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Intracameral anesthesia
Ophthalmic Technology Assessment
Intracameral Anesthesia A Report by the American Academy of Ophthalmology Carol L. Karp, MD, Terry A. Cox, MD, PhD, Michael D. Wagoner, MD, Reginald G. Ariyasu, MD, PhD, Deborah S. Jacobs, MD Objective: This document describes the technique of intracameral anesthesia and examines the available evidence to address questions about its effectiveness, possible corneal endothelial and retinal toxicity, and the optimal and maximal dose. Methods: A literature search conducted for the years 1968 to 2000 retrieved over 180 citations that matched the search criteria. Panel members and a methodologist reviewed this information, and it was evaluated for the quality of the evidence presented. Results: Some studies report effectiveness of intracameral anesthesia while others report no effect. In those studies showing an effect, levels of pain in the groups that were compared were low. Short-term studies seem to indicate that preservative (methylparaben)-free lidocaine 1% is well tolerated by the corneal endothelium but that higher concentrations of lidocaine are toxic. There is some evidence of electroretinogram changes after exposure to lidocaine or bupivacaine. Conclusions: The ideal timing and placement of intracameral anesthesia has not been determined. Because topical anesthesia alone is effective, surgeons may elect to use intracameral anesthesia for incremental pain control in patients who cannot be adequately managed with topical alone. Appropriate patient selection is important when using this method of anesthesia. While short-term studies seem to indicate safety, long-term effects are unknown. Patient preferences for anesthesia are not well studied. Ophthalmology 2001;108: 1704 –1710 © 2001 by the American Academy of Ophthalmology. The American Academy of Ophthalmology (AAO) prepares the Ophthalmic Technology Assessments (OTAs) to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an OTA is to evaluate the peer-reviewed published scientific literature, to distill what is well established about the technology, and to help refine the important questions to be answered by future investigations. After appropriate review by all contributors, including legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements.
Background Topical and intracameral anesthesia are new options for pain control in modern cataract surgery. Topical anesthesia has been shown to be a safe and effective alternative to retrobulbar and peribulbar anesthesia.1 Topical and intracameral anesthetics have potential safety advantages over Originally received: June 15, 2001. Accepted: June 15, 2001. Manuscript no. 210407. Prepared by the Ophthalmic Technology Assessment Committee Anterior Segment Panel and approved by the American Academy of Ophthalmology’s Board of Trustees June 10, 2001.
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© 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
traditional retrobulbar and peribulbar injections,2 which rarely can be complicated by globe perforation, retinal vascular occlusion, retrobulbar hemorrhaging, strabismus, ptosis, optic nerve damage, and even cardiac or respiratory arrest.3–5 In addition to avoiding the above complications, topical administration of anesthesia also provides patients with immediate visual recovery. Although topical administration of anesthesia does provide immediate onset of action, there are limitations to this form of anesthesia. These include lack of akinesis and inadequate blockade of the sensory nerves in the iris and ciliary body when only topical drops are used. Patients may therefore experience discomfort during iris and lens manipulation and intraocular lens (IOL) implantation, and surgeons may be uncomfortable initially with patient movement and lid squeezing. The lack of optic nerve blockade may also result in intolerance to the microscope light. Some surgeons who use topical anesthesia have found it necessary to supplement with subconjunctival or sub-Tenon’s anesthesia to improve patient comfort.3 More recently, intracameral anesthesia has been introduced as a possible method for providing additional anesthetic effect. Intracameral techniques have included the use of preservative-free (PF) lidocaine hydrochloride 1% or PF bupivacaine hydrochloride 0.5%. These anesthetics have been injected in ISSN 0161-6420/01/$–see front matter PII S0161-6420(01)00793-X
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment doses of 0.1 to 0.5 ml into the anterior chamber prior to phacoemulsification. Since these drugs are not formulated for intraocular use, there is concern about the efficacy and safety of this procedure, particularly possible toxicity to the corneal endothelium and retina.
FDA Status Intracameral use of PF lidocaine hydrochloride 1% or PF bupivacaine hydrochloride 0.5% is not approved by the U.S. Food and Drug Administration (FDA), and is considered off-labeled use of FDA-approved drug products. Therefore, any studies of intracameral lidocaine or bupivacaine should be conducted under an Investigational New Drug Exemption.
Resource Requirements An Evidence Report sponsored by the Agency for Healthcare Research and Quality on anesthesia management during cataract surgery used a model to study cost considerations as part of their report.2 The method used for the comparison was to estimate the cost to the Medicare Program of various anesthesia strategies, and calculations were based on costs from The Johns Hopkins Hospital and the average wholesale price for drugs. The cost of all drugs was based on the most commonly administered medications for an average 45-minute case. Using this model, the investigators calculated that the costs of topical anesthesia (including intracameral block) and the costs of peribulbar or retrobulbar block anesthesia were $5 per case (range $1 to $9). The cost of converting from topical to block anesthesia was $5 per case (range $1 to $9). The cost of oral sedation was $5 per case (range $1 to $9) and of intravenous sedation was $30 per case (range $15 to $50).
these papers and selected 87 articles of possible clinical relevance to the assessment to read. Of these, 33 were found relevant to the assessment questions and were reviewed by the panel methodologist. Thirteen papers described experimental animal studies, and one paper was a case report. In the remaining 19 papers the methodologist assigned one of the following ratings of level of evidence to each of the selected articles. A Level I rating is assigned to properly conducted, well-designed randomized clinical trials; a Level II rating is assigned to well-designed cohort and case-control studies; and a Level III rating is assigned to case series. During methodological review, statistical analyses were repeated and papers with statistical inconsistencies resulting in inconclusive P values are not presented as evidence. The quality of statistical methods used in the studies reviewed was assessed using a scale from A to F. Papers with scores of D and F were considered to be unacceptable as medical evidence, C was borderline, and A and B were acceptable. On this statistical quality rating scale, 6 of 10 Level I randomized controlled trials, 2 of 4 Level II comparative studies, and 2 of 5 Level III studies received an A or B rating. After review, there were 10 Level I randomized clinical trials comparing topical anesthesia with supplemental intracameral lidocaine to intracameral balanced salt placebo or intracameral lidocaine to intracameral bupivacaine, some of which evaluated corneal or retinal toxicity.6 –15 In addition to the randomized clinical trials, there were also 4 Level II cohort or case control studies,16 –19 5 Level III studies,20 –24 and 13 experimental animal studies25–37 investigating drug uptake and toxicity. The animal studies are helpful in indicating potential toxicity, but application and relevance to human in vivo conditions is limited.
