Download Ocular perfusion pressure and choroidal blood flow in the

Ocular Perfusion Pressure and Choroidal Blood
Flow in the Rabbit
J. W. Kiel and W. A.J. van Heuven
Purpose. To compare choroidal blood pressure versus flow relationships obtained by three
different methods of changing the ocular perfusion pressure.
Methods. Experiments were performed in pentobarbital-anesthetized rabbits with occluders
on the aorta and inferior vena cava to control mean arterial pressure (MAP). The central ear
artery was cannulated to measure MAP. Two 23-gauge needles were inserted through the pars
plana into the vitreous: one connected to a saline-filled syringe to vary the ocular volume and
the other to a pressure transducer to measure intraocular pressure (IOP). Choroidal perfusion
was measured by laser-Dopplerflowmetrywith the probe in the vitreous over the posterior
pole. In group 1 (n = 15), the MAP was varied while holding the IOP at 10, 15, 20, 25 and
30 mm Hg. In group 2 (n = 19), the IOP was increased while holding the MAP at 80, 70,
60, 50, 40, 30 and 20 mm Hg. In group 3 (n = 21), the MAP was varied without controlling
the IOP.
Results. Group 1 baseline choroidal flows were similar at the five IOPs. When the flow was
plotted against MAP, the curves diverged and extrapolated to intersect the pressure axis when
the MAP equaled the set IOP. Group 2 baseline flows were similar at MAPs greater than 40
mm Hg. When the flow was plotted against the IOP, the curves diverged and intersected the
pressure axis when the IOP equaled the MAP. In both groups, plotting the flow against the
perfusion pressure (i.e., MAP minus IOP) collapsed the data points into single curves. Choroidal autoregulation occurred in all three groups; however, the low end of the autoregulatory
perfusion pressure range was ==50 mm Hg in group 1, »40 mm Hg in group 2, and ^30
mm Hg in group 3.
Conclusions. The results show that the effective choroidal perfusion pressure gradient equals
the MAP minus the IOP, and that choroidal autoregulation is most effective when the MAP
varies and IOP is not controlled. Invest Ophthalmol Vis Sci. 1995; 36:579-585.
A he driving force for the movement of blood
through the choroid is the arteriovenous pressure gradient. Because the choroidal venous pressure slightly
exceeds the intraocular pressure (IOP) when the IOP
is varied across a wide range,'l2 a reasonable approximation of the effective choroidal perfusion pressure
is the mean arterial pressure (MAP) in the ophthalmic
artery minus the IOP.3'4 If this premise is correct, it
Supported by National Institutes of Health grant EY09702 and by an unrestricted
research grant from Research to Prevent Blindness Inc., Neiv York, Neto York. JWK
is the recipient of a Research to Prevent Blindness Miriam and Benedict Wolf
Scholar Award.
Proprietary interest category: N.
Submitted for publication July 14, 1994; revised September 19, 1994; accepted
October 19, 1994.
Reprint requests: J. W. Kiel, Department of Ophthalmology, University of Texas
Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.
follows that raising the IOP at different MAPs should
generate a family of pressure-flow curves when the
data are plotted against IOP that resolve into a single
curve when plotted against perfusion pressure. Similarly, decreasing the MAP at different IOPs should
also generate a family of curves when plotted against
MAP that form a single curve when plotted against
the perfusion pressure. Although these flow responses
have been observed in physical models5'6 they have
not been demonstrated in the choroid. Thus, one goal
of this study is to fill this gap in our knowledge of
choroidal blood flow.
In contrast to previous studies that found little
evidence of choroidal pressure-flow autoregulation,7"9 our recent studies indicate that the choroid is
capable of vigorous autoregulation.1011 One possible
explanation for these discrepant findings is the differ-
Invesligative Ophthalmology & Visual Sci< e, March 1995, Vol. 36, No. 3
Copyright © Association for Research in ' on and Ophthalmology
579
From the Department of Ophthalmology, University of Texas Health Science Center,
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Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No. 3
ence in the methods used to vary the perfusion pressure. Therefore, the second goal of the present study is
to compare the choroidal pressure-flow relationships
obtained when the perfusion pressure gradient is varied by three different methods.
