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Departments of 1 Neurology and
4 Internal Medicine, University
Hospital, CH-8091 Zürich, Switzerland;
2 Department of Internal Medicine
III, To evaluate the pathogenetic role of cerebral
blood flow (CBF) changes occurring before and during the development of
acute mountain sickness (AMS), peak mean middle cerebral artery flow velocities (
altitude illness; cerebral hemodynamics; ultrasonics
ACUTE MOUNTAIN SICKNESS (AMS) may develop in subjects
who rapidly ascend to altitudes above 2,500 m (7). During a sojourn at
high altitude, cerebral blood flow (CBF) increases, probably because
the stimulating effect of hypoxemia dominates the flow-depressant effect of hypocapnia, which results from hyperventilation (9, 12, 15,
27, 29). Most studies evaluating the pathogenetic role of CBF in AMS
were performed within 12-24 h after arrival at high altitude (3,
9, 12, 15, 21, 23, 27, 29), although AMS develops within the first
6-12 h (11, 29). CBF alterations occurring before and during the
development of AMS, and their association with this altitude illness,
have not yet been studied.
Incipient hydrostatic edema of the brain, resulting from greater fluid
leakage, has been postulated as the cause of the cerebral features of
AMS (17). The leakage is assumed to be related to high hydrostatic
pressure, resulting from hypoxemic vasodilatation and increased
filtration through altered blood-brain capillaries. Hydrostatic
pressure of cerebral capillaries might be further augmented by arterial
blood pressure increases during exercise and by the cold (30).
The purpose of the present study was to compare relative changes in CBF
velocity assessed by transcranial Doppler (TCD) sonography with the
development of AMS in healthy volunteers during a 6-h decompression to
a simulated altitude of 4,559 m.
Subjects.
Ten healthy white male volunteers, aged 20-24 (mean 22 yr) yr and
living at altitudes below 500 m, were examined in a decompression chamber. No subject was exposed to altitudes higher than 3,500 m or had
suffered from AMS. With the exception of subject
4, who spent 5 h at an altitude of 2,700 m 26 days
before the present study, no subject was exposed to altitudes higher
than 1,000 m within the 2 mo immediately before this study. Written
informed consent was obtained, and our study protocol was reviewed and approved by the Ethical Committee of the University Hospital
(Zürich).
Study design.
Baseline examinations were performed at an altitude of 490 m
[barometric pressure, 721 ± 6 (SD) mmHg; temperature, 20.4 ± 0.6°C]. They consisted of the evaluation of CBF
velocity by means of TCD assessment of peak mean flow velocities in the
right middle cerebral artery
(
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) were
assessed by transcranial Doppler sonography in 10 subjects at 490-m
altitude, and during three 12-min periods immediately
(SA1), 3 (SA2), and 6 (SA3) h after decompression to a
simulated altitude of 4,559 m. AMS cerebral scores increased
from 0.16 ± 0.14 at baseline to 0.44 ± 0.31 at SA1, 1.11 ± 0.88 at
SA2
(P < 0.05), and 1.43 ± 1.03 at
SA3
(P < 0.01); correspondingly, three,
seven, and eight subjects had AMS. Absolute and relative
at simulated
altitude, expressed as percentages of low-altitude values
(%), did not
correlate with AMS cerebral scores. Average
% remained
unchanged, because %
increased in three and remained unchanged or decreased in seven
subjects at SA2 and SA3. These results suggest that
CBF is not important in the pathogenesis of AMS and shows substantial
interindividual differences during the first hours at simulated altitude.
INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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MATERIALS AND METHODS
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MCA),
completion of an environmental symptom questionnaire (ESQ) (26),
monitoring of arterial O2 saturation (SaO2), and measurement of
blood pressure and heart rate.
MCA
measurements were continued. MCA velocimetry was repeated for 12 min
after 3 (SA2) and 6 h
(SA3) at simulated altitude. Blood pressure, heart rate, and
SaO2 measurements were
repeated after decompression, and at the beginning as well as at the
end of SA1,
SA2, and
SA3. ESQ testing was repeated
after termination of SA1,
SA2, and
SA3. The median time for
recompression to low altitude was 20 min (range 14-48 min).
TCD examinations.
