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Journal of Cerebral Blood Flow & Metabolism logoLink to Journal of Cerebral Blood Flow & Metabolism
. 2015 Mar 25;35(8):1323–1330. doi: 10.1038/jcbfm.2015.51

Cerebrovascular reactivity is increased with acclimatization to 3,454 m altitude

Daniela Flück 1,2, Christoph Siebenmann 2, Stefanie Keiser 1,2, Adrian Cathomen 3, Carsten Lundby 1,2,4,*
PMCID: PMC4528007  PMID: 25806704

Abstract

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO2 reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAvmean) CVR was assessed during hyperventilation (hypocapnia) and CO2 administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26±4 years (mean±s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAvmean was not altered. Hypercapnic CVR was decreased at HA0 (1.16%±0.16%/mm Hg, mean±s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13%±0.18% and 2.96%±0.10%/mm Hg) and HA22 (3.32%±0.12% and 3.24%±0.14%/mm Hg) compared with SL (1.98%±0.22% and 2.38%±0.10%/mm Hg; P<0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAvmean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude.

Keywords: brain blood flow, cerebrovascular conductance, CO2 reactivity, hypoxia, middle cerebral artery, TCD

Introduction

Ensuring an adequate cerebral blood flow (CBF) and O2 delivery is crucial and is in normoxia largely regulated by the arterial partial pressure of CO2 (PaCO2).1 Elevations in PaCO2 (hypercapnia) lead to vasodilation, whereas decreases in PaCO2 (hypocapnia) facilitate vasoconstriction of the cerebrovasculature.1 The cerebrovasculature is less sensitive to changes in the arterial O2 partial pressure (PaO2), with vasodilation only occurring when PaO2 declines below ~50 to 60 mm Hg.2, 3 With acute exposure to high altitude, the hypoxic vasodilatory effect facilitates an elevation in CBF, however, with acclimatization to altitude is counteracted by the hypoxic ventilatory response, which causes a reduction in PaCO2 and thus CBF declines toward sea level (SL) values.4, 5 Cerebrovascular CO2 reactivity (CVR), a measure of cerebrovascular function,6 may intuitively be expected to be decreased in response to the ventilatory-induced reduction in PaCO2 to preserve CBF. Yet, several studies have assessed CVR in response to hypoxic exposure7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and the outcomes are highly controversial, ranging from increased,8, 10, 14, 15 unchanged11, 13, 16 to reduced7, 9, 12 CVR. These differences possibly derive in part from inconsistencies in study protocols and methods applied. In this regard, the CVR tests have been conducted with background oxygen levels ranging from being hypoxic,7, 11, 12, 13 normoxic7, 11 to hyperoxic.8, 9, 10, 12, 14 This may influence the results as peripheral chemoreceptor sensitivity is increased in response to chronic hypoxia17 and in addition, the hypoxic vasodilatory effect may affect CVR.2 In addition, the majority of studies have assessed CBF by means of transcranial Doppler ultrasound (TCD),8, 9, 10, 11 which for an accurate determination of flow, relies on unchanged vessel diameter. In conditions above >5,000 m (or the equivalent degree of hypoxia)3, 18 or changes in PaCO2 more than 15 mm Hg19 above resting values, changes in middle cerebral artery (MCA) diameter have been reported. Therefore, when interpreting TCD-derived data, these shortcomings need to be acknowledged. Moreover, the time points of CVR assessment in the above mentioned studies vary not only between studies from several minutes to 16 days at hypoxia, but also within studies where measurements were conducted, e.g., within 2 to 4 days.9 Finally, only a few studies have taken changes in blood pressure into account when assessing CVR,8, 10 despite the demonstrated effects of hypoxia, hypercapnia and hypocapnia on blood pressure20 and cerebral autoregulation.21, 22 Furthermore, most studies have been conducted under conditions similar to a mountain expedition9, 10, 12, 16 including a trekking ascent over several days, board and lodging, which contrast markedly with subject's usual environment and habits, all being potential confounding factors.