METHODS
The animals used in this study were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Animal Preparation
Locally obtained New Zealand albino rabbits of both
sexes were housed in the institutional animal care facility and given food and water ad libitum for at least
2 days before the experiments. At 8 AM, the animals
were anesthetized with pentobarbital sodium (30 mg/
kg, intravenously, supplemented every 30 minutes),
intubated through a tracheostomy and respired with
room air. Expired PCO2 was monitored (Datex Normocap 200, Tewksbury, MA) and maintained between 40
and 45 mm Hg. A heating pad was used to maintain
normal body temperature (38°C to 39°C). The animals
were killed with an overdose of anesthetic (100 mg/
kg) at the end of the experiments.
Hydraulic occluders were placed around the thoracic descending aorta and inferior vena cava through
a right thoracotomy to control ocular MAP. The aortic
occluder was used to redirect the cardiac output to
the upper half of the body, thus increasing the MAP
at the eye. The caval occluder was used to impede
venous return, thus lowering cardiac output and reducing MAP throughout the circulation. To estimate
ocular MAP, a cannula was inserted into the left central ear artery and connected to a pressure transducer
(BLPR, World Precision Instruments, Sarasota, FL) to
measure MAP at roughly the same height above the
heart as the eye.
The animals were then mounted in a stereotaxic
head holder. Two 23-gauge needles were inserted into
the vitreous through the pars plana to control and
measure intraocular pressure. One needle was connected to a saline-filled syringe to change the ocular
volume. The second needle was connected to a pressure transducer to measure the IOP.
A laser-Doppler flowmeter (PF-2B, Perimed,
Stockholm, Sweden) was used to measure two indices
of choroidal perfusion: the concentration of moving
blood cells (CMBC) and the red blood cell flux.12 In
brief, the technique is based on the spectral broadening of laser light in perfused tissue caused by photon
interaction with moving blood cells. Two perfusion
parameters are continuously derived from the resultant Doppler-broadened spectrum. The mean red cell
velocity is determined from the intensity-normalized
first moment of the spectrum, and the CMBC is determined from the total power spectral density. The
product of these two parameters is the red blood cell
flux, which varies linearly with blood flow in a wide
variety of tissues.12
The flowmeter used in this study uses a 2 mW HeNe laser light source and a probe (Pf 303, Perimed,
Stockholm, Sweden) with three fiber optic light
guides, one to transmit the light to the tissue and two
to capture the light re-emitted from the tissue. The
flowmeter frequency cut-off was set at 12 kHz in group
1 and at 24 kHz in the other two groups. (The higher
frequency cut-off was not available on the flowmeter
used in group 1.) The time constant was set at 0.2
seconds and the gain at 1. The flowmeter was calibrated by placing the probe in a suspension of latex
particles at 22°C and adjusting the internal gain so
that the instrument read 250 perfusion units. During
the experiments, the "total backscatter" (i.e., the DC
voltage at the photodetector) was maintained constant
between 2 to 4 volts.10
To measure choroidal perfusion, the probe was
advanced through the pars plana with a micromanipulator so that the probe tip was positioned in the vitreous near the retinal surface over the posterior pole.
The volume of tissue sampled by the instrument is
approximately 1 mm3, which is sufficient to measure
perfusion in both the retina and the choriocapillaris
and perhaps the conduit vessels in the outer choroid.
Because the rabbit retina is largely avascular,13 the flux
and CMBC signals in this preparation are measures
of choroidal perfusion.