Published Results Questions for Assessment The focus of this assessment is to address the following questions: ● ● ●
Is intracameral anesthesia effective? What is the corneal endothelial and retinal toxicity of intracameral anesthesia? Is there any evidence to recommend an optimal and maximal dose of intracameral anesthesia?
Description of Evidence A literature search of MEDLINE was conducted for the years 1968 to 2000 and was limited to articles in English. It used combinations of the MeSH terms phacoemulsification, anesthesia, lidocaine, retina/drug effects, corneal endothelium/drug effects, and toxicity, with text words topical, ocular, intraocular, and intracameral. This search retrieved over 180 citations, and the reference lists of these articles were consulted for additional citations. Panel members reviewed
Effectiveness The first objective of this assessment was to evaluate the efficacy of intracameral anesthesia. The literature includes 10 randomized clinical trials that examined combined topical and intracameral anesthesia versus peribulbar anesthesia, topical anesthesia with the adjunct of intracameral anesthesia versus placebo, or intracameral lidocaine versus bupivacaine. Anders et al6 performed a randomized clinical trial comparing 200 patients who underwent cataract surgery with either peribulbar anesthesia or combined topical and intracameral anesthesia. Six ml of peribulbar prilocaine hydrochloride (injected in lower orbital rim) were used in one group, and the other received 0.15 ml of intracameral 1% nonpreserved lidocaine combined with topical oxybuprocaine topical drops applied to the conjunctiva with a cellulose sponge at the incision site for 5 minutes. Scleral incisions were performed in all cases. Intraoperative and postoperative pain levels were evaluated by means of a questionnaire. The paper did not specify when the patients
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Ophthalmology Volume 108, Number 9, September 2001 completed the questionnaire, but tables indicate pain evaluations 2, 4, and 6 hours after surgery. In comparing the reported intraoperative pain of the two patient groups, the patients who received the intracameral lidocaine reported more pain during cauterization of the sclera and at the final step of coagulation of the conjunctiva at the end of the surgery (P ⫽ 0.01). The other steps of the surgery showed no significant difference in pain level. As expected, eye movement and squeezing was significantly less frequent after peribulbar anesthesia (P ⫽ 0.01). However, no increase in complications was found due to eye movement or lid squeezing. The peribulbar group had elevated vitreous pressure more frequently (7%) than the intracameral group (3%). Fourteen percent of the peribulbar group also had eyelid hemorrhage, while 12% of the lidocaine groups had mild epithelial changes in the cornea due presumably to the anesthetic drops. The epithelial changes disappeared a few hours after surgery. Postoperatively, more pain was reported in the intracameral group (P ⫽ 0.0017). The discomfort occurred within the first 2 hours of surgery. After 4 and 6 hours, there was no significant difference between the groups. The vision was better in the intracameral group immediately after surgery, but there was no significant difference between the two groups on the first postoperative day. Electroretinograms (ERG) were performed preoperatively and approximately 40 minutes postoperatively on 15 patients selected randomly from each group, and evaluation of b-wave implicit times and amplitudes were conducted. There was no difference between the preoperative and postoperative implicit times and amplitudes between the two groups. The studies reached different conclusions about the effectiveness of intracameral anesthesia as an adjunct to topical anesthesia. Three randomized clinical trials9,12,13 report that the adjunct of intracameral lidocaine 1% decreased pain at various points during the surgery and after the surgery compared with groups receiving topical anesthesia and placebo intracamerally. Carino et al9 performed a randomized double-masked prospective study of topical tetracaine 0.5% with either 0.2 ml of intracameral balanced salt solution (BSS) or 0.2 ml of intracameral PF lidocaine 1%. The intracameral medication was given at the beginning of surgery through a corneal paracentesis. Temporal corneal incisions were made in all cases. The pain levels were rated at several points during the procedure including preoperatively, after the capsulorrhexis, after phacoemulsification, and at the end of surgery. Surgeon satisfaction was also rated. The intracameral BSS group had a higher intraoperative pain score and postoperative pain score compared with the lidocaine group (P ⫽ 0.019 and P ⫽ 0.014, respectively). In particular, the pain seemed to be most pronounced after the phacoemulsification and at the end of the procedure. The pain level was the same in both groups preoperatively and after the capsulorrhexis. Intravenous sedation for increased comfort was required more often in the BSS group (5 of 30 eyes) than in the lidocaine group (0 of 30 eyes, P ⫽ 0.052). There was no significant difference in patient satisfaction with the anesthesia between the two groups; however, surgeons were less satisfied with the intracameral BSS group
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(P ⬍ 0.001). Endothelial cell loss was measured at 1 month and was similar for both groups. However, measurements at 1 month do not necessarily reflect possible long-term endothelial changes. While the difference in mean pain scores was statistically significant, both groups had minimal pain. The mean intraoperative pain score for the BSS group was 0.63 ⫾ 0.7 and was 0.23 ⫾ 0.4 for the lidocaine group, where (0) was no pain and (1) was mild pain. Gills et al12 performed a prospective controlled study comparing topical anesthesia and either 0.1 ml of PF lidocaine 1% or 0.1 ml of BSS in a double-masked fashion. These drugs were injected intracamerally 1 minute before phacoemulsification. Pain was measured by the nurse anesthetist using a predefined uniform scale at various times following injection: 1 minute, 3 minutes, 5 minutes, midway through phacoemulsification and midway through IOL insertion. Important advantages of this study and of Carino et al9 were that the evaluation was done at multiple points during the procedure. Gills et al found a statistically significant decrease in intraoperative discomfort in the lidocaine 1% group (9% vs. 26%, P ⬍ 0.001). Elevated discomfort/ pain scores described as increased pressure (uncomfortable) or moderate pain seemed more frequent during IOL insertion than during phacoemulsification. The lidocaine group also had a slightly larger mean pupil diameter, although this was not statistically significant. Postoperative intraocular pressure and anterior chamber inflammation showed no difference. In a second, noncomparative study of 300 patients, Gills et al increased the dose to 0.5 ml of intraoperative PF lidocaine and found that the rate of discomfort was 1.7%. While this result compares favorably with the rate of discomfort using the smaller dosage in the first study, the lack of concurrent controls precludes any definitive conclusion about relative dose effects. Endothelial cell counts were measured 2 weeks postoperatively in the 0.5 ml