Cerebral autoregulation index at high altitude assessed by leg cuff and transfer function analysis...

This is an Accepted Article that has been peer-reviewed and approved for publication in the Experimental Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an Accepted Article; doi: 10.1113/expphysiol.2014.082479. This article is protected by copyright. All rights reserved. 1

Cerebral autoregulation index at high altitude assessed by leg cuff and transfer

function analysis techniques

Andrew W. Subudhi1, 2, Katalin Grajzel3, Robert J. Langolf4, Robert C. Roach2, Ronney B.

Panerai5, John E. Davis4

1. University of Colorado Colorado Springs, Department of Biology, Colorado Springs,

Colorado USA

2. University of Colorado Altitude Research Center, Department of Emergency

Medicine, Aurora, Colorado USA

3. University of Colorado Colorado Springs, Department of Psychology, Colorado

Springs, Colorado USA

4. Alma College, Department of Integrative Physiology and Health Science, Alma,

Michigan USA

5. University of Leicester, Department of Cardiovascular Sciences and NIHR

Biomedical Research Unit, United Kingdom

Running Head: Cerebral autoregulation at altitude

Key Words: hypoxia, transcranial Doppler, cerebral blood flow, middle cerebral artery,

arterial blood pressure

Corresponding author:

Andrew W. Subudhi, PhD

Associate Professor

Department of Biology

1420 Austin Bluffs Parkway

Colorado Springs, Colorado 80918

Email: [email protected]

Phone: 719-255-3938

This article is protected by copyright. All rights reserved. 2

New Findings

What is the central question of this study?

Whether cerebral autoregulation (CA) is impaired at high altitude and associated with

acute mountain sickness remains controversial. We sought to compare two of the most

common methods to assess dynamic CA in subjects that ascended and acclimatized to

3424m.

What is the main finding of this study?

We found that CA was reduced at 3424m when assessed by the classic leg cuff

inflation/deflation technique, but not when evaluated by transfer function analysis.

These findings suggest that the cerebral vasculature of healthy individuals may become

less able to buffer a large, abrupt drop in ABP, while still maintaining the ability to

regulate slow rhythmical oscillations, during periods of moderate hypoxemia.

Abstract

The occurrence and implications of changes in cerebral autoregulation (CA) at high

altitude are controversial and confounded by differences in methods used to assess CA.

To compare two of the most common methods of dynamic CA assessment, we studied

11 young, healthy sea-level residents (6 female, 5 male; 20.5 ± 2.3 years) as they

ascended and acclimatized to 3424 m over 13 days. A common autoregulation index

(ARI) was calculated from 1) transfer function analysis (TFA ARI) of resting oscillations

in arterial blood pressure (ABP; finger plethysmography) and middle cerebral artery

blood velocity (MCAv; transcranial Doppler), and 2) MCAv responses following large,

abrupt drops in ABP using the classic leg cuff technique (Cuff ARI). Symptoms of acute

mountain sickness (AMS) were monitored using the Lake Louise AMS Questionnaire.

Cuff ARI scores decreased (P=0.021) as subjects ascended from low (4.7± 1.5) to high

altitude (3.2 ± 1.6) and did not change after 13 days of acclimatization (2.9 ± 1.3). TFA

ARI scores were not affected by ascent or acclimatization to 3424 m. Neither Cuff nor

TFA ARI scores were correlated with AMS symptoms. These findings suggest that the

cerebral vasculature of healthy individuals may become less able to buffer large step

changes in ABP, while still maintaining the ability to regulate slow rhythmical

oscillations, during periods of moderate hypoxemia. Given the inherent differences in

the autoregulatory stimulus between methods, multiple assessment techniques may be

needed to clarify the implications of changes in cerebrovascular regulation at high

altitude.


Introduction

Cerebral autoregulation (CA) describes the ability of cerebral blood vessels to maintain

relatively consistent blood flow despite changes in perfusion pressure (Paulson et al.,

1990). A reduction in CA reflects a more passive relation between perfusion pressure

and blood flow and has negative connotations because of its association with

cerebrovascular disorders (Steinmeier et al., 1996; Panerai et al., 1998; Aries et al.,

2010). However, reduced CA is not always associated with poor health. Independent

findings from several laboratories have reported reduced CA in healthy, active

individuals at high altitude (Jansen et al., 2000; Ainslie et al., 2008; Iwasaki et al., 2011;

Subudhi et al., 2014). These findings have raised the possibility that a more passive

pressure-flow relation in the brain may be a benign, or perhaps even a positive,

response to hypoxemia at high altitude (Bailey, 2010; Subudhi et al., 2014).