To overcome, at least in part, these limitations, we performed a study at the Jungfraujoch research station (3,454 m) where living conditions are comparable to subject's daily life and allow for measurements immediately after a 2-hour train ascent. Hypo- and hypercapnic CVR were assessed in background hypoxia and normoxia at SL and then again exactly after 30 minutes, 3 and 22 days of hypoxic exposure. We hypothesized that hypo- and hypercapnic CVR would be unaffected during acute exposure to high altitude, but would increase with acclimatization.

Materials and methods

All experimental protocols and procedures conformed to the Declaration of Helsinki and were approved by the Ethical Committee of the Swiss Federal Institute of Technology Zurich (EK 2011-N-51). Prior to participation, a detailed verbal and written explanation of the study was provided, and written informed consent to participation was obtained from each participant.

Nine young and healthy SL residents (one woman) with a mean age of 26±4 years (mean±s.d.), height 179±9 cm and weight 75±10 kg volunteered to participate in the study. They were not taking any medication and had no history of cardiovascular, cerebrovascular or respiratory disease. Subjects refrained from sleeping at >2,500 m within the last 3 months before the study. They were instructed to avoid caffeine, alcohol and exercise within 12 hours before the experiments reported here.

Study Design

After a full familiarization trial of the experiment detailed below, volunteers underwent four experimental trials: one in Zurich, Switzerland (SL, 432 m) and three at the Jungfraujoch research station (3,454 m): one 30 minutes after a 2-hour ascent by train (HA0), one after 3 days (HA3) and the last after 22 days (HA22). Each subject traveled to the research station individually to allow testing at the same daytime throughout all experimental trials as well as after the same duration spent at high altitude.

Hypo- and Hypercapnic Cerebrovascular CO2 Reactivity Protocol

All experimental protocols were conducted with study volunteers in a semirecumbent position. A 10-minute resting period, which included 5-minute baseline data collection, preceded the hypo- and hypercapnic CVR protocol. The hypo- and hypercapnic CVR protocol included four different levels of end-tidal partial pressure of CO2 (PETCO2) with each conducted at two different levels of background oxygenation (partial pressure of inspired O2, PIO2) simulating 432 m (normoxia) and 3,454 m (hypoxia) in a randomized order. During the first step of the hypo- and hypercapnic protocol, study volunteers were instructed to hyperventilate for 2 minutes to reduce PETCO2 to 17 to 20 mm Hg (hyperventilation (HV)). The second step served to normalize PETCO2 (plus0) and represents the resting PETCO2 value at each time point of acclimatization. Based on this second step, PETCO2 was increased by 5 and 10 mm Hg for the third (plus5) and fourth (plus10) step of the hypo- and hypercapnic protocol, respectively. The duration of each step was 3 minutes with the aim to attain at least 2 minutes with the desired levels of PIO2 and PETCO2. To reach the desired levels of PIO2 and PETCO2 a modified gas mixing system (AltiTrainer, SMTEC, Nyon, Switzerland) was connected to the inspiratory valve of the mouthpiece. The gas mixing system consisted of a Douglas bag where air and experimental gases (nitrogen, O2, and CO2) were mixed. A continuous feedback from the spirometer (Cosmed Quark b2, Rome, Italy) allowed for precise adjustments to reach the desired levels of PETCO2 and PIO2.

Experimental Measures

Middle cerebral artery mean velocity (MCAvmean) was assessed using TCD (Doppler Box, DWL, Sipplingen, Germany) with a 2-MHz probe placed over the right temporal window, prepared with ultrasound gel. The probe was held in place with a headgear. To insonate the same site for each repeated measurement, notes and a photo of the angle were taken and the position of the probe during the first visit to the laboratory. Mean arterial pressure (MAP) was recorded continuously via finger photoplethysmography (Nexfin, BMEYE B.V, Amsterdam, Netherlands) and heart rate and oxygen saturation (SpO2) were assessed by a pulse oximetry (Nellcor Oximax N-600, Mansfield, MA, USA). Middle cerebral artery mean velocity, MAP, heart rate, and SpO2 were sampled at 1,000 Hz and stored for offline analysis (LabChart 7 Pro v7.3.5 and Powerlab, ADInstruments, Bella Vista, NSW, Australia).

