Shinshu Med J, 69⑷：179～187, 2021

Hypoxic Ventilatory Response to Acute and Prolonged Hypoxic
Exposures in Subjects Susceptible to High-altitude Pulmonary Edema
Kazuhisa Urushihata, Yunden Droma, Michiko Ito and Masayuki Hanaoka＊
First Department of Medicine, Shinshu University School of Medicine

Background : The low hypoxic ventilatory response (HVR) has been suggested to be one of the pathophysiologi­
cal features in high-altitude pulmonary edema (HAPE). Ventilatory responses to hypoxia vary widely dependingon the length of hypoxic exposure. The pathophysiological role of HVR in the development of HAPE has not yet
been well understood.
Methods : Isocapnic hypoxic exposure was induced to 12 Japanese HAPE susceptible subjects (HAPE-s) and 10
HAPE resistant subjects (HAPE-r) in Shinshu University at an altitude of 600 meters (m). A slope linear regres­sion relating minute ventilation (V̇E, L/min) to oxygen saturation (SpO2, ％), V̇E＝α＊SpO2＋β, was obtained in eachof the subjects of HAPE-s and HAPE-r after 10-minutes (min) and 30-min isocapnic hypoxic exposure, respec­tively. The slope α parameter was the ratio of change of V̇ E (ΔV̇E) to change of SpO2 (ΔSpO2) and the absoluteslope α value was used for evaluation of HVR. In addition, the hypoxic ventilation decline (HVD) was calculated
in the later phase of hypoxic exposures.
Results : The HVR was significantly lower in the HAPE-s than the HAPE-r subjects at 10-min (0.29±0.18 vs1.13±1.21, p＝0.03) and 30-min (0.16±0.09 vs 1.01±1.08, p＝0.01) hypoxic exposure. Moreover, the HVR continu­
ously declined in the HAPE-s subjects over the prolonged hypoxic exposure from 0.29±0.18 at 10-min hypoxic
exposure to 0.16±0.09 at 30-min hypoxic exposure, resulting in 29.3 ％ of HVD in HAPE-s, in contrast to 3.1 ％of HVD in the HAPE-r subjects over the prolonged hypoxia.
Conclusion : The HVR was not only significantly blunted but also continuously declined in the HAPE-s over a
prolonged hypoxic exposure, which contributed to the failure in acclimatization to high-altitude hypoxia.
Shinshu Med J 69 : 179―187, 2021
(Received for publication December 24, 2020 ; accepted in revised form February 18, 2021)
Key words : acclimatization, hypoxic ventilatory response, high-altitude pulmonary edema

Ⅰ Introduction

stimulus is diminished, ventilation remains stable orcontinues to increase. This phenomenon is known

Hypoxic ventilatory response (HVR), which is a

as ventilatory acclimatization that prevents high-measurement of ventilatory response to a reduced

altitude sicknesses4）. A blunted HVR was thought toarterial blood oxygen tension (PaO2) independent of

be one of the pathophysiological features in high-the effect of carbon dioxide, increases in conscious

altitude pulmonary edema (HAPE) susceptible indi­

humans after exposure to hypoxia to compensate

viduals (HAPE-s) who develop this life-threatening

for the loss of oxygen

1）-3）. Under a sustained hypoxic

disease after 4-6 hours of rapid exposure to altitudes

condition at high altitudes, even if the PaO2 related

over 2,500 meters (m) above sea level4）-6）. Reviewing
the abundance of research literature regarding the＊Corresponding author : Masayuki Hanaoka
First Department of Medicine,
Shinshu University School of Medicine, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : masayuki@shinshu-u.ac.jp

No. 4, 2021

HVR in HAPE-s, the published data were mostly
obtained over a relatively short period of several
minutes of hypoxia4）-6）. In fact, ventilatory responses
to hypoxia vary widely depending on the length of179

Urushihata・Droma・Ito et al.

hypoxic exposure7）. HVR is time-dependent and theand chest roentgenographic infiltrates consistent withisocapnic HVR includes two phases, a first phasepulmonary edema. All subjects with HAPE met the(0-10 minutes) of immediate ventilation increase,

criteria at the onset of the disorder and recovered

followed by a second phase (10-30 minutes) of slow

promptly and well with hospitalization. Examinations

ventilation decline7）8）. There is still a lack of data re­and cardiovascular tests were conducted in-hospitalgarding the HVR of HAPE-s in a relatively prolong­after their recovery to exclude any preexisting car­ed hypoxic exposure. The pathophysiological roles of

diopulmonary diseases. They were all completely re­

HVR including both the increase and decline phases

covered without any complications and discharged

have not yet been completely understood in the de­from the hospital after 7-14 days of hospitalization.

velopment of HAPE.