Unfortunately, progress in this area has been somewhat hampered by the lack of a gold

standard technique to assess and interpret cerebral pressure-flow relations.

Assessments of CA are generally classified as being static or dynamic . Static CA refers to steady-state relations between arterial blood pressure (ABP) and cerebral

blood flow (CBF), while dynamic CA characterizes changes in CBF relative to more

abrupt changes in ABP. Using phenylephrine to alter steady-state ABP, Jansen et al.

(Jansen et al., 2000) were the first to show proportional increases in ABP and CBF -

indicative of lost static CA - among healthy high-altitude natives living at 4243 m. Later,

using the same technique on residents of various altitudes, they reported that static CA

was unchanged up to ~3400 m, but lost at higher elevations without outward

complications on cerebrovascular health (Jansen et al., 2007). These studies suggested

that reduced static CA may be an inherent facet of life at high altitude, but the more

variable responses observed in newcomers to high altitude (Jansen et al., 2000) left

open the possibility that reduced CA might be involved in the development of acute

mountain sickness (AMS).

Due to the invasive nature of static CA techniques and contraindications of performing

phenylephrine injections in those suffering from AMS, others have used non-invasive

means to gauge dynamic CA. The most widely accepted of these methods is the leg cuff


test (Aaslid et al., 1989), which evaluates the CBF response following a large drop in

ABP induced by rapid cuff deflation. Results can be scored in terms of composite

autoregulation index (ARI) on a 10-point scale (Tiecks et al., 1995). Surprisingly, the

classic leg cuff test has only been used once at high altitude. Van Osta et al. (Van Osta et

al., 2005), reported no change in CA from sea level to 4559 m, but noted some indirect

evidence that ARI scores were related to AMS symptoms. More recently Cochand et al.

(Cochand et al., 2011) found that those with the lowest leg cuff ARI scores at sea level

appeared to be more prone to AMS during a subsequent mountain climbing expedition;

yet, no measures of CA at high altitude were reported (Cochand et al., 2011). It thus

remains to been seen if the classic leg cuff test reveals meaningful changes in CA at high

altitude.

The majority of studies reporting reduced CA at high altitude have applied transfer

function analysis (TFA) to spontaneous oscillations in ABP and CBF. This alternative

dynamic CA technique is appealing because it is non-invasive and requires only ~5 min

of resting data collection. In the frequency domain, the dynamic relation between the

ABP and CBF is expressed by their auto- and cross-spectra, leading to three different

metrics: coherence (similar to linear correlation), gain (relative ratio of CBF and ABP

spectra) and phase shift (delay between ABP and CBF). These metrics can be combined

to yield an ARI score (Panerai et al., 1998), akin to that of the cuff test. Theoretically,

decreased CA should be reflected by increased coherence and gain along with decreased

phase shift and ARI scores. In general, authors have reported reduced CA in hypoxic

conditions by TFA and little to no association with AMS, but results are not consistent.

Only three studies have shown hypoxia-induced changes in all CA metrics in the

aforementioned directions (Subudhi et al., 2010; Iwasaki et al., 2011; Subudhi et al.,

2014). Other studies have only found changes in subsets of the metrics (Ainslie et al.,

2008; Subudhi et al., 2009; Nishimura et al., 2010; Smirl et al., 2014), or no changes at

all (Ogoh et al., 2010). Differences in experimental designs (e.g. ascent rates, elevations

of study, timing of measurements), and technical settings used in the TFA (e.g. sampling

frequency, normalization, detrending, filtering, window size), make direct comparisons

between studies difficult (Meel-van den Abeelen et al., 2014) and cloud the

interpretation of TFA results at high altitude.


In the absence of a gold standard method to assess CA and with the understanding that

each assessment technique may reflect slightly different components of cerebral

pressure-flow regulation (Tzeng et al., 2012), it is unfortunate that no studies have

utilized both leg cuff and TFA methods of assessing CA at high altitude. Evaluating how

different methods respond to hypoxia may further our understanding of cerebral

pressure-flow relations in healthy and ill individuals. In this study, we compared leg cuff

and TFA CA assessments in subjects who ascended and acclimatized to high altitude

over a two-week period. We hypothesized that the ARI calculated from both methods

would be reduced upon ascent and after acclimatization, but not related to AMS

symptoms.