Experimental Protocols
Three series of experiments were performed. A representative set of tracings from each protocol is shown
in Figure 1. In the first series (group 1, n = 15), the
perfusion pressure (MAP minus IOP) was varied by
changing the MAP while holding the IOP at 10, 15,
20, 25, and 30 mm Hg. In the second series (group
2, n = 19), the perfusion pressure was decreased by
progressively increasing the IOP by saline infusion at
0.5 fj\/sec while holding the MAP at 80, 70, 60, 50,
40, 30, and 20 mm Hg. In the third series, (group 3,
n = 21), the perfusion pressure was varied by changing
the MAP without controlling the IOP after setting it
to an initial baseline value of 15 mm Hg.
Data Analysis
All measured variables were recorded with a MacLab
(World Precision Instruments) data acquisition system
connected to an Apple Macintosh SE30 computer
(Apple, Cupertino, CA). The digitized values for the
measured variables were averaged in 5 mm Hg bins
of MAP for groups 1 and 3 and of IOP for group 2.
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581
Ocular Perfusion Pressure and Choroidal Blood Flow
Protocol #1
Protocol #2
Protocol #3
Arterial
Pressure
(mmHg)
Intraocular
Pressure
(mmHg)
FIGURE 1. In group 1, the perfusion pressure (MAP minus IOP) was decreased by progressively occluding the vena cava to lower the MAP while holding the IOP at different levels by
adjusting the ocular volume. In group 2, the perfusion pressure was decreased by continuous
infusion of saline at 0.5 /xl/sec to raise the IOP while holding the MAP constant at different
levels by partially occluding the descending aorta or inferior vena cava. In group 3, the
.perfusion pressure was decreased by lowering the MAP without controlling the IOP (time
in seconds). MAP = mean arterial pressure; IOP = intraocular pressure.
The results are expressed as the mean ± the standard
error of the mean.
RESULTS
Immediately upon cannulation of the eye, the average
MAP and IOP for all animals were 75.49 ± 1.26 mm
Hg and 16.22 ± 0.50 mm Hg, respectively. The pressure-flow results for the three groups are shown in
Figure 2. The left column of graphs shows the choroidal flux values plotted against the manipulated pressure, and the right column shows the choroidal flux
data replotted against the perfusion pressure gradient.
Figure 2A presents the choroidal flow responses
when the MAP was decreased at different fixed IOPs
(group 1). The actual IOPs were: 9.8 ± 0.1, 14.5 ±
0.1, 20.1 ± 0.3, 24.0 ± 0.4, and 29.8 ± 0.4 mm Hg.
The left graph shows that the baseline flux values were
similar at all five IOPs, but, as the MAP was decreased,
the pressure-flow curves diverged, resulting in a family
of curves that extrapolate to intersect the pressure axis
when the MAP approximately equals the set IOP. The
right graph shows that, when the choroidal flux values
are plotted against the perfusion pressure, the individual pressure-flow curves form a common curve with a
projected zero intercept.
Figure 2B shows the choroidal flow responses
when the IOP was increased at different fixed MAPs
(group 2). The actual MAPs were: 80.9 ± 0 . 1 , 70.9 ±
0.1, 61.9 ± 0.2, 51.4 ± 0.1, 41.6 ± 0.1, 31.5 ± 0.2, and
20.7 ± 0 . 1 mm Hg. The left graph shows that the
baseline flux values were similar at MAPs between 80
and 50 mm Hg and reduced in a pressure-dependent
manner at the lower MAPs. As in group 1, the individual curves intersect the pressure axis when the IOP
approximately equals the set MAP. The right graph
shows the choroidal flux values plotted against the
perfusion pressure, and, as in group 1, the individual
curves resolve into a common curve intersecting the
pressure axis at approximately 0 mm Hg.
Figure 2C shows the choroidal flow responses
when the MAP was decreased without controlling the
IOP (group 3). Under this protocol, the single pressure-flow curve obtained when the choroidal flux values are plotted against the manipulated pressure (left
graph) is shifted to the left when plotted against the
perfusion pressure (right graph).
