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Department of Anesthesiology, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Nepal International Clinic, Naxaul, Kathmandu, Nepal
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ABSTRACT |
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 Top
 Abstract
 Introduction
Methods
Results
Discussion
References
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The purpose of this study was twofold:
1) to determine whether at high
altitude cerebral blood flow (CBF) as assessed during CO2 inhalation and during
hyperventilation in subjects with acute mountain sickness (AMS) was
different from that in subjects without AMS and
2) to compare the CBF as assessed
under similar conditions in Sherpas at high altitude and in subjects at
sea level. Resting control values of blood flow velocity in the
middle cerebral artery (VMCA), pulse
oxygen saturation (SaO2), and
transcutaneous PCO2 were measured at
4,243 m in 43 subjects without AMS, 17 subjects with AMS, 20 Sherpas,
and 13 subjects at sea level. Responses of
CO2 inhalation and
hyperventilation on
VMCA,
SaO2, and transcutaneous PCO2 were measured, and the cerebral
vasomotor reactivity (VMR = 
VMCA/PCO2)
was calculated as the fractional change of
VMCA per Torr
change of PCO2, yielding a
hypercapnic VMR and a hypocapnic VMR. AMS subjects showed
a significantly higher resting control
VMCA than did
no-AMS subjects (74 ± 22 and 56 ± 14 cm/s, respectively;
P < 0.001), and
SaO2 was significantly lower (80 ± 8 and 88 ± 3%, respectively; P < 0.001). Resting control VMCA values in
the sea-level group (60 ± 15 cm/s), in the no-AMS group, and in
Sherpas (59 ± 13 cm/s) were not different. Hypercapnic VMR values
in AMS subjects were 4.0 ± 4.4, in no-AMS subjects were 5.5 ± 4.3, in Sherpas were 5.6 ± 4.1, and in sea-level subjects were 5.6 ± 2.5 (not significant). Hypocapnic VMR values were significantly higher in AMS subjects (5.9 ± 1.5) compared with no-AMS subjects (4.8 ± 1.4; P < 0.005) but were
not significantly different between Sherpas (3.8 ± 1.1) and the
sea-level group (2.8 ± 0.7). We conclude that AMS subjects have
greater cerebral hemodynamic responses to hyperventilation, higher
VMCA
resting control values, and lower SaO2 compared with no-AMS
subjects. Sherpas showed a cerebral hemodynamic pattern
similar to that of normal subjects at sea level.
mountain sickness; Sherpa; transcranial Doppler; transcutaneous carbon dioxide
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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ACUTE MOUNTAIN SICKNESS (AMS) is usually a benign and self-limiting illness that strikes healthy individuals who ascend to altitudes above 2,500 m without sufficient acclimatization (10). Failure to acclimatize may lead to AMS, which may develop into high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE), both being lethal complications of AMS. The process of acclimatization involves the onset of progressive hyperventilation secondary to the hypoxia from reduced ambient air pressure (23). It results in hypocapnia, which causes cerebral vasoconstriction and a decrease of cerebral blood flow (CBF). This effect of hypocapnia on CBF is counterbalanced by the effect of hypoxia, resulting ultimately in a net increase of CBF at high altitude (4, 16, 27, 28). In an attempt to treat subjects with AMS, the addition of 3% CO2 to the inspired air showed in one study an increase of CBF in half of the subjects (11), whereas in another study an increase of CBF velocity (VCBF), measured with transcranial Doppler, could not be demonstrated (3). Otis and co-workers (22) showed that in subjects inhaling 5% CO2, first at sea level and later at high altitude where some of the subjects developed AMS, VCBF increased more at sea level than at high altitude. In contrast, it has been demonstrated that in healthy subjects the increase of VCBF during hypercapnic hyperoxia at altitude was greater than the increase of VCBF at sea level (15).