Methods

Subjects

Following institutional ethical board approval, twelve volunteers from the staff and

student body of Alma College gave their written consent to participate in the study in

accordance with the Declaration of Helsinki. All subjects were healthy and physically fit

with no exposure to altitudes above 1500 m in the past 3 months.

Design

Subjects were transported by car from near sea level (Alma, Michigan: elevation 224 m)

to low altitude (Denver, Colorado: elevation 1,650 m) over 24 hours. Following a 24-

hour stay at low altitude, subjects ascended by car to high altitude (Vail Pass: elevation

3251m) over 3 hours, then snowshoed to the Shrine Mountain Inn (elevation 3424 m;

39 ’ 8. N, ’ . W) over 1.5 hours. Subjects resided at the Shrine

Mountain Inn for 14 days and participated in recreational activities, such as

snowshoeing and skiing, at altitudes ranging from 3250 to 4349 m. Longitudinal

assessments of CA were made at low altitude (Baseline) and on the second (ALT2) and

13th (ALT13) day at the Shrine Mountain Inn. Measurements on each subject were

performed at the same time of day to limit the influence of activity, diet, and diurnal

variations.


Protocol

Subjects were seated upright with their heads, arms and feet supported throughout the

~40 min protocol. Resting data were collected for a minimum of 6 min. Bilateral thigh

cuffs were then inflated (>30 mmHg above systolic blood pressure) to partially occlude

leg blood flow (E20 AG101 Rapid Cuff Inflation System with CC22 contoured cuffs, D.E.

Hokanson, Bellview, WA USA). Subjects were instructed to remain relaxed and were not

given feedback regarding elapsed time during cuff occlusion. After 3 min of occlusion,

the cuffs were rapidly deflated and physiologic responses were monitored for an

additional 1 min while subjects remained still. The cuff procedure was repeated 2 or 3

times with 5 min breaks between trials.

Measurements

Physiologic variables Continuous measurements of arterial blood pressure (ABP) were

obtained by finger plethysmography (Nexfin HD, Edwards Lifesciences, Irvine, CA USA).

Corresponding blood velocity measurements were taken in the left middle cerebral

artery (MCAv) by transcranial Doppler (EZ-Dop, DWL USA, San Juan Capistrano, CA

USA) at depths ranging from 45 to 55 mm. Subsequent repositioning of the 2 MHz

Doppler probe was facilitated by photographs documenting the position and angle

relative to the supporting headset (Spencer technologies, Seattle, WA USA). Partial

pressures of end-tidal oxygen (PETO2) and carbon dioxide (PETCO2) were determined

from air sampled through a nasal cannula by a fast-response gas analyzer (O2cap,

Oxigraf, Mountain View, CA USA). Arterial oxygen saturation was monitored by finger

pulse oximetry (SpO2; Nellcor N-200, Covidien, Mansfield, MA USA). Heart rate was

measured by lead II electrocardiography (Bioamp, ADInstruments, Colorado Springs, CO

USA). Analog signals from all instruments were recorded at 200 Hz for offline analysis

(Powerlab 26T ADInstruments, Colorado Springs, CO USA).

Acute Mountain Sickness Self-reported sections of the Lake Louise AMS Questionnaire

(LLQ) were used to assess symptoms of AMS as subjects ascended and acclimatized to

high altitude. Composite LLQ scores ≥ , which included at least a mild headache, were

considered positive for AMS (Roach et al., 1993).


Analyses

Cuff tests The MCAv response relative to the drop in ABP following cuff deflation was

quantified using the ARI (Tiecks et al., 1995). Briefly, if CA is completely absent, the

initial drop and subsequent recovery of ABP will be reflected by parallel changes in

MCAv and assigned a Cuff ARI score of 0. Incremental improvements in CA are assigned

values up to 9, as the drop in MCAv is blunted and its recovery is hastened. Cuff ARI

analyses were performed using custom software (Cerebral Hemodynamic Analysis

written by R. Aaslid). Continuous recordings of ABP and MCAv were down sampled

from 200 to 100 Hz and low-pass filtered with a cut-off frequency of 0.5 Hz prior to ARI

curve fitting. Trials in which the drop in ABP was < 15 mmHg were excluded from

analysis (Tiecks et al., 1995). The remaining Cuff ARI values for each individual were

averaged across each time point (Baseline, ALT2, ALT13) for statistical analyses.