We recruited them to participate in the current study

Thus, investigation of HVR over prolonged hypoxia

on condition that the recovery from HAPE was overis required for thoroughly understanding the role of

one year previously. None of them had traveled to

HVR in the development of HAPE. For this reason,

high-altitude within six months of the present study.

in order to illustrate the progress of HVR over a pro­

The control group consisted of elite mountaineers

longed hypoxia in the development of HAPE, we ex­

who repeated alpine-style climbing to peaks above

tended the hypoxic course over more than 30 min­2,800 m but did not have any symptoms of HAPE or

utes and measured the HVR in the HAPE-s andacute mountain illnesses at high altitudes. They were

HAPE-r subjects after 10-min and 30-min hypoxic

defined as subjects with resistance to HAPE (HAPE-r)

exposures.

in this study. The physical examinations excluded
Ⅱ

Subjects and Methods

This study and the investigational protocol wereany preexisting cardiopulmonary disorders in the
HAPE-r group in the recruitment. They had done nomountaineering within six months of the present

approved by the institutional ethics review board ofstudy.

Shinshu University for human study and written in­

Ｂ

Isocapnic hypoxic exposure

formed consent was obtained from each case and

The study was carried out in a respiratory institutecontrol subject after a full explanation of the study.

in Shinshu University at an altitude of 600 m. To

The procedures used in this human study were incontrol the effect of PaCO2 on HVR, a progressive

accordance with the principles found in the Helsinki

isocapnic hypoxic exposure was applied to the current

9）

Declaration .

experiment with a computerized spirometer system

Ａ(Duograph, Chest Inc., Tokyo, Japan, Fig. 1A). Sub­

Study population
The HAPE-s and controls were recruited fromJapanese residing in Japan.

jects sat up right in a chair and spent a variable timebreathing room air through a rebreathing valve withThe HAPE-s subjects in the present study were

mouthpiece until steady ventilation was obtained

defined as individuals who had previously experi­(Fig. 1A). The isocapnic hypoxic exposure was in­enced HAPE at least one occasion while climbing

duced by switching the rebreathing valve to let it

the Japan Alps ranging from 2,758 to 3,190 m, andconnect to a big balloon that contained hypoxic gas

had been admitted to Shinshu University hospital.

mixed with oxygen (O2), nitrogen (N2), and carbon

The diagnosis of HAPE was based upon the follow­

dioxide (CO2) in a closed circuit, so that the subjects

ing criteria

10）: onset at a high altitude of the typicalstarted to breathe the hypoxic gas. Sensors in thesymptoms, including cough and dyspnea at rest ;rebreathing valve sensed signals of real-time partial

absence of signs of infection ; presence of pulmonarypressure of end-tidal oxygen (PETO2) and partial pres­rales and cyanosis ; disappearance of symptoms andsure of end-tidal carbon dioxide (PETCO2) breath-by-signs within 3 days of the start of treatment withbreath and all these data were input into the computer­bed rest and supplemental oxygen at low altitudes ;ized spirometer (Duograph, Chest Inc., Tokyo, Japan)

180

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HVR in HAPE susceptible subjects

A

B
Mo

Sw

PETO2

Re

Cs
Ga

Ta

Mp

PETCO2Sb

Tidal
volumePulse rate
SpO2

Ox
Co

Fig. 1 Measurement of hypoxic ventilatory response (HVR) by the computerized spirometer system (Duograph,
Chest Inc., Tokyo, Japan) in the current study. A : Subjects sat up right in a chair and breathed mixed
hypoxic gas through a rebreathing valve with mouthpiece for the measurement of HVR ; B : The monitor
of the computerized spirometer system displayed the real-time PETO2, PETCO2, tidal volume, pulse rate andSpO2 during the isocapnic hypoxic exposure.
 Abbreviations : Co, CO2 absorber ; Cs, computerized spirometer system ; Ga, gas balloon ; Mo, monitor ; Mp,
mouthpiece ; PETCO2, partial pressure of end-tidal carbon dioxide ; PETO2, partial pressure of end-tidal

oxygen ; Re, Rebreathing valve and oxygen sensor ; Sb, subject ; Ox, oxygen pulse oximeter ; SpO2, oxygen
saturation ; Sw, switch connecting hypoxic circuit ; Ta, gas tanks of oxygen, nitrogen and carbon dioxide.