The data from these previous studies might suggest that CO2 inhalation produced a smaller increase of CBF in subjects with AMS than in healthy subjects. However, responses to CO2 variations on CBF have not been studied in subjects with and without AMS at altitude. The hypothesis of this study was that the cerebral hemodynamic response to CO2 inhalation and to hyperventilation, expressed as vasomotor reactivity (VMR = fractional change of VCBF per Torr change of PCO2), was different in subjects with AMS compared with subjects without AMS. Accordingly, the purpose of the present study was to determine VMR in an attempt to identify a mechanism for altered CBF at altitude. Therefore, we assessed at 4,243-m altitude in newcomers with and without AMS the response of the blood flow velocity of the middle cerebral artery (MCA) (VMCA), measured with transcranial Doppler (TCD) sonography, to CO2 inhalation and to voluntary hyperventilation. In addition, because there are inadequate data on CBF responses to changes of CO2 in high-altitude residents, the VMCA was assessed under similar conditions of high and low CO2 in a group of healthy Sherpas and was compared with a control group at sea level.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjects and AMS score. The study was approved by the Institutional Human Investigation Committee of the Academic Medical Centre. It was carried out at the health post run by volunteer doctors of the Himalayan Rescue Association in Pheriche, a village situated at 4,243 m in the Khumbu valley in Nepal. The investigation took place during the months of October and November. Trekkers from many parts of the world who come to climb Kala Patar (5,545 m), a mountain adjacent to Mount Everest, normally stay for 1 or 2 nights in Pheriche. The trekkers who during their stay in Pheriche volunteered to participate in the study were previously healthy, smoking and nonsmoking, male and female subjects of varying background. They all resided normally at <600 m above sea level. Before they were studied, they stayed above 2,800 m (Lukla) at least for 4 nights, of which 3 nights were above 3,440 m (Namche Bazar). All volunteers were accepted for participation in the study, whether they came to Pheriche over land from Kathmandu, or after flying to Lukla, or by reaching Pheriche after crossing the Chola pass (5,420 m). Some of the trekkers with serious signs and symptoms of AMS were referred by the doctors of the health post.
AMS was assessed by using the Lake Louise AMS scoring system, which is a standard scoring system involving a self-reporting questionnaire to assess AMS (29). This self-report questionnaire includes five main symptoms of AMS: headache, gastrointestinal symptoms (anorexia, nausea, or vomiting), fatigue and/or weakness, dizziness and/or lightheadedness, and difficulty in sleeping. Each symptom is rated on a scale ranging from zero to three points. The AMS self-report score is the sum of responses to these five symptoms. In this study, a total score of three or more points in the presence of at least a mild headache was considered as AMS (AMS group) (29). From zero to two points was considered as no AMS (no-AMS group). Subjects with three or more points but no headache were considered as not having AMS. However, three subjects who had three or more points and no headache, but who showed signs of HAPE and HACE, were included in the AMS group. The questionnaire was completed by each trekker before the measurements were performed. Data of 43 trekkers without AMS (mean age 35 ± 12 yr; 37 men and 6 women) and of 17 trekkers with AMS (mean age 38 ± 12 yr; 13 men and 4 women) were used for the study. A group of 20 healthy Sherpas (mean age 37 ± 12 yr; 12 men and 8 women), who are Himalayan natives of Tibetan ancestry, were born in the Khumbu area and were living in and around Pheriche, were also studied, as well as a group of 13 healthy Dutch hospital workers (mean age 31 ± 6 yr; 9 men and 4 women) who were studied at sea level and who served as control group. In total, data of 93 subjects, divided into four different groups (no AMS, AMS, Sherpa, sea level), were analyzed.Measurements. Pulse oxygen saturation (SaO2) and transcutaneous PCO2 were measured by using the Fastrac Respiratory Status Monitor (model 765500-101, Sensormedics). The transcutaneous PCO2 sensor was heated to a temperature of 42°C and then was attached to the skin below the clavicle with a double-sided adhesive ring. The barometric pressure of the Fastrac monitor was set at 447 Torr, corresponding to the altitude of 4,243 m in Pheriche.