group, and there were no differences in the mean preoperative and postoperative endothelial counts. Postoperative endothelial counts were collected 2 weeks postoperatively in 20% of the lidocaine and control groups, and no significant between-groups differences were noted. Several other studies showed minimal difference in pain control between intracameral lidocaine and placebo when using topical anesthesia.8,10,11,15 Boulton et al8 performed a prospective double-masked randomized control trial of 200 patients undergoing routine phacoemulsification under topical 1% tetracaine. The patients were randomized to 0.5 ml of intracameral PF lidocaine 1% or BSS. No intravenous sedation was used at all. The medication was given after the clear corneal incision. Patients were evaluated following surgery in the recovery room, and no difference was found in the rating of intraoperative pain. Possible limitations of the study are that the rating was done following the procedure rather than during it. However, no systemic intravenous medication was given to cloud the patients’ perception, and no evaluation of postoperative pain was conducted. Other studies also found no significant overall difference in pain from topical procedures with intracameral anesthesia compared with an intracameral placebo. There was an increased perception of tissue manipulation10 and increased
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment discomfort from the microscope light.11 The pain evaluations for all of the trials that showed no difference were conducted at the end of the procedure8,10,15 or the next day.11 Furthermore, one study15 placed the lidocaine into the capsular bag during hydrodissection rather than into the anterior chamber. This study also used scleral incisions. Studies judged Level II16 –19 and Level III20 –24 were also evaluated. A small series that examined the efficacy of intracameral lidocaine found that combined topical proparacaine 1% and 0.5 ml of intracameral lidocaine 1% was associated with more comfortable surgery than single-dose topical lidocaine jelly 2% or topical proparacaine 1% only.19 A large retrospective review performed by Masket20 evaluated 352 cases in which topical 4% lidocaine and tetracaine 0.5% were used compared with 279 cases in which the same topical lidocaine and tetracaine with the adjunct of 0.2 to 0.5 ml of PF lidocaine 1% intracamerally was used. The authors reported that 43% (150/352) of the patients with topical-only anesthesia required injection of subconjunctival or posterior sub-Tenon’s anesthetic for patient comfort compared with 0.36% (1/279) of patients who received the two topical anesthetics as well as intracameral lidocaine. This was found to be statistically significant. However, this study is limited because it is retrospective, the parameters for extra anesthesia were not well defined, and the technique of phacoemulsification was changed from divide and conquer to phaco chop within the second group.
Corneal Toxicity The second objective of this assessment was to consider the evidence of corneal toxicity from intracameral anesthesia. Several of the randomized clinical studies did examine postoperative endothelial cell counts in the short term.12,13,18 The dose ranged from 0.1 ml to 0.5 ml of PF lidocaine 1%, and early endothelial studies that ranged from 2 weeks,12,14 1 month22 or 3 months13,21 showed no change in endothelial cell counts compared with control. There was also no difference in blood aqueous barrier permeability between lidocaine and control groups at 1 month.21 Many other experimental animal studies were performed looking at endothelial toxicity.7,16,25,30,31,35,36,38 Kim et al31 evaluated the in vitro effect of PF lidocaine 1% on the corneal endothelium of human and rabbit corneas perfused with either PF lidocaine 1% or control. After a 1-hour stabilization period with control fluid, the eyes were exposed to the drug or control for 15 minutes followed by a washout. Both human and rabbit corneas had transient, reversible edema during lidocaine perfusion that reversed after the control washout perfusion. Three human corneas were exposed to the lidocaine for 15 minutes followed by a 15-minute washout. A live cell-dead cell assay of the tissue showed no significant changes compared with controls. Kadonosono et al30 injected PF lidocaine in concentrations of 0.02%, 0.2%, and 2% intracamerally into one eye of rabbits and BSS in the fellow eye control. Continuous irrigation was performed for 10 minutes and the rabbits were sacrificed. Scanning electron microscopy revealed no abnormal findings in the eyes injected with either lidocaine 0.02% or 0.2% when compared with control, but the eyes
injected with lidocaine 2% showed irregular hexagonal endothelial cells and significant loss of microvilli. Similarly, Werner et al36 performed an in vitro study of rabbit cornea exposed to lidocaine 1%, lidocaine 5%, and a control of BSS. These were exposed for 20 minutes and then evaluated with trypan blue and alizarin red. Studies showed that none of the rabbit eyes had staining with trypan blue. There was no difference in cell loss, but the cells exposed to lidocaine 5% had more irregular shapes and borders. No long-term studies about the reversibility or changes due to pH and osmolarity were performed. A study done by Eggeling et al38 exposed porcine corneas to PF lidocaine hydrochloride at 1%, 5%, and 10% for 60 minutes. A small subset was exposed to lidocaine hydrochloride 1% only for 30 minutes to simulate the clinical situation. The study found that lidocaine 1% in contact with the endothelium for 30 minutes or 60 minutes in porcine corneas did not cause any significant corneal endothelial damage compared with the control. Significant corneal endothelial cell loss was observed with the lidocaine 5% and lidocaine 10% groups (P ⬍ 0.001 in both groups). Ohguro et al35 performed an in vivo study in cats. Intracameral 0.5% lidocaine was given along with sodium hyaluronate (0.25 ml), and no washout was performed. The eyes were evaluated clinically preoperatively and at 1, 4, and 7 days after drug delivery. Specular microscopy was also performed. The study found that the eyes injected with lidocaine had only mild edema and specular microscopic analysis revealed that the percentage of cell loss and percentage of hexagonal cells did not change significantly through the observational period. The percentage of hexagonal cells did tend to decrease at 7 days. Scanning electron microscopy was essentially normal in appearance after sacrifice at 7 days. While lidocaine is the most commonly used medication, some studies have also looked at bupivacaine. Anderson et al7 performed a double-masked randomized clinical study, which found no significant difference in pain between intracameral bupivacaine 0.5% and lidocaine 1%. They also performed a rabbit study in which corneal swelling was observed in rabbits exposed to bupivacaine 0.5% for 1 hour. Corneal changes, however, did not occur when the bupivacaine was diluted 1:1 with glutathione bicarbonate Ringer’s solution. Judge and co-authors25 found that intracameral injection of tetracaine hydrochloride 0.5% did not produce any significant corneal thickening in rabbits, but PF lidocaine hydrochloride 4%, bupivacaine hydrochloride 0.75%, and proparacaine hydrochloride 0.5% did produce significant thickening and opacification.
