Download The mechanism of intraocular pressure rise during

The Mechanism of Intraocular Pressure Rise
During Cyclocryotherapy
Orna Geyer,* Adi Michaeli-Cohen,*
and Moshe Lazar *
David M. Silver,f Meira Neudorfer,*
Purpose. Intraocular pressure (IOP) spikes that occur during cyclocryotherapy for advanced
glaucoma may further injure the already damaged glaucomatous optic nerve and be responsible for visual impairment that may occur after this treatment. The authors investigated the
mechanism of pressure rise to see whether it can be avoided and thus prevent further optic
nerve injury. The authors postulated diat intraocular ice forms during the cryo procedure
and causes the pressure changes.
Methods. Intraocular pressure was monitored using a pneumatonometer during 15 cryocycles
of four patients with advanced glaucoma and 21 cryocycles of five normal rabbits. A simple
thermal model was developed to analyze the relation between volume expansion and pressure
rise in the eye. The physical effect of freezing rabbit eye structures was investigated in vitro.
Results. The largest pressure spikes observed during the cryocycles in this work were increases
of 32 mm Hg for humans and 25 mm Hg for rabbits. The mean value of the IOP immediately
before and after the cryo freezing stage was 53 ± 1 and 68 ± 2 mm Hg, respectively, for
humans and 22 ± 1 and 32 ± 1 mm Hg for rabbits. The parameters of the thermal model
were determined from the observed IOP spikes. Calculated thaw times were consistent with
measured times for return to precryo IOPs. In vitro cryoapplication (rabbit eye) showed the
formation of an ice ball internal to the eye.
Conclusions. Volumetric increase of the intraocular content, related to the formation of an
ice ball in the eye, is the mechanism of pressure spikes during cyclocryotherapy. Because this
complication is unavoidable, other cyclodestructive methods may be more prudent, particularly in patients with advanced glaucoma. Invest Ophthalmol Vis Sci. 1997; 38:1012-1017.
J. he use of a freezing source as the cyclodestructive
element was suggested by Bietti1 in 1950. However,
this procedure received little clinical recognition until
1968, when a large clinical study reported by DeRoetth 2 showed that primary open-angle glaucoma
could be controlled in more than 60% of patients by
cyclocryotherapy. Cyclocryotherapy constitutes a valuable adjunct for the care of cases in which other operations repeatedly have failed or are thought to be con-
From the "Department of Ophthalmology, Sourasky Medical Center, Tel-Aviv
University, Tel-Aviv, Israel; and f The Johns Hopkins University Applied Physics
Laboratory, Laurel, Maryland.
Presented at the annual meeting of the Association for Research in Vision and
Ophthalmobgy, May 1995, Ft. Lauderdale, Florida.
Supported in part by the U.S. Department of the Navy under Contract N00039-95C-0002.
Submitted for publication June 10, 1996; revised November 22, 1996; accepted
November 25, 1996.
Proprietary interest category: N.
Reprint requests: David M. Silver, Apjilied Physics Laboraloty, The Johns Hopkins
University, Laurel, MD 20723-6099.
1012
traindicated. The complications associated with cyclocryotherapy include uveitis, transient intraocular
pressure (IOP) rise immediately after the procedure,
hyphema, hypotony, choroidal detachment, cataract,
macular edema, and phthisis bulbi. These complications are associated with a significant loss of vision.
However, visual loss after cyclocryotherapy may occur
without any apparent cause and despite eventual decrease in IOP. 3 " 6
Pressure spikes during the freezing phase of cyclocryotherapy have been mentioned once in the previous literature, 7 and it was suggested that these spikes
may further injure the already damaged optic nerve
in patients with advanced glaucoma. We propose that
the mechanism of the pressure increase is the formation of ice (frozen intraocular fluid) within the ocular
globe during the cryofreezing phase. The intraocular
volume expansion on freezing water to ice causes the
rise in IOP.
Investigative Ophthalmology & Visual Science, April 1997, Vol. 38, No. 5
Copyright © Association for Research in Vision and Ophthalmology
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Mechanism of Cyclocryotherapy
The hypothesis to be explored here is that an ice
ball forms within the eye during the freezing phase
of cyclocryotherapy, increasing the eye volume and
causing the IOP to rise. If true, then the following
should be true:
1. The amount of ice formed should be consistent
with the increase in volume from the transformation from liquid water to ice, leading to increase
in IOP
2. The measured thaw time, which is the time observed for the fall in IOP during the thaw phase,
should be consistent with the calculated thaw time
for ice melting.