VMCA was measured by using a 2-MHz pulsed TCD probe (T2-64B EME, Ueberlingen). TCD insonation of the stem of the MCA was performed according to the methods described by Aaslid (1). The mean VMCA is calculated and displayed automatically by this TCD instrument. It is computed as the time mean of the peak velocity envelope, being the trace of the peak flow velocities as a function of time, and is expressed in centimeters per second. Doppler signals from the left MCA were identified through the temporal window with a hand-held probe and measured at a depth of 45-55 mm, corresponding to the proximal segment of the MCA. In each subject, a constant depth-range and angle of insonation were kept throughout the study. When the Doppler signal was inadequate at the left side, the right MCA was insonated. VMCA values, as calculated by the TCD apparature over four to five heart cycles, were registered, and, for every individual VMCA measurement, four consecutive registrations were averaged.Study protocol.
Subjects rested in the supine position for ~15 min, after which
SaO2, trancutaneous
PCO2, and
VMCA were
measured at three different levels of
PCO2.
1) First, the values were
measured with the subjects at rest while breathing ambient air (resting
control value). 2) Then, the values
were measured during hypercapnia. Hypercapnia was produced by
CO2 inhalation. CO2 (0.6-1 l/min) was added
to the ambient air and inhaled through a nonreturning valve connected
to a mouthpiece. In this study, the inspiratory
CO2 concentration was not
controlled exactly. However, with a mean minute ventilation of 12 l/min
as has been measured in subjects after 3-5 days at 4,300 m, the
inspiratory CO2 concentration is
calculated to be at least 5% (12). Measurements were made when
transcutaneous PCO2 and
SaO2 remained stable for 
5 min.
3) Finally, the values were measured
during hypocapnia. Hypocapnia was induced by forced voluntary
hyperventilation with a fixed respiratory frequency of ±25/min, and
the same set of measurements was performed when transcutaneous
PCO2 and
SaO2 remained stable during 5 min. VMR
was calculated for the hypercapnic state as well as for the hypocapnic
state, yielding a hypercapnic VMR and a hypocapnic VMR.
Data analysis. Comparisons between resting control values and between effects of CO2 challenges were assessed by using ANOVA, and, when significance was found, a post hoc test (Bonferroni-Dunn) was performed to delineate where differences lay. The relationships between variables were subjected to linear correlation analysis by using Pearson's correlation coefficient. Comparisons and correlations were considered significant when P < 0.05. Data are expressed as means ± SD.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Resting control measurements.
The age did not differ among the four groups. Resting control values of
VMCA,
SaO2, and transcutaneous
PCO2 of the four groups are presented
in Table 1. Regression analysis showed a
weak negative correlation between the resting control values of
VMCA and
SaO2 in the no-AMS group
(r = 
0.43,
P = 0.0038) as well as in the AMS
group (r = 0.58,
P = 0.0138). In the Sherpa group, no
correlation could be demonstrated (r = 0.07, P = 0.77). No correlations were
found between the resting control values of
VMCA and
transcutaneous PCO2 in any of the
four groups.
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VMR during CO2 inhalation.
Responses of CO2 inhalation on
VMCA,
SaO2, and transcutaneous
PCO2 are shown in Fig.
1. The absolute increases as well as the
fractional increases of
VMCA were not
significantly different among any of the four groups. The increased
ventilation from the CO2
stimulation produced an increase in SaO2
in all three groups at altitude, and this increase was significantly
greater in the AMS group compared with the no-AMS group (10 ± 6 and
5 ± 3% respectively; P < 0.0001). Increases of PCO2 were not
significantly different among any of the four groups. Hypercapnic VMR
values, as shown in Table 1, were not significantly different between
any of the four groups.
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VMR during hyperventilation.
Responses of hyperventilation on
VMCA,
SaO2, and trancutaneous
PCO2 are shown in Fig. 1. The
absolute decrease of VMCA in the AMS
group was significantly greater compared with the other three groups.