Retinal Toxicity Retinal toxicity of intracameral lidocaine is another concern if it diffuses posteriorly to the retina. There have been anecdotal reports of patients losing light perception temporarily following intracameral anesthesia.9,29 Similarly, vision has been lost following an inadvertent intravitreal injection of lidocaine.33 Several in vitro experimental studies have suggested that lidocaine and/or bupivacaine may be toxic to the reti-
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Ophthalmology Volume 108, Number 9, September 2001 na.27,28,33,34 Mondragon and Frixione34 found that in vitro lidocaine may interfere with the dark adapting migration of screening pigments in crayfish photoreceptors and frog retinal pigment epithelial cells. The inhibition of dark adaptation was reversible and dependent on levels of calcium and sodium. Incubated chick retinas in vitro exposed to lidocaine (3 to 7 mM) for 30 minutes had a dose-dependent decrease in propagation, amplitude, and duration of the slow potential change of spreading depression. In a study by Grosskreutz et al,28 lidocaine was injected intravitreally in rats, and 1 week later the cells were evaluated histologically. Intravitreal lidocaine was toxic to the rat ganglion cells in a dosedependent fashion. This toxicity was blocked by nimodipine, which is a glutamate antagonist and seems to prevent neuronal death. The study also noted a dose-dependent toxicity to rat ganglion cells. Lower concentrations of lidocaine (0.5 mM and 1.0 mM) were nontoxic, but higher levels showed toxicity (2.0 mM, 6.0 mM, 12 mM). While no correlation can be made from in vitro rat cells to human in vivo cells, it is interesting to note that a 0.5 ml dose of lidocaine 1% distributed evenly in the human eye could produce a concentration of approximately 5 mM. While the above in vitro studies raise concern, other clinical6 and experimental32,33,37 studies have shown no long-term effect of the intracameral anesthetics on retinal cells. In the randomized clinical trial done by Anders et al,6 15 patients from both treatment (lidocaine 1% 0.15 ml) and control groups had ERGs evaluated preoperatively and 40 minutes postoperatively, as described above. There was a decrease of the b-wave amplitude 40 minutes postoperatively in both groups, but there was no significant change in the control versus the lidocaine group in terms of implicit time of amplitudes. Zemel et al37 evaluated the effect of intravitreal injections of lidocaine (5 mg and 10 mg) and bupivacaine (0.5 mg) in rabbits. Electroretinograms and visual evoked potentials (VEP) were performed 10 minutes following injection and 1 week later. Histopathology was also performed. The study found that intravitreal lidocaine 5 mg or 10 mg and bupivacaine 0.5 mg did not produce any ERG or VEP changes at the 1-week mark, and histopathology revealed normal histopathology in the lidocaine 5 mg and bupivacaine 0.5 mg group. The 10 mg group had structural changes only at the site of the injection. Other experimental studies also suggest that ERGs normalize in cats33 and rabbits32 following intravitreal injection of lidocaine. Liang et al32 injected 0.2 ml of lidocaine (2%, 1%, 0.5%, 0.25%) and bupivacaine (0.75%, 0.5%, 0.25%). No a-wave changes were noted and b-waves showed a dose-dependent decrease in amplitude and implicit time that normalized within 24 hours. No histological changes were noted at 1 week. In order to evaluate the pharmacodynamics of lidocaine, Anderson et al26 performed a laboratory study of uptake, washout, and metabolism of 1% lidocaine hydrochloride in the iris and ciliary body in the cornea of rabbits and humans. The authors reported that there is a rapid uptake of radiolabeled 1% lidocaine in the iris ciliary body tissue (50% to 60% in 5 minutes) and a rapid washout with a half-life of 8
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to 9 minutes. The corneal uptake and washout was also rapid and no lidocaine metabolites were detected. This study showed no difference between pigmented and nonpigmented eyes. Wirbelauer et al24 evaluated the systemic levels of lidocaine after intracameral injection of 0.5 ml of PF lidocaine 1%. The levels were measured at 1 minute, 2 minutes, 5 minutes, and 15 minutes after injection, and there was no detectable systemic level of lidocaine in the blood systems of the patients.
Conclusions Ten Level I randomized clinical trials have been performed to evaluate the effectiveness of intracameral anesthesia, primarily with PF lidocaine 1%. Several studies have indicated that the adjunct of intracameral anesthesia to topical drops provides increased patient comfort, particularly during iris manipulation, changes in the iris lens diaphragm, and IOL insertion. Studies that actually evaluated patient comfort during the surgery seemed to indicate that patients experienced more discomfort during certain portions of the surgery when placebo was used compared to intracameral anesthesia.9,12,13 Overall, however, the pain levels for both intracameral placebo and lidocaine were low because topical anesthesia alone is very effective. Four studies show no significant difference8,10,11,15 between intracameral anesthesia and intracameral BSS pain control except for the experience of increased light sensitivity from the microscope light and sensation of tissue manipulation. These studies may be limited in that the pain assessment was done in the recovery room at the end of surgery or on the first postoperative day. No long-term studies on corneal endothelial toxicity are available yet. Short-term studies seem to indicate that PF lidocaine 1% up to a dose of 0.5 ml is well tolerated by the corneal endothelium in the short term.12,13,18 This is corroborated by several animal studies where low-dose lidocaine is well tolerated.30,31,35 However, higher concentrations of lidocaine are indeed toxic to the corneal endothelium.30,36,38 There is some evidence of possible retinal toxicity, specifically of ERG changes following exposure to lidocaine or bupivacaine.27,28,33,34 Studies indicate that these changes are dose dependent32,37 and transient.6,32,38 Only the Anders et al6 study was done in the setting of a randomized clinical trial, and only 15 patients in each group were studied. Because of the small sample size, this study may have had inadequate power to detect clinically important differences.
