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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 Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017 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 Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017 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 HJ - //ft 40 35 30 • 2 25- E E ST 20 • D 15 105 • »XjL Tl 4F r e e z e T h a w I i i n . t e r V a I F W r e e z e T h a w t [\ *1 i 4 n t e r F r e e z e V a I \V n * T h a w JV J 1 t e r i V a 1 F r e e z e 1 1 T 1 T h a w 1 PI e v a 1 0 0 100 200 300 400 500 600 700 800 Time (sec) FIGURE 3. Representative intraocular pressure measurements during cyclocryotherapy on a rabbit normal eye. Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017 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) Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017 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- Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017 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. 6. 7. 8. 9. 10. 11. 12. 13. 14. 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. References 1. Bietti G. Surgical intervention on the ciliary body./ AmMedAssoc. 1950; 142:889-897. 2. DeRoetth AJr. Cryosurgery for treatment of advanced 18. 19. 20. chronic simple glaucoma. Am J Ophthalmol. 1968; 66:1034-1041. Bellows AR, Grant WM. Cyclocryotherapy in advanced inadequately controlled glaucoma. Am J Ophthalmol. 1973; 73:679-684. Feibel RM, Bigger JF. Rubeosis iridis and neovascular glaucoma. Evaluation of cyclocryotherapy. AmJ Ophthalmol. 1972; 74:862-867. Krupin T, Mitchell KB, Becker B. Cyclocryotherapy in neovascular glaucoma. Am J Ophthalmol. 1978;86:24-26. Caprioli J, Strang S, Speath GL, Poryzees EH. Cyclocryotherapy in the treatment of advanced glaucoma. Ophthalmology. 1985; 92:947-954. Caprioli J, Sears M. Regulation of intraocular pressure during cyclocryotherapy for advanced glaucoma. Am J Ophthalmol. 1986; 101:542-545. Carslaw HS, Jaeger JC. Conduction ofHeat in Solids. 2nd ed. Oxford: Clarendon Press; 1959. Gebhart B. Heat Conduction and Mass Diffusion. New York: McGraw-Hill; 1993. Williams GC, Smith KA. Transmission of heat by conduction and convection. In: Avallone EA, Baumeister T III, eds. Marks' Standard Handbook for Mechanical Engineers. 9th ed. New York: McGraw-Hill; 1987:4.794.91. Lide DR, ed. CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton: CRC Press; 1994:6.10,6.249,12.165. 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Friedenwald JS. Contribution to the theory and practice of tonometry. AmJ Ophthalmol. 1937; 20:985-1024. Collins R, van der Werff TJ. Mathematical Models of the Dynamics of the Human Eye. Berlin: Springer; 1980:3,9,42. Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933200/ on 05/12/2017