The right column of graphs in Figure 2 shows that
choroidal autoregulation occurred in all three groups.
However, the perfusion pressure below which choroidal flow became pressure-dependent varied between
groups, occurring at approximately 50 mm Hg in
group 1, 40 mm Hg in group 2, and 30 mm Hg in
group 3.
Figure 3 presents the CMBC data plotted against
the perfusion pressure for the three groups. The
CMBC parameter is an index of blood volume. Figure
3A shows that the CMBC was relatively constant at
perfusion pressures greater than 20 mm Hg when the
MAP was decreased at fixed IOPs (group 1). Figure
3B shows that when the IOP was increased at fixed
MAPs (group 2), the CMBC increased slightly as the
perfusion pressure decreased from 60 to 20 mm Hg,
then fell in a pressure-dependent manner. Figure 3C
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582
Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No.
A.
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MAP@40
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80 -10
0
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1000 -i
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o
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20 30 40 50
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FIGURE 2. Choroidal pressure-flow relationships plotted as a function of the manipulated
pressure {left column) and the perfusion pressure {right column). (A) Choroidalfluxresponses
to decreasing the MAP at different IOPs. (B) Choroidal flux responses to increasing the
IOP at different fixed MAPs. (C) Choroidal flux responses to decreasing the MAP without
controlling the IOP. MAP = mean arterial pressure; IOP = intraocular pressure.
shows that when the MAP was decreased without controlling the IOP (group 3), the CMBC tended to increase as the perfusion pressure was reduced from 60
to 5 mm Hg.
DISCUSSION
The goals of this study were twofold: to provide a
systematic demonstration of the ocular perfusion pressure gradient and its effect on choroidal blood flow
and to determine whether the method used to vary
the perfusion pressure alters the efficacy of choroidal
autoregulation.
Ocular Perfusion Pressure
A basic premise of choroidal blood flow studies is that
the choroidal perfusion pressure is well approximated
by the pressure gradient between the MAP in the ophthalmic artery and the IOP. However, this has never
been demonstrated systematically, probably because
of the limitations of techniques previously used for
measuring choroidal blood flow. For example, the ra-
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583
Ocular Perfusion Pressure and Choroidal Blood Flow
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Underlying Mechanism
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dioactive microsphere technique is inherently discontinuous and, as validated by Aim et al,14 is limited
to one measurement per eye. The various clearance
techniques9'15 permit multiple measurements, but
they are also discontinuous and require several minutes to complete. Thus, the large number of measurements needed to obtain multiple pressure-flow
curves by systematic manipulation of the perfusion
pressure have not been feasible. By contrast, laserDoppler flowmetry provides a continuous measurement that makes such a study possible.
If the choroidal perfusion pressure equals the
MAP minus the IOP, then varying one pressure while
holding the other pressure constant at different levels
should result in a family of pressure-flow curves when
the data are plotted against the manipulated variable
and a single common curve when the data are plotted
against the perfusion pressure. The results shown in
Figure 2 demonstrate this pattern of choroidal flow
behavior both when the MAP is the manipulated variable (Fig. 2A) and when the IOP is the manipulated
variable (Fig. 2B). Similar results were obtained by Fry
et al,16 who analyzed the flow behavior in a collapsible
tube passing through a pressurized chamber.
70
FIGURE 3. Choroidal pressure-blood volume relationships.
Graphs show the concentration of moving blood cells
(CMBC) plotted as a function of the perfusion pressure
when the MAP is reduced at fixed IOPs (A), the IOP is
increased at fixed MAPs (B), and the MAP is reduced without controlling IOP (C). MAP = mean arterial pressure;
IOP = intraocular pressure.
Moses5 likened the effect of IOP on the intraocular
veins to a Starling resistor whose cross-sectional area
is a function of the transmural pressure gradient. In
other words, the balance of the pressures inside and
outside the veins determines their caliber and resistance to flow. In support of this hypothesis, raising
the IOP causes a parallel shift in the blood pressures
"upstream" in the choroidal veins1'2 and choriocapillaris2 across a wide range of IOPs.