By breathing through a mouthpiece with the nose occluded (Hans Rudolph, Kansas City, MO, USA) respiratory parameters were measured breath by breath using a spirometer

Capillary blood samples were obtained from the right ear lobe at baseline and at the end of all steps during the hypo- and hypercapnic CVR protocol. Capillary partial pressure of O2 (PCAPO2), PCAPCO2, pH, and HCO3− were measured using a blood gas analyzer (ABL800, Radiometer, Copenhagen, Denmark).

Cerebral tissue oxygenation (cStO2) was continuously assessed on the left and right forehead by near-infrared spectroscopy (Invos-5100c, Covidien, Mansfield, MA, USA).

Data Analysis

Data were recorded continuously. Values are presented as means±s.e.m. Data parameters were averaged over the last minute of each step during the hypo- and hypercapnic CVR protocol. Cerebrovascular conductance (CVC) was calculated as MCA vmean divided by MAP.

For each study participant, hypo- and hypercapnic CVR were calculated separately for the hypo- and hypercapnic range, respectively. Absolute and relative changes in MCAvmean and relative changes in CVC (CVCR) were divided by the changes in PETCO2 from baseline to hypercapnia (plus10) and hypocapnia (HV).

Comparisons of values were made using a repeated two-way analysis of variance with the main factor being time (SL, HA0, HA3, and HA22) and condition (normoxia and hypoxia). Tukey's range test was applied for post hoc analysis. The Pearson product-moment correlation was used to examine the relationship between CVR and CVCR and bicarbonate. Statistical significance was set at P<0.05. Statistical analyses were performed using SAS Enterprise Guide (4.3, SAS Institute, Cary, NC, USA).

Results

All nine volunteers completed the entire study protocol at sl and high altitude.

Cardiovascular, respiratory, and cerebrovascular parameters at SL, HA0, HA3, and HA22 are presented in Table 1. Briefly, heart rate, MAP, and MCAvmean did not change (P>0.25) in response to short- and long-term exposure to high altitude. Ventilation increased by 41%±7% from SL to HA22 (P<0.01) and was associated to a decline in PETCO2 by 24%±2% (P<0.01). PETO2 decreased to 54.4±1.7 mm Hg (P<0.01) in response to high-altitude exposure at HA0, but thereafter increased with prolonged exposure to high altitude compared with HA0 (P<0.01).

Table 1. Cardiovascular, respiratory, cerebrovascular, and capillary parameters at SL, 30 minutes (HA0), 3 days (HA3), and 22 days (HA22) after ascent to altitude (3,454 m).

  SL 3454 m
 P-value
    HA0 HA3 HA22  
HR (bpm) 69±5 75±5 71±3 70±4 0.53
MAP (mm Hg) 93.0±4.2 94.3±3.0 99.5±4.7 95.8±4.6 0.25
VE (L/min) 9.5±0.6 10.4±0.4 11.2±0.73* 13.3±0.8* † ‡ <0.01
BF (L/min) 15.2±1.4 17.0±1.5 17.4±1.1 18.1±1.5 0.08
VT (L) 0.67±0.07 0.67±0.09 0.67±0.07 0.79±0.09 0.28
PETO2 (mm Hg) 91.5±1.1 54.4±1.7* 58.0±0.8* 64.2±1.2* † ‡ <0.01
PETCO2 (mm Hg) 39.5±0.5 37.1±0.9* 32.3±0.5* † 30.0±0.6* † ‡ <0.01
SpO2 (%) 97.2±0.6 88.5±1.8* 89.5±0.9* 93.1±0.5† <0.01
MCAvmean (cm/s) 61.2±3.4 62.0±3.9 59.5±3.7 58.2±2.9 0.68
CVC (cm/s/mm Hg) 0.67±0.05 0.67±0.05 0.61±0.05 0.62±0.04 0.14
cStO2 (%) 75.6±2.5 64.1±2.4* 69.0±3.3* 71.9±2.1† <0.01
pH 7.38±0.01 7.40±0.01 7.40±0.01 7.39±0.01 0.06
PCAPCO2 (mm Hg) 38.7±0.8 36.5±1.2 32.0±0.6*† 30.8±0.6*† <0.01
PCAPO2 (mm Hg) 72.0±1.8 50.6±1.7* 55.3±1.1* 59.8±1.1*† <0.01
HCO3− (mmol/L) 22.6±0.3 22.6±0.2 21.1±0.5*† 20.4±0.4*† <0.01
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Abbreviations: BF, breathing frequency; cStO2, cerebral tissue oxygenation; CVC, cerebrovascular conductance; HCO3−, bicarbonate concentration; HR, heart rate; MAP, mean arterial pressure; MCAvmean, middle cerebral artery mean velocity; PCAPCO2, capillary partial pressure of CO2; PCAPO2, capillary partial pressure of O2; PETCO2, end-tidal partial pressure of CO2; PETO2, end-tidal partial pressure of O2; SL, sea level; SpO2, oxygen saturation; VE, ventilation; VT, tidal volume.