Recommendations Straight topical anesthesia appears to be effective for the appropriately selected patient population. Surgeons may elect to use intracameral anesthesia for incremental pain control in patients who cannot be adequately managed with topical alone. Topical anesthesia with supplemental intracameral anesthesia offers rapid visual rehabilitation and,
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment depending on individual surgeon’s circumstances, a potential reduction in length of room turnover time compared to retrobulbar or peribulbar anesthesia. Appropriate patient selection is important when using intracameral anesthesia. Patient cooperation, anticipated duration of surgery, possibility of complications, axial length, and anticoagulation status of the patient are some factors to consider when choosing whether or not to use this type of anesthesia. It is recommended that the minimal amount and concentration of intracameral anesthesia be used based on the surgeon’s surgical technique and patient needs. Preservative-free lidocaine 1% in doses of 0.1 ml to 0.5 ml has not been associated with short-term problems in patients, but experimental studies suggest that higher concentrations may be associated with corneal endothelial toxicity. Most reports studied lidocaine that was injected directly into the aqueous humor (compared with using lidocaine solution for hydrodissection, for example), but the optimal timing and placement of administration has not been studied. While the short-term studies seem to indicate safety, there are still many unknowns, including the long-term effect on the corneal endothelium, the possible toxicity
relating to posterior diffusion of the anesthetics through an intact posterior capsule and zonules, and the effect of administering multiple doses. Intracameral bupivacaine in cataract surgery is not as well studied as lidocaine. Bupivacaine 0.5% or 0.75% may be more toxic to the corneal endothelium than 1% lidocaine. An advantage over lidocaine has not been established, suggesting that 1% lidocaine may be a more reasonable choice.
Future Research Long-term studies in humans still need to be done to evaluate corneal endothelial toxicity. Additional short-term and long-term human retinal studies are also required to ensure that intracameral anesthesia is indeed safe. Additional questions to be answered include: ● ● ● ●
Specifically, how does intracameral compare to retrobulbar or peribulbar anesthesia? Which method of anesthesia do patients prefer? What is the ideal timing and placement of intracameral anesthesia? What is the cost-effectiveness of different anesthesia strategies?
Preparation was coordinated by the Ophthalmic Technology Assessment Committee Anterior Segment Panel. Original Draft by: Ophthalmic Technology Assessment Committee Anterior Segment Panel
Edited by: Managing Editors:
Approved by:
Carol L. Karp, MD, OTAC Anterior Segment Panel Michael D. Wagoner, MD, Chair Reginald G. Ariyasu, MD, PhD Deborah S. Jacobs, MD Terry A. Cox, MD, Methodologist Susan Garratt Flora Lum, MD Nancy Collins, RN, MPH Margo Leslie Board of Trustees, June 10, 2001
*Proprietary Interests N N N N N N N N N
*Proprietary interests stated Category
Abbrev
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P Pc I Ic C___
Financial interest in equipment, process, or product presented. Such interest in potentially competing equipment, process, or product. Financial interest in a company or companies supplying the equipment, process, or product presented. Such interest in a potentially competing company. Compensation received within the past 3 years for consulting services regarding the equipment, process, or product presented. Such compensation received for consulting services regarding potentially competing equipment, process, or product. Examples of compensation received include: 1. Retainer 2. Contract payments for research performed 3. Ad hoc consulting fees 4. Substantial nonmonetary perquisites 5. Contribution to research or research funds 6. Contribution to travel funds 7. Reimbursement of travel expenses for presentation at meetings or courses 8. Reimbursement of travel expenses for periods of direct consultation No financial interest. May be stated when such interests might falsely be suspected.
Investor Consultant
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None
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or or or or or or or or
Cc1 Cc2 Cc3 Cc4 Cc5 Cc6 Cc7 Cc8
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References 1. Patel BCK, Byrnes TA, Crandall A, et al. A comparison of topical and retrobulbar anesthesia for cataract surgery. Ophthalmology 1996;103:1196 –203. 2. Evidence Report/Technology Assessment: Number 16. Anesthesia Management During Cataract Surgery. Rockville, MD: Agency for Healthcare Research and Quality, 2000. AHRQ Pub. No. 00-E015. 3. Morgan CM, Schatz H, Vine AK, et al. Ocular complications associated with retrobulbar injections. Ophthalmology 1988; 95:660 –5. 4. Capo H, Roth E, Johnson T, et al. Vertical strabismus after cataract surgery. Ophthalmology 1996;103:918 –21. 5. Nicoll JM, Acharya PA, Ahlen K, et al. Central nervous system complications after 6,000 retrobulbar blocks. Anesth Analg 1987;66:1298 –302. 6. Anders N, Heuermann T, Ruther K, Hartmann C. Clinical and electrophysiologic results after intracameral lidocaine 1% anesthesia: a prospective randomized study. Ophthalmology 1999;106:1863– 8. 7. 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. 8. Boulton JE, Lopatatzidis A, Luck J, Baer RM. A randomized controlled trial of intracameral lidocaine during phacoemulsification under topical anesthesia. Ophthalmology 2000;107: 68 –71. 9. 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– 8. 10. Crandall AS, Zabriskie NA, Patel BC, et al. A comparison of patient comfort during cataract surgery with topical anesthesia versus topical anesthesia and intracameral lidocaine. Ophthalmology 1999;106:60 – 6. 11. Gillow T, Scotcher SM, Deutsch J, et al. Efficacy of supplementary intracameral lidocaine in routine phacoemulsification under topical anesthesia. Ophthalmology 1999;106:2173–7. 12. Gills JP, Cherchio M, Raanan MG. Unpreserved lidocaine to control discomfort during cataract surgery using topical anesthesia. J Cataract Refract Surg 1997;23:545–50. 13. Martin RG, Miller JD, Cox CC 3rd, et al. Safety and efficacy of intracameral injections of unpreserved lidocaine to reduce intraocular sensation. J Cataract Refract Surg 1998;24:961–3. 14. Nielsen PJ, Allerod CW. Evaluation of local anesthesia techniques for small incision cataract surgery. J Cataract Refract Surg 1998;24:1136 – 44. 15. Tan JH, Burton RL. Does preservative-free lignocaine 1% for hydrodissection reduce pain during phacoemulsification? J Cataract Refract Surg 2000;26:733–5. 16. 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 –31. 17. Bellucci R, Morselli S, Pucci V, et al. Intraocular penetration of topical lidocaine 4%. J Cataract Refract Surg 1999;25: 642–7. 18. Garcia A, Loureiro F, Limao A, et al. Preservative-free lidocaine 1% anterior chamber irrigation as an adjunct to topical anesthesia. J Cataract Refract Surg 1998;24:403– 6.