Fry et al6 performed a systematic analysis of the
flow behavior in a simple Starling resistor device by
varying the tubing pressure gradient at different
chamber pressures. At zero chamber pressure, the
pressure-flow relationship was linear when plotted
against the tubing pressure gradient. At progressively
increased chamber pressures, the pressure-flow curves
consisted of two linear segments: an initial segment
with reduced slopes as the tubing pressure gradient
was raised from zero to the prevailing chamber pressure and a second segment where the slopes were
parallel to that at zero chamber pressure. The slope
change at positive chamber pressures occurred when
the tubing geometry changed from a partially collapsed to a fully distended configuration. In this simple passive model, plotting the flow data against the
pressure gradient defined as the inlet pressure minus
the chamber pressure resulted in a single common
function.
In the present study, the protocol for group 1, in
which the MAP was reduced at set IOPs, most closely
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Investigative Ophthalmology & Visual Science, March 1995, Vol. 36, No. 3
replicates the pressure manipulations in the Starling
resistor device studied by Fry et al.6 Although the results are remarkably similar, there are several noteworthy differences between the two studies. First, the venous pressure outside the eye was not measured so
the vascular pressure gradient analogous to the tubing
pressure gradient is unavailable. Instead, the data are
plotted against the MAP (Fig. 2), and it is assumed
the change in extraocular venous pressure during the
MAP manipulation is relatively small as observed in a
previous study." Second, it was not possible consistently to lower the MAP below the IOP and, therefore,
it is uncertain whether the choroid exhibits an initial
reduced slope analogous to that seen when the tubing
pressure gradient was less than the chamber pressure.
Third, unlike the choroid, the Starling resistor device
is inherendy passive and incapable of the pressureflow autoregulation seen at the higher MAPs (Fig. 2).
Despite these caveats, the similar flow behavior in the
choroid and the Starling resistor device supports the
assertion by Moses5 that the choroidal veins function
as biologic Starling resistors.
The Starling resistor mechanism is also consistent
with the CMBC responses shown in Figure 3. As noted
earlier, the CMBC is an index of choriocapillaris blood
volume. In all three groups, the CMBC either remained constant or increased slightly as the perfusion
pressure gradient was decreased from s=»65 to «*20
mm Hg. With further reductions in the perfusion pressure, the CMBC then fell in groups 1 and 2, in which
the IOP was controlled, but not in group 3, in which
the IOP was not controlled. As predicated by the Starling resistor mechanism, the fall in the CMBC indicates the partial collapse of the vessels under the
probe as the extravascular pressure begins to overcome the intravascular pressure. The fact that the IOP
was not artificially maintained or elevated in group 3
suggests that the IOP fell sufficiently for the vessels to
remain distended.
Choroidal Autoregulation
Previous choroidal pressure-flow studies differ in their
methods used to manipulate the perfusion pressure
gradient and in their findings regarding choroidal autoregulation.7""'15 The present results also indicate a
link between the method of pressure manipulation
and the efficacy of choroidal autoregulation. The right
column of graphs in Figure 2 shows that choroidal
autoregulation is least evident when the MAP is decreased and the IOP fixed, it is more pronounced
when the IOP is increased and the MAP held constant,
and it occurs over the widest perfusion pressure range
when the MAP is varied without controlling the IOP.
Although rarely used in choroidal pressure-flow studies,11 this latter protocol most closely simulates the
in vivo situation; hence, it is not surprising that the
autoregulatory mechanism is most effective under this
condition.
It is possible that the arterial baroreflex may have
altered the choroidal sympathetic nerve activity and,
by changing the intraocular vascular resistance, so altered the pressure-flow relation and the autoregulatory range. However, if the sympathetic tone to the
choroid were under baroreflex control, the pressureflow curves for group 2 would not superimpose when
plotted against perfusion pressure. Instead, baroreflex
withdrawal of sympathetic tone at the higher MAPs
would cause vasodilation, whereas baroreflex activation at the lower MAPs would cause vasocontriction.
