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Effects of Apraclonidine on Intraocular Pressure and Blood-aqueous Barrier Permeability After Phacoemulsification and Intraocular Lens Implantation
Effects of Apraclonidine on Intraocular Pressure and Blood-aqueous Barrier Permeability After Phacoemulsification and Intraocular Lens Implantation Makoto Araie, M.D., and Kiyoshi Ishi, M.D. To evaluate the effect of topical apraclonidine on early postoperative intraocular pressure and blood-aqueous barrier permeability, we conducted a double-masked clinical trial in which 37 patients undergoing uncomplicated phacoemulsification and posterior chamber intraocular lens implantation were randomly assigned to treatment with 1% apraclonidine or its vehicle. One drop of 1 % apraclonidine or its vehicle was instilled tfz hour preoperatively and immediately postoperatively. In addition to intraocular pressure, aqueous Bare intensity was also determined before and after the operation by using a laser Bare-cell meter. In the apraclonidine group, intraocular pressure showed no significant postoperative increase, whereas it showed a significant increase at six hours in the vehicle group (P < .01). Difference between intraocular pressure recorded at the end of the operation with the Tone-Pen II and that measured postoperatively was significantly greater in the vehicle group by 3.5 to 7.0 mm Ug (P < .05 to .01). In the apraclonidine group, the aqueous Bare intensity was about half that in the vehicle group with significant differences at six (P < .05) and 24 (P < .01) hours. CATARACT EXTRACTION is often associated with marked postoperative increases in intraocular pressure .1-4 Profound postoperative increases in intraocular pressure are hazardous to visual function, especially in eyes with preexisting glaucomatous damage or compromised blood supply to the optic nerve head." In an attempt to
Accepted for publication March 29, 1993. From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan. Reprint requests to Makoto Araie, M.D., Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113, Japan.
©AMEJuCAN JOURNAL OF OPHTHALMOLOGY
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suppress the marked intraocular pressure increase after cataract extraction, many agents, including mloticsv'" and aqueous suppressants,":" have been studied, among which intracameral carbachol injection appears to be the most effective.v'" Pilocarpine, a muscarinic agonist, however, compromises the integrity of the blood-aqueous barrier." and thus carbachol, a long-acting muscarinic agonist, should probably be avoided to prevent postoperative inflammation. Furthermore, intracameral carbachol was reported to cause prolonged mioSiS,9,17 which would not be favorable in patients in whom a posterior chamber intraocular lens has been implanted and postoperative fibrin reaction is possible. Apraclonidine hydrochloride, a selective oc2 agonist, is a relatively new ocular hypotensive agent." Recently, a study disclosed that in addition to potent aqueous suppressant activity,I9 topical apraclonidine reduces blood-aqueous barrier permeability in healthy humans," which suggests the potential for a beneficial effect on postoperative inflammation and resulting intraocular pressure increase. Topical apraclonidine is known to prevent early intraocular pressure increases after anterior segment laser operations.t':" As for cataract extraction, Wiles, MacKenzie, and Ide24 found that preoperative topical apraclonidine reduced the early increase in intraocular pressure after planned extracapsular cataract extraction with posterior chamber intraocular lens implantation. However, we did not find published reports on the effect of topical apraclonidine on the postoperative intraocular pressure after phacoemulsification with posterior chamber intraocular lens implantation, a method now widely used for cataract extraction. Further, whether the effect of topical apraclonidine on reducing the permeability of the blood-aqueous barrier is the same in eyes on which cataract extraction has been performed as in normal eyes" is not known. 1993
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To determine the short-term effect of topical apraclonidine on the postoperative blood-aqueous barrier and intraocular pressure in eyes on which phacoemulsification and posterior chamber intraocular lens implantation have been performed, we performed a double-masked clinical study in which patients were randomly assigned to treatment with apraclonidine or its vehicle.