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19. Koch PS. Efficacy of lidocaine 2% jelly as a topical agent in cataract surgery. J Cataract Refract Surg 1999;25:632– 4. 20. Masket S, Gokmen F. Efficacy and safety of intracameral lidocaine as a supplement to topical anesthesia. J Cataract Refract Surg 1998;24:956 – 60. 21. Elvira JC, Hueso JR, Martinez-Toldos J, et al. Induced endothelial cell loss in phacoemulsification using topical anesthesia plus intracameral lidocaine. J Cataract Refract Surg 1999;25: 640 –2. 22. Iradier MT, Fernandez C, Bohorquez P, et al. Intraocular lidocaine in phacoemulsification: an endothelium and bloodaqueous barrier permeability study. Ophthalmology 2000;107: 896 –900; discussion 900 –1. 23. John T. Simplified anesthesia technique for scleral tunnel phacoemulsification. J Cataract Refract Surg 1998;24:1562–5. 24. Wirbelauer C, Iven H, Bastian C, Laqua H. Systemic levels of lidocaine after intracameral injection during cataract surgery. J Cataract Refract Surg 1999;25:648 –51. 25. Judge AJ, Najafi K, Lee DA, Miller KM. Corneal endothelial toxicity of topical anesthesia. Ophthalmology 1997;104: 1373–9. 26. Anderson NJ, Woods WD, Kim T, et al. Intracameral anesthesia: in vitro iris and corneal uptake and washout of 1% lidocaine hydrochloride. Arch Ophthalmol 1999;117:225–32. 27. Chebabo SR, do Carmo RJ, Martins-Ferreira H. Effects of local anaesthetics on retinal spreading depression. Exp Brain Res 1993;96:363– 4. 28. Grosskreutz CL, Katowitz WR, Freeman EE, Dreyer EB. Lidocaine toxicity to rat retinal ganglion cells. Curr Eye Res 1999;18:363–7. 29. Hoffman RS, Fine IH. Transient no light perception visual acuity after intracameral lidocaine injection. J Cataract Refract Surg 1997;23:957– 8. 30. Kadonosono K, Ito N, Yazama F, et al. Effect of intracameral anesthesia on the corneal endothelium. J Cataract Refract Surg 1998;24:1377– 81. 31. Kim T, Holley GP, Lee JH, et al. The effects of intraocular lidocaine on the corneal endothelium. Ophthalmology 1998; 105:125–30. 32. Liang C, Peyman GA, Sun G. Toxicity of intraocular lidocaine and bupivacaine. Am J Ophthalmol 1998;125:191– 6. 33. Lincoff H, Zweifach P, Brodie S, et al. Intraocular injection of lidocaine. Ophthalmology 1985;92:1587–91. 34. Mondragon R, Frixione E. Conditional inhibition of screening-pigment aggregation by lidocaine in crayfish photoreceptors and frog retinal pigment epithelium. J Exp Biol 1992;166: 197–214. 35. Ohguro N, Matsuda M, Kinoshita S. The effects of denatured sodium hyaluronate on the corneal endothelium in cats. Am J Ophthalmol 1991;112:424 –30. 36. Werner LP, Legeais JM, Obsler C, et al. Toxicity of Xylocaine to rabbit corneal endothelium. J Cataract Refract Surg 1998; 24:1371– 6. 37. Zemel E, Loewenstein A, Lazar M, Perlman I. The effects of lidocaine and bupivacaine on the rabbit retina. Doc Ophthalmol 1995;90:189 –99. 38. Eggeling P, Pleyer U, Hartmann C, Rieck PW. Corneal endothelial toxicity of different lidocaine concentrations. J Cataract Refract Surg 2000;26:1403– 8.
Intracameral Anesthesia A Report by the American Academy of Ophthalmology Carol L. Karp, MD, Terry A. Cox, MD, PhD, Michael D. Wagoner, MD, Reginald G. Ariyasu, MD, PhD, Deborah S. Jacobs, MD Objective: This document describes the technique of intracameral anesthesia and examines the available evidence to address questions about its effectiveness, possible corneal endothelial and retinal toxicity, and the optimal and maximal dose. Methods: A literature search conducted for the years 1968 to 2000 retrieved over 180 citations that matched the search criteria. Panel members and a methodologist reviewed this information, and it was evaluated for the quality of the evidence presented. Results: Some studies report effectiveness of intracameral anesthesia while others report no effect. In those studies showing an effect, levels of pain in the groups that were compared were low. Short-term studies seem to indicate that preservative (methylparaben)-free lidocaine 1% is well tolerated by the corneal endothelium but that higher concentrations of lidocaine are toxic. There is some evidence of electroretinogram changes after exposure to lidocaine or bupivacaine. Conclusions: The ideal timing and placement of intracameral anesthesia has not been determined. Because topical anesthesia alone is effective, surgeons may elect to use intracameral anesthesia for incremental pain control in patients who cannot be adequately managed with topical alone. Appropriate patient selection is important when using this method of anesthesia. While short-term studies seem to indicate safety, long-term effects are unknown. Patient preferences for anesthesia are not well studied. Ophthalmology 2001;108: 1704 –1710 © 2001 by the American Academy of Ophthalmology. The American Academy of Ophthalmology (AAO) prepares the Ophthalmic Technology Assessments (OTAs) to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an OTA is to evaluate the peer-reviewed published scientific literature, to distill what is well established about the technology, and to help refine the important questions to be answered by future investigations. After appropriate review by all contributors, including legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements.
Background Topical and intracameral anesthesia are new options for pain control in modern cataract surgery. Topical anesthesia has been shown to be a safe and effective alternative to retrobulbar and peribulbar anesthesia.1 Topical and intracameral anesthetics have potential safety advantages over Originally received: June 15, 2001. Accepted: June 15, 2001. Manuscript no. 210407. Prepared by the Ophthalmic Technology Assessment Committee Anterior Segment Panel and approved by the American Academy of Ophthalmology’s Board of Trustees June 10, 2001.