Values are mean±s.e.m.

P values represent analysis of variance results.

*P<0.05 versus SL. †P<0.05 versus HA0. ‡P<0.05 versus HA3.

Hypo- and Hypercapnic Cerebrovascular CO2 Reactivity Protocol

Figure 1 illustrates PETCO2 and PETO2 during the hypo- and hypercapnic CVR protocols. In background normoxia (Figure 1A) PETO2 values were 118±1.3 mm Hg and in hypoxia (Figure 1B) 74.1±1.3 mm Hg. During HV PETCO2 values decreased to 18.7±0.1 mm Hg (Figures 1A and 1B) from 33.9±0.3 mm Hg (plus0) and was increased to 43.6±0.4 mm Hg during the hypercapnic challenge (plus10, Figure 1).

Figure 1.

Figure 1

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End-tidal partial pressure of CO2 (PETCO2, dashed lines) and inspired partial pressure of O2 (PIO2; solid lines) during hyperventilation (HV), no additional CO2 (plus0), plus 5 mm Hg CO2 (plus5), and plus 10 mm Hg CO2 (plus10) are presented in near sea level (SL; A, normoxia) and 3,454 m (B, hypoxia) conditions conducted at SL (circle), 30 minutes (square), 3 days (diamond), and 22 days (triangle) after ascent to high altitude.

Middle Cerebral Artery Mean Velocity, Mean Arterial Pressure, Cerebrovascular Conductance, and Ventilation during Hypo- and Hypercapnic Cerebrovascular CO2 Reactivity Test

Percent changes in hypo- and hypercapnic CVR are presented in Figure 2. CVR conducted in either a normoxic or hypoxic background was elevated at HA3 and HA22 compared with SL and HA0 (P<0.01). Overall percent changes in hypo- and hypercapnic CVR were higher with a normoxic background compared with the hypoxic background (2.33%±0.11% versus 2.09%±0.11%/mm Hg, P<0.01). Similar changes were assessed as absolute changes in CVR in response to hypo- and hypercapnia. From SL to HA22 absolute changes in hypocapnic CVR tested in normoxia and hypoxia were elevated from 1.50±0.14 and 1.34±0.06 cm/s/mm Hg to 2.07±0.17 and 1.70±0.13 cm/s/mm Hg (P<0.01), respectively. Absolute changes in CVR to hypercapnia at HA0 were reduced compared with SL (0.68±0.10 versus 1.26±0.15 cm/s/mm Hg, P<0.01) and thereafter increased (P<0.01) compared with SL and HA0.

Figure 2.

Figure 2

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Individual (gray) and mean (black) middle cerebral artery mean velocity (MCAvmean) percent change cerebrovascular CO2 reactivity (CVR) in response to hypocapnic (A and C) and hypercapnia (B and D) in background normoxia (A and B) and hypoxia (C and D) at sea level (SL), 30 minutes (HA0), 3 days (HA3), and 22 days (HA22) after ascent to high altitude. P-values represent analysis of variance results. *P<0.05 versus SL. †P<0.05 versus HA0.