Patients and Methods Thirty-nine patients (24 women and 15 men) participated in our study. The average age was 67.7 ± 12.3 years. The patients had no history of ocular diseases, ocular operations, or systemic diseases except for mild hypertension. In 37 patients, only one eye was scheduled for cataract extraction and it was randomly assigned to the apraclonidine or vehicle group. In two patients scheduled for cataract extraction in both eyes, one randomly chosen eye was assigned to the apraclonidine group and the fellow eye to the vehicle group. The study was approved by the Ethics Committee of the University of Tokyo School of Medicine and informed consent was obtained from each patient after a full explanation. On the day before the operation between 5:00 and 6:00 P.M., the baseline intraocular pressure and aqueous flare intensity (flare value) were measured by using a Goldmann applanation tonometer and a laser flare-cell meter (Kowa Optical Co. Ltd., Tokyo, Japan), respectively. The capacity of the laser flare-cell meter to measure aqueous flare intensity has been described previously.16,20,25 The operation was performed between 9:00 A.M. and 12:00 noon. Except for apraclonidine or vehicle instillation, all patients underwent the same procedures. From two to 1/2 hours preoperatively, one drop of 0.5% tropicamide, one drop of 5% phenylephrine, and one drop 0.1 % diclofenac were instilled in four sets at 3D-minute intervals. Thirty minutes preoperatively, 50 J.LI of 1 % apraclonidine hydrochloride or the vehicle was instilled. After achieving a facial block according to a modified O'Brien's method (4.0 ml) and retrobulbar block (3.5 ml) with 2% mepivacaine with hyaluronidase, a Honan balloon set at 40.0 mm Hg was applied for five minutes. Uncomplicated phacoemulsification and implantation of a single-piece (diameter of optics, 6.0 mm) or a three-piece (diameter of optics, 6.5 mm) poster-
ior chamber intraocular lens were performed, using Balanced Salt Solution Plus that contained 0.00002 % epinephrine as an intraocular irrigating solution. Intracameral sodium hyaluronate was routinely used just before the start of phacoemulsification and intraocular lens implantation and was thoroughly aspirated before final closure of the limbal incision. Intracameral injection of 0.25 ml of 1% acetylcholine was routinely given to prompt miosis. The limbal incision was closed with a tight running shoelace suture with 10-0 nylon. The intraocular pressure at the end of the operation was measured by using the Tone-Pen 11, which was equipped with a sterilized tip cover. Intraocular pressure was adjusted to give a reading between 11.0 and 15.0 mm Hg if the first reading was not between 11.0 and 15.0 mm Hg. Before patching, 50 J.LI of 1 % apraclonidine was administered with a sterilized disposable applicator to the eyes assigned to apraclonidine treatment and 50 J.LI of vehicle that was sterilized by passing it through a Millipore filter was administered to the eyes assigned to vehicle treatment. Postoperative intraocular pressure and flare value were measured by using a Goldmann applanation tonometer and a laser flare-cell meter, respectively, at six, 24, and 30 hours postoperatively. In measuring the intraocular pressure, horizontal and vertical values were averaged. The patient, surgeon, and examiner of intraocular pressure and flare value were all masked to the apraclonidine or vehicle treatment.
Results Twenty-one eyes were assigned to the apraclonidine group and 20 eyes to the vehicle group. Between the two groups, no marked difference was seen in patient age, baseline intraocular pressure, baseline flare value, type of posterior chamber intraocular lens used, time needed for phacoemulsification, total volume of intraocular irrigating solution used, intraocular pressure measured at the end of the operation, or time needed for the whole procedure. In the apraclonidine group, the intraocular pressure showed no significant increase postoperatively, whereas a marked intraocular pressure increase was observed six hours postoperatively in the vehicle group (one-way analysis
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Apraclonidine and Cataract Extraction
Vol. 116, No. 1
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Fig, 1 (Araie and Ishi). Mean intraocular pressure
(± standard
deviation) before and after the operation in apraclonidine (closed circles) and vehicle (open circles) groups. 'Intraocular pressure was measured with the Tone-Pen II. tBetween-group difference was significant at P < .01. of variance and Dunnet test for multiple comparison) (Fig. 1). Six hours postoperatively, the intraocular pressure was higher by about 5.0 mm Hg in the vehicle group (Wilcoxon rank sum test, P < .01). Difference between the intraocular pressure recorded with the TonoPen II at the end of the operation and that recorded at six, 24, and 30 hours postoperatively was calculated. The difference was greater in the vehicle group than in the apraclonidine group by 7.0 (Wilcoxon rank sum test, P < .01), 3.9 (P < .05) and 3.5 mm Hg (P < .05) on the average at six, 24, and 30 hours postoperatively, respectively. Postoperatively, the flare value in the apraclonidine group was about half that in the vehicle group and the difference was significant at six (P < .05) and 24 hours (P < .01) (Fig. 2). No postoperative complications developed in any eye.
