Viscoanesthesia Part II: Toxicity to intraocular structures after phacoemulsification in a rabbit model Tamer A. Macky, MD, Liliana Werner, MD, PhD, David J. Apple, MD, Andrea M. Izak, MD, Suresh K. Pandey, MD, Rupal H. Trivedi, MD
Purpose: To investigate the toxicity of a solution that combines sodium hyaluronate 1.5% with lidocaine (0.5%, 1.0%, or 1.65%) to intraocular structures. Setting: Center for Research on Ocular Therapeutics and Biodevices, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA. Methods: Phacoemulsification was performed in both eyes of 29 rabbits. They were divided into 3 groups; in each group (n ⫽ 7), 1 viscoanesthetic solution was used before capsulorhexis. After irrigation/aspiration, 0.2 mL of the solution was purposely left in the capsular bag. In 1 rabbit in each group, the solution was injected into the vitreous cavity through a posterior capsulorhexis. In 8 rabbits used as controls, balanced salt solution (BSS姞) (n ⫽ 4) or sodium hyaluronate 1.5% (n ⫽ 4) was injected into the vitreous cavity. Enucleations were performed 15, 30, and 60 days postoperatively. Histological sections were cut and stained with hematoxylin-eosin, periodic acid-Schiff, and Masson trichrome stains. Results: Light microscopic evaluation of the eyes enucleated after 15, 30, and 60 days in the study and control groups showed similar findings in intraocular structures such as the ciliary body and retina. No evidence of an inflammatory reaction, cell necrosis, or cell degeneration was observed in the histological sections. Conclusions: The use of viscoanesthesia during phacoemulsification appeared to be safe, with no histologic abnormalities observed with the 3 lidocaine concentrations. The efficacy of the anesthetic effects of these solutions will be addressed in clinical trials. J Cataract Refract Surg 2003; 29:556 –562 © 2003 ASCRS and ESCRS
ills and coauthors1 were the first to introduce the concept of using intracameral lidocaine as an adjunct to topical anesthesia during cataract surgery. Since their 1995 report, several studies have looked at the efficacy and safety of intracameral lidocaine and other anesthetic agents in their effect on the corneal endothelium, aqueous flare and cells, and retinal photoreceptor cells.2–15 Most clinical studies suggest that the use of up to 0.5 mL of unpreserved lidocaine 1% intracamerally is safe.5,6,8 Anderson et al.8 report that irrigation during phacoemulsification provides a washout effect and thereby limits the exposure of ocular tissues to lidocaine. In par-
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© 2003 ASCRS and ESCRS Published by Elsevier Science Inc.
ticular, intracameral lidocaine injections occur in most surgeries after the use of an ophthalmic viscosurgical device (OVD) to maintain the anterior chamber, allowing the corneal endothelium to be coated with the OVD, which will prevent direct contact with the lidocaine. Ciba Vision Corp. recently developed a solution combining an OVD with lidocaine. The use of a new formulation of intraocular solutions raises the possibility of deleterious effects on intraocular structures. Incorporating lidocaine into an OVD could theoretically increase the risk for toxicity to ocular structures by allowing direct contact between lidocaine and 0886-3350/03/$–see front matter doi:10.1016/S0886-3350(02)01603-6
LABORATORY SCIENCE: TOXICITY OF VISCOANESTHETIC AGENT TO INTRAOCULAR STRUCTURES
Table 1. Distribution of rabbit eyes in the study and control groups that had phacoemulsification with and without a purposely ruptured posterior capsule. Lidocaine Concentration
Control
0.50%
1%
1.65%
BSS
Ophthalin Plus
PC Perforation
PC Perforation
PC Perforation
PC Perforation
PC Perforation
Enucleation (D)
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
15
2
2
2
2
2
2
1
1
1
1
30
2
2
2
2
2
2
1
1
1
1
60
2
2
2
2
2
2
1
1
1
1
D ⫽ days; PC ⫽ posterior capsule
these structures and by prolonging the duration of contact. The effect of viscoanesthetic solutions on corneal endothelial cells was evaluated in Part I of this study.16 In Part II, the effect of a solution combining sodium hyaluronate 1.5% with 3 concentrations of lidocaine (0.5%, 1%, and 1.65%) on intraocular structures was assessed. Histological analyses of ocular structures of rabbit eyes, ie, the iris, lens capsular bag, ciliary body, and retina, were performed at various times after intraocular injection of the solutions. As complete removal is important in preventing the potential toxic effects of residual solutions, ease of removal of the viscoanesthetic solutions is addressed in Part III.17
Materials and Methods Twenty-nine Dutch Belted, pigmented rabbits weighing 2.0 to 2.5 kg were used in this study. The care and treatment of animals conformed to the ARVO Statement for Use of Accepted for publication July 3, 2002. From the Center for Research on Ocular Therapeutics and Biodevices, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
Animals in Ophthalmic and Vision Research. Phacoemulsification was performed in both eyes of the 29 rabbits. In 21 rabbits, 1 viscoanesthetic solution was used during the procedure (7 rabbits or 14 eyes/solution): sodium hyaluronate 1.5%–lidocaine 0.5%; sodium hyaluronate 1.5%–lidocaine 1.0%; or sodium hyaluronate 1.5%–lidocaine 1.65%. In 4 rabbits (8 eyes), balanced salt solution (BSS威) was used as a control. In the other 4 rabbits, sodium hyaluronate 1.5% without lidocaine was used as a control. The sodium hyaluronate 1.5% solution used in all groups was Ophthalin Plus威.