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© 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
traditional retrobulbar and peribulbar injections,2 which rarely can be complicated by globe perforation, retinal vascular occlusion, retrobulbar hemorrhaging, strabismus, ptosis, optic nerve damage, and even cardiac or respiratory arrest.3–5 In addition to avoiding the above complications, topical administration of anesthesia also provides patients with immediate visual recovery. Although topical administration of anesthesia does provide immediate onset of action, there are limitations to this form of anesthesia. These include lack of akinesis and inadequate blockade of the sensory nerves in the iris and ciliary body when only topical drops are used. Patients may therefore experience discomfort during iris and lens manipulation and intraocular lens (IOL) implantation, and surgeons may be uncomfortable initially with patient movement and lid squeezing. The lack of optic nerve blockade may also result in intolerance to the microscope light. Some surgeons who use topical anesthesia have found it necessary to supplement with subconjunctival or sub-Tenon’s anesthesia to improve patient comfort.3 More recently, intracameral anesthesia has been introduced as a possible method for providing additional anesthetic effect. Intracameral techniques have included the use of preservative-free (PF) lidocaine hydrochloride 1% or PF bupivacaine hydrochloride 0.5%. These anesthetics have been injected in ISSN 0161-6420/01/$–see front matter PII S0161-6420(01)00793-X
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment doses of 0.1 to 0.5 ml into the anterior chamber prior to phacoemulsification. Since these drugs are not formulated for intraocular use, there is concern about the efficacy and safety of this procedure, particularly possible toxicity to the corneal endothelium and retina.
FDA Status Intracameral use of PF lidocaine hydrochloride 1% or PF bupivacaine hydrochloride 0.5% is not approved by the U.S. Food and Drug Administration (FDA), and is considered off-labeled use of FDA-approved drug products. Therefore, any studies of intracameral lidocaine or bupivacaine should be conducted under an Investigational New Drug Exemption.
Resource Requirements An Evidence Report sponsored by the Agency for Healthcare Research and Quality on anesthesia management during cataract surgery used a model to study cost considerations as part of their report.2 The method used for the comparison was to estimate the cost to the Medicare Program of various anesthesia strategies, and calculations were based on costs from The Johns Hopkins Hospital and the average wholesale price for drugs. The cost of all drugs was based on the most commonly administered medications for an average 45-minute case. Using this model, the investigators calculated that the costs of topical anesthesia (including intracameral block) and the costs of peribulbar or retrobulbar block anesthesia were $5 per case (range $1 to $9). The cost of converting from topical to block anesthesia was $5 per case (range $1 to $9). The cost of oral sedation was $5 per case (range $1 to $9) and of intravenous sedation was $30 per case (range $15 to $50).
these papers and selected 87 articles of possible clinical relevance to the assessment to read. Of these, 33 were found relevant to the assessment questions and were reviewed by the panel methodologist. Thirteen papers described experimental animal studies, and one paper was a case report. In the remaining 19 papers the methodologist assigned one of the following ratings of level of evidence to each of the selected articles. A Level I rating is assigned to properly conducted, well-designed randomized clinical trials; a Level II rating is assigned to well-designed cohort and case-control studies; and a Level III rating is assigned to case series. During methodological review, statistical analyses were repeated and papers with statistical inconsistencies resulting in inconclusive P values are not presented as evidence. The quality of statistical methods used in the studies reviewed was assessed using a scale from A to F. Papers with scores of D and F were considered to be unacceptable as medical evidence, C was borderline, and A and B were acceptable. On this statistical quality rating scale, 6 of 10 Level I randomized controlled trials, 2 of 4 Level II comparative studies, and 2 of 5 Level III studies received an A or B rating. After review, there were 10 Level I randomized clinical trials comparing topical anesthesia with supplemental intracameral lidocaine to intracameral balanced salt placebo or intracameral lidocaine to intracameral bupivacaine, some of which evaluated corneal or retinal toxicity.6 –15 In addition to the randomized clinical trials, there were also 4 Level II cohort or case control studies,16 –19 5 Level III studies,20 –24 and 13 experimental animal studies25–37 investigating drug uptake and toxicity. The animal studies are helpful in indicating potential toxicity, but application and relevance to human in vivo conditions is limited.
Published Results Questions for Assessment The focus of this assessment is to address the following questions: ● ● ●
Is intracameral anesthesia effective? What is the corneal endothelial and retinal toxicity of intracameral anesthesia? Is there any evidence to recommend an optimal and maximal dose of intracameral anesthesia?
Description of Evidence A literature search of MEDLINE was conducted for the years 1968 to 2000 and was limited to articles in English. It used combinations of the MeSH terms phacoemulsification, anesthesia, lidocaine, retina/drug effects, corneal endothelium/drug effects, and toxicity, with text words topical, ocular, intraocular, and intracameral. This search retrieved over 180 citations, and the reference lists of these articles were consulted for additional citations. Panel members reviewed
Effectiveness The first objective of this assessment was to evaluate the efficacy of intracameral anesthesia. The literature includes 10 randomized clinical trials that examined combined topical and intracameral anesthesia versus peribulbar anesthesia, topical anesthesia with the adjunct of intracameral anesthesia versus placebo, or intracameral lidocaine versus bupivacaine. Anders et al6 performed a randomized clinical trial comparing 200 patients who underwent cataract surgery with either peribulbar anesthesia or combined topical and intracameral anesthesia. Six ml of peribulbar prilocaine hydrochloride (injected in lower orbital rim) were used in one group, and the other received 0.15 ml of intracameral 1% nonpreserved lidocaine combined with topical oxybuprocaine topical drops applied to the conjunctiva with a cellulose sponge at the incision site for 5 minutes. Scleral incisions were performed in all cases. Intraoperative and postoperative pain levels were evaluated by means of a questionnaire. The paper did not specify when the patients