However, the relative decrease of
VMCA was not
significantly different between the AMS and the no-AMS group. The
increase of SaO2 during hyperventilation
was significantly higher in the AMS group compared with the no-AMS
group (13 ± 9 and 6 ± 6%, respectively;
P < 0.0001). During active
hyperventilation, the decreases of
PCO2 were significantly different
between the sea-level group (12 ± 2 Torr) on the one hand and the
no-AMS (9 ± 2 Torr) and the AMS groups (9 ± 3 Torr) on the
other hand. Hypocapnic VMR values of the four groups are
shown in Table 1. VMR values in the AMS group were significantly higher
compared with the no-AMS group (P < 0.005). There was a significant negative correlation between the
hypocapnic VMR and the decrease of
PCO2 in the no-AMS group as well as
in the AMS group (Fig. 2). This correlation
was weak in the Sherpa group and could not be demonstrated in the
sea-level group.
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Responses in Sherpas. Responses to CO2 challenges in Sherpas are shown in Table 1 and Fig. 1. During CO2 inhalation, the Sherpa group showed no significant differences with any of the three groups concerning the absolute and relative increase of VMCA, the increase of PCO2, and the VMR. However, the Sherpas had a significantly smaller increase in SaO2 compared with the AMS group (6 ± 3 and 10 ± 6%, respectively; P < 0.05). During hyperventilation, the absolute and relative decreases of VMCA in Sherpas were significantly lower compared with the AMS group but were not significantly different between the Sherpa group and the sea-level group. The increase of SaO2 in the Sherpa group showed no significant difference with the no-AMS group and the AMS group. There was also no significant difference among any of the three groups concerning the decrease of PCO2. The hypocapnic VMR values in the Sherpa group were not significantly different compared with the sea-level group but were significantly lower compared with the no-AMS (P < 0.005) and the AMS group (P < 0.0001).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In this cross-sectional study, subjects at altitude with AMS showed an increased cerebral hemodynamic response to hyperventilation compared with healthy subjects, but the response to CO2 inhalation was not different. The study demonstrated that Sherpas had resting control VCBF and cerebral VMR values to CO2 inhalation and to hyperventilation that were not different from those of native sea-level dwellers. The study also confirmed earlier findings that subjects with AMS had significantly higher resting control VCBF and lower SaO2 values compared with those of healthy subjects (4).
TCD sonography. TCD was used as a noninvasive device to measure CBF. Although TCD does not provide a direct measure of CBF, relative changes in VMCA accurately reflect relative changes in CBF, provided that the diameter of the insonated vessel remains constant (5, 6, 19). There is now ample direct and indirect evidence to support the contention that the diameter of the MCA does not change significantly with changes in PCO2 (6, 14). Jensen et al. (15, 16) showed in two studies during isocapnic hypoxia with SaO2 levels to 60-70%, a good agreement between TCD data and CBF measurements. This may suggest that the diameter of the stem of the MCA did not dilate significantly at the moderate degrees of hypoxia as were measured in our study.
Transcutaneous PCO2. Normally, end-expiratory PCO2 and transcutaneous PCO2 give both good correlations with arterial PCO2. End-expiratory PCO2 is normally 3-5 Torr below arterial PCO2 in patients without lung disease. In one study, where the Fastrac monitor was used with the sensor heated to 42°C, mean transcutaneous PCO2 was 1.7 Torr below arterial PCO2 (17). In our study, we measured transcutaneous PCO2 in subjects with AMS, who may have had some degree of pulmonary edema, possibly leading to a larger arterial-to-alveolar PCO2 difference than in no-AMS subjects. In these AMS subjects, end-expiratory PCO2 would underestimate arterial PCO2 compared with no-AMS subjects.
Resting control measurements at rest. VMCA was similar in the three groups who were healthy, despite different environmental (no AMS, sea level) and adaptive (Sherpa) backgrounds. The normal value of VMCA at sea level varies from 41 to 94 cm/s, with an average of 60 cm/s during the awake and resting state (2). This is in accordance with the mean VMCA of 60 cm/s of the sea-level group in our study.
