Intracameral injection of medications is often necessary in routine cataract extractions or phacoemulsification procedures. For example, carbachol 0.01% preparations are often used for miosis at the end of phacoemulsification.1 In recent years, topical anesthesia for cataract surgery2 has been shown to be a safe and effective alternative to conventional techniques of retrobulbar and peribulbar anesthesia with associated risks and benefits.3–6 Topical anesthesia cannot provide adequate motor and sensory anesthesia, however, and leads to intraoperative complications because of free eye movement and intraoperative pain.5 Therefore, intracameral injection of unpreserved lidocaine 1% has commonly been used as an adjunctive anesthetic agent during phacoemulsification.7
Although intracameral injection of lidocaine into the anterior chamber is considered beneficial in reducing patient discomfort and a few studies report no adverse effects on human and animal corneal endothelial cells, its toxicity is still a serious concern for most surgeons.8 Because of the increasingly frequent use of this form of anesthesia in routine cataract surgery, several researchers have studied issues related to its safety.9–13 For example, in vitro perfusion of carbachol 0.01% has been shown to affect the rabbit corneal endothelium.14,15 Birnbaum and coauthors,16 however, have shown that reformulated carbachol 0.01% could reduce the toxicity on endothelial cell ultrastructures, and only transient corneal swelling was noted after intracameral injection.
In our study, we sought to assess whether corneal endothelial cells would be damaged by intracameral injection of lidocaine by detecting morphologic and corneal thickness changes in vivo in an animal model.
Materials and Methods
Forty eyes of 20 New Zealand White rabbits were divided equally into 2 groups. The animal protocol adhered to the Association for Research in Vision and Ophthalmology Statement for Use of Animals in Ophthalmic and Vision Research and was approved by the Institutional Animal Care and Use Committee of National Taiwan University Hospital. The rabbits were anesthetized with ketamine hydrochloride (50 mg/kg; Ketalar®) and lidocaine 2% (Xylocaine®) before each examination. The rabbit eyes were photographed through a specular microscope (Topcon SP2000) before intracameral injection. Images (0.2 × 0.5 mm; ×170 magnification on the instrument display) from the center of the cornea of each eye were obtained. After 20 endothelial cells in each image were manually designated, cell density was calculated using the instrument's computer program. In the first group, 1 eye of 10 rabbits was injected with 0.02 mL of preservative-free lidocaine 1% and the fellow eye with 0.02 mL of normal saline as a control. In the second group, 1 eye of the other 10 rabbits was injected with 0.02 mL of carbachol 0.01% and the fellow eye with 0.02 mL of normal saline. Specular photomicroscopy of rabbit eyes was performed again at 2 hours postinjection and 1 week and 1 month later.
Two rabbit eyes of each group were enucleated 1 month after intraocular lidocaine and carbacol injection, and the corneal buttons were cut into equal parts. One half was stained with alizarin red (Sigma) and trypan blue (TCI) according to Steffen's method.17 The other corneal button halves were cut into pieces about 2 × 4 mm and prepared for scanning electron microscopy according to the method of Wang and Hu.18 The tissue blocks were examined and photographed under a Hitachi S570 scanning electron microscope. Comparison of the endothelial count was tested with 1-way repeated-measures analysis of variance and multiple comparison among and between each group. P values less than 0.05 were considered statistically significant.
The endothelial cell count densities for 3 groups (lidocaine, carbachol, and normal saline) obtained from specular microscopy are compared in Table 1. There was no significant difference in endothelial cell density between groups. The corneal thickness was also measured in all eyes using specular microscopy. No significant difference in corneal thickness was found between groups (Table 2).
The integrity of the endothelial sheet of the rabbit cornea was examined by alizarin red and trypan blue stains and by scanning electron microscopy. The morphology of all groups showed normal corneal endothelial appearance (Figures 1 and 2). The hexagonal shape of corneal endothelium was preserved. No abnormal endothelial cells, such as bleb formation and disintegration of cellular border, were found. Smooth and distinct cell borders were detected between each endothelial cell. Intercellular border thickness was also normal in all groups.
Topical anesthesia combined with intracameral lidocaine injection has been shown to be an effective and safe method for cataract surgery.3–6 This method has the advantages of rapid onset and short duration of action, decreased risk of globe perforation, extraocular muscle injury, retrobulbar hemorrhage, optic nerve damage, and intravascular-intrathecal penetration.3,7,19,20 Patients also benefit from an earlier return of visual acuity without the drawback of postoperative ptosis, diplopia, ecchymosis, subconjunctival hemorrhage, or chemosis. The major concern with the use of intracameral lidocaine is the possibility of damage to the corneal endothelium from lidocaine.
Anderson and coauthors21 found that in vitro perfusion of bupivacaine 0.5% damages the corneal endothelium of rabbits except when the drug was diluted 1:1 with glutathione bicarbonate Ringer solution; lidocaine 1.0% does not damage the corneal endothelium of rabbits, however. These researchers also found that lidocaine can be taken up quickly by the iris/ciliary body and cornea, then rapidly removed from these tissues after washout with BSS Plus®.6 Kim and coauthors22 demonstrated that lidocaine HCl 1% causes a transient endothelial cell edema in the in vitro perfused endothelium of human and rabbit corneas. Garcia and coauthors8 found no morphologic damage to corneal endothelial cells in rabbit eyes after injection of low concentration of lidocaine (≤1%) into the anterior chamber, but a higher concentration of lidocaine (>1%) did damage the corneal endothelium. Werner and coauthors9 demonstrated that lidocaine HCL 1% caused transient endothelial cell edema with a normal morphological cell pattern and ultrastructure in both groups after in vitro perfusion of human and rabbit corneal endothelium. Although these studies indicate that intraocular lidocaine injection is a safe anesthesia for cataract surgery, no experiment has studied the long-term effects of intraocular lidocaine on the corneal endothelium. Our results also revealed that there was no morphologic damage to corneal endothelial cells even 30 days after lidocaine intracameral injection. In a series of specular photography, rabbit corneal endothelial cells showed a regular hexagonal pattern, smooth and distinct cell borders, and no significant cell loss in every examination.
For miotic agents, Birnbaum and coauthors16 showed that intraocular carbachol 0.01% preparation may cause increased corneal swelling that returns to a normal rate of swelling after reperfusion with Krebs Ringer bicarbonate solution. The low pH of the older carbachol preparation was responsible for the swelling. A similar study was performed with new and reformulated carbachol 0.01%, specifically changing the vehicle from water to a balanced salt solution and increasing pH from 5.2 to 6.95.16 The corneal swelling rate decreased, and no ultrastructural alterations of corneal endothelial was found.
We have demonstrated that there was no loss of corneal endothelial cells in the rabbit. Corneal thickness also was not affected, nor was corneal swelling detected at 1 hour postinjection. The trypan blue and alizarin red stain of the corneal button showed that the integrity of corneal endothelial cells was preserved. Scanning electrical microscopy examination revealed no ultrastructure damage.
We believe that clearance of the lidocaine and carbachol from the anterior chamber can be rapid, and aqueous humor may be more protective than corneal perfusion solutions. In our study, the 5-fold larger volume of aqueous humor in the anterior chamber rapidly diluted the small amount of intracameral medication. Additionally, an aqueous humor flow rate of 3 μL/min may have a washout effect. There is likely a difference between aqueous humor and the solutions normally used for in vitro corneal perfusions because the cornea starts to swell at 24 hours even when optimal corneal preparations with the most refined perfusing solution are used. In conclusion, lidocaine 1% and carbachol 0.01% did not produce morphologic changes to the corneal endothelial cells of rabbits.
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