3. The ice ball should be observable within the eye.
We studied the IOP response to cyclocryotherapy
in vivo on glaucomatous human and normal rabbit
eyes. Calculations were performed using the thermal
properties of water to show the self-consistency of the
proposed ice mechanism with the measured IOP
spikes. Physical effects of applying the cryotreatment
to rabbit eye structures were investigated in vitro.
MATERIAL AND METHODS
Four patients with neovascular glaucoma and five normal rabbits were included in the study. With respect
to the humans, tenets of the Declaration of Helsinki
were followed, informed consent was obtained, and
Institutional Human Experimentation Committee approval was granted. For the rabbits, the investigation
adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Neovascular
glaucoma was diagnosed in the four patients on the
basis of very poor visual acuity (1/60 or less), very
high IOP (over 40 mm Hg) while taking medications,
marked conjunctival congestion, edematous cornea,
and the presence of iris or angle neovascularization
or both. In two of the patients, neovascular glaucoma
was caused by central retinal vein occlusion, and in
the other two, it was caused by advanced diabetic retinopathy. Cyclocryotherapy was performed on these
eyes to reduce the pressure, which could not be controlled on maximal-tolerated medical therapy, or to
alleviate pain. Anesthesia of the patients was achieved
with a retrobulbar injection of 2.0 ml bupivacaine
0.5% and 2.5 ml lidocaine 1%. Anesthesia of the
rabbits was achieved with intramuscular injection of
15 mg/kg ketamine and 0.15 ml/kg xylazine (20
mg/ml).
Cyclocryotherapy was performed with a 2.5-mm
diameter probe using nitrous oxide gas, with a probe
temperature of -80°C. IOP measurements were performed with a pneumatonometer (Bio-Rad, Cambridge, MA). Firm contact was made by pressing the
cryoprobe against the conjunctiva to begin the freeze,
1013
Experimental Design
IOP Monitoring
IOP Monitoring
I
Baseline
Baseline
j | Probe
Freezing Thaw
T , Probe
Interval
Freezing Thaw
Time (sec)
FIGURE 1. Diagram of the cyclocryotherapy procedure.
then during the procedure, the pressure exerted by
the probe on the eye was relaxed to minimize IOP
increase from globe compression. The probe was
placed 2.0 mm posterior to the limbus. The design of
the experimental procedure is shown schematically in
Figure 1. Baseline IOP was recorded for 10 seconds
(starting at time t = 0 seconds), then the cryoprobe
was placed on the globe without freezing for 10 seconds (starting at time t = 10 seconds). The freezing
cycle (cryocycle) of the eye was started next (at time
t = 20 seconds) and was continued for 60 seconds
(until time t = 80 seconds), then allowed to thaw for
60 seconds (from time t = 80 seconds until time t =
140 seconds). The interval between the end of the
thaw and the beginning of the next freeze was 60
seconds (from time t = 140 seconds to time t = 200
seconds). IOP was measured continuously throughout
the cryocycle, from baseline (t = 0 second) through
end of thaw (t = 140 seconds) for a total of 140 seconds. Three to five cryo applications were placed equidistant over the inferior 180° of each human and rabbit eye.
After cyclocryotherapy, human patients were observed for 48 hours. They continued their antiglaucoma medications, and in addition, atropine 1% and
dexamethasone 0.1% four times daily were added and
IOP was monitored by Goldmann applanation tonometry every 2 hours for the first 6 hours, then at 6-hour
intervals for 48 hours after the procedure. Rabbits
were killed after the cyclocryotherapy and their eyes
enucleated and studied in vitro, while maintaining the
eye at normal body temperature. A rabbit eye was cut
at the limbus, and the cornea and lens were removed.
The cryoprobe was applied to the outer sclera 2.0 mm
from the limbus. Cryoapplication was performed for
60 seconds to observe the effect of cryoapplication on
eye structures. Although normal blood flow did not
occur during this in vitro observational procedure on
enucleated rabbit eyes, the results should mimic the
in vivo situation because the in vivo flow of blood
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1014
Investigative Ophthalmology & Visual Science, April 1997, Vol. 38, No. 5
Human Glaucoma Eye
A
n
500
Time (sec)
FIGURE 2. Representative intraocular pressure measurements during cyclocryotherapy on a
human glaucomatous eye.
would serve as a mechanism for maintaining the eye
as a constant temperature thermal reservoir.