that could regulate the breathing O2 and CO2 con­Ｃ

Measurement of hypoxic ventilatory response

centrations with the experimental designed concen­

The measurements were adjusted for age, body

trations (Fig. 1A, B). The current hypoxic protocol

weight, and gender based on equations formulated(Fig. 2) was designed as the PETO2 reduced from 120

for Japanese by using the computerized spirometer

Torr at the beginning of the experiment to 60 Torrsystem that recorded real-time of the tidal volume,

after 10 min of breathing hypoxic gas at a rate of 6

SpO2, PETO2, and PETCO2 in every 10 seconds of each

Torr/min resulting from the metabolic consumption

rebreathing during hypoxic exposure (Fig. 3). The

of O2 during rebreathing the mixed gas in the closed

linear regression in relating the V̇ E to SpO 2 ofcircuit. A CO2-absorbing bypass was connected inbreath-by-breath, V̇E＝α＊SpO2＋β, was obtained in

the closed-circuit to adjust PETCO2 constantly aroundeach of the subjects after 10-min and 30-min hypox­

40 Torr within±2 Torr deviation. The SpO2 (％) was

ic exposure, respectively (Fig. 4A-D). The coefficientmonitored by a pulse oximeter via a finger probe on

α was a slope parameter showing the ratio of change

the subjects, which was set up around 80 ％ over theof V̇E (ΔV̇E) to change of SpO2 (ΔSpO2) between any

time course of hypoxia (Fig. 1B), corresponding to an

two distinct points on this linear regression. As illus­

altitude of about 4,000 m. The rebreathing hypoxic

trated in Fig. 4E, supposing that the y axis rep­gas was terminated within 40 min of hypoxic breath­resents V̇ E and x axis represents SpO2, the coeffi­

ing. The hypoxic breathing could terminate at any

cient α was a slope parameter representing thetime if the subjects showed signs of intolerance ofratio of change of y or V̇E (Δy or ΔV̇E) to change of x

the hypoxia. Careful observation was done for any

or SpO2 (Δx or ΔSpO2) between any two distinct

unexpected acute hypoxic sicknesses in the subjects

points along the linear regression (Δy/Δx or ΔV̇E/

during and after the hypoxic exposure.

ΔSpO2), which determined the steepness of the line.

No. 4, 2021

181

Urushihata・Droma・Ito et al.

PETO2 (Torr)
140
120

Starting rebreathing of hypoxic gas in the closed circuit
PETO2 = 120 Torr, PETCO2 =40 Torr

6 mmHg /minRoom airRoom air

Isocapnic hypoxia
PETO2 = 60 Torr
(SpO2 ≒ 80%)
PETCO2 =40 Torr

100
80
60

40 Obtaining slope line forventilatory hypoxic sensitivity
20 after 10 min of hypoxic breathing
-20

0

-10

0

10

20
Time (min)Obtaining slope line forventilatory hypoxic sensitivity
after 30 min of hypoxic breathing
30

40

50

60

Fig. 2 The protocol of the current isocapnic hypoxic experiment. The hypoxic protocol was programmed
as the partial pressure of end-tidal oxygen (PETO2) reduced from 120 Torr at the beginning of theexperiment to 60 Torr after 10 min of breathing hypoxic gas at a rate of 6 Torr/min resulting fromthe metabolic consumption of O2 during rebreathing the mixed gas in the closed circuit. A CO2-

absorbing bypass was connected in the closed-circuit to adjust the partial pressure of end-tidal
carbon dioxide (PETCO2) constantly around 40 Torr within±2 Torr deviation. The percutaneousarterial oxygen saturation (SpO 2 ) was set up around 80 ％ over the time course of hypoxia,
corresponding to an altitude of about 4,000 m.