Mean arterial pressure decreased in response to hypocapnia and increased during hypercapnia (P<0.01; Figure 3). CVCR values are presented in Figure 4. In response to hypocapnia CVCR was elevated after HA22 compared with SL independent of the background level of oxygen (P<0.01). A trend was observed within the CVCR values in normoxic and hypoxic background (P=0.07). In addition, there was a trend for a reduction in hypercapnic CVCR from SL to HA0 (P=0.07).

Figure 3.

Figure 3

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Mean arterial pressure (MAP) absolute values during hyperventilation (HV), no additional CO2 (plus0), plus 5 mm Hg CO2 (plus5), and plus 10 mm Hg CO2 (plus10) are presented in near sea level (SL; A, normoxia) and 3,454 m (B, hypoxia) conditions conducted at SL (circle), 30 minutes (square), 3 days (diamond), and 22 days (triangle) after ascent to high altitude.

Figure 4.

Figure 4

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Individual (gray) and mean (black) cerebrovascular conductance percent change cerebrovascular CO2 reactivity (CVCR) in response to hypocapnia (A and C) and hypercapnia (B and D) in background normoxia (A and B) and hypoxia (C and D) at sea level (SL), 30 minutes (HA0), 3 days (HA3), and 22 days (HA22) after ascent to high altitude. P-values represent analysis of variance results. *P<0.05 versus SL. †P<0.05 versus HA0.

Ventilation during the hypercapnic CVR protocol was increased with exposure to high altitude (e.g., SLplus10, 24.1±3.1; HA22plus10, 38.8±4.4 L/min; P<0.01) as well as with elevated PETCO2 in background normoxia (e.g., SLplus0, 7.1±0.4; SLplus10, 24.1±3.1 L/min; P<0.01) and hypoxia (e.g., SLplus0, 8.4±0.6; SLplus10, 19.6±2.5 L/min; P<0.01). During the hypocapnic CVR protocol ventilation decreased with exposure to high altitude independent of background oxygen levels (e.g., SLHV, 61.1±7.2, HA22HV, 34.3±2.6 L/min; P<0.01).

Capillary Blood Samples

Capillary partial pressure of O2 and PCAPCO2 followed the same pattern as PETO2 and PETCO2, an initial decrease followed by an increase and a decline throughout the exposure to high altitude, respectively (Table 1). Bicarbonate was decreased at HA3 and HA22 (P<0.01; Table 1) compared with SL and HA0.

Cerebrovascular CO2 Reactivity and Bicarbonate Correlations

Hypercapnic CVR correlated with the bicarbonate values in response to high altitude (P<0.01; Figure 5) independent of background oxygen levels.

Figure 5.

Figure 5

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Relation between hypercpanic middle cerebral artery mean velocity (MCAvmean) cerebrovascular CO2 reactivity (CVR; A and B) and cerebrovascular conductance CO2 reactivity (CVCR; C and D) percent changes and bicarbonate (HCO3−) in background normoxia (A and C) and hypoxia (B and D) at sea level (black circles), 30 minutes (dark gray squares), 3 days (gray diamonds) and 22 days (white triangles) on ascent to high altitude.

Discussion

In this study, we determined the effect of high-altitude (3,454 m) exposure on CVR in controlled settings where confounding factors were minimized. Our findings extend those from previous studies by showing (1) an initial decline in hypercapnic CVR observed 30 minutes after high-altitude exposure, which was followed by (2) an enhanced hypercapnic CVR at HA3 and HA22 in background normoxia and hypoxia. (3) Furthermore, hypocapnic CVR was increased with acclimatization and (4) when accounting for changes in blood pressure this led to attenuated changes in hyper- and hypocapnic CVRs.

