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Changes in ocular flow induced
by hypo- and hypercapnia
relate to static visual acuity 
in humans 
Naoyuki Hayashi, Tsukasa Ikemura, 
Nami Someya
Institute of Health Science and Graduate
School of Human-Environment Studies,
Kyushu University, Kasuga, Japan 

Abstract 

We investigated whether the change in ocu-
lar blood flow, induced by hypo- and hypercap-
nia, is related to static visual acuity. Eleven
healthy subjects (26±5 years) underwent three
treatments. A three-treatment three-period
crossover design was used. In the hypocapnia
treatment (HYPO), the subjects controlled
their minute ventilation (VE) to a target of 25
L/min for 6 min. In the hypercapnia treatment
(HYPER), the subjects inspired high-fraction
CO2 gas (FICO2 = 4%) for 6 min. In the control
treatment (CON), VE was not manipulated. We
measured choroidal and retinal blood flow by
laser speckle flowmetry as ocular blood flow,
and static visual acuity using the Landolt C
chart. End-tidal partial pressure of CO2 dif-
fered significantly among HYPO, HYPER and
CON (21±1, 48±1, and 42±1 mmHg, respec-
tively). Retinal blood flow decreased signifi-
cantly from the baseline in HYPO (-22±5%),
but increased significantly in HYPER (+3±9%)
compared to CON. Decimal visual acuity was
significantly lower in HYPO than in the CON
(0.21±0.1 vs. 0.24±0.1 P<0.05). These results
suggest that changes in ocular blood flow
induced by changes in arterial CO2 partial
pressure influences visual acuity.

Introduction

A continuous blood supply to the retina is
essential for the maintenance of eye function
because O2 is in high demand and is not stored
in the retina and surrounding tissue1.
Nutrition to the retina comes from the retinal
and choroidal vessels.2 Loss of ocular blood
flow regulation associated with pathological
conditions, such as diabetes and glaucoma, is
related to impaired visual function.1-4 In
extreme cases, loss of myelinated axons in the
optic nerve is observed by the pharmacological
decrease in ocular blood flow in rabbits;5 how-
ever, the effect of acute changes in ocular
blood flow on visual function has not been elu-

cidated in healthy humans. On the other hand,
increase in choroidal blood flow was observed
with improved contrast sensitivity in healthy
subjects after sidenafil administration.6 Thus
we can simply hypothesize that acute change
in ocular blood flow alters vision. The main
purpose of the present study was to examine
the hypothesis that increased ocular blood flow
improves visual acuity, and decreased ocular
blood flow decreases visual acuity. The present
study was designed to observe change in visu-
al acuity and ocular blood flow associated with
change in arterial CO2 partial pressure
(PaCO2) induced by change in ventilation. For
functional relevance, the decrease in ocular
blood flow could be attributed to impairment of
visual acuity after high intensity exercise,7

which induces hyperventilation and conse-
quent decrease in ocular flow. Additionally, we
compared the CO2 sensitivity in ocular and
cerebral blood vessels since it is well known
that ocular blood vessels are, like cerebral
blood vessels, very sensitive to variations in
PaCO2.2,8,9,10

Materials and Methods

Subjects
Eleven healthy non-smokers (5 males and 6

females, 26±5 years, 171±14 cm, 64±14 kg,
mean±SD) participated in this study. All sub-
jects were free of any known autonomic dys-
function, cardiovascular and ocular disease,
and were not using medications. The Ethics
Committee of the Institution of Health
Science, Kyushu University, Japan, approved
the experimental protocol, and all subjects pro-
vided written informed consent to participate
prior to the commencement of the study. All
protocols conformed to the Declaration of
Helsinki. Before the experiments, each subject
visited the laboratory for familiarization with
the techniques and procedures of the protocol.