Discussion Given the necessary tight wound closure, the following factors may contribute to the early intraocular pressure increase after cataract extraction: outflow facility reduced by tissue edema, structural distortion caused by corneoscleral sutures," increased protein content in the postoperative aqueous," or viscoelastic material remaining in the anterior chamber." Change in the blood-aqueous barrier permeability caused by postoperative inflammation has also
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Fig. 2 (Araie and Ishi). Mean flare intensity (±
standard deviation) before and after the operation in apraclonidine (closed circles) and vehicle (open circles) groups. 'Between-group difference was significant at P < .05. tBetween-group difference was significant at P < .01. been suggested to be one of the contributing factors." In our study, effects of topical apraclonidine on the early postoperative intraocular pressure and aqueous flare intensity were investigated in patients who underwent uncomplicated phacoemulsification and posterior chamber intraocular lens implantation with the use of viscoelastic material and intracameral acetylcholine. As compared with extracapsular cataract extraction, phacoemulsification requires a much smaller incision and is reportedly associated with milder early postoperative intraocular pressure increase" and inflammation." Mean increase from the baseline intraocular pressure in the present vehicle-treated eye appeared to be smaller than those reported after extracapsular cataract extraction and posterior chamber lens implantation with the use of viscoelastic material and intracameral acetylcholine." The results of our study demonstrated that topical instillation of 1 % apraclonidine in eyes on which phacoemulsification was performed further reduced the early postoperative intraocular pressure increase, virtually preventing any increase. Further, topical apraclonidine halved the early postoperative increase in aqueous flare intensity, which roughly parallels aqueous protein concentration, Because the inhibitory effect of topical apraclonidine on aqueous flow per se should reduce the loss of aqueous protein from the anterior chamber and result in an increase in the aqueous protein concentration.P:" the net effect of topical apraclonidine on the post-
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operative aqueous protein concentration might be even greater. A study in: normal human eyes demonstrated that topical 0.5% apraclonidine reduced the blood-aqueous barrier permeability to plamsa protein by 20%.20 Most likely, this unique action of topical apraclonidine was responsible for the reduced increase in the postoperative aqueous protein concentration in our study. Although the exact mechanism by which apraclonidine reduces the permeability of the blood-aqueous barrier is not entirely understood, the results suggest that topical apraclonidine can be used with corticosteroids and noncorticosteroidal anti-inflammatory agents to reduce early postoperative inflammation and its associated complications. As for the effect on early postoperative intraocular pressure increase after cataract extraction, our results generally confirmed those of Wiles, Mackenzie, and Ide. 24 New information obtained in our study was as follows. We first demonstrated that topical apraclonidine could virtually prevent the early postoperative intraocular pressure increase in eyes on which phacoemulsification followed by posterior chamber intraocular lens implantation was performed, a now widely used method for cataract extraction. To prevent miosis during cataract extraction, preoperative instillation of a noncorticosteroidal anti-inflammatory agent is now routinely performed. However, a noncorticosteroid anti-inflammatory agent was not used in the study of Wiles, Mackenzie, and Ide,24 who were concerned with the possibility that preoperative use of a noncor ticosteroidaI antiinflammatory agent may affect the ocular effect of apraclonidine." In our study, preoperative instillation of a noncorticosteroidal anti-inflammatory agent was used because we wanted to estimate the effect of topical apraclonidine in eyes on which a current standard procedure for cataract extraction was performed. Topical apraclonidine was effective in eyes pretreated with a noncor ticosteroidaI anti-inflammatory agent. In one study immediate postoperative treatment with topical apraclonidine was not effective in reducing early postoperative intraocular pressure increase after cataract extraction." Conversely, previous studies have demonstrated that postoperative treatment with a topical ~-blocker reduced the range of early postoperative intraocular pressure increase after cataract extraction.P:" and another study demonstrated that immediate postoperative application of
apraclonidine after argon laser trabeculoplasty prevented intraocular pressure increase as effectively as its application both before and immediately after laser treatment." The proper effect to the preoperative or immediate postoperative treatment with apraclonidine will have to be elucidated in future studies. We found that preoperative and immediate postoperative treatment with topical apraclonidine reduced the early postoperative increase in the blood-aqueous barrier permeability by at least 50% and virtually prevented the early postoperative intraocular pressure increase in eyes on which uncomplicated phacoemulsification and posterior chamber intraocular lens implantation were performed. These effects of topical apraclonidine are thought to be especially beneficial in eyes with precompromised blood-aqueous barriers or those at risk for visualloss from high intraocular pressure, or both. ACKNOWLEDGMENT
Alcon Laboratories Co. (Ft. Worth, Texas) supplied 0.1 % apraclonidine ophthalmic solution and its vehicle.