Cerebral blood flow is commonly reported elevated within the first days at high altitude because of the vasodilatory effect of hypoxia.4, 9 However, as a result of an increased hypoxic ventilatory response with acclimatization, PetCO2 becomes further reduced and hence facilitates cerebral vasoconstriction, which ultimately causes CBF to decline toward SL values.4, 5, 9 In the present study, MCAvmean did not increase after the first 30 minutes of exposure to high altitude, despite a decrease in PETO2 (Table 1) below the suggested vasodilatory threshold.2, 3 This, however, is in agreement with other studies7, 12, 23 and is likely related to the fact that PETO2 was only slightly reduced below the vasodilatory threshold, while the simultaneous decline in PETCO2 likely induced vasoconstriction and thereby counteracted the hypoxic vasodilatory effect. Previous studies have assessed MCAvmean using TCD8, 9, 10, 11 as also the case in the current study, and alternative to the above, the application of this technique may have underestimated the changes in CBF given that hypoxia may increase vessel diameter.3 This will be discussed in greater detail elsewhere.

The consequence of high-altitude exposure on cerebrovascular function is controversial, as CVR has been reported to be increased,8, 10, 14, 15 unchanged,11, 13, 16 or even reduced.7, 9, 12 In the present study, we observed a decreased hypercapnic CVR at HA0 followed by an increased hypercapnic CVR at HA3 and HA22 compared with SL. In most previous studies acute measurements were not feasible because of limited accessibility to the high-altitude research facilities. In an attempt to overcome this limitation, Fan et al8 supplied their volunteers with supplemental oxygen during the 3-hour ascent from 1,525 to 5,260 m. However, volunteers flew to 4,000 m and descended to 1,525 m for 48 h before ascending to 5,260 m, and thus they were not assessed in strictly acute altitude conditions. Consequently, this may have led to the increased CVR compared with SL, which contrasts the results of the present study. However, in agreement with the present results, is the reported reduction in CVR in response to normobaric hypoxia in a controlled laboratory setting.7 Other studies have reported decreases in CVR but then only after 2 to 15 days of high-altitude exposure.9, 11 A proposed mechanistic explanation here fore is enhanced sympathetic activation. However, increased sympathetic nerve activity with hypoxia is not limiting for further dilation of larger extracranial blood vessels.24 Furthermore, the influence of the vasodilatory effect of PaO2 could potentially limit CVR with acute exposure to hypoxia.7 However, the reduced CVR assessed in the MCA in response to acute hypoxia could also derive from a redistribution of blood flow to the posterior cerebral circulation to maintain essential homeostatic functions of the brainstem.25

Moreover, an interaction of CVR and central chemoreceptor-mediated ventilatory drive has been suggested.21, 26, 27 This interaction is manifested by changes in CVR, which affect the magnitude of hydrogen ion washout at the level of the central chemoreceptors that may consequently disturb the stability of the ventilatory response.28, 29 A blunted CVR, accordingly, leads to a diminished washout of brain tissue hydrogen ions, which subsequently facilitates a greater change in brain tissue PCO2 for a given change in PaCO2.29 Therefore, with acute hypoxia where brain tissue pH is increased,30 a reduced hypercapnic CVR may serve to limit brain tissue pH to rise even further. This could be promoted by diminishing the washout of hydrogen ions and facilitating the hyperventilatory response to altitude exposure by an increased ventilatory drive.

With prolonged exposure to high altitude the increase in brain tissue pH is counterbalanced by renal acid–base compensation, manifested by a reduction in HCO3−.30 Thus, a given change in PaCO2 leads to a greater decrease in brain tissue PCO2 because of reduced buffering capacity as a result of the reduction in HCO3−. Accordingly, an increase in PaCO2 leads to a greater reduction in pH, since the association between PaCO2 and pH is logarithmic,29, 31 and concomitantly to a higher CBF per increase in PaCO2. This phenomenon has previously been suggested linked to the increased hypercapnic CVR after 2 to 4 and 16 days at high altitude.8, 10, 15 In addition, the association between hypercapnic CVR and resting capillary HCO3− at SL, HA0, HA3, and HA22 (Figure 5) observed in the present study, supports this notion.