Procedures
All experiments were performed at a room

temperature at 24ºC, illuminated at 90-100 lx.
The subjects arrived at the laboratory after
having abstained from caffeinated beverages
and exercise for 6 h, and from a light meal for
at least 2 h. 
For instruction and probe setting, the sub-

ject rested in a chair. Two minutes of baseline
data were recorded while the subjects breathed
room air. A three-treatment three-period
crossover design was used. All subjects per-
formed three 6-min experimental procedures
after the baseline period, consisting of eupnea
(CON), hypocapnia (HYPO) and hypercapnia
(HYPER). Washout period was 30 min between
treatments. In the CON treatment, ventilation

was not controlled. In the HYPO treatment, the
subjects controlled their minute ventilation
(VE) at 25 L/min with 1 L tidal volume and 25
times/min respiratory rate with auditory feed-
back using a metronome and an experimenter.
In the HYPER treatment, the subjects inspired
high-fraction CO2 gas (FICO2=4%) from a
Douglas bag. In all treatments, subjects
inspired through a Y-shaped valve from a
Douglas bag filled with the gas or air. The
expired gas was sent to the outside. The sub-
jects wore a nose clip. The order of the treat-
ments was randomized. For allocation of the
participants, a computer-generated list of ran-
dom numbers was used. Subjects who wore
glasses or contact lens took these off during
the experiment. 

Measurement
Standard electrocardiogram was recorded

continuously (ECG; MEG2100; Nihon-kohden,
Tokyo, Japan). Beat-by-beat blood pressure
was monitored with an automatic sphygmo-
manometer on the left middle finger
(Finometer; Finapres Medical System,
Amsterdam, the Netherlands). The mean blood
velocity (MCAV) of the right middle cerebral
artery (MCA) was obtained by transcranial
Doppler ultrasonography (WAKI; Atys Medical,
Soucieu-en-Jarrest, France). A 2 MHz Doppler
probe was placed on the right temporal window

Eye Reports 2011; volume 1:e8

Correspondence: Naoyuki Hayashi, Institute of
Health Science, Kyushu University, Kasuga,
Fukuoka 816-8580, Japan. 
Tel. +81.92.583.7848 - Fax: +81.92.583-7848. 
E-mail: naohayashi@ihs.kyushu-u.ac.jp

Key words: ventilation, CO2, vision, ocular circu-
lation.

Acknowledgement: the authors are grateful for a
grant from the Yamaha Motor Foundation for
Sports to NH. 

Contributions: NH, study design, data acquisition
and interpretation, article drafting, revising and
final approval; TI, data analysis and article revis-
ing; NS, data acquisition and article revising.

Conflict of interest: the authors report no con-
flicts of interest. 

Received for publication: 18 May 2011.
Accepted for publication: 6 September 2011.

This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).

©Copyright N.i Hayashi et al., 2011
Licensee PAGEPress, Italy
Eye Reports 2011; 1:e8
doi:10.4081/eye.2011.e8

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[Eye Reports 2011; 1:e8] [page 21]

and fixed with an adjustable headband. The
MCAV waveform was obtained 47-51 mm from
the skin surface. The signals from the ECG,
sphygmomanometer and MCAV were sampled
and recorded at 1 kHz using an A/D converter
(PowerLab 8/30; ADInstruments, CO, USA).
Minute-by-minute heart rate and mean arteri-
al pressure (MAP) were calculated from ECG
and blood pressure recordings. The subjects
breathed through a mouthpiece connected to a
hot wire flowmeter (RM-300; Minato Medical
Sciences, Osaka, Japan) for the measurement
of VE and end-tidal CO2 partial pressure
(PETCO2). The flowmeter was calibrated using
a 2-L syringe. A small sample of respired gas (1
mL/s) was continuously withdrawn from the
mask and analyzed for CO2 with a mass spec-
trometer (WSMR-1400; Westron Corp., Chiba,
Japan). The mass spectrometer was calibrated
with fresh air and precision gas. Static visual
acuity of the right eye was estimated for the
last two minutes of the resting baseline and
each gas inspiration using the Landolt C chart
1 m from the subjects’ eyes. Three different
charts were used randomly not to allow sub-
jects to memorize the chart. Visual acuity was
expressed as decimal acuity (no unit), i.e.,
20:20 and 20:200 correspond to 1.0 and 0.1,
respectively.
Laser speckle for four seconds was

