Ebihara et al.
Journal of Physiological Anthropology(2023) 42:6
https://doi.org/10.1186/s40101-023-00322-7

Journal of
Physiological Anthropology

Open Access

SHORT REPORT

Association between high cardiac output
at altitude and acute mountain sickness:preliminary study on Mt. Fuji
Takeshi Ebihara1* , Kentaro Shimizu1, Yumi Mitsuyama1, Hiroshi Ogura1 and Jun Oda1

Abstract
Background Acute mountain sickness (AMS) affects around 30% of people climbing Mt. Fuji, but its pathogenesis isincompletely understood. The influence of a rapid ascent to high altitude by climbing and summiting Mt. Fuji on cardiac function in the general population is unknown, and its association with altitude sickness has not been clarified.
Methods Subjects climbing Mt. Fuji were included. Heart rate, oxygen saturation, systolic blood pressure, cardiac
index (CI) and stroke volume index were measured multiple times at 120 m as baseline values and at Mt. Fuji Research
Station (MFRS) at 3,775 m. Each value and its difference from the baseline value (Δ) of subjects with AMS (defined as
Lake Louise Score [LLS] ≥ 3 with headache after sleeping at 3,775 m) were compared with those of non-AMS subjects.
Results Eleven volunteers who climbed from 2,380 m to MFRS within 8 h and stayed overnight at MFRS were
included. Four suffered AMS. Compared with the non-AMS subjects, CI in the AMS subjects was significantly higher
than that before sleeping (median [interquartile range]: 4.9 [4.5, 5.0] vs. 3.8 [3.4, 3.9] mL/min/m2; p = 0.04), and their
ΔCI was significantly higher before sleeping (1.6 [1.4, 2.1] vs. 0.2 [0.0, 0.7] mL/min/m2; p < 0.01) and after sleeping (0.7
[0.3, 1.7] vs. -0.2 [-0.5, 0.0] mL/min/m2; p < 0.01). ΔCI in the AMS subjects dropped significantly after sleeping versus
before sleeping (3.8 [3.6, 4.5] vs. 4.9 [4.5, 5.0] mL/min/m2; p = 0.04).
Conclusions Higher values of CI and ΔCI were observed at high altitude in the AMS subjects. A high cardiac output
might be associated with the development of AMS.
Keywords Cardiac function, Mt. Fuji, Mt. Fuji research station, Non-invasive hemodynamic monitor
Background
Mt. Fuji, the highest mountain in Japan, was registeredas a UNESCO World Heritage site in 2013. Hundredsof thousands of travelers climb the mountain every year.
Travelers usually arrive at an altitude of around 2,300 m
by bus or other transportation and climb to the summit at 3,776 m within a short time. This rapid elevation*Correspondence:
Takeshi Ebihara
ebihara.830@hp-emerg.med.osaka-u.ac.jp
1
Department of Traumatology and Acute Critical Medicine, Osaka
University Graduate School of Medicine, 2‑15 Yamadaoka, Suita City,
Osaka 565‑0871, Japancauses about 30% of the climbers to suffer from acutemountain sickness (AMS) [1, 2].
AMS was reported as a nonspecific condition in whichheadache, nausea, fatigue, respiratory distress and sleep
disturbance can occur after a short ascent to an altitudeof 2,500 m or more [3]. AMS is defined at least as headache and total Lake Louise Score (LLS) of > 3. Headache,nausea, fatigue, respiratory disease and sleep disturbanceare not parallel [4]. Moreover, Roach et al. [5] recently
revisited the LLS and excluded sleep disturbance as afactor. AMS symptoms are exacerbated during the firstnight at high altitude and improve after one to two days
or by descending to a lower altitude [6, 7]. Most cases are© The Author(s) 2023, corrected publication 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes
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Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

not fatal, but cerebral edema and pulmonary edema may
occur in some and become critical [8].
Previous studies have investigated numerous factors
as potential risks for AMS. Altitude attained [9] and rateof ascent [7] were established as risk factors. A study ofthe prevalence of AMS on Mt Fuji showed no association
with sex or age [1], and a meta-analysis showed no association between age and risk of AMS [10]. A higher bodymass index was reported as a possible risk factor [11].
The relation of various vital signs with AMS was also
assessed. Although the association between heart rate(HR) variability and AMS remains controversial [12, 13],a low ­SpO2 and higher respiratory rate at high altitudes
are reportedly associated with developing AMS [14, 15].
Sleeping at high altitudes may also exacerbate symptomsof AMS [2, 16, 17].
The increase in cardiac output observed when moving
to high altitude is considered an adaptation to maintain­O2 delivery [18, 19]. However, changes in cardiac function caused by rapid ascent to high altitude by climbing
and summiting Mt. Fuji and their relationship with altitude sickness are not clarified. We hypothesized that in
subjects not showing increased cardiac output at highaltitudes, AMS might be a result of tissue hypoxia. We
thus aimed to evaluate cardiac function using a non-invasive hemodynamic monitoring device and to clarify the
relationship between cardiac function and AMS.