Previous studies have shown an initial increase of CBF (16, 27, 28) and of VCBF (4, 13, 22) on arrival of the subjects at altitude. These increases returned to sea-level values after 3-5 days (13, 16, 27, 28). In the present study, all volunteers, with and without AMS, stayed at least 4 nights above 2,800 m, of which 3 nights were above 3,440 m. Thus VMCA in these volunteers could have been expected to have returned to within preascent values, because the measured VMCA in the healthy subjects at altitude was similar to that of the sea-level group. Several authors established a relationship between the increases in CBF (27) or VMCA (9, 22) and the occurence of AMS. But in two other studies this relationship was not evident (16, 24). Baumgartner and co-workers (4), however, demonstrated a significant correlation between the increase of VMCA and the presence of symptoms of AMS, probably from a lower arterial PO2 than in healthy subjects. The results of our study are in agreement with those of Baumgartner et al. We demonstrated a significantly higher resting control VMCA and lower resting control SaO2 in the AMS group compared with the no-AMS group. There was also a significant inverse relationship between the resting control values of SaO2 and VMCA in the no-AMS group and in the AMS group. These findings suggest that the lower SaO2 in the AMS group, compared with the no-AMS group, may be one of the mechanisms that could explain the higher VMCA.VMR. VMR was calculated as the relative change of VMCA per Torr change of PCO2 (5, 19). Correspondingly, the sea-level group showed a relative increase of VMCA of 5.6 ± 2.5% per Torr PCO2 change at the hypercapnic level, and a relative decrease of the VMCA of 2.8 ± 0.7% per Torr PCO2 change at the hypocapnic level. This corresponds to a CBF increase of 6% and a CBF decrease of 2% per Torr PCO2 change, respectively, as found in normotensive healthy men (30), indicating that the changes in TCD values we measured can be taken to reflect changes in CBF (6).
In this study, no significant difference in the hypercapnic VMR values could be demonstrated among any of the four groups (Table 1). However, hypocapnic VMR values were significantly different between each of the four groups, except between the Sherpa group and the sea-level group. Normally, at sea level, VMR values are unchanged in the same subject when SaO2 remains unchanged during CO2 inhalation and during hyperventilation, because the VMR is independent of the change of PCO2 within the range of 25-50 Torr PCO2 (18, 25). However, during CO2 inhalation and during hyperventilation at altitude, the increase of the ventilation produced substantial improvements of arterial oxygenation, which were under both circumstances larger in the AMS group (10 and 13% SaO2, respectively) than in the no-AMS group (5 and 6% SaO2, respectively). These effects of changes of PCO2 as well as of SaO2 on VMCA are opposite at the hypercapnic level and additive at the hypocapnic level. However, it was not the aim of this study to define the relative contributions of the CO2 and hypoxia effects on VMCA. Measurement of VMR at altitude is an attempt to evaluate whether other mechanisms than the direct effect of PO2 changes contribute in the regulation of CBF at altitude. Besides the effect of hypoxia on the VCBF (15), there are two other factors that might explain the difference in VMR between the no-AMS and the AMS groups in our study. First, the gradual declines of PCO2 and cerebrospinal fluid bicarbonate during the process of acclimatization at altitude result in larger pH changes per Torr PCO2 change and consequently in larger VMCA changes per Torr PCO2 change. Second, the respiratory alkalosis from the acute and active hyperventilation in our subjects might have produced an increased affinity of oxygen to hemoglobin (Bohr effect). This Bohr effect results in less oxygen availability and causes the VCBF to respond to hypoxia (31). However, with the resting control PCO2 values and the PCO2 changes during hyperventilation being similar in the no-AMS group and the AMS group, it is possible that these two factors do not play an important role in explaining the difference in VMR values between these two groups. During hyperventilation, a significant negative correlation between VMR and the decrease of PCO2 could be detected in the AMS and the no-AMS group (Fig. 2), but not in the sea-level group, since VMR is at sea level relatively independent of the change of PCO2 within the range that we measured. The subjects with small decreases of PCO2 produced large relative decreases of VMCA. A possible explanation might be that the contribution of the SaO2 increase on VMCA has a great effect on VMCA when the changes of PCO2 are small. On the other hand, with large changes of PCO2, the same increase of SaO2 contributes relatively little to the change of VMCA. Ringelstein and co-workers (25) measured in humans at sea level total vasomotor reactivity (TVMR), defined as the sum of the fractional VMCA increase (52.5%) during maximal dilatation of the cerebral vessels from 5 to 6% CO2 inhalation and the fractional VMCA decrease (35.5%) during maximal vasoconstriction from hyperventilation. By using this method to calculate TVMR in our groups (Fig. 3), we found in the sea-level group, the no-AMS group, and the AMS group a pattern of resetting of TVMR in which the hypercapnic section becomes smaller in favor of a larger hypocapnic section. Otis and co-workers (22) found in subjects at sea level during 5% CO2 inhalation a hypercapnic section of TVMR of 45%. This is similar to the 39% observed in our sea-level group. After ascent to 4,100-m altitude, the hypercapnic section decreased significantly to 23% in their group, compared with 24% in our AMS group. They attributed this blunted hypercapnic response to CO2 inhalation at altitude to the exhausted potential of cerebral resistance vessels to further dilate. The explanation for the pattern of resetting of TVMR in our study may be the increased vasoconstriction of the brain resistance vessels caused by the SaO2 improvements in these groups. An additional contributing factor to this pattern of resetting of TVMR could be the increased sensitivity of the VCBF to hypoxia, as reported by Jensen and co-workers (15) in newcomers after 5 days at altitude.