obtained 3 or 4 times for 0.5-2 min for the
baseline and 4-6 min for each treatment
(LSFG; SoftCare-Ltd, Fukuoka, Japan).
Subjects were asked to open their right eye
for more than four seconds during the meas-
urement. No drug administration such as
mydriatic was used. LSFG is a non-invasive
technique to measure real-time, two-dimen-
sional relative blood flow velocity of ocular
microcirculation using the laser speckle phe-
nomenon,11 which is recognized as an inter-
ference phenomenon of coherent light
sources, such as lasers.12 When tissue is illu-
minated under laser radiation, a speckle pat-
tern appears, the structure of which changes
rapidly according to blood flow velocity.13 A
laser beam emitted from a laser diode (wave-
length 830 nm) is transmitted into part of the
intraocular tissue. The observation field
included the optic nerve head and the macu-
lar area. The blood flow map is obtained from
the mean blur rate (30 frames per second), a
quantitative index of relative blood flow veloc-
ity. From the data, two-dimensional perfusion
maps are determined (Figure 1), quantifying
blood flow velocity using commercially avail-
able software (LSFG Analyzer ver. 3.0.33.0
SoftCare-Ltd, Fukuoka, Japan). The mean
velocity of blood flow was calculated from
three or more entire cardiac cycles. Ocular
blood flow velocity was obtained from retinal
and choroidal capillary vessels (RCV). RCV
was obtained from a given observation field of
capillary vessels between the optic nerve head

and the macula. This field was the same
among subjects. So RCV represents blood flow
velocity. This measurement does not separate
retinal and choroidal flow. Ocular blood flow
was obtained from inferior temporal retinal
arteriole (ITRA), and superior temporal reti-
nal arteriole (STRA). The cross section of the
target arteriole was automatically selected by
the software, and the blood flow was calculat-
ed from the integral of a cross sectional map
of perfusion. The software can identify the
arteriole, but not the capillaries. Thus, it pro-
vides relative blood flow of the arterioles
according to the integral of a cross sectional
map of perfusion. 

Data analysis
PaCO2 was estimated from VE and PETCO2.14

Ocular blood flow measurements were used for
analysis only when clear laser speckle imaging
was obtained in two or more consecutive heart
beats during a 4-s recording period. These flow
data were averaged in each condition and cal-
culated as a relative value to the resting base-
line value. Data are expressed as the
mean±SE. The effect of treatments was exam-
ined by repeated-measures ANOVA. When a
significant F value was detected, this was ana-
lyzed further against the CON value using
Dunnett’s post-hoc test. Likewise, the relative
response from the resting baseline in each
vasculature to different ventilations was com-
pared by repeated-measures ANOVA and
Dunnett’s test to compare with the MCAV
value. Pearson correlation coefficient was cal-
culated for the responses to CO2 among vascu-
latures, and between acuity changes and rela-
tive changes in blood flow in various vascula-
tures. Multiple regression analysis was per-
formed to reveal effects of blood flow in RCV
and MCA on visual acuity. The level of statisti-
cal significance was set at P<0.05. These sta-

tistical analyses were performed with SAS
(version 8.2; SAS Institute, Cary, NC, USA) at
the Computing and Communications Center,
Kyushu University, Japan.

Results

Systemic change
Hypercapnia increased both MAP and HR,

while hypocapnia decreased MAP and
increased HR (Table 1). These changes were
slight but significant. Hypercapnia significant-
ly increased MCAV, while hypocapnia signifi-
cantly decreased it (Table 1). PETCO2 differed

Article

Table 1. MAP, HR, MCAV, PaCO2 and VE during baseline and treatment.