PETO2 (Torr)
PETCO2 (Torr)A

PETCO2

100
40

PETO2
Tidal volume
4

12

PETO2 (Torr)
PETCO2 (Torr)

100
40

20

28

36

Time (min)B

PETCO2
PETO2

Tidal volume
4

12

20

28

36

Time (min)Fig. 3 Spirographs of the hypoxic response in subjects. A : a very weak hypoxic ventilatory response(HVR) in a HAPE-s subject (No. 1 of HAPE-s group in Table 1) ; B : a remarkable HVR in a HAPE-r
subject (No. 4 of HAPE-r group in Table 1).
 Abbreviations : PETCO2, partial pressure of end-tidal carbon dioxide ; PETO2, partial pressure of endtidal oxygen.

182

Shinshu Med J

ol. 69

HVR in HAPE susceptible subjectsyE(0, β)ΔxΔyα = Δy/ΔxxFig. 4 The spirographs showed a typical response of V̇ E (L/min) to SpO2 (％) in a HAPE-s subject (A-B) and in a
HAPE-r subject (C-D). A : The V̇E＝－0.026＊SpO2＋9.80 after 10-min hypoxic exposure in a HAPE-s subject (No.
1 of HAPE-s group in Table 1, absolute α＝0.026) ; B : The V̇E＝0.001＊SpO2＋7.25 after 30-min hypoxic exposure in
the same HAPE-s subject (No. 1 of HAPE-s group in Table 1, absolute α＝0.001) ; C : The V̇E＝－4.10＊SpO2＋405
after 10-min hypoxic exposure in a HAPE-r subject (No. 4 of HAPE-r group in Table 1, absolute α＝4.10) ; D : The V̇ E＝－3.63＊SpO2＋360 after 30-min hypoxic exposure in the same HAPE-r subject (No. 4 of
HAPE-r group in Table 1, absolute α＝3.63) ; E : A mathematical illustration for understanding the slope linear
regression relating minute ventilation (V̇E, L/min) to oxygen saturation (SpO2, ％), V̇E＝α＊SpO2＋β. Supposing thatthe y axis represents V̇E and x axis represents SpO2, the coefficient α was a slope parameter representing theratio of change of y or V̇E (Δy or ΔV̇E) to change of x or SpO2 (Δx or ΔSpO2) between any two distinct points
along the linear regression (Δy/Δx or ΔV̇E/ΔSpO2), which determined the steepness of the line.

Thus, the absolute α value was used to indicate HVR

The continuous variables were expressed as means

based on the definition of ΔV̇E/ΔSpO2. The negative±standard deviation (SD). The differences of mea­

value of slope α indicated decreasing direction of thesurements between the HAPE-s and HAPE-r groups

line resulting from increasing V̇E in relation to de­were compared using an unpaired Student’s t-test.

creasing SpO2. The β was a deduced vertical asymp­

Meanwhile, the differences of measurements be­tote in V̇E for infinitely responding to SpO2 (Fig. 4E).

tween 10-min and 30-min hypoxic exposure in eachＤ Evaluation of minute ventilation during hypoxic

group were compared by paired Student’s t-test.

exposure

A two-tailed p＜0.05 indicated statistical signifi­

The V̇E was estimated by the linear regression (V̇ E

cance.

＝α＊SpO2＋β) at SpO2 of 80 ％ after 10-min and 30-

Ⅲ

min hypoxic exposures in each subject, respectively(Table 1). According to studies by Dahan et al.11） and12）

Ａ

Results

Subjects

Teppema et al. , we defined the decline of V̇E fromThe case group consisted of 12 HAPE-s subjects

10-min to 30-min hypoxic exposures as hypoxic ven­

including 10 males and 2 females with an averagetilation decline (HVD) during this period (Table 1),

age of 50.7±1.4 years old and the control group was

which was estimated by the percentage of the V̇E

composed of 10 HAPE-r subjects including 9 males

decline from 10-min to 30-min hypoxic exposuresand 1 female with an average of 50.9±1.4 years old.

[HVD (％)＝(V̇E after 10-min hypoxia-V̇E after 30-min hypoxia)/V̇E after

The age, gender, ethnicity, and previous history of

10-min hypoxia

hypoxic exposure were comparable between the twoＥgroups. All subjects were unrelated Japanese, born].