References 1. Rich, W. J., Radtke, N. D., and Cohan, B. E.: Early ocular hypertension after cataract extraction. Br. J. Ophthalmol. 58:725, 1974. 2. Galin, M. A., Long-Kuanglin, L., and Obstbaum, S. A.: Cataract extraction and intraocular pressure. Trans. Ophthalmol. Soc. U.K. 98:124,1978. 3. Kooner, K. 5., Dulaney, D. D., and Zimmerman, T. J.: Intraocular pressure following extracapsular cataract extraction and posterior chamber intraocular lens implantation. Ophthalmic Surg. 19:471, 1988. 4. Gross, J. G., Meyer, D. R., Robin, A. L., Filar, A. A., and Kelley, J. 5.: Increased intraocular pressure in the immediate postoperative period after extracapsular cataract extraction. Am. J. Ophthalmol. 105:466, 1988. 5. Hayreh, S. 5.: Anterior ischemic optic neuropathy. IV. Occurrence after cataract extraction. Arch. Ophthalmol. 98:1410, 1980. 6. Ruiz, R. 5., Wilson, C. A., Musgrove, K. H., and Prager, T. c.: Management of increased intraocular pressure after cataract extraction. Am. J. Ophthalmol. 103:487, 1987. 7. Hollands, R. H., Drance, S. M., and Schulzer. M.: The effect of acetylcholine on early postoperative intraocular pressure. Am. J. Ophthalmol. 103:749, 1987. 8. - - : The effect of intracameral carbachol on
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intraocular pressure after cataract extraction. Am. J. Ophthalmol. 104:225, 1987. 9. Woods, O. T.: Effect of carbachol on postoperative intraocular pressure. J. Cataract Refract. Surg. 14:654, 1988. 10. Ruiz, S. R., Rhem, M. N., and Prager, T. c.: Effects of carbachol and acetylcholine on intraocular pressure after cataract extraction. Am. J. Ophthalmol. 107:7, 1989. 11. Rich, W. J. C. C.: Further studies on early postoperative ocular hypertension following cataract extraction. Trans. Ophthalmol. Soc. U.K. 89:639,1969. 12. Obstbaum, S. A., and Galin, M. A.: The effects of timolol on cataract extraction and intraocular pressure. Am. J. Ophthalmol. 88:1017, 1979. 13. Haimann, M. H., and Phelps, C. D.: Prophylactic timolol for the prevention of high intraocular pressure after cataract extraction. A randomized, prospective, double-blind trial. Ophthalmology 88:233,1981. 14. Packer, A. J., Fraioli, A. J., and Epstein, D. 1.: The effect of timolol and acetazolamide on transient intraocular pressure elevation following cataract extraction with alpha-chymotrypsin. Ophthalmology 88:239,1981. 15. West, D. R., Lischwe, T. D., Thompson, V. M., and Ide, C. H.: Comparative efficacy of the ers for the prevention of increased intraocular pressure after cataract extraction. Am. J. Ophthalmol. 106:168,1988. 16. Mori, M., Araie, M., Sakurai, M., and Oshika, T.: Effects of pilocarpine and tropicamide on bloodaqueous barrier permeability in man. Invest. Ophthalmol. Vis. Sci. 33:416, 1992. 17. Beasley, H.: Miotics in cataract surgery. Arch. Ophthalmol. 88:49, 1972. 18. Abrams, D. A., Robin, A. 1., Pollack, I. P., deFaller, J. M., and DeSantis, L.: The safety and efficacy of topical 1 % ALO 2145 (p-aminoclonidine hydrochloride) in normal volunteers. Arch. Ophthalmol. 105:1205,1987. 19. Gharagozloo, N. Z., ReIf, S. J., and Brubaker, R. F.: Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology 95:1217,1988. 20. Mori, M., and Araie, M.: Effect Qf apraclonidine on blood-aqueous barrier permeability to plasma protein in man. Exp. Eye Res. 54:555, 1992. 21. Robin, A. 1., Pollack, I. P., and deFaller, J. M.: Effects of topical ALO 2145 (p-aminoclonidine hydrochloride) on the acute intraocular pressure rise after argon laser iridotomy. Arch. Ophthalmol. 105:1208,1987.