Transfer function analysis Spontaneous fluctuations in ABP and MCAv across the last 6

min of the resting period were used to derive TFA ARI scores using custom software

(written by R.B. Panerai), as previously described (Subudhi et al., 2009, 2010). Briefly,

data were cleaned to remove spikes in the Doppler spectrum by linear interpolation and

normalized to characterize percent change from the beginning of the recording period,

thereby minimizing potential effects of changes in ABP and MCAv over the study. Beat-

by-beat averages of ABP and MCAv were resampled at 5 Hz and transformed into the

frequency domain by Fast Fourier Transformations (512 point window, 40% overlap).

The dynamic relation between the resulting ABP to MCAv spectra was expressed in

terms of coherence, gain, and phase shift in the very low frequency range (0.02 - 0.07

Hz), where dynamic CA is most active, as well as in low (0.07 to 0.20 Hz) and high (0.20

to 0.40 Hz) frequency ranges. The inverse transformation of the resulting gain and

phase shift was used to express results in the time domain as a step function that was

fitted to one of the 10 ARI curves described above. This process yielded TFA ARI scores

that were conceptually similar to the Cuff ARI scores.


Statistics

Data were analyzed by repeated measures ANOVAs with planned pairwise Sidak-Holm

contrasts to control for Type I error. Relations between Cuff and TFA ARI

measurements were evaluated by Pearson product moment correlations. Relations

between ARI measurements and LLQ scores were evaluated by Spearman correlations.

Statistical significance was considered when P < 0.05. Data are presented as mean ±

standard deviation.

Results

Resting data

Of the 12 consenting volunteers, one was excluded from the study at Baseline because

of an insufficient acoustic window for Doppler measurements. The remaining 11

subjects (6 females, 5 males; 20.5 ± 2.3 years; 172.0 ± 6.7 cm; 68.5 ± 10 kg) showed

typical responses upon ascent to high altitude at ALT2, including increased heart rate

and reduced SpO2 and PETCO2 (all P < 0.001; Table 1), without changes in ABP or MCAv.

Two subjects reported mild AMS (LLQ of 3 and 5 with headaches) at ALT2. Over 11 days

of high-altitude residence, AMS symptoms resolved and subjects showed clear signs of

ventilatory acclimatization, reflected by increased SpO2 and reduced PETCO2 without

changes in ABP or MCAv from ALT2 to ALT13 (both P < 0.001).

Leg cuff tests

Data from one additional subject were excluded from statistical analysis because of

insufficient reductions in ABP following cuff deflation (< 10 mmHg on three trials) at

Baseline. Rapid cuff deflation reduced ABP by 22 ± 6, 23 ± 4, and 23 ± 6 mmHg at

Baseline, ALT2, and ALT13, respectively. Overall Cuff ARI responses were indicative of

reduced CA at high altitude (P=0.021). Cuff ARI was reduced ~30% from Baseline to

ALT2 (P=0.037). This response was consistent after acclimatization, as the change from

Baseline to ALT13 was also ~30% (P=0.037; Table 1; Figure 1).


Transfer function analysis

The TFA analysis did not show evidence of reduced CA from Baseline to high altitude in

any of the frequency ranges analyzed. Although the repeated measures ANOVA for TFA

ARI approached significance (P = 0.065), no changes in underlying measures of

coherence, gain or phase shift were detected (Table 1, Figure 2).

Relations between ARI and AMS scores

There was a moderately strong relation between Cuff and TFA ARI assessments (r =

0.45, P < 0.01, Figure 3). Cuff and TFA ARI scores measured at either Baseline or ALT2

were not related to LLQ scores at ALT2 (r range -0.40 to 0.08, all P > 0.10). The two

subjects with mild AMS at ALT2 had mid range Cuff (3.4 and 4.8) and TFA (3.2 and 4.1)

ARI scores.

Discussion

The key new findings of this study were that 1) the classic leg cuff technique detected

reductions in dynamic CA upon ascent and after acclimatization to 3424 m, while 2) the

TFA method did not, and 3) neither Cuff nor TFA ARI scores were associated with mild

symptoms of AMS. These findings imply that cerebral vasculature of healthy individuals

may become less able to buffer large step changes in ABP, while still maintaining the

ability to regulate slow rhythmical oscillations during periods of moderate hypoxemia.