Methods
Subjects

This study included 11 healthy subjects who climbed
mountains of > 2000 m once or twice per year. None had
a medical history including respiratory and cardiovascular disease, took any medications, or smoked. All had
a body mass index < 25 kg/m2. They had travelled from
Fujinomiya city (120 m) to the starting point (2,380 m)of the climb by car in early morning. They climbed to
Mt. Fuji Research Station (MFRS) at 3,775 m, very nearthe 3,776-m summit of Mt. Fuji, within 8 h. After staying overnight at the MFRS, they descended to the starting point (Fig. 1A). The AMS subjects in this study were
defined as those with an LLS [5] ≥ 3 with headache after
sleeping at the MFRS.
This study was performed according to the principlesof the Declaration of Helsinki and received approval fromthe institutional review board of Osaka University Hospital (Permit Number: 18090). Informed consent was
obtained from all subjects.
Measurements

The symptoms of AMS were scored based on the LLS,
with its maximum point sum of 12: headache (0 = without

Page 2 of 7

headache, 1 = mild headache, 2 = moderate headache,
3 = severe headache); dizziness (0 = without dizziness,
1 = mild dizziness, 2 = moderate dizziness, 3 = severedizziness); gastrointestinal symptoms (0 = without
and 1 = with gastrointestinal symptoms); and fatigue(0 = without and 1 = with fatigue) [17].
SpO2, HR and blood pressure were measured by apocket pulse oximeter (LUKLA-2800 ma; UBIX Corporation, Philippines) and portable blood pressure monitor (HEM-7130; Omron Healthcare Co. Ltd, Japan),respectively. Mean arterial blood pressure (MAP) was
calculated by (2 × Diastolic blood pressure + Systolicblood pressure) / 3. These parameters were evaluated at
120 m as baseline values, three times during climbing,two times (before and after sleeping) during the stay at
the MFRS and three times during the descent. Cardiac
index (CI) and stroke volume index (SVI) were measured by a non-invasive hemodynamic monitoring device(ClearSight system; Edwards Lifesciences, Irvine, CA)
at 120 m as baseline values and twice (before and after
sleeping) during the stay at the MFRS. This device began
to be used in the intensive care unit in 2015. It measures
the arterial pressure curve via a sensor wrapped aroundthe finger and calculates a beat-to-beat stroke volume(SV) by dividing the area under the systolic portion of
the arterial pressure curve by aortic input impedance[20]. Beat-to-beat cardiac output is calculated by multiplying beat-to-beat SV by instantaneous HR. Moreover,CI and SVI measured in this study were normalized bybody surface area for use in future studies. The agreement between CI derived by this method and that bythermodilution [20], Doppler echocardiography [21] andInnocor inert gas rebreathing [22] were reported to be
acceptable. We measured cardiac function at high altitude using this device with the idea of future feasibility:i.e., that anyone can measure these parameters any place
and at any time. The measurements were carried out for
at least 5 min under a steady state following 3 h of rest
after the subjects arrived at MFRS. Approximately 1 mLof venous blood was sampled from the cubital vein at
120 m and at high altitude before sleeping. The pH, ­CO2,­HCO3 and lactate levels were analyzed by iSTAT (Abbot
Point-of-Care, Princeton, NJ, USA).
Statistical analysis

Values are reported as n (%) or median [interquartile
range]. Statistical analysis was performed with the Wilcoxon rank-sum test to compare differences between two
independent groups and the Wilcoxon matched-pairs
signed rank test to compare differences between two
paired groups. A p-value < 0.05 was considered statistically significant. The data were analyzed using JMP Pro

Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

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Fig. 1 Time course of study and changes of LLS and physiological parameters. A The X axis shows the times after departing from Fujinomiya city
at 120 m. The Y axis shows the altitude. B In this study, AMS was defined as a LLS ≥ 3 with headache after sleeping at 3775 m. Dotted line indicates
LLS of 3. C Change in ­SpO2, HR, sBP, dBP and MAP. All values are expressed as the mean ± SD. D ­SpO2, HR, CI and SVI values of the AMS and non-AMS
subjects at 120 m and 3775 m. #Indicates a statistically significant difference between the AMS and non-AMS subjects (p < 0.05). E The ΔSpO2,
ΔHR, ΔCI and ΔSVI values of the AMS and non-AMS subjects at 120 m and 3775 m. #Indicates a statistically significant difference between the AMS
and non-AMS subjects (p < 0.05). All values are expressed as the mean ± SD. AMS acute mountain sickness, CI cardiac index, dBP Diastolic bloodpressure, HR heart rate, LLS Lake Louise Score, MAP Mean arterial pressure, MFRS Mt. Fuji Research Station, sBP Systolic blood pressure, SD standard
deviation, SVI stroke volume index

Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

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Fig. 1 continued

version 14 (SAS Institute Inc., Cary, NC) and are presented using Graph Pad Prism, version 6.04 (GraphPad
Software, La Jolla, CA).