The method used for the theoretical development
was to assume a simplified model and use approximate
thermal diffusion theory8'9 with the following assumptions:
2. The heat transfer is by conduction only and takes
place isotropically from a uniform thermal bath
(the eye).
3. A hemispherical block of ice is formed during
the application of the cryoprobe.
Based on these assumptions, the calculations proceed as follows:
1. From the measured pressure rise and the known
1. The intraocular fluid has the physical and thermal properties10"12 of water.
Rabbit Normal Eye
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100
200
300
400
500
600
700
800
Time (sec)
FIGURE 3. Representative intraocular pressure measurements during cyclocryotherapy on a
rabbit normal eye.
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Mechanism of Cyclocryotherapy
TABLE 1.
Human
Rabbit
1015
Intraocular Pressure Values Before, During, and After Cryocycles
N*
Mean Prefreezing
IOPi (mm Hg)
Mean End of Freezing
IOPX (mmHg)
Mean Postcryo-IOP§
:
(mmHg)
Mean IOP Rise\\
(mm Hg)
Maximum IOP
Rise^ (mm
Hg)
15
21
53.1 ± 1.2
22.0 ± 0.7
67.8 ± 1.6
32.3 ± 1.3
50.0 ± 1.2
17.7 ± 0.7
14.7 ± 1.5
10.3 ± 1.1
32
25
IOP = intraocular pressure.
* N = number of freeze-thaw cycles.
f Mean of the N IOPs immediately prior to freeze period.
J Mean of the N IOPs at end of the freeze period.
§ Mean of the N IOPs immediately after each thaw period.
|| Mean of the N IOP rises during the freeze periods.
H Maximum IOP rise during the freeze period for any of the N cycles.
pressure-volume relation for the eye, calculate
the corresponding change in volume of the eye
and the mass of ice formed
2. From the heat capacity, thermal conductivity,
and latent heat of fusion of water, calculate the
time for heating and melting the ice, which is
t h e calculated
M = AV/[(l/p i c e ) — (1/Pwater,s7c)] ( m g)
with p ice = 0.917 gm/cm 3 and p ^ e r ^ c = 0.99336 gm/
cm 3 . The volume, V ^ ^ , equivalent to a mass M of
fluid in the liquid (water) phase is:
thaw time
. Vwater =
3 . C o m p a r e t h e calculated thaw time with t h e mea-
sured thaw time, which is the time observed for
the IOP to fall.
The volume, Vice, equivalent to a mass M of fluid
in the solid (ice) phase is:
The change in volume, AV, during the cryoprobe
application is:
£y
=
f(pm ) — f(p
) (n\\
where Pmax is the maximum IOP during cryoapplication, Ppre-crro is the precryo IOP, and f(P) is a pressure volume relation for the human eye1
= -43.7 + 42.21 X log10(P) + 0.6975 X
Vice = M/p ice (//I)
The radius, R, of a hemispheric ice block formed
within the eye adjacent to the cryoprobe during die
cryoapplication is:
R
= [Vice/(l/2 X 4TT/3)]1/3
(mm)
The time, twarm, required to raise the temperature
of the ice block from a coldest temperature, Tcold (obs e n , e d t o b e _ 1 ( r c ) > t o t h e me^ng
temperature,
or a pressure-volume relation for the rabbit eye14
frabbit(P) = [lo gl0 (P) - lo gl0 (10.121)]/0.024( M l)
t ™ = [M X C/(a/€) X K] X log[(T ambient
- T cold )/(T ambiem - T melt )] (sec)
For human eyes, the pressure-volume relation,
fhuman(P), used here is a representation 13 of the measurements made over the pressure range, 8 to 61 mm
Hg, on living human eyes15"18 rather than the cadaveric eye values of Friedenwald.19 The mass, M, of fluid
that gets frozen during the cryoapplication is:
TABLE 2.