MCA was
measured by means of a TCD device (TC2-64B, EME,
Überlingen, Germany) equipped with a 2-MHz probe. Through the
temporal window the optimum strength and clarity of the right MCA
signal at insonated depths of 50-55 mm was found. The monitoring probe (Trans-cran FP 2 monitoring, EME) was fixed with a headband and
detached after SA1,
SA2, and
SA3. Both the exact position of
the monitoring probe with respect to a line joining the intertragal incision with the lateral angle of the eye and the depth of insonation were carefully noted for each subject. The rationale was to maintain identical insonation angles and depths for
MCA
measurements at SA2 and
SA3.
MCA values
calculated by the machine every 8 s, the 4 min before and during
decompression, as well as during
SA1,
SA2, and
SA3 were noted. In each subject,
the relative changes in
MCA
(%) occurring
during decompression, SA1,
SA2, and
SA3 were calculated, defining the
average MCA obtained during the 4 min before decompression as 100%. All TCD studies were performed by the same examiner (R. W. Baumgartner). The
subjects were relaxed in a supine position, with their eyes closed.
Attention was paid to provide a calm environment.
Assessment of signs and symptoms of AMS.
The ESQ was translated into German and used as described previously
(2). Subjects were considered to suffer from AMS when the AMS-cerebral
(AMS-C) score was 
0.70 in at least one examination at simulated altitude.
SaO2 measurements. SaO2 measurements were performed by using a pulse oximeter attached to an earlobe (Biox 3700, Ohmeda, Boulder, CO).
Statistical analysis.
Testing according to Lilliefors indicated that the following variables
were not normally distributed at baseline:
%, AMS-C score,
SaO2, and systolic and diastolic blood
pressures (25). Therefore, changes from baseline were compared by
nonparametric analysis of variance according to Friedman, followed by
post hoc testing according to Wilcoxon and Wilcox in the case of
overall significance. The relationship of various variables obtained
after decompression with the corresponding values of
% were determined by
Pearson correlation analysis. Because all except for the
above-mentioned baseline variables were normally distributed, we report
mean values and SDs unless otherwise stated.
P < 0.05 was considered significant.
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Average %
did not change with simulated altitude
(P = 0.46; Table
1). During
SA2 and
SA3,
% increased in three
subjects, but remained unchanged or decreased in seven (Table
2, Fig.
1). The AMS-C score,
SaO2, blood pressure, and heart rate
showed no difference when subjects with and without increased
% were compared at
SA2 and
SA3 (Fig.
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SaO2 decreased over time at simulated altitude (P < 0.001). The decrease remained essentially unchanged at simulated altitude during the whole stay and was significant for SA1 (P < 0.05), SA2 (P < 0.01), and SA3 (P < 0.05) compared with baseline values.
Blood pressure remained unchanged from baseline. Heart rate increased over time at simulated altitude (P < 0.001). The increase was significant for SA3 compared with baseline values (P < 0.01).
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CBF showed no correlation with the AMS-C score in this study. Furthermore, there was no difference in AMS-C scores in a comparison of subjects with and without raised CBF at SA2 and SA3. These findings are in accordance with the results of several therapeutic trials reporting successful treatment of AMS despite completely different reactions of CBF (2, 8, 10, 15, 23). CBF increases of 22% were observed after oral administration of 1.5 g acetazolamide (15); CBF rose by 25% (10) or remained unchanged (8) after 3% CO2 was added in ambient air (10), whereas O2 administration (33%) caused CBF to drop 20% (2). In the above-cited trials (2, 8, 10, 15, 23), arterial PO2, SaO2, or both increased during different treatments, indicating that these changes are more important than alterations of CBF in the pathogenesis of AMS. This notion is also supported by the observation that headache, the leading symptom of AMS, is not related to blood flow velocity measured in the internal carotid artery (23).
Although the statistical power of this study is lowered by the small sample size, the present findings and the results of previous studies (2, 8, 10, 15, 23) suggest that CBF alterations occurring before and during the development as well as during successful therapy of AMS are probably not relevant in the pathogenesis of this altitude illness.
Three subjects fulfilled the diagnostic criteria of AMS at SA1 and seven subjects at SA2, although most authors assume that AMS develops within 6-12 h of exposure to high altitude (11, 16, 29). No subject fulfilling the criteria of AMS at SA1 recovered at SA2 or SA3, and no subject who fulfilled the criteria of AMS at SA2 recovered at SA3. The temperature in the decompression chamber was normal, and the subjects spent most of the time in either the supine or the sitting position, were adequately hydrated, had normal arterial blood pressures, and showed no signs and symptoms of agoraphobia. Thus it is very unlikely that other diseases that may cause AMS-like signs and symptoms, such as cold, exhaustion, dehydration, hypotension, and agoraphobia, were present. Our data suggest that in some individuals AMS may already be detected by the AMS-C score within the first 3 h at simulated altitude.