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22. Pollack, I. P., Brown, R. H., Crandall, A. 5., Robin, A. 1., Stewart, R. H., and White, G. L.: Prevention of the rise in intraocular pressure follOWing neodymium-YAG posterior capsulotomy using topicall % apraclonidine. Arch. Ophthalmol. 106:754, 1988. 23. Brown, R. H., Stewart, R. H., Lynch, M. G., Crandall, A. 5., Mandell, A. I., Wilensky, J. T., deFaller, J. M., and Higginbotham, E. J.: ALO 2145 reduces the intraocular pressure elevation after anterior segment laser surgery. Ophthalmology 95:378, 1988. 24. Wiles, S. B., MacKenzie, D., and Ide, C. H.: Control of intraocular pressure with apraclonidine hydrochloride after cataract extraction. Am. J. Ophthalmol. 111:184, 1991. 25. Sawa, M., Tsurumaki, Y., Tsuru, T., and Shimizu, H.: New quantitative method to determine protein concentration and cell number in aqueous in vivo. Jpn. J. OphthalmoI. 32:132, 1988. 26. Rothkoff, 1., Biedner, B., and Blumenthal, M.: The effect of corneal section on early increased intraocular pressure after cataract extraction. Am. J. Ophthalmol. 85:337, 1978. 27. Epstein, D. 1., Hashimoto, J. M., and Grant, W. M.: Serum obstruction of aqueous outflow in enucleated eyes. Am J. Ophthalmol. 86:101, 1978. 28. Glasser, D. B., Matsuda, M., and Edelhauser, H. F.: A comparison of the efficacy and toxicity of and intraocular pressure response to viscous solutions in the anterior chamber. Arch. Ophthalmol. 104:1819, 1986. 29. Sears, D., and Sears, M.: Blood-aqueous barrier and alpha-chymotrypsin glaucoma in rabbits. Am. J. Ophthalmol. 77:378, 1974. 30. Oshika, T., Yoshimura, K., and Miyata, N.: Postsurgical inflammation after phacoemulsification and extracapsular extraction with soft or conventional intraocular lens implantation. J. Cataract Refract. Surg. 18:356, 1992. 31. Wang, R. F., Camras, C. B., Podos, S. M., Lee, K. W., Bhuyan, K. C., and Bhuyan, D. K.: The role of prostaglandins in the para-aminoclonidine-induced reduction of intraocular pressure. Trans. Am. Ophthalmol. Soc. 87:94, 1990. 32. Holmwood, P. c., Chase, R. D., Krupin, T., Rosenberg, 1. F., Ruderman, J. M., Tallman, B. A., Brodstein, D. E., Chopra, H., and Goldenfeld, M.: Apraclonidine and argon laser trabeculoplasty. Am. J. Ophthalmol. 114:19, 1992.
Accepted for publication March 29, 1993. From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan. Reprint requests to Makoto Araie, M.D., Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113, Japan.
©AMEJuCAN JOURNAL OF OPHTHALMOLOGY
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JULY,
suppress the marked intraocular pressure increase after cataract extraction, many agents, including mloticsv'" and aqueous suppressants,":" have been studied, among which intracameral carbachol injection appears to be the most effective.v'" Pilocarpine, a muscarinic agonist, however, compromises the integrity of the blood-aqueous barrier." and thus carbachol, a long-acting muscarinic agonist, should probably be avoided to prevent postoperative inflammation. Furthermore, intracameral carbachol was reported to cause prolonged mioSiS,9,17 which would not be favorable in patients in whom a posterior chamber intraocular lens has been implanted and postoperative fibrin reaction is possible. Apraclonidine hydrochloride, a selective oc2 agonist, is a relatively new ocular hypotensive agent." Recently, a study disclosed that in addition to potent aqueous suppressant activity,I9 topical apraclonidine reduces blood-aqueous barrier permeability in healthy humans," which suggests the potential for a beneficial effect on postoperative inflammation and resulting intraocular pressure increase. Topical apraclonidine is known to prevent early intraocular pressure increases after anterior segment laser operations.t':" As for cataract extraction, Wiles, MacKenzie, and Ide24 found that preoperative topical apraclonidine reduced the early increase in intraocular pressure after planned extracapsular cataract extraction with posterior chamber intraocular lens implantation. However, we did not find published reports on the effect of topical apraclonidine on the postoperative intraocular pressure after phacoemulsification with posterior chamber intraocular lens implantation, a method now widely used for cataract extraction. Further, whether the effect of topical apraclonidine on reducing the permeability of the blood-aqueous barrier is the same in eyes on which cataract extraction has been performed as in normal eyes" is not known. 1993
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To determine the short-term effect of topical apraclonidine on the postoperative blood-aqueous barrier and intraocular pressure in eyes on which phacoemulsification and posterior chamber intraocular lens implantation have been performed, we performed a double-masked clinical study in which patients were randomly assigned to treatment with apraclonidine or its vehicle.