Human
Rabbit
where C is the heat capacity of ice (0.5 cal/gm deg),
a is the surface area for heat transfer, £ is the characteristic distance between ambient and cold, K is the
thermal conductivity of ice (0.005209 cal/cm sec deg),
and T ambiem is the temperature of the ambient heat
Calculated Iceball Parameters and Measured Thaw Times
AV Calculated
Volume
Change (/AI)
M Calculated
Mass of Frozen
Fluid (mg)
R Calculated
Radius of Ice
Ball (mm)
ta,^ Calculated
Thaw Time
(seconds)
tthau Measured
14.7
7.0
175.3
83.1
4.5
3.5
16.7
10.2
18.9 ± 1.2
14.4 ± 0.8
Thaw Time
(seconds)
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Investigative Ophthalmology & Visual Science, April 1997, Vol. 38, No. 5
1G16
FIGURE 4. Photograph of the rabbit eye during cryoprobe application showing the hypothesized ice ball.
bath provided by the eye. The thermal influence of
blood flowing into the eye (less than 20 /u.€/second
for human eyes and approximately 18 /il/second for
rabbit eyes of a total internal eye volume of approximately 6000 jxt, for human eyes and 1500 \it for rabbit
eyes)20 is to help maintain the eye as a thermal reservoir at the temperature Ta,,,bient. The time, tmek, required to melt the ice at its melting temperature, Tmeit,
tWi, = [M X \ / ( a / € ) X K X (Tambient - TmcIl)] (sec)
where X is the latent heat of fusion of ice (80 cal/
gm). The thaw time, t,haw, is the total time required
to warm the ice to its melting point and then to melt
it by heat transfer from the ambient temperature bath:
Uaw = Lrm + Wit (sec)
RESULTS
A total of 15 cryocycles of four eyes of four patients
with glaucoma and 21 cryocycles of nine normal eyes
of five rabbits were evaluated. Representative curves
of the measured IOPs during the freeze-thaw cycles
are shown for a human glaucomatous eye and a nor-
mal rabbit eye in Figures 2 and 3, respectively. The
mean values of the IOP before, during, and after the
cryocycles for all the eyes are compiled in Table 1. In
addition, the maximum rise in pressure seen in all of
the cryocycles is given in Table 1 for the human and
rabbit. No clinically significant rises in IOP were noticed within the 48-hour postsurgery monitoring period for the patients with glaucoma.
For human and rabbit eyes, the calculated parameters for the ice ball as well as the measured thaw
times are listed in Table 2. The calculated thaw time
is expected to be less than the measured thaw time,
because of the simplifying assumptions of the model.
There is consistency between the calculated and measured thaw times. This suggests that ice formation
within the globe during the freezing phase of cyclocryotherapy is responsible for the IOP spikes.
As a further proof of the ice ball hypothesis, a
direct view of the effects of freezing on the internal
structures of the rabbit eye was attained in vitro, which
showed the formation of an ice ball, as illustrated in
Figure 4.
DISCUSSION
Some insight into the physical processes occurring
during cyclocryotherapy can be derived from the pres-
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Mechanism of Cyclocryotherapy
ent experiments and calculations. A dramatic increase
in IOP occurs during the freezing phase of cyclocryotherapy. Previous investigators7 had described these
increases in IOP as "probably a consequence of scleral
contraction during freezing, causing a decrease in intraocular volume" and consequent increase in IOP.
In this work, we have postulated that the pressure
spikes are a consequence of a volumetric increase of
the intraocular content related to the formation of an
ice ball in the eye. During the time of contact, the
cryoprobe cools and freezes some of the intraocular
fluid within the eye adjacent to the probe. When this
intraocular fluid undergoes the transition from liquid
(water) to solid (ice), it expands by ~ 8 % in volume.
This volume expansion within the eye causes a rise
in the IOP. When the cryoprobe is off, the frozen
intraocular fluid melts from solid (ice) to liquid (water), contracts in volume, and the IOP decreases. Because the formation of ice is inherent to the cryoprobe
operation, the accompanying IOP spikes are unavoidable.
It has not been proved that pressure spikes for a
short period can harm the optic nerve. However, it
may well be that in glaucoma with advanced damaged
optic nerve, spikes of IOP may impair ocular circulation and thus cause further injury, which may contribute to visual loss after cryotherapy. To eliminate these
pressure spikes, Caprioli and Sears7 suggested manometric regulation of the IOP during cyclocryotherapy.
It may be even more prudent to use other cyclodestructive methods, such as cyclophotocoagulation. In
the latter case, laser heating is not expected to produce IOP spikes, because volume expansion of water
on heating is minimal, especially compared to the volume expansion of water on freezing.
1017
3.
4.
5.
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9.
10.
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15.
16.
Key Words
cyclocryotherapy, glaucoma, glaucoma surgery, intraocular
pressure, mechanism
17.
Acknowledgment
The authors thank Teva for the opportunity to perform
this study in the Biological Laboratory of the Innovative
Research and Development Department.
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