The variation in CBF at simulated altitude was evaluated by repetitive
assessment of relative changes in
MCA. Careful measures to minimize changes in insonation angles and depths, as well
as restriction of observation to one examiner, have provided reliable
intraobserver reproducibility for repeat
measurements (19,
31). TCD velocity measurements performed during alterations in arterial
PCO2
(PaCO2) and arterial PO2 are reliable, because several
human studies have shown that only the diameter of cerebral resistance
vessels changes and that the diameter of the insonated MCA remains
essentially unchanged (6, 13, 22). Ringelstein et al. (24) reported a
highly significant linear correlation
(r = 0.96) when comparing CO2-induced relative changes in
measured by TCD with
relative changes in CBF measured by the xenon-133-inhalation technique.
Maeda et al. (18) found a high correlation coefficient of
r = 0.95 by comparing relative changes
in measured by TCD
with relative changes in flow in the internal carotid artery measured
by an electromagnetic flow probe during carotid endarterectomies. Therefore, we assume that the diameter of the insonated MCA did not
change significantly during hypocapnic hypoxia. Consequently, relative
changes in reflected
flow alterations in this artery, which provides ~80% of all blood
supplied to the cerebral hemisphere (1).
CBF responses to simulated altitude in the present study showed substantial differences among diverse subjects, ranging from increases of 48% to decreases of 32%. Consequently, average CBF remained unchanged at simulated altitude. These findings are in accordance with ultrasonic data reported in the extracranial internal carotid and vertebral arteries by Huang et al. (12) and Reeves et al. (23). They found normal flow velocities caused by large interindividual differences, ranging from an increase of 52% to a decrease of 30% 2-4 h after an exposure to altitudes between 4,300 and 4,800 m. These data (12, 23) and ours suggest that, during the first hours at hypobaric hypoxia, CBF may decrease, remain unchanged, or increase, independent of the development of AMS. In contrast, several authors have reported increases in CBF of between 20 and 27% in subjects 12-24 h after their arrival at altitudes ranging between 3,475 and 4,559 m (3, 12, 15, 21).
The cause of the different CBF responses observed in our subjects at
SA2 and
SA3 is difficult to explain.
Changes in blood pressure are an unlikely cause because all subjects
had normal values. Animal (14, 20) and human (28) studies indicate that
CBF rises with decreasing
SaO2. However,
SaO2 values showed no correlation with
CBF and were identical in a comparison of subjects with and without
increased CBF. The level of PaCO2 has important effects on cerebral resistance vessels and CBF and is essentially determined by the amount of hyperventilation occurring during the first 6 h at hypobaric hypoxia. Although the
SaO2 values were identical in subjects
with and without raised CBF, it is possible that differences in
ventilation caused distinct PaCO2 values
and CBF changes. Fencl et al. (5) have demonstrated that cerebral
vessels in humans with stable metabolic alkalosis fail to constrict in
response to a sustained hypocapnic stimulus, presumably because of a
resetting of HCO
3 concentrations in
the cerebrospinal fluid (4). Thus only subjects with increased CBF may
have already "reset" cerebral vasoreactivity.
Compared with our own field studies (2, 3), which evaluated CBF changes in and the development of AMS after 24 h at 4,559-m altitude, the present investigation assessed alterations in CBF and AMS scores during the first 6 h at the same simulated altitude. Furthermore, the present study differs from our field studies (2, 3) in the absence of exercise, cold, and other adjuncts to the mountaineering experience. Although we have no data suggesting that this difference in examination conditions might have a relevant impact on the findings obtained in this study, our results should be extrapolated with caution.
In conclusion, we have shown that CBF changes occurring before and during the development of AMS revealed no correlation with AMS-C scores, suggesting that CBF is not relevant in the pathogenesis of AMS. In addition, our data indicate that CBF changes show substantial interindividual differences during the first hours at simulated altitude.
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Address for reprint requests and other correspondence: R. W. Baumgartner, Dept. of Neurology, Univ. Hospital, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland.
Received 29 September 1998; accepted in final form 30 December 1998.
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DISCUSSION
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