Statistical analysis

No. 4, 2021

183

184

V̇ E (L/min)＝α＊SaO2＋β

179.0
12.6
10.8
405.0
71.8
146.0
124.0
158.0
65.8
32.4

37.6±17.9

9.8
21.7
20.1
29.5
52.3
29.6
65.1
58.8
62.0
31.1
31.6
42.8

V̇ E (L/min)

0.02

119.6±116.1

b－1.67＊SaO2＋170.0－0.047＊SaO2＋3.98－0.206＊SaO2＋31.3－3.63＊SaO2＋360.0－0.623＊SaO2＋66.6－1.01＊SaO2＋106.9－1.34＊SaO2＋142.0－1.18＊SaO2＋131.0－0.376＊SaO2＋47.1－0.037＊SaO2＋9.98

0.001＊SaO2＋7.25－0.106＊SaO2＋18.5－0.079＊SaO2＋14.6－0.201＊SaO2＋29.8－0.276＊SaO2＋36.2－0.09＊SaO2＋20.2－0.177＊SaO2＋27.4－0.156＊SaO2＋24.8－0.305＊SaO2＋38.5－0.035＊SaO2＋18.3－0.285＊SaO2＋34.1－0.168＊SaO2＋27.7

V̇ E (L/min)＝α＊SaO2＋β a

0.01

1.670
0.047
0.206
3.630
0.623
1.012
1.340
1.180
0.376
0.037
1.01±1.08d(P＝0.11)

0.001
0.106
0.079
0.201
0.276
0.090
0.177
0.156
0.305
0.035
0.285
0.168
0.16±0.09d(P＝0.004)

Absolute slope
α value(ΔV̇ E/ΔSpO2)
7.25
18.5
14.6
29.8
36.2
20.2
27.4
24.8
38.5
18.3
34.1
27.7
24.7±9.3d(P＝0.005)

V̇ E (L/min)

0.01

170.0
3.98
31.3
360.0
66.6
106.9
142.0
131.0
47.1
9.98
106.1±104.9d(P＝0.07)b

Over 30 minutes of hypoxia

c

3.1

5.0
68.4
－189.8
11.1
7.2
27.4
－14.5
17.1
28.4
69.2

29.3

26.0
14.7
27.4
－1.0
30.8
31.8
57.9
57.8
37.9
41.2
－7.9
35.3

HVD (％)

Abbreviations : HAPE-s, high-altitude pulmonary edema susceptible subjects ; HAPE-r, high-altitude pulmonary edema resistant subjects ; HVD, hypoxic ventilation
decline ; No., number of subjects ; V̇E (L/min), minute ventilation (litter/minute) ; SD, standard deviation.
a: This linear regression was expressed as V̇E (L/min)＝α＊SaO2＋β, in which the slope parameter α value was the ratio of change of V̇E (ΔV̇E) to change of SpO2 (ΔSpO2).
b: The V̇E was estimated by the linear regression (V̇E＝α＊SpO2＋β) at SpO2 of 80 ％ after 10-min and 30-min hypoxic exposures in each subject, respectively.
c: HVD (％)＝(V̇E after 10-min hypoxia-V̇E after 30-min hypoxia)/V̇E after 10-min hypoxia).
d: P values were compared with 10-min hypoxic exposure by paired t-test in each group.
e: P values were compared between the HAPE-s and HAPE-r groups by unpaired t-test.

P values(HAPE-s vs. HAPE-r)
0.03

1.13±1.21

Mean±SD

e

1.760
0.047
0.011
4.100
0.673
1.350
1.150
1.460
0.572
0.201

－1.76＊SaO2＋179.0－0.047＊SaO2＋12.6－0.011＊SaO2＋10.8－4.10＊SaO2＋405.0－0.673＊SaO2＋71.8－1.35＊SaO2＋146.0－1.15＊SaO2＋124.0－1.46＊SaO2＋158.0－0.572＊SaO2＋65.8－0.201＊SaO2＋32.4

HAPE-r
1
2
3
4
5
6
7
8
9
10

0.026
0.140
0.137
0.200
0.446
0.192
0.579
0.442
0.557
0.167
0.259
0.327

Absolute slope
α value(ΔV̇ E/ΔSpO2)

0.29±0.18－0.026＊SaO2＋9.80－0.14＊SaO2＋21.7－0.137＊SaO2＋20.1－0.2＊SaO2＋29.5－0.446＊SaO2＋52.3－0.192＊SaO2＋29.6－0.579＊SaO2＋65.1－0.442＊SaO2＋58.8－0.557＊SaO2＋62.0－0.167＊SaO2＋31.1－0.259＊SaO2＋31.6－0.327＊SaO2＋42.8

aMean±SD

HAPE-s
1
2
3
4
5
6
7
8
9
10
11
12

No.