Results
Change of physiological parameters and venous blood
analysis data at high altitude

In this study, 4 of the 11 subjects fulfilled the criteria for
AMS. There were no differences in the baseline physiologic parameters and data of venous blood gas analyses
between the two groups (Table 1). The change of LLS
score is shown in Fig. 1B, and those of ­SpO2, HR andsystolic blood pressure are shown in Fig. 1C. The S­ pO2
dropped to around 75% in both groups at MFRS. The CIof the AMS subjects was significantly higher than that of
the non-AMS subjects before sleeping (4.9 [4.5, 5.0] vs.

3.8 [3.4, 3.9] mL/min/m2; p = 0.04) (Fig. 1D). The ΔCIof the AMS subjects was significantly higher than thatof the non-AMS subjects measured before sleeping (1.6
[1.4, 2.1] vs. 0.2 [0.0, 0.7] mL/min/m2; p < 0.01) and after
sleeping (0.7 [0.3, 1.7] vs. -0.2 [-0.5, 0.0] mL/min/m2;
p < 0.01) (Fig. 1E). There were no significant differencesin pH, ­CO2, ­HCO3− and lactate levels between the AMS
and non-AMS subjects at MFRS (Table 2).
Changes in LLS, S­ pO2, HR, SVI and CI before and after
sleeping at high altitude

At MFRS, LLS improved in 4 of the 7 non-AMS subjects
after sleeping, but it did not improve in any of the AMS
subjects after sleeping (Fig. 2A). ΔHR and ΔCI dropped
in 10 of the 11 subjects following sleeping. Among the
AMS subjects, ΔCI after sleeping was significantly lower

Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

Table 1 Baseline characteristics
AMS (-)(n = 7)

AMS ( +)

p Value(n = 4)Sex, male, n (%)

3 (42.9)2 (50.0)

0.819

Age

26 (24–29)

42 (34–42)

0.018*

Body surface area ­(m2)

1.6 (1.5–1.8)

1.6 (1.4–1.7)

0.571 ­SpO2 (%)

98 (98–99)

98 (97–99)

0.756

HR (bpm)

67 (66–77)

67 (56–76)

0.569

sBP (mmHg)

113 (56–128)

110 (95–121)

0.448

SVI (mL/m2)

53 (47–56)

51 (39–52)

0.394

CI (L/min/m2)

3.4 (2.9–4.1)

3.0 (2.7–3.5)

0.156

7.35 (7.35–7.38)

7.37 (7.34–7.40)

0.636

50.9 (45.9–56.0)

53.7 (52.0–58.9)

0.508 ­HCO3− (mmol/L)

28.7 (27.4–30.9)

31.2 (30.8–31.8)

0.155

Lactate (mmol/L)

0.55 (0.30–0.67)

0.63 (0.47–0.98)

0.298

Physiologic parameters

Venous gas analysispH ­CO2 (mmHg)

Data are given as number (%) or median (25th-75th percentile). Significance wasdetermined by Pearson’s chi-squared test or Mann–Whitney U-test
AMS Acute mountain sickness, CI Cardiac index, HR Heart rate, sBP Systolic bloodpressure, SpO2 Peripheral arterial blood oxygen saturation, SVI Stroke volume
index*

Statistically significant (p < 0.05)

Table 2 Venous blood gas analysis at the Mt. Fuji Research
StationAMS (-)(n = 7)

AMS ( +)

p Value(n = 4)pH

7.41 (7.37–7.7.44)

7.40 (7.39–7.42)

1.000

CO2 (mmHg)

41.5 (40.3–47.8)

44.5 (41.5–50.2)

0.508

HCO3− (mmol/L)

27.8 (27.1–28.3)

27.4 (27.0–30.1)

0.155

Lactate (mmol/L)

0.99 (0.63–1.31)

0.87 (0.71–1.95)

0.298

Data are given as number (%) or median (25th-75th percentile). Significance wasdetermined by Mann–Whitney U-test
AMS Acute mountain sickness*

Statistically significant (p < 0.05)

than that before sleeping (3.8 [3.6, 4.5] vs. 4.9 [4.5, 5.0]
mL/min/m2; p = 0.04) (Fig. 2B).