Surgical Procedure Tables 1 and 2 show the distribution of rabbit eyes according to the solutions and surgical technique. The basic surgical technique was as follows: The rabbits were anesthetized with an intramuscular injection of xylazine (5 to 8 mg/kg) and ketamine hydrochloride (35 to 44 mg/Kg). After the pupils were dilated with tropicamide and phenylephrine 10% eyedrops, a 3.2 mm limbal incision was performed at 12 o’clock with a precalibrated keratome. The anterior chamber was entered, and 1 to 2 mL of heparin (10,000 units/mL) were injected into the anterior chamber. This is required to control the intraocular fibrin formation usually seen in this animal. Table 2. Distribution of rabbit eyes in the study and control groups that had phacoemulsification with an intravitreous injection of the BSS or Ophthalin Plus viscoanesthetic solution.
Presented in part at the Symposium on Cataract, IOL and Refractive Surgery, Philadelphia, Pennsylvania, USA, June 2002. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, USA. None of the authors has a financial or proprietary interest in any product mentioned. Reprint requests to Liliana Werner, MD, PhD, John A. Moran Eye Center, 5th Floor, 50 North Medical Drive, Salt Lake City, Utah 84132, USA. E-mail:
[email protected].
Lidocaine Concentration
Control
Enucleation (D)
0.50%
1%
1.65%
BSS
Ophthalin Plus
15
0
0
0
0
0
30
0
0
0
0
0
60
2
2
2
2
2
D ⫽ days; PC ⫽ posterior capsule
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The OVD/viscoanesthetic solution was injected into the anterior chamber and also behind the iris (according to the indications of the manufacturer). A 5.0 mm capsulorhexis was performed with a Utrata forceps (Katena Products Inc.), followed by hydrodissection and phacoemulsification/aspiration. In the control rabbits (n ⫽ 8), the capsulorhexis was performed under Ophthalin Plus. After complete evacuation of the capsular bag, 0.2 mL of the viscoanesthetic solution (or BSS in 8 control eyes and Ophthalin Plus in the other 8 control eyes) was injected into the capsular bag. The limbal incision was closed with a single 10-0 nylon suture. A subconjunctival injection of dexamethasone and gentamicin was given at the end of the procedure. Part A. In 24 rabbits (48 eyes), the right eye was operated on as described above. The left eye had the same procedure except that the posterior capsule was intentionally perforated before the viscoanesthetic solution (or BSS or Ophthalin Plus) was injected into the capsular bag. Part B. A separate group of 5 rabbits had the same procedure. After the posterior capsule in all 10 eyes was ruptured, the same amount of viscoanesthetic solution (or BSS or Ophthalin Plus) was injected into the vitreous cavity. Injection of solutions into the capsular bag after posterior capsule perforation (A) and direct intravitreal injection (B) were purposely done to analyze possible retinal toxicity secondary to retained viscoanesthetic solutions. The postoperative topical therapy included eye ointment containing dexamethasone, polymyxin B, and neomycin once a day for 2 weeks and cyclopentolate eyedrops once a day for 1 week. Slitlamp examinations were performed weekly to evaluate the presence of corneal edema and inflammatory reaction in the anterior chamber.