Patients and Methods Thirty-nine patients (24 women and 15 men) participated in our study. The average age was 67.7 ± 12.3 years. The patients had no history of ocular diseases, ocular operations, or systemic diseases except for mild hypertension. In 37 patients, only one eye was scheduled for cataract extraction and it was randomly assigned to the apraclonidine or vehicle group. In two patients scheduled for cataract extraction in both eyes, one randomly chosen eye was assigned to the apraclonidine group and the fellow eye to the vehicle group. The study was approved by the Ethics Committee of the University of Tokyo School of Medicine and informed consent was obtained from each patient after a full explanation. On the day before the operation between 5:00 and 6:00 P.M., the baseline intraocular pressure and aqueous flare intensity (flare value) were measured by using a Goldmann applanation tonometer and a laser flare-cell meter (Kowa Optical Co. Ltd., Tokyo, Japan), respectively. The capacity of the laser flare-cell meter to measure aqueous flare intensity has been described previously.16,20,25 The operation was performed between 9:00 A.M. and 12:00 noon. Except for apraclonidine or vehicle instillation, all patients underwent the same procedures. From two to 1/2 hours preoperatively, one drop of 0.5% tropicamide, one drop of 5% phenylephrine, and one drop 0.1 % diclofenac were instilled in four sets at 3D-minute intervals. Thirty minutes preoperatively, 50 J.LI of 1 % apraclonidine hydrochloride or the vehicle was instilled. After achieving a facial block according to a modified O'Brien's method (4.0 ml) and retrobulbar block (3.5 ml) with 2% mepivacaine with hyaluronidase, a Honan balloon set at 40.0 mm Hg was applied for five minutes. Uncomplicated phacoemulsification and implantation of a single-piece (diameter of optics, 6.0 mm) or a three-piece (diameter of optics, 6.5 mm) poster-
ior chamber intraocular lens were performed, using Balanced Salt Solution Plus that contained 0.00002 % epinephrine as an intraocular irrigating solution. Intracameral sodium hyaluronate was routinely used just before the start of phacoemulsification and intraocular lens implantation and was thoroughly aspirated before final closure of the limbal incision. Intracameral injection of 0.25 ml of 1% acetylcholine was routinely given to prompt miosis. The limbal incision was closed with a tight running shoelace suture with 10-0 nylon. The intraocular pressure at the end of the operation was measured by using the Tone-Pen 11, which was equipped with a sterilized tip cover. Intraocular pressure was adjusted to give a reading between 11.0 and 15.0 mm Hg if the first reading was not between 11.0 and 15.0 mm Hg. Before patching, 50 J.LI of 1 % apraclonidine was administered with a sterilized disposable applicator to the eyes assigned to apraclonidine treatment and 50 J.LI of vehicle that was sterilized by passing it through a Millipore filter was administered to the eyes assigned to vehicle treatment. Postoperative intraocular pressure and flare value were measured by using a Goldmann applanation tonometer and a laser flare-cell meter, respectively, at six, 24, and 30 hours postoperatively. In measuring the intraocular pressure, horizontal and vertical values were averaged. The patient, surgeon, and examiner of intraocular pressure and flare value were all masked to the apraclonidine or vehicle treatment.
Results Twenty-one eyes were assigned to the apraclonidine group and 20 eyes to the vehicle group. Between the two groups, no marked difference was seen in patient age, baseline intraocular pressure, baseline flare value, type of posterior chamber intraocular lens used, time needed for phacoemulsification, total volume of intraocular irrigating solution used, intraocular pressure measured at the end of the operation, or time needed for the whole procedure. In the apraclonidine group, the intraocular pressure showed no significant increase postoperatively, whereas a marked intraocular pressure increase was observed six hours postoperatively in the vehicle group (one-way analysis
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69
Apraclonidine and Cataract Extraction
Vol. 116, No. 1
L 1-----1
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24
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30
Hours after surgery
Fig, 1 (Araie and Ishi). Mean intraocular pressure
(± standard
deviation) before and after the operation in apraclonidine (closed circles) and vehicle (open circles) groups. 'Intraocular pressure was measured with the Tone-Pen II. tBetween-group difference was significant at P < .01. of variance and Dunnet test for multiple comparison) (Fig. 1). Six hours postoperatively, the intraocular pressure was higher by about 5.0 mm Hg in the vehicle group (Wilcoxon rank sum test, P < .01). Difference between the intraocular pressure recorded with the TonoPen II at the end of the operation and that recorded at six, 24, and 30 hours postoperatively was calculated. The difference was greater in the vehicle group than in the apraclonidine group by 7.0 (Wilcoxon rank sum test, P < .01), 3.9 (P < .05) and 3.5 mm Hg (P < .05) on the average at six, 24, and 30 hours postoperatively, respectively. Postoperatively, the flare value in the apraclonidine group was about half that in the vehicle group and the difference was significant at six (P < .05) and 24 hours (P < .01) (Fig. 2). No postoperative complications developed in any eye.