Baseline Treatment

MAP (mmHg) HYPER 87.6±3.6 88.9±3.7*
HYPO 87.4±3.8 84.5±3.6* 

CON 87.4±3.2 85.8±2.6 
HR (bpm) HYPER 65.7±3.7 68.0±3.8* 

HYPO 67.1±4.6 78.9±5.5* 
CON 63.9±3.5 65.6±3.6 

MCAV (cm/s) HYPER 76.2±4.4 81.7±4.9* 
HYPO 79.1±3.8 46.1±2.6* 

CON 79.3±4.3 77.1±4.0 
PaCO2 (mmHg) HYPER 42.5±1.3 48.4±0.6* 

HYPO 43.2±0.6 23.9±0.3* 
CON 43.1±1.4 43.2±1.0 

VE (L/min) HYPER 6.8±0.4 12.1±0.9* 
HYPO 7.1±0.5 22.9±1.4* 

CON 7.0±0.4 7.7±0.4
Values are the mean±SE. All variables during the treatment significantly changed from the resting baseline values, except in the CON treat-
ment. *P<0.05 vs. baseline.

Figure 1. Examples of the velocity data
obtained in a subject at eupnia (CON,
upper) and hypocapnia (HYPO, bottom).
Color bars shown in the right side indi-
cates the blood flow velocity. Note decrease
in blood flow velocity in HYPO, compared
to CON treatment. 

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[page 22] [Eye Reports 2011; 1:e8]

significantly among CON, HYPO, and HYPER
treatments (42±1, 21±1, and 48±1 mmHg,
respectively). Accordingly, there were signifi-
cant differences in estimated PaCO2 among
treatments (Table 1). 

Ocular and cerebral blood flow 
The eupnea (CON) did not significantly

alter blood flow velocity in MCA, and blood flow
in RCV, ITRA and STRA from the baseline value
(P>0.1). 
Hyperventilation resulting in hypocapnia

(HYPO) significantly decreased blood flow
velocity in MCA, blood flow velocity in RCV, and
blood flow in ITRA and STRA by 42±4%,
22±15%, 15±8% and 13±18%, respectively
(Figure 2). The decrease in MCAV was signifi-
cantly greater than in other vasculatures.
High-fraction CO2 gas inspiration (HYPER)
slightly but significantly changed blood flow

velocity in MCA and RCV (8±9 % and 3±9%,
respectively), but not blood flow in ITRA and
STRA. The increase in MCAV was significantly
greater than in ITRA flow.

Visual acuity
Visual acuity with HYPO, CON and HYPER

treatments was 0.21±0.1, 0.24±0.1 and
0.25±0.1, respectively (Figure 3). Visual acuity
was significantly lower in HYPO and tended to
be greater in HYPER than in the CON treat-
ment. The difference in visual acuity in HYPO
and HYPER treatments compared with the
CON treatment was significantly and positive-
ly correlated with the relative changes in blood
flow in RCV and MCA (r=0.52 and 0.51, respec-
tively, n=22) (Figure 4). The correlation was
still observed between visual acuity and RCV in
HYPO treatment (r=0.67, n=11). Except for
this case, there was no significant correlation
in changes between blood flow and visual acu-
ity when HYPO and HYPER were separately
examined. However, when deleting an extreme
point in RCV and visual acuity relationship, we
lost the significant correlation. On the other
hand, in the MCA and visual acuity relation-
ship, while even after deleting one to five
extreme points, significant correlation was
still present between MCA and visual acuity
relationship. Multiple regression revealed the
significant effect on a change in visual acuity
of changes in blood flow both in MCA and RCV:
1,000 V = 0.7 R + 0.4 M + 2.3; where V repre-
sents the change in visual acuity from base-
line, R and M are the relative changes in RCV
blood flow and MCAV, respectively.

Relationship in CO2 reactivity
among vasculatures
The correlation coefficient among relative

responses in vasculature to HYPO treatment

was significant between ITRA and RCV
(r=0.60), but no significant correlations were
obtained among other ocular and cerebral
blood flow responses (r ranged from -0.04 to
0.50, P>0.1). 

