rather than blood flow, in the middle cerebral artery. Nevertheless, the majority of research suggests that MCAv is a reliable index of cerebral blood flow (10, 19, 38, 39). Finally, although the time course underlying the change in CA from acute hypoxia to high altitude could not be identified in the present study, it is possible that the mechanism of change in CA would be invoked sometime before the arrival at 5,400 m. As mentioned, a recent report indicates that static CA is impaired in permanent high-altitude residents who live above 4,000 m, whereas it is intact in residents residing at lower elevations (17). It is currently unknown whether adapted high-altitude residents show different cerebrovascular responses to hyperoxia compared with newcomers to high altitude from sea level.

In conclusion, compared with the acute hypoxia and hyperoxia, our findings indicate that hyperoxia at high altitude can alleviate some of the impairment in dynamic CA with smaller effects on MCAv and paradoxically lower BP. The mechanism(s) underlying such changes during acute hypoxia or at high altitude warrants future research.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
For the high-altitude studies, we acknowledge the financial support from the Peninsula Health Care P/L (Sydney) and Prof. John Remmers, and advice and assistance from Professor William Whitelaw at the University of Calgary.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The enthusiasm and humor provided by the volunteers are greatly appreciated. We thank Spencer Technologies (Nicolet Instruments, Madison, WI) for the loan of a Doppler ultrasound system; Finapres Medical Systems (Belgium) for the loan of a Portapress system; and ADInstruments (Colorado Springs, CO) for the loan of a data-acquisition system.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. N. Ainslie, Dept. of Physiology, Univ. of Otago, Dunedin, New Zealand (e-mail: philip.ainslie{at}stonebow.otago.ac.nz)

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
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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