Discussion Given the necessary tight wound closure, the following factors may contribute to the early intraocular pressure increase after cataract extraction: outflow facility reduced by tissue edema, structural distortion caused by corneoscleral sutures," increased protein content in the postoperative aqueous," or viscoelastic material remaining in the anterior chamber." Change in the blood-aqueous barrier permeability caused by postoperative inflammation has also
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,
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Fig. 2 (Araie and Ishi). Mean flare intensity (±
standard deviation) before and after the operation in apraclonidine (closed circles) and vehicle (open circles) groups. 'Between-group difference was significant at P < .05. tBetween-group difference was significant at P < .01. been suggested to be one of the contributing factors." In our study, effects of topical apraclonidine on the early postoperative intraocular pressure and aqueous flare intensity were investigated in patients who underwent uncomplicated phacoemulsification and posterior chamber intraocular lens implantation with the use of viscoelastic material and intracameral acetylcholine. As compared with extracapsular cataract extraction, phacoemulsification requires a much smaller incision and is reportedly associated with milder early postoperative intraocular pressure increase" and inflammation." Mean increase from the baseline intraocular pressure in the present vehicle-treated eye appeared to be smaller than those reported after extracapsular cataract extraction and posterior chamber lens implantation with the use of viscoelastic material and intracameral acetylcholine." The results of our study demonstrated that topical instillation of 1 % apraclonidine in eyes on which phacoemulsification was performed further reduced the early postoperative intraocular pressure increase, virtually preventing any increase. Further, topical apraclonidine halved the early postoperative increase in aqueous flare intensity, which roughly parallels aqueous protein concentration, Because the inhibitory effect of topical apraclonidine on aqueous flow per se should reduce the loss of aqueous protein from the anterior chamber and result in an increase in the aqueous protein concentration.P:" the net effect of topical apraclonidine on the post-
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AMERICAN JOURNAL OF OPHTHALMOLOGY
operative aqueous protein concentration might be even greater. A study in: normal human eyes demonstrated that topical 0.5% apraclonidine reduced the blood-aqueous barrier permeability to plamsa protein by 20%.20 Most likely, this unique action of topical apraclonidine was responsible for the reduced increase in the postoperative aqueous protein concentration in our study. Although the exact mechanism by which apraclonidine reduces the permeability of the blood-aqueous barrier is not entirely understood, the results suggest that topical apraclonidine can be used with corticosteroids and noncorticosteroidal anti-inflammatory agents to reduce early postoperative inflammation and its associated complications. As for the effect on early postoperative intraocular pressure increase after cataract extraction, our results generally confirmed those of Wiles, Mackenzie, and Ide. 24 New information obtained in our study was as follows. We first demonstrated that topical apraclonidine could virtually prevent the early postoperative intraocular pressure increase in eyes on which phacoemulsification followed by posterior chamber intraocular lens implantation was performed, a now widely used method for cataract extraction. To prevent miosis during cataract extraction, preoperative instillation of a noncorticosteroidal anti-inflammatory agent is now routinely performed. However, a noncorticosteroid anti-inflammatory agent was not used in the study of Wiles, Mackenzie, and Ide,24 who were concerned with the possibility that preoperative use of a noncor ticosteroidaI antiinflammatory agent may affect the ocular effect of apraclonidine." In our study, preoperative instillation of a noncorticosteroidal anti-inflammatory agent was used because we wanted to estimate the effect of topical apraclonidine in eyes on which a current standard procedure for cataract extraction was performed. Topical apraclonidine was effective in eyes pretreated with a noncor ticosteroidaI anti-inflammatory agent. In one study immediate postoperative treatment with topical apraclonidine was not effective in reducing early postoperative intraocular pressure increase after cataract extraction." Conversely, previous studies have demonstrated that postoperative treatment with a topical ~-blocker reduced the range of early postoperative intraocular pressure increase after cataract extraction.P:" and another study demonstrated that immediate postoperative application of
apraclonidine after argon laser trabeculoplasty prevented intraocular pressure increase as effectively as its application both before and immediately after laser treatment." The proper effect to the preoperative or immediate postoperative treatment with apraclonidine will have to be elucidated in future studies. We found that preoperative and immediate postoperative treatment with topical apraclonidine reduced the early postoperative increase in the blood-aqueous barrier permeability by at least 50% and virtually prevented the early postoperative intraocular pressure increase in eyes on which uncomplicated phacoemulsification and posterior chamber intraocular lens implantation were performed. These effects of topical apraclonidine are thought to be especially beneficial in eyes with precompromised blood-aqueous barriers or those at risk for visualloss from high intraocular pressure, or both. ACKNOWLEDGMENT
Alcon Laboratories Co. (Ft. Worth, Texas) supplied 0.1 % apraclonidine ophthalmic solution and its vehicle.