The leg cuff technique may thus offer insight into hypoxia-induced changes in the

cerebral pressure-flow relation that are not captured with TFA alone.

Autoregulation index assessed by leg cuff tests

Our results demonstrate that the leg cuff test is a sensitive method for assessing

changes in dynamic CA at high altitude. The mid-range Cuff ARI scores observed at low

altitude (4.7± 1.5) were in accordance with average values (4.9 ± 1) originally reported

in individuals at sea level (Tiecks et al., 1995) and support the assumption that travel

from near sea level to low altitude had little effect on Baseline CA assessments. The

consistently large drops in ABP following rapid leg cuff deflation (~23 mmHg) provided

a standard stimulus by which to evaluate changes in the cerebral pressure-flow relation

between altitudes. A greater drop and/or delayed recovery in MCAv was observed in 9

of 10 individuals upon ascent to 3424 m and explained the ~30% reduction in Cuff ARI


scores. These effects were consistent in 8 of 10 subjects after two weeks of

acclimatization. Together, these results clearly demonstrate a more passive response in

MCAv for a given step change in ABP, indicative of reduced, but not lost, dynamic CA at

3424 m.

Our findings extend those from laboratory studies showing that acute inhalation of

hypoxic gas (< 10 min) reduces cuff derived CA scores during moderate (PIO2 ~ 100

mmHg) (Ogoh et al., 2010) and severe hypoxia (PIO2 ~ 70 mmHg) (Subudhi et al., 2009).

The similarity in findings between laboratory and field studies implies that the Cuff ARI

response in simulated altitude (normobaric hypoxia) may be comparable to that at

terrestrial altitudes (hypobaric hypoxia). More detailed laboratory studies may thus be

designed to unravel the underlying mechanisms of the response without having to go to

the field. Our results differ from the only other field study to use the leg cuff technique

(Van Osta et al., 2005). Although their application of the leg cuff technique and analysis

of data were similar to ours, the lack of reduction in their subjects’ ARI scores upon

ascent to high altitude may have been confounded by prior administration of tadalafil

and dexamethasone, two drugs shown to improve ARI (Van Osta et al., 2005). Thus,

despite a limited number of observations at high altitude, or with hypoxic gas mixtures,

the leg cuff test appears to be sensitive to changes in the regulation of cerebral blood

flow during acute periods of moderate and severe hypoxia. Our observation that the

reduction in Cuff ARI persists after two weeks of acclimatization is a testament to the

reliability of the measurement and supports the notion that reduced CA is a hallmark

characteristic of life at high altitude (Jansen et al., 2000; Subudhi et al., 2014). Why this

is so and whether reduced CA may promote successful acclimatization remain to be

answered. While our study was not designed to elucidate the mechanism of reduced CA

at high altitude, the sensitivity and reliability of Cuff ARI scores make the leg cuff test an

attractive test for future investigations.

Autoregulation index assessed by transfer function analysis

The TFA results did not show evidence of reduced CA in this study. TFA ARI scores

exhibited a downward trend when subjects were acutely exposed and acclimatized to

high altitude, but the individual metrics of coherence, gain and phase were not different

from Baseline. While there is some debate on the relative importance of changes in


individual metrics, a robust reduction in CA should result in increased coherence and

gain and decreased phase and ARI scores. The lack of change in these metrics in the

present study is in contrast to previous reports showing significant changes in all

metrics when subjects traveled between sea level and 5260 m (Iwasaki et al., 2011;

Subudhi et al., 2014) as well as between 1650 m and 4878 m (Subudhi et al., 2010). We

speculate that differences between the present and prior studies may be related to the

altitudes at which the studies were conducted. Two previous reports suggested that CA

remains intact until a threshold elevation is crossed, somewhere between 2600 and

3440 m (Iwasaki et al., 2007; Jansen et al., 2007). In the present study, we observed

relatively mild hypoxemia upon arrival at high altitude (SpO2 ~90%) compared to

studies at higher elevations (SpO2 ~75%). Thus, the degree of hypoxemia at 3424 m

may have been insufficient to cause significant changes in the relation between resting

oscillations in ABP and MCAv. Alternatively, it is possible that our small sample size

yielded insufficient statistical power to detect reduced CA (Subudhi et al., 2009), yet we

have recently shown significant changes in each metric with a similar sample size at

higher altitude (Subudhi et al., 2014). The consistency of each metric and maintenance

of mid-range ARI scores across the study indicate that autoregulatory mechanisms that

offset small oscillations in ABP remained intact at 3424 m.