Over 10 minutes of hypoxia

Table 1 Linear regressions of the ventilatory response to hypoxia in HAPE-s and HAPE-r subjects

Urushihata・Droma・Ito et al.

Shinshu Med J

ol. 69

HVR in HAPE susceptible subjects

P = 0.03

Hypoxic ventilatory response(absolute slope α value)

2.5

P = 0.01

2

1.5

1.13

1

1.01

P = 0.004

0.5
0.29
0

0.16

After 10 min ofHypoxia

After 30 min ofHypoxia

After 10 min ofHypoxia

HAPE-sAfter 30 min ofHypoxia

HAPE-rFig. 5 The absolute slope α value was significantly lower in the HAPE-s than the
HAPE-r groups both after 10-min (0.29±0.18 vs. 1.13±1.21, P＝0.03) and after 30min hypoxic exposures (0.16±0.09 vs. 1.01±1.08, P＝0.01). The absolute slope α
value was significantly reduced from 0.29±0.18 after 10-min hypoxic exposure to
0.16±0.09 after 30-min hypoxic exposure in the HAPE-s group (P＝0.004). There
was no significant reduction of the absolute slope α value from 10-min to 30-min
hypoxic exposures in the HAPE-r group (1.13±1.21 vs. 1.01±1.08, P＝0.11). The
number in the bar was the mean value for each event.

and residing at low altitudes.

value was significantly reduced from 0.29±0.18 afterＢ

10-min hypoxic exposure to 0.16±0.09 after 30-min

Hypoxic status of the subjects
All subjects including HAPE-s and HAPE-r com­hypoxic exposure in the HAPE-s group (P＝0.004,

pleted the present hypoxic experiment without se­

Fig. 5) with a reduced rate of 44.8 ％. However, there

vere hypoxic symptoms requiring termination of thewas no significant reduction of the absolute slope α

hypoxic exposure. The SpO2 was significantly re­value from 10-min to 30-min hypoxic exposures in

duced from 98.4±0.9 ％ under normoxia to 79.6±

the HAPE-r group (P＝0.11, Fig. 5) with a reduced

3.4 ％ after 30 min of isocapnic hypoxic exposure in

rate of 10.6 ％. As a result, the declines of V̇E fromthe HAPE-s group (p＜0.0001), and from 98.4±1.0 ％10-min to 30-min hypoxic exposures (HVD) were

to 80.8±3.3 ％ in HAPE-r group (p＜0.0001). There

29.3 ％ in the HAPE-s and 3.1 ％ in the HAPE-r sub­were no significant differences of the SpO2 between

jects (Table 1).

the two groups either under normoxic or under hy­
poxic conditions (P＞0.05).
Ｃ

Hypoxic ventilatory response

Ⅳ Discussion
By the property of linear regression of V̇ E＝α＊The linear regressions of V̇E＝α＊SpO2＋β in each

SpO2＋β, the absolute slope α value determined thesubject of the two groups are shown in Table 1. The

steepness of the line in a ratio of change of V̇E (ΔV̇E)

absolute slope α value was significantly lower in theto change of SpO2 (ΔSpO2) between any two distinct

HAPE-s than the HAPE-r groups both after 10-min

points on this line. Thus, the absolute slope α value(0.29±0.18 vs. 1.13±1.21) and 30-min (0.16±0.09 vs.

was used to quantitatively express the ratio of ΔV̇ E/

1.01±1.08) hypoxic exposures (P＝0.03 and P＝0.01,

ΔSpO2 in the line obtaining at any time-domain

respectively, Fig. 5). Moreover, the absolute slope αthroughout the hypoxic exposure. The HVR was usu­