flammatory reactions with cells and flare in the anterior chamber and corneal edema: 1 eye in the 0.5% viscoanesthesia group, 4 eyes in the 1% viscoanesthesia group, 2 eyes in the 1.65% viscoanesthesia group, and 2 eyes in the Ophthalin Plus group. No eye in the BSS group showed signs of moderate to severe inflammation. In most of these eyes, the inflammatory reaction and corneal edema resolved in the second postoperative week. Only 3 eyes developed permanent corneal opacities. The other rabbit eyes (n ⫽ 49) presented a mild inflammatory reaction in the first 2 days that resolved by the end of the first week, leaving minimal posterior synechias in some cases. These eyes remained clinically quiet during the follow-up. Histopathologically, no eye in the study or control group showed signs of toxicity. Light microscopy examination of multiple sections from each eye showed normal iris tissue, ciliary body epithelium, lens epithelium, and neurosensory retina. No differences were found among the various groups at 15, 30, and 60 days (Figures 1 to 3). Also, there was no difference in the appearance of the neurosensory retina between eyes that received intravitreal injections of the viscoanesthetic solutions and those that received only in-the-bag injections (with and without posterior capsule perforation).
Histopathological Examination Part A. After intramuscular anesthesia, 2 rabbits from each viscoanesthetic group were killed with an intravenous (IV) injection of pentobarbital at 15, 30, and 60 days. Two rabbits from the control group (1 in the BSS group and 1 in the Ophthalin Plus group) were killed at each time. Part B. One rabbit from each viscoanesthetic group and 2 rabbits from the control group (1 in the BSS group and 1 in the Ophthalin Plus group) were killed with an IV injection of pentobarbital at 60 days. After enucleation, all eyes were prepared for histological evaluation. Histological sections were stained with hematoxylin-eosin, periodic acid-Schiff (PAS), and Masson trichome stains. Analyses focused on the presence of possible inflammatory reactions in structures such as the iris, lens capsular bag, ciliary body, and retina, as well as signs of cell necrosis or degeneration.
Results All the surgery was uneventful. In the first postoperative week, 9 rabbit eyes had moderate to severe in558
Discussion The most important development in cataract surgery anesthesia in the past decade has been the introduction of topical anesthesia, which is increasing in popularity. Topical anesthesia is the preferred technique of cataract surgeons in the United States (56%) according to a recent survey.18 The survey reveals that as many as 80% of respondents using topical anesthesia prefer eyedrops in association with intracameral injection of lidocaine.18 This has been catalyzed by the advent of clear corneal phacoemulsification and small-incision cataract surgery with implantation of foldable IOLs.19 –21 Although topical eyedrop anesthesia alone has been shown to be safe and effective, various investigators have documented an increase in patients’ subjective experience of pain during parts of the surgery that involve iris manipulation, globe expansion, and intraocular lens im-
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Figure 1. (Macky) Photomicrographs from the ciliary body (left) and retina (right) of rabbit eyes in the BSS and 1% viscoanesthesia groups. Both rabbits had the posterior capsule purposely ruptured during the procedure and were killed 15 days postoperatively (PAS stain; original magnification ⫻100 and ⫻200).
Figure 2. (Macky) Photomicrographs from the ciliary body (left) and retina (right) of rabbit eyes in the BSS and 1% viscoanesthesia groups. Both rabbits were killed 30 days postoperatively (PAS stain; original magnification ⫻100 and ⫻200).
plantation.3,10,11 Topically applied agents block the trigeminal nerve endings in the cornea and, to a less extent, the conjunctiva. The analgesic effect on the iris and ciliary body depends on penetration of the anesthetic agent into the anterior chamber. Bellucci et al.15 show that topical lidocaine 4% eyedrop administration results in intracameral penetration that increases with the number of applications. Behndig and Linde´n12 measured aqueous humor concentrations of lidocaine after intracameral administration and report it is 100 times higher than that after topical administration. Hence, to decrease pa-
tient discomfort, it has been proposed that the anterior chamber be irrigated with unpreserved lidocaine 1% at the beginning of surgery. Lidocaine gel formulation has the potential advantage of increased contact time with the ocular surface, thus providing sustained release and a prolonged anesthetic effect. The safety of lidocaine 2% gel for ocular use during cataract surgery was investigated by Barequet and coauthors.22 They show that an application of a 6.5 mm (0.25 in) strip of lidocaine 2% gel to the conjunctival fornix of rabbit eyes for up to
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Figure 3. (Macky) Photomicrographs from the ciliary body (left) and retina (right) of rabbit eyes in the BSS and 1% viscoanesthesia groups. Both rabbits had an intravitreal injection of the solutions during the procedure and were killed 60 days postoperatively (PAS stain; original magnifications ⫻100 and ⫻200).