References 1. Rich, W. J., Radtke, N. D., and Cohan, B. E.: Early ocular hypertension after cataract extraction. Br. J. Ophthalmol. 58:725, 1974. 2. Galin, M. A., Long-Kuanglin, L., and Obstbaum, S. A.: Cataract extraction and intraocular pressure. Trans. Ophthalmol. Soc. U.K. 98:124,1978. 3. Kooner, K. 5., Dulaney, D. D., and Zimmerman, T. J.: Intraocular pressure following extracapsular cataract extraction and posterior chamber intraocular lens implantation. Ophthalmic Surg. 19:471, 1988. 4. Gross, J. G., Meyer, D. R., Robin, A. L., Filar, A. A., and Kelley, J. 5.: Increased intraocular pressure in the immediate postoperative period after extracapsular cataract extraction. Am. J. Ophthalmol. 105:466, 1988. 5. Hayreh, S. 5.: Anterior ischemic optic neuropathy. IV. Occurrence after cataract extraction. Arch. Ophthalmol. 98:1410, 1980. 6. Ruiz, R. 5., Wilson, C. A., Musgrove, K. H., and Prager, T. c.: Management of increased intraocular pressure after cataract extraction. Am. J. Ophthalmol. 103:487, 1987. 7. Hollands, R. H., Drance, S. M., and Schulzer. M.: The effect of acetylcholine on early postoperative intraocular pressure. Am. J. Ophthalmol. 103:749, 1987. 8. - - : The effect of intracameral carbachol on
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intraocular pressure after cataract extraction. Am. J. Ophthalmol. 104:225, 1987. 9. Woods, O. T.: Effect of carbachol on postoperative intraocular pressure. J. Cataract Refract. Surg. 14:654, 1988. 10. Ruiz, S. R., Rhem, M. N., and Prager, T. c.: Effects of carbachol and acetylcholine on intraocular pressure after cataract extraction. Am. J. Ophthalmol. 107:7, 1989. 11. Rich, W. J. C. C.: Further studies on early postoperative ocular hypertension following cataract extraction. Trans. Ophthalmol. Soc. U.K. 89:639,1969. 12. Obstbaum, S. A., and Galin, M. A.: The effects of timolol on cataract extraction and intraocular pressure. Am. J. Ophthalmol. 88:1017, 1979. 13. Haimann, M. H., and Phelps, C. D.: Prophylactic timolol for the prevention of high intraocular pressure after cataract extraction. A randomized, prospective, double-blind trial. Ophthalmology 88:233,1981. 14. Packer, A. J., Fraioli, A. J., and Epstein, D. 1.: The effect of timolol and acetazolamide on transient intraocular pressure elevation following cataract extraction with alpha-chymotrypsin. Ophthalmology 88:239,1981. 15. West, D. R., Lischwe, T. D., Thompson, V. M., and Ide, C. H.: Comparative efficacy of the ers for the prevention of increased intraocular pressure after cataract extraction. Am. J. Ophthalmol. 106:168,1988. 16. Mori, M., Araie, M., Sakurai, M., and Oshika, T.: Effects of pilocarpine and tropicamide on bloodaqueous barrier permeability in man. Invest. Ophthalmol. Vis. Sci. 33:416, 1992. 17. Beasley, H.: Miotics in cataract surgery. Arch. Ophthalmol. 88:49, 1972. 18. Abrams, D. A., Robin, A. 1., Pollack, I. P., deFaller, J. M., and DeSantis, L.: The safety and efficacy of topical 1 % ALO 2145 (p-aminoclonidine hydrochloride) in normal volunteers. Arch. Ophthalmol. 105:1205,1987. 19. Gharagozloo, N. Z., ReIf, S. J., and Brubaker, R. F.: Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology 95:1217,1988. 20. Mori, M., and Araie, M.: Effect Qf apraclonidine on blood-aqueous barrier permeability to plasma protein in man. Exp. Eye Res. 54:555, 1992. 21. Robin, A. 1., Pollack, I. P., and deFaller, J. M.: Effects of topical ALO 2145 (p-aminoclonidine hydrochloride) on the acute intraocular pressure rise after argon laser iridotomy. Arch. Ophthalmol. 105:1208,1987.
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