Discussion

A main finding in the present study is that
hypo- and hypercapnia altered RCV with a con-
comitant change in static visual acuity, sup-
porting our hypothesis that RCV correlates
with static visual acuity. Another finding was
that the magnitude of vessels response to CO2

in ocular vessels is less than in cerebral one,
supporting a previous study which reported
MCA blood flow response was greater to hyper-
capnia than retinal blood flow.15

Effect of ocular circulation on visual acuity 
The present results demonstrate for the first
time that both acute increase and decrease of
RCV correlate with the improvement and
impairment of visual acuity in healthy
humans, supporting our hypothesis. There was
also a significant positive correlation between
RCV and visual acuity. The finding is consis-
tent with previous findings that increased
blood flow was related to the improvement of
contrast sensitivity.16 Concomitant increases
in choroid flow and contrast sensitivity were
found in healthy subjects after sildenafil
administration.6 These findings could be sup-
ported by evidence for the relationship
between chronic change in ocular blood flow
and vision,1-4 though some previous studies
have reported no relationship between ocular
blood flow and visual function during hypo-
and hypercapnic, pharmacologic and altitude
stimulus.17,18 Chronic reduction in ocular blood
flow is well known to be related to impaired

Article

Figure 2. Relative changes in blood flow
velocity in middle cerebral artery (MCAV),
blood flow velocity in retinal and choroidal
vessels (RCV), and blood flow in inferior
temporal retinal arteriole (ITRA) and supe-
rior temporal retinal arteriole (STRA) in
response to hypocapnia (HYPO), eupnia
(CON) and hypercapnia (HYPER). HYPO
significantly decreased blood flow in MCA,
RCV, ITRA and STRA. The decrease in
MCAV was significantly greater than in the
other vasculatures. HYPER treatment
slightly but significantly changed blood
flow in MCA and RCV, but not in ITRA
and STRA. The increase in MCAV was sig-
nificantly greater than in ITRA. n=11.
*P<0.05 vs CON, =P<0.05 vs MCA 

Figure 3. Visual acuity during hypocapnia
(HYPO), eupnia (CON) and hypercapnia
(HYPER). This was significantly less in
HYPO and tended to be greater in HYPER
than in the CON treatment. n=11. *P<0.05
vs CON (*)P=0.08 

Figure 4. Relationship between changes in visual acuity and blood flow velocity in the
retinal and choroidal vessels (RCV, left panel) and middle cerebral artery (MCA, right).
The difference in visual acuity from the eupnea (CON) treatment was significantly corre-
lated with the relative changes of blood flow velocity in RCV and MCA (r=0.52 and 0.51,
respectively, n=22, P<0.05). Circles show the response to hypocapnea (HYPO) and trian-
gles show that to hypercapnea (HYPER). 

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[Eye Reports 2011; 1:e8] [page 23]

visual function in diseases and animal mod-
els.1-5 Acute loss of contrast sensitivity in glau-
coma patients was improved by hypercapnia.19

These findings could support the relevance of
acute change in ocular blood flow on the con-
comitant change in visual acuity. 
The relationship between changes in ocular

flow and visual acuity could provide an impor-
tant translational implication, if ocular blood
flow is relevant to various visual variables,
such as dynamic visual acuity, visual field and
contrast sensitivity as well as static visual acu-
ity. For example, the present finding is useful
to find how to maintain or improve visual acu-
ity during work. It was reported that high
intensity exercise induces temporary impair-
ment of visual acuity.7 High intensity exercise
relates to hyperventilation, which induces
hypocapnea. Thus the relationship of ocular
blood flow to visual acuity has implications in
preventing the decreased vision.

Effect of CO2 on ocular and cere-
bral vascular responses 
Blood flow velocity reduced in both ocular

capillary and arterioles in response to
decreased PaCO2, and partly increased in
response to increased PaCO2. The response of
ocular blood flow or blood flow velocity to
hypercapnia has been well documented in reti-
nal capillary, superior temporal peripapillary
retina, and ophthalmic and central retinal
arteries.18,20,21 The response to hypocapnia was
also reported.18 The present study supports
that both retinal arteriole and retinal-choroidal
vasculatures respond to both hypo- and hyper-
capnia.
The response to hypo- and hypercapnia was

greater in MCAV than blood flow velocity in ocu-
lar vessels and blood flow in retinal arterioles
both in groups and individuals, indicating
weaker reactivity in ocular than the cerebral
vessels. Few previous studies have compared
the ocular vessel and cerebral vessel response
to CO2.15,22,23 A weaker reactivity in ocular ves-
sels to CO2 has physiological relevance. The
function of the retina is vulnerable to overperfu-
sion.2,9 Weak reactivity could serve for the rela-
tively easy stabilization of ocular perfusion.