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Sherpas. Resting control VMCA of the Sherpa group was similar to that of the sea-level group. To our knowledge, no studies are available in which CBF has been measured in Himalayan highlanders. However, several studies performed in Andean high-altitude natives indicate that their CBF is significantly below normal sea-level values (20, 21, 29). A possible factor that might contribute to this discrepancy between the Andean high-altitude natives and the Sherpas is the hematocrit, which is an important marker of blood viscosity and which has a marked influence on CBF at sea level and at altitude (21). Winslow and co-workers (31) found that the hematocrit in Sherpas in Nepal was significantly lower than in high-altitude Andean natives (48.4 ± 4.5 and 52.2 ± 4.6%, respectively; P < 0.003). This difference in hematocrit might contribute to the higher VMCA in the Sherpas compared with the Andean natives.
Interestingly, the Sherpas exhibited similar VMR values as the sea-level control group during CO2 inhalation as well as during hyperventilation. However, in contrast to the sea-level group, they showed increases of 6% SaO2 during CO2 inhalation and of 9% during hyperventilation. Milledge and Sørensen (21) demonstrated that the cerebral vasodilatory response to hypoxia was preserved in Andean high-altitude residents, even after lifelong exposure to hypoxia. Despite this preserved vasodilatory response to hypoxia, the hypercapnic and hypocapnic VMR values in the Sherpa group and the sea-level group were similar. An explanation for the similar VMR values is that a higher blood viscosity in the Sherpas, due to a higher hematocrit, has a slowing-down effect on the changes of VMCA during the alterations of arterial oxygen and CO2 tensions. The Sherpas, who are Himalayan natives of Tibetan ancestry, and who have lived in the Himalaya far longer than the high-altitude natives in the Andes, show a cerebral hemodynamic pattern that is normal by sea-level standards. Similar patterns of adaptation to lifelong hypoxia on the Tibetan plateau have recently been shown in other studies (7, 8). In the present study we showed that in subjects with AMS the cerebral hemodynamic response to acute hyperventilation is increased compared with subjects without AMS. We confirmed that in AMS subjects at rest the CBF velocity is higher and SaO2 is lower. We also found that Sherpas, studied at high altitude, have the same VMCA and essentially the same VMR pattern as do native sea-level dwellers.| |
ACKNOWLEDGEMENTS |
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The authors acknowledge the subjects for their cooperation and the doctors of the Himalayan Rescue Association, Fiona McPherson and Caroline MacKenzie, for their enthusiasm and motivation of their patients to participate in the study. The authors thank Dr. Joseph Odoom for critically reviewing the manuscript and Prof. Can Ince for constructive criticism.
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FOOTNOTES |
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Address for reprint requests: G. F. A. Jansen, Dept. of Anesthesiology, H-1-Z, Academic Medical Centre, Univ. of Amsterdam, PO Box 22600, 1100 DE Amsterdam, The Netherlands.
Received 23 November 1996; accepted in final form 30 September 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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