Discussion
This study identified a relationship between CI and AMS.
Higher values of CI and ΔCI were observed at high altitude in the AMS subjects.
A study measuring CI by electrical cardiometry of subjects arriving at 3,800 m by cable car showed a significant
increase in HR, and SVI and CI tended to increase frombaseline [19]. A study on Mt. Everest also revealed that

Page 5 of 7

HR, SV and CI were increased more at 5,020 m than at
sea level [23] as an adaptation to maintain ­O2 delivery[18]. To our knowledge, no study has evaluated CI in
subjects exposed to high altitude over a short time as in
the present study. Contrary to our hypothesis, high CI
was observed in the AMS subjects. Blood lactate before
sleeping was within the normal range, suggesting that the
subjects developing AMS after sleeping had no metaboliccrises before sleeping. However, we did not evaluate lactate levels after sleeping when AMS was diagnosed, so
whether lactate levels were elevated in the AMS subjects
remains unclear. Further study is needed to clarify thebalance between oxygen demand and supply.
Sleeping altitude is reported to be associated with
AMS [2], with one reason being the drop in oxygen
saturation while sleeping [17]. We evaluated CI before
and after sleeping at high altitude and observed that CI
had decreased in 8 of the 11 subjects. Another hypothesis might be that high CI was caused by low systemic
vascular resistance index (SVRI). Our data showed nodifferences between MAP with or without AMS. SVRI
was calculated as SVRI ∝ (MAP—central venous pressure) / CI. Although not evaluated, if central venous
pressure was assumed to be the same between AMS
and non-AMS subjects, SVRI was in inverse proportion to CI. A decrease in SVRI was associated withvasodilation, one of the pathogeneses of AMS [24, 25].
Significant decreases in ΔHR and ΔCI were observedin the subjects developing AMS after sleeping. The
increased CI was mainly achieved by increasing HR
through stimulation of the cardiac β-adrenergic receptors by cardiac sympathetic nerves and circulating
adrenaline (epinephrine) [26]. The influence of sleepon the nervous system will also require further evaluation in the future.
A study by Wolsk et al. found that younger participants had higher CI and SVI during exercise comparedto older participants, but their hemodynamic parameters were similar at rest [27]. The present AMS subjects who were older than non-AMS subjects showeda higher CI (4.9 vs. 3.8 mL/min/m2). An increase in
cardiac output at high altitude maintains ­O2 delivery.
Further study is needed to determine whether subjects
with high cardiac output conditions and age-related
cardiac impairment develop AMS.
This study has several limitations. Although this isa pilot study, future studies with a larger sample size
are needed. Cardiac function was impaired by age, andAMS subjects were older than non-AMS subjects. Agerelated cardiac impairment might have affected thedevelopment of AMS.

Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

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Fig. 2 Change in LLS, ΔSpO2, ΔHR, ΔCI and ΔSVI before and after sleeping at 3,775 m. A Change in LLS. B Changes in ΔSpO2, ΔHR, ΔCI and ΔSVI.
*Indicates a significant difference in each value between before sleeping and after sleeping (p < 0.05). All values are expressed as the mean ± SD.
AMS acute mountain sickness, CI cardiac index, HR heart rate, LLS Lake Louise Score, SD standard deviation, SVI stroke volume index

Conclusion
Cardiac function was assessed at high altitude. Higher
values of CI and ΔCI were observed at high altitudein the AMS subjects. A high cardiac output might beassociated with the development of AMS.
Abbreviations
AMS	Acute mountain sickness
CI	Cardiac index
HR	Heart rate
LLS	Lake Louise Score
MFRS	Mt. Fuji Research Station
SV	Stroke volume
SVI	Stroke volume index
SVRI	Systemic vascular resistance index

violates any of these. All authors meet the authorship criteria detailed in thesubmission guidelines, and all authors agree with the content of the manuscript. The author(s) read and approved the final manuscript.
Funding
None declared.
Availability of data and materials
The datasets used and/or analyzed during the current study are available fromthe corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
This study was performed according to the principles of the Declaration of
Helsinki and received approval from the institutional review board of Osaka
University Hospital (Permit Number:18090). Informed consent was obtained
from all subjects.

Acknowledgements
We greatly appreciate the volunteers involved in this study. This work was supported by the Certified Nonprofit Organization Mount Fuji Research Station.
The authors appreciate the great help from Dr. Rika Ide.

Consent for publication
Not applicable.

Authors’ contributions
TE conceived and designed this study, acquired the data, and analyzed andwrote the manuscript. KS helped with study design and data interpretationand conducted the literature review. YM helped to perform experiments. HO
and JO conducted the literature review. All authors have read and understood
the journal’s policies and believe that neither the manuscript nor the study

Received: 7 January 2023 Accepted: 29 March 2023

Competing interests
None declared.

Ebihara et al. Journal of Physiological Anthropology(2023) 42:6

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