Relationship between responses in
various vessels
Retinal vessels are routinely inspected dur-

ing physical examinations and used to esti-
mate clinical cerebral vessel conditions. A cor-
relation between vascular reactivity to CO2 in
retinal and cerebral vessels has been report-
ed.24 Studies have been performed based on
analogy of ocular vessels to the cerebral circu-
lation; however, no published study to our
knowledge has investigated the relationship
between cerebral and ocular vessel responses

to CO2. The present result does not show a
relationship among these responses. This
implies that the magnitude of response to
vasoconstrictive and vasodilative mechanisms
is not necessarily the same in ocular and cere-
bral vasculatures in an individual. 
Limited correlation even in ocular flow
responses might be due to the effect of this
complex flow nature in the retina. RCV is a
combination of retinal and choroidal flow
velocity; the retinal circulation component is
characterized by a low level of flow and is sup-
plied by the central retinal artery, which is con-
nected to the ITRA and the STRA, whereas the
choroidal circulation component has relatively
higher flow and is supplied by ciliary arter-
ies.9,25 Unfortunately, we cannot separate these
signals in the present study. 

Limitations
The increase in PaCO2 was limited since

increase in inspired CO2 stimulates ventila-
tion. HYPER treatment did not provide a corre-
sponding change in PaCO2 to HYPO treatment.
As a result, the decrease of ocular blood flow
was limited and the change of visual acuity did
not reach statistical significance. Increase in
ventilation could increase PaO2. In our prelim-
inary measurement in the same experimental
setting, we observed 10% increase in PETO2 in
four of subjects during HYPO treatment. An
increase of 13% in PETO2 has been reported
during hypercapnia.26 Thus, arterial oxygen
tension accompanied by increased ventilation
might reduce the ocular blood flow. Results
obtained during hypocapnia could be mixed
with the effect of increased oxygen tension.
However the effect of oxygen tension is more
limited than previous studies comparing ocu-
lar blood flow between air and carbogen. Using
carbogen leads PETO2 up to 400 mmHg,27 while
the present study might have roughly increase
it by 115 mmHg. In turn, we can conclude that
hypercapnea increases ocular blood flow since
the effect of hypercapnia overwhelms the
effect of increased oxygen, if any. 
It should be noted that the change of PCO2

also alters the oxygen dissociation curve of
hemoglobin (Hb), i.e., the Bohr effect and the
converse of the Bohr effect. In fact, the possi-
bility of impeding O2 unloading even in human
muscle tissues has been reported.28 The pres-
ent study does not allow us to conclude that the
single effect of blood flow alters the visual acu-
ity. In turn, there remains the possibility that
the shift of oxygen dissociation curve of Hb
modified the acuity; any factor modifying visu-
al acuity associated with respiratory manipula-
tion should be carefully interpreted.
Altered cerebral perfusion could affect visu-

al acuity as shown in the concomitant change
and significant correlation in changes of MCAV
and visual acuity, though MCA dynamics may

be different in nature than posterior cerebral
artery dynamics.29 There is also indirect evi-
dence that altered cerebral perfusion could
affect visual acuity: a relationship between
MCA blood flow and visual acuity and contrast
sensitivity in primary open-angle glaucoma in
a cross-sectional study.4 It is difficult to obtain
direct evidence that cerebral perfusion relates
to visual function because the nature of both
cerebral and ocular flows are similar to many
physiological stimulations. Thus there is room
for argument as to whether or not cerebral
blood flow changes the visual acuity. 
In summary, we compared the ocular and

cerebral blood flow among hyper-, hypo-, and
normo-capnia conditions. We demonstrated
that the ocular blood flow change induced by
both hypo- and hyper-capnia are associated
with concomitant changes in visual acuity.
These findings are useful for further under-
standing the physiological nature of ocular
blood flow and its relation to visual function.  

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