The results of the present study extend the current body of knowledge regarding the role of cerebrovascular function with acclimatization to high altitude. Cerebrovascular function is involved in homeostatic regulation and thus also affects ventilatory drive via the central chemoreceptors.21, 28 As mentioned above a decrease in CVR leads to greater changes in brain tissue PCO2 for a given change in PaCO2. Consequently, HV leads to an even greater decline in brain tissue PCO2 and thereby reduces ventilatory drive. This has been suggested to induce breathing instability,32 and could at least partially be responsible for the periodic breathing observed during sleep at high altitude.29, 32 In the present study, CVR was elevated after HA3 and HA22, thus possibly making the subjects less susceptible to periodic breathing with acclimatization. Nevertheless the cause–effect relationship of changes in CVR at high altitude is still unclear and further research is needed. Therefore, it is difficult to state whether changes in CVR are an effect of various acclimatization processes and/or whether they have a direct function to improve acclimatization to high altitude.

Only a limited number of studies assessing CVR have distinguished between the hypo- and hypercapnic range. Fan et al8 estimated a MCAvmean-CO2 slope including the hypo- and hypercapnic range, although the effect of altitude on cerebrovascular responses has been suggested to differ between the hypo- and hypercapnic range9, 11 as also showed in the current study. Previous studies assessing hypo- and hypercapnic CVR separately have shown an elevated hypocapnic CVR in response to high altitude.9, 10 This is in agreement with the present study reporting increased hypocapnic CVR at HA3 and HA22.

Background oxygen levels during CVR tests are a further methodological consideration possibly yielding different CVR results. In the present study, normoxic and hypoxic background levels during the CVR tests were chosen, simulating SL at 3,454 m and 3,454 m at SL, respectively, resulting in comparable responses of CVR. This is in agreement with Fan et al8 who also showed an enhanced CVR with acclimatization to high altitude, when assessed in a hyperoxic background. Thus background oxygen level seems not to exert a significant effect on CVR in response to exposure to high altitude.

Changes in PETCO2 may lead to changes in blood pressure and thus affect CVR.33, 34 In addition, alterations in cerebral autoregulation in response to hypercapnia35 and hypoxia7, 36, 37 have been reported. To overcome the potential influence of MAP, we monitored MAP (Figure 3) continuously throughout the experiments and calculated CVCR (Figure 4) as it has been suggested20 to reveal direct effects of changes in MAP on CVR. In comparison to CVR, CVCR resulted in attenuated responses to high-altitude acclimatization, decreased hypercapnic CVR at H0 and increased hypocapnic CVR at HA3 disappeared.

A limitation of the present study is the use of TCD to assess MCAvmean, a surrogate for CBF. Middle cerebral artery mean velocity is a measure of blood flow velocity and not a flow in absolute terms. Thus, an accurate CBF measurement relies on an unchanged MCA diameter. Middle cerebral artery mean velocity and CBF have in the past been shown to being highly correlated.38 However, recent studies have reported changes in vessel diameter in response to hypercapnia and hypoxia3, 18, 19 albeit of greater magnitude, than those induced in the present study. In the present study, PetCO2 was elevated 10 mm Hg above resting values, whereas changes in MCA diameter have been reported only with increases in 15 mm Hg or more. Moreover, dilation of the MCA in hypoxic conditions has been shown in altitudes >5,000 m,3, 18, 39 and vessel diameter changes at 3,454 m are less likely to have occurred.40 Nonetheless, if hypercapnia and/or hypoxia facilitated vessel diameter changes in the present study, this would have resulted in an underestimation of CBF. Thus, the present CVR results would have been even more prominent.

A further methodological consideration of the CVR assessment is whether to use the steady state or rebreathing technique. During the steady-state technique, as used in the present study, a gradient between brain tissue PCO2 and PaCO2 is present, whereas during the rebreathing technique this gradient is abolished.21 Nonetheless, the two different techniques have shown similar cerebrovascular and ventilatory reactivities to CO2 in response to altitude exposure,8 thus this concern can likely be neglected.

In conclusion, the present study represents a controlled high-altitude study and extends previous findings by showing an elevated hypo- and hypercapnic CVR with acclimatization to high altitude.

The authors declare no conflict of interest.

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