Figure 2B shows that this did not occur. Moreover,
if the baroreflex was responsible for the shift in the
autoregulatory range, one would expect the range to
be the same in groups 1 and 3 because the MAP was
manipulated in the same manner in both groups. Instead, the autoregulatory range was smallest in group
1 and largest in group 3. Thus, it does not appear
that the baroreflex is responsible for the shift in the
autoregulatory range between protocols.
The present results indicate that the choice of
experimental protocol for varying the perfusion pressure may partly explain the discrepancies in the choroidal autoregulation literature. Differences in blood
flow measuring methodologies may also account for
the discrepant findings.'' Lastly, anatomic differences
between species may be involved. For example, unlike
primates, rabbits do not have a retinal circulation,13
and their inner retina relies on anaerobic metabolism.15 Thus, rabbits might require choroidal autoregulation, whereas species with a vascularized retina may
not. The problem with this hypodiesis is the underlying assumption that choroidal autoregulation is linked
to retinal metabolism. This is unlikely given the long
diffusion distance between the inner retina and the
choroidal resistance vessels, the negligible choroidal
oxygen extraction,4 and the high anaerobic capacity
of the rabbit retina.16 An alternative possibility supported by previous studies1011 is that choroidal autoregulation is myogenic and that it functions to prevent
large MAP-dependent changes in choroidal blood volume and consequent changes in IOP. Such a protective mechanism would be a beneficial adaptation in
rabbits or humans.
Clinical Significance
Any attempt to extrapolate animal studies to humans
must be viewed with caution and, at present, the autoregulatory capacity of the human choroid is unknown.
However, the foveal avascular zone and a large portion
of the outer human retina are nourished by the choroid4 and susceptible to choroidal ischemia. Given the
possibility that the human choroid may have some
autoregulatory ability, we offer the following as two
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585
Ocular Perfusion Pressure and Choroidal Blood Flow
examples of where the present results may be clinically
relevant.
Hayreh'7 has hypothesized that nocturnal arterial
hypotension underlies the development of glaucoma
in patients with seemingly normal IOP. This hypothesis can be described graphically using the flow plotted
against the perfusion pressure (Fig. 2A, right) by selecting a point on the graph representing a normal
daytime MAP and IOP and then moving that point to
the left into the pressure-dependent portion of the
curve to show the potential for ischemia associated
with nocturnal arterial hypotension. However, by also
considering the graph of flow plotted against MAP at
different IOPs (Fig. 2A, left), it is further appreciated
that a nocturnal fall in MAP has a smaller effect on
blood flow at an IOP of 10 mm Hg than at 20 mm
Hg, although these values bracket the normal range
of IOP.
Another clinical situation in which this study may
have importance is during closed vitrectomy surgery
in patients with low blood pressure. This scenario can
occur in any patient who may have a hypotensive period resulting from anesthesia, but it is especially apt
to occur in very young patients undergoing surgery
for stage V retinopathy of prematurity. In such patients, the MAP is often between 30 and 80 mm Hg,
whereas the IOP is frequently maintained at 25 to 35
mm Hg and even higher if intraocular hemostasis is
desired. During the relatively long and complex procedure, the IOP may not even be known because the
ocular infusion bottle is simply hung at an empiric
height, which minimizes bleeding. It is interesting to
speculate how much the ensuing choroidal ischemia
contributes to poor visual results after vitrectomy for
retinopathy of prematurity.18
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Key Words
arterial pressure, intraocular pressure, choroidal autoregulation, eye, peripheral circulation
15.
16.
Acknowledgments
The authors thank Leslie McBride for her technical assistance, and A. P. Shepherd, PhD, and R. Whitaker, Jr., MD,
for their advice and encouragement.
17.
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