General differences between leg cuff and transfer function assessments

Together, our results suggest that the leg cuff and TFA methods may capture different

components of the overall autoregulatory response to hypoxia. Previous studies have

shown strong agreement between these methods in patients with cardiovascular

disease (Panerai et al., 1998; Saeed et al., 2013). However, in the present study of young,

disease-free subjects, the two measurements only shared ~20% of their variance

(square of the correlation coefficient, r=0.45), meaning the techniques had relatively

little in common when CA was altered by hypoxia. These findings are similar to our

previous comparison of Cuff and TFA ARI scores in healthy individuals exposed to

hypobaric hypoxia (Subudhi et al., 2009) and likely reflect the discrepancies in the

nature of the ABP stimuli evaluated by each test. While the cuff test monitors the

response to a single, large and rapid drop in ABP, TFA evaluates rhythmical, small

amplitude oscillations in ABP over a longer timeframe. Our results imply that one may

lose the ability to maintain CBF when challenged by large, abrupt changes in ABP, while


still preserving the ability to handle smaller, rhythmical changes in ABP during

moderate levels of hypoxemia experienced at 3424 m. Our findings are somewhat in

contrast to a recent study in which TFA was used to evaluate CA at rest and while

subjects performed repeated squatting motions to induce larger, rhythmical

fluctuations in ABP (Smirl et al., 2014). They reported reductions in CA from sea level to

5050 m when measured at rest, but no changes when measured during the repeated

squat test. Inequalities in the nature of the ABP stimuli (single drop vs. rhythmical

fluctuations), altitudes of study, and analysis techniques make direct comparisons

difficult, but the differential responses to small and large fluctuations in ABP should be

noted. Whether a threshold exists in the magnitude and/or frequency of the ABP

stimulus needed to affect CA and whether such a threshold is altitude specific remain to

be determined. Given such differences in responses between techniques, we advocate

that future investigations use multiple methods of assessing CA at multiple altitudes to

provide a more comprehensive view of CA in hypoxia.

Significance

Whether the CBF responses to these varied stimuli have practical relevance remains to

be determined. For example, we question whether the reduction in Cuff ARI might be

associated with increased incidence of syncope at high altitude (Nicholas et al., 1992;

Blaber et al., 2003), but remain skeptical that CA measurements based solely on drops

in pressure will reveal much about the potential impact of heightened perfusion, such as

has been hypothesized in the etiology of AMS and high-altitude cerebral edema (Lassen

& Harper, 1975). Given the multifactorial nature of AMS, it was not surprising that our

baseline Cuff ARI data showed no predictive ability to forecast mild AMS at 3424 m, nor

were Cuff ARI scores on arrival related to AMS. These findings are in contrast to the

results of two previous studies (Van Osta et al., 2005; Cochand et al., 2011), but could be

attributed to the low incidence and severity of AMS symptoms in our subjects. It is also

possible that reduced CA may be a permissive element predisposing one to AMS when

combined with other as-yet-unidentified factors (Subudhi et al., 2014). With respect to

TFA, although resting oscillations in ABP and CBF are real, the absolute changes are

small (~10 mmHg) and slow (~20 s/cycle) and thus may not pose a threat to healthy

individuals at these altitudes. Even at higher altitudes, where TFA analyses reveal a

more passive pressure-flow relation, no studies have demonstrated that reduced resting


CA has any detrimental effects. In general it appears that measured reductions in

dynamic CA at high altitude do not have outward negative effects on cerebrovascular

health.

Limitations

Assessments of dynamic CA in this study were based on blood flow velocity, using the

assumption that MCA diameter was unchanged from low to high altitude. We believe

this was a reasonable assumption since changes in MCA diameter have not been

reported below 5,300 m (Wilson et al., 2011), but acknowledge the need to consider

even small changes in vessel diameter in future studies to more accurately describe

responses in volumetric blood flow. Likewise, although finger plethysmography is a

suitable method of assessing systemic blood pressure, more direct methods that can

capture pulse pressure in the cerebral arteries is needed to truly characterize CA.