30 minutes did not cause clinical or histopathologic changes in the corneal endothelium. Furthermore, intentional replacement of the aqueous humor with gel for 15 minutes, after which the rabbits were killed, did not cause histopathologic corneal endothelial changes. In the clinical part of their study, Barequet and coauthors22 also show that a single application of lidocaine 2% gel is as effective as topical tetracaine 0.5% drops for patients’ subjective experience of pain. Koch23 reports that a double application of lidocaine 2% gel is even more effective, making the pain scores comparable to those with topical proparacaine 1% plus 0.5 mL intracameral lidocaine 1%. Assia et al.24 used 3 to 5 applications of lidocaine 2% gel to demonstrate that this type of anesthesia can be used not only for phacoemulsification but also for manual extracapsular cataract extraction. Our study investigated the toxicity of a new viscoanesthetic solution composed of sodium hyaluronate 1.5% with different concentrations of lidocaine (0.5%, 1%, and 1.65%) to ocular tissues, especially the iris, lens capsular bag, ciliary body, and retina. The main objective of using such solutions is to maintain the anesthetic level of intraocular tissue by prolonging and maintaining the duration of ocular tissue exposure to lidocaine. This is expected to decrease patient discomfort and pain 560
during intraocular manipulations, especially of iris tissue with surgical instruments or by the rapid change in anterior chamber depth during surgery. Because of the prolonged exposure, a study of the toxicity of the new solution was essential. We purposely left 0.2 mL of the solutions in each rabbit eye at the end of the surgical procedure. This was done to evaluate the potential effects of having viscoanesthetic solutions in these eyes after uneventful or eventful (posterior capsule rupture) cataract surgery. Clinical and histopathological examinations showed no apparent toxicity to intraocular structures. There were no differences between the study and control groups at 15, 30, and 60 days or between the groups receiving in-the-bag injection and intravitreal injection. The viscoanesthetic solutions appeared to be well tolerated by intraocular tissues for 60 days. The moderate to severe inflammatory reactions and corneal edema observed in some eyes were probably due to the relatively large amount of residual OVD material purposely left in the eye, which caused a rise in intraocular pressure (IOP). This cannot be attributed to the lidocaine per se as it was observed in eyes receiving Ophthalin Plus alone (without lidocaine) but not in eyes receiving BSS. Unfortunately, we were unable to check the IOP of the rabbit eyes during the first postoperative week to confirm this hypothesis.
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We observed that the viscoanesthetic solutions helped maintain pupil dilation during surgery, although this was not a specific objective of the study. Eyes operated on with viscoanesthetic solutions (0.5%, 1%, or 1.65%) maintained better pupil dilation during phacoemulsification and up to the end of the surgery than eyes operated on with Ophthalin Plus. We believe that pupil dilation was significantly different between the study and control groups, but further investigation of this phenomenon is essential before definitive conclusions can be drawn. To summarize, the results of the present study indicate that intracameral or intravitreal administration of the newly proposed viscoanesthetic solutions induced no toxic effects to intraocular tissues. No histological evidence of toxicity to uveal tissue or neurosensory retina was observed in rabbit eyes 15, 30, and 60 days postoperatively. Inflammatory reactions and corneal edema observed in some eyes were related to the presence of residual viscoelastic material. We cannot definitively rule out the possibility of subthreshold toxic effects to the rabbit retina without electroretinogram and/or electron microscopy studies. Also, clinical trials are necessary to address the issue of the efficacy of viscoanesthesia in providing long-duration anesthetic effects compared to the effects of an intracameral injection of aqueous lidocaine.
References 1. Gills JP, Cherchio M, Raanan MG. Unpreserved lidocaine to control discomfort during cataract surgery using topical anesthesia. J Cataract Refract Surg 1997; 23:545– 550 2. Masket S, Gokmen F. Efficacy and safety of intracameral lidocaine as a supplement to topical anesthesia. J Cataract Refract Surg 1998; 24:956 –960 3. Carino NS, Slomovic AR, Chung F, Marcovich AL. Topical tetracaine versus topical tetracaine plus intracameral lidocaine for cataract surgery. J Cataract Refract Surg 1998; 24:1602–1608 4. Kim T, Holley GP, Lee JH, et al. The effects of intraocular lidocaine on corneal endothelium. Ophthalmology 1998; 105:125–130 5. Anderson NJ, Nath R, Anderson CJ, Edelhauser HF. Comparison of preservative-free bupivacaine vs lidocaine for intracameral anesthesia: a randomized clinical trial and in vitro analysis. Am J Ophthalmol 1999; 127:393– 402
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Yanoff M, Ducker JS, eds, Ophthalmology. St Louis, MO, Mosby, 1999; 4.21.1–4.21.6 22. Barequet IS, Soriano ES, Green WR, O’Brien TP. Provision of anesthesia with single application of lidocaine 2% gel. J Cataract Refract Surg 1999; 25:626 – 631
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