No. 4, 2021

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Urushihata・Droma・Ito et al.

ally calculated by dividing the change of ventilation(ΔV̇E) by the change of SpO2 (ΔSpO2) in a hypoxic

HVR in the development of HAPE.
The significant HVD might be involved with the

4）-6）. In agreement with thiscontinuously blunted HVR over prolonged hypoxia.

definition, the absolute slope α value was used to quan­

However, the HVR and HVD are highly variable be­titatively evaluate HVR in the present study.

tween species, gender, genetic factors, and experi­

exposure (ΔV̇E/ΔSpO2)

The remarkable findings demonstrated that in ad­ments15）. The roles of up-regulation inhibitory (i.e.,

dition to the significantly lower HVR in HAPE-s

dopaminergic) and down-regulation excitatory (i.e.,than HAPE-r over the 10-min hypoxic exposure, theglutamatergic) signaling in the carotid body chemo­

HVR constantly declined at a reduction rate of 44.8 ％receptors for responding to hypoxia are thought toover 30-min hypoxic exposure in the HAPE-s group,

be involved in the mechanisms of HVR and HVD

resulting in a significantly lower ventilation in HAPE-sover prolonged hypoxic exposure15）16）. The present

than HAPE-r over the prolonged hypoxic exposures.

results suggested that the ventilatory depression

To our knowledge, this was the first extended model

dominated in HAPE-s while counterbalanced in HAPE-

of hypoxic study to investigate the HVR over a pro­r in the prolonged acute hypoxia. Taken together,longed hypoxic exposure in HAPE-s subjects.

the constantly low HVR with significant HVD over

The HVR is a quick compensation for challenging
oxygen deprivation by attempting to increase alveo­

prolonged hypoxia contributes to the development of
HAPE.

1）

The major limitation of this human hypoxic study

Matsuzawa and coworkers found that the HVR was

was the small sample size that might cause type I

lower in 8 out of 10 HAPE-s subjects than in HAPE-r

error in statistical analysis. The present method of

subjects, while 2 out of the HAPE-s did not show themeasurement of HVR was novel, thus there was lessreduction of the HVR over 10 minutes of hypoxic

opportunity to compare the current results withlar ventilation to overcome the hypoxic breathing .
6）5）reported that

other related results for deep discussion of the issues

there was minimal overlap of the HVR in the HAPE-sof HVR and HVD over prolonged hypoxia. Replica­and healthy controls within 10 minutes of hypoxic

tion studies elsewhere are required to confirm theexposure. On the other hand, Selland and associ­present results. In addition, the neurotransmitters of

exposure. Hohenhaus and colleagues

13）

stated that HAPE occurred in susceptible indi­

carotid body chemoreceptors in responding to hy­

viduals despite the presence of normal or high HVR.

poxia were not analyzed in the present study due to

However, these studies did not investigate the HVR

the small sample size. Nevertheless, a significant con­in HAPE-s subjects over a long-term of hypoxia.

stant reduction of HVR with significant HVD over

ates

1）

Easton and coworkers demonstrated that isocapnic

prolonged hypoxia in the HAPE-s subjects was orig­

hypoxia caused an initial increase of ventilation toinally found in the present study. Further investiga­

161 ％ of baseline with a significant fall after 25 min­tion is necessary for elucidating the pathophysiologi­

utes to 121 ％. This hypoxic ventilatory decline (HVD)

cal roles of HVR and HVD exposed to high-altitude

is a reduction of V̇E in the second phase of a hypoxic

hypoxia in the development of HAPE.

12）exposure

and it can be sustained for prolonged hy­
14）

In conclusion, in addition to the blunted HVR, thepoxia in adult humans at high altitudes . The present

constantly declined HVR with remarkable HVD overresults revealed that the HVD was indeed significantly

a prolonged hypoxic exposure was one of the con­present in the HAPE-s in the later phase of prolonged

tributing elements in the development of HAPE.

hypoxic exposure, probably due to the continuously
low HVR in that group. We propose that the blunted
HVR following significant HVD in the later phase of
prolonged hypoxic exposure is an additionally essen­tial element for further understanding of the role of
186

Shinshu Med J

ol. 69

HVR in HAPE susceptible subjects

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（2020. 12. 24 received ; 2021. 2. 18 accepted）

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