We did not attempt to control for changes in PETO2 or PETCO2 that occurred with ascent

and acclimatization to 3424 m because we wanted to evaluate functional changes in CA

resulting from integrated physiological responses to high altitude. In general, CA

worsens as PETO2 falls, but improves as PETCO2 falls (Paulson et al., 1990). It is thus

possible that some of the reduction in CA expected from low PETO2 at high altitude was

offset by reduced PETCO2 subsequent to increased ventilatory drive. Future multivariate

studies that experimentally control PETO2 and PETCO2 are needed to determine the

isolated mechanisms underlying integrative CA response at high altitude.

Conclusions

Hypoxemia associated with travel to 3424 m reduces dynamic CA at rest as assessed by

the leg cuff technique, but not by TFA. We interpret these findings to suggest that the

cerebral vasculature may become relatively less able to protect against large, abrupt

changes in ABP, but still has the ability to maintain CBF across resting oscillations in

ABP. The consistency of these findings across acclimatization and the lack of correlation

with AMS symptoms lead us to believe that these changes are relatively innocuous

effects of mild hypoxemia. Given the differences between the two dynamic CA

techniques, we encourage others to consider multiple means of assessment to better

understand implications of altered CA at high altitude.


Funding

This project was funded in part by the Medical Education Research Institute of Colorado

to AWS.

Author contributions

AWS and JED conceived and designed the experiments. AWS, KG, RJL, and JED collected,

analyzed, and interpreted the data. All authors contributed to writing and revising the

manuscript.

Acknowledgements

The authors express their sincere gratitude to the students and staff at Alma College for

their participation.

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Table 1. Physiological responses after two (ALT2) and 13 (ALT13) days at 3424 m

Variable Baseline ALT2 ALT13

HR bpm 70 ± 9 86 ± 10* 72 ± 8^

ABP mmHg 91 ± 11 89 ± 9 90 ± 10

MCAv cm/s 47 ± 10 48 ± 7 42 ± 8*

SpO2 mmHg 98 ± 2 90 ± 3* 93 ± 2*^

PETO2 mmHg 78 ± 4 57 ± 3* 63 ± 2*^

PETCO2 mmHg 38 ± 3 33 ± 4* 27 ± 2*^

Cuff ARI

4.7 ± 1.5 3.2 ± 1.6* 2.9 ± 1.3*

TFA ARI

5.6 ± 1.1 4.7 ± 1.3 4.5 ± 1.1

PSD ABP %^2/Hz 7.7 ± 5.1 8.2 ± 6.0 9.0 ± 8.7

PSD MCAv %^2/Hz 11.9 ± 8.1 14.4 ± 9.2 15.8 ± 17.3

Coherence

0.43 ± 0.14 0.50 ± 0.20 0.48 ± 0.17

Gain %/% 0.84 ± 0.33 1.01 ± 0.47 0.89 ± 0.26

Phase Shift radians 0.61 ± 0.22 0.48 ± 0.47 0.43 ± 0.27

Different from Baseline (*) and/or ALT2 (^) at P < 0.05. Heart rate (HR), mean arterial

blood pressure (ABP), mean middle cerebral artery blood velocity (MCAv), arterial

pulse oxygen saturation (SpO2), partial pressures of end tidal oxygen and carbon

dioxide (PETO2, PETCO2), cuff and transfer function analysis (TFA) autoregulation

indexes (ARI), very low frequency (0.02 to 0.07 Hz) power spectral density (PSD),

coherence, gain, and phase shift.


Figure 1. Individual changes (n=11) in the autoregulation index (ARI) assessed by the

leg cuff technique (Cuff) and transfer function analysis of resting data (TFA) at low

altitude (Baseline; 1650 m), and after ascent (ALT2) and 13 days of acclimatization

(ALT13) to high altitude (3424 m). * Average Cuff ARI values at ALT2 an ALT13 were

lower than Baseline (P < 0.05).


Figure 2. Average power spectral density (PSD) of arterial blood pressure (ABP) and

middle cerebral artery blood velocity (MCAv), transfer function analysis (TFA) metrics

of coherence, gain, and phase, and the resulting step responses at low altitude (Baseline;

1650m; solid line) and after ascent (ALT2; dotted line) and 13 days of acclimatization

(ALT13; dashed line) to high altitude (3424 m). Standard deviations are not shown for

clarity.


Figure 3. Correlation between autoregulation index (ARI) assessed by the leg cuff

technique (Cuff) and transfer function analysis of resting data (TFA). The plot

represents combined measurements at low altitude (1650 m) and after 2 and 13 days at

high altitude (3424 m).

Cerebral autoregulation index at high altitude assessed by leg cuff and transfer function analysis...

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