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Ophthalmology Volume 108, Number 9, September 2001 completed the questionnaire, but tables indicate pain evaluations 2, 4, and 6 hours after surgery. In comparing the reported intraoperative pain of the two patient groups, the patients who received the intracameral lidocaine reported more pain during cauterization of the sclera and at the final step of coagulation of the conjunctiva at the end of the surgery (P ⫽ 0.01). The other steps of the surgery showed no significant difference in pain level. As expected, eye movement and squeezing was significantly less frequent after peribulbar anesthesia (P ⫽ 0.01). However, no increase in complications was found due to eye movement or lid squeezing. The peribulbar group had elevated vitreous pressure more frequently (7%) than the intracameral group (3%). Fourteen percent of the peribulbar group also had eyelid hemorrhage, while 12% of the lidocaine groups had mild epithelial changes in the cornea due presumably to the anesthetic drops. The epithelial changes disappeared a few hours after surgery. Postoperatively, more pain was reported in the intracameral group (P ⫽ 0.0017). The discomfort occurred within the first 2 hours of surgery. After 4 and 6 hours, there was no significant difference between the groups. The vision was better in the intracameral group immediately after surgery, but there was no significant difference between the two groups on the first postoperative day. Electroretinograms (ERG) were performed preoperatively and approximately 40 minutes postoperatively on 15 patients selected randomly from each group, and evaluation of b-wave implicit times and amplitudes were conducted. There was no difference between the preoperative and postoperative implicit times and amplitudes between the two groups. The studies reached different conclusions about the effectiveness of intracameral anesthesia as an adjunct to topical anesthesia. Three randomized clinical trials9,12,13 report that the adjunct of intracameral lidocaine 1% decreased pain at various points during the surgery and after the surgery compared with groups receiving topical anesthesia and placebo intracamerally. Carino et al9 performed a randomized double-masked prospective study of topical tetracaine 0.5% with either 0.2 ml of intracameral balanced salt solution (BSS) or 0.2 ml of intracameral PF lidocaine 1%. The intracameral medication was given at the beginning of surgery through a corneal paracentesis. Temporal corneal incisions were made in all cases. The pain levels were rated at several points during the procedure including preoperatively, after the capsulorrhexis, after phacoemulsification, and at the end of surgery. Surgeon satisfaction was also rated. The intracameral BSS group had a higher intraoperative pain score and postoperative pain score compared with the lidocaine group (P ⫽ 0.019 and P ⫽ 0.014, respectively). In particular, the pain seemed to be most pronounced after the phacoemulsification and at the end of the procedure. The pain level was the same in both groups preoperatively and after the capsulorrhexis. Intravenous sedation for increased comfort was required more often in the BSS group (5 of 30 eyes) than in the lidocaine group (0 of 30 eyes, P ⫽ 0.052). There was no significant difference in patient satisfaction with the anesthesia between the two groups; however, surgeons were less satisfied with the intracameral BSS group
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(P ⬍ 0.001). Endothelial cell loss was measured at 1 month and was similar for both groups. However, measurements at 1 month do not necessarily reflect possible long-term endothelial changes. While the difference in mean pain scores was statistically significant, both groups had minimal pain. The mean intraoperative pain score for the BSS group was 0.63 ⫾ 0.7 and was 0.23 ⫾ 0.4 for the lidocaine group, where (0) was no pain and (1) was mild pain. Gills et al12 performed a prospective controlled study comparing topical anesthesia and either 0.1 ml of PF lidocaine 1% or 0.1 ml of BSS in a double-masked fashion. These drugs were injected intracamerally 1 minute before phacoemulsification. Pain was measured by the nurse anesthetist using a predefined uniform scale at various times following injection: 1 minute, 3 minutes, 5 minutes, midway through phacoemulsification and midway through IOL insertion. Important advantages of this study and of Carino et al9 were that the evaluation was done at multiple points during the procedure. Gills et al found a statistically significant decrease in intraoperative discomfort in the lidocaine 1% group (9% vs. 26%, P ⬍ 0.001). Elevated discomfort/ pain scores described as increased pressure (uncomfortable) or moderate pain seemed more frequent during IOL insertion than during phacoemulsification. The lidocaine group also had a slightly larger mean pupil diameter, although this was not statistically significant. Postoperative intraocular pressure and anterior chamber inflammation showed no difference. In a second, noncomparative study of 300 patients, Gills et al increased the dose to 0.5 ml of intraoperative PF lidocaine and found that the rate of discomfort was 1.7%. While this result compares favorably with the rate of discomfort using the smaller dosage in the first study, the lack of concurrent controls precludes any definitive conclusion about relative dose effects. Endothelial cell counts were measured 2 weeks postoperatively in the 0.5 ml group, and there were no differences in the mean preoperative and postoperative endothelial counts. Postoperative endothelial counts were collected 2 weeks postoperatively in 20% of the lidocaine and control groups, and no significant between-groups differences were noted. Several other studies showed minimal difference in pain control between intracameral lidocaine and placebo when using topical anesthesia.8,10,11,15 Boulton et al8 performed a prospective double-masked randomized control trial of 200 patients undergoing routine phacoemulsification under topical 1% tetracaine. The patients were randomized to 0.5 ml of intracameral PF lidocaine 1% or BSS. No intravenous sedation was used at all. The medication was given after the clear corneal incision. Patients were evaluated following surgery in the recovery room, and no difference was found in the rating of intraoperative pain. Possible limitations of the study are that the rating was done following the procedure rather than during it. However, no systemic intravenous medication was given to cloud the patients’ perception, and no evaluation of postoperative pain was conducted. Other studies also found no significant overall difference in pain from topical procedures with intracameral anesthesia compared with an intracameral placebo. There was an increased perception of tissue manipulation10 and increased
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment discomfort from the microscope light.11 The pain evaluations for all of the trials that showed no difference were conducted at the end of the procedure8,10,15 or the next day.11 Furthermore, one study15 placed the lidocaine into the capsular bag during hydrodissection rather than into the anterior chamber. This study also used scleral incisions. Studies judged Level II16 –19 and Level III20 –24 were also evaluated. A small series that examined the efficacy of intracameral lidocaine found that combined topical proparacaine 1% and 0.5 ml of intracameral lidocaine 1% was associated with more comfortable surgery than single-dose topical lidocaine jelly 2% or topical proparacaine 1% only.19 A large retrospective review performed by Masket20 evaluated 352 cases in which topical 4% lidocaine and tetracaine 0.5% were used compared with 279 cases in which the same topical lidocaine and tetracaine with the adjunct of 0.2 to 0.5 ml of PF lidocaine 1% intracamerally was used. The authors reported that 43% (150/352) of the patients with topical-only anesthesia required injection of subconjunctival or posterior sub-Tenon’s anesthetic for patient comfort compared with 0.36% (1/279) of patients who received the two topical anesthetics as well as intracameral lidocaine. This was found to be statistically significant. However, this study is limited because it is retrospective, the parameters for extra anesthesia were not well defined, and the technique of phacoemulsification was changed from divide and conquer to phaco chop within the second group.
Corneal Toxicity The second objective of this assessment was to consider the evidence of corneal toxicity from intracameral anesthesia. Several of the randomized clinical studies did examine postoperative endothelial cell counts in the short term.12,13,18 The dose ranged from 0.1 ml to 0.5 ml of PF lidocaine 1%, and early endothelial studies that ranged from 2 weeks,12,14 1 month22 or 3 months13,21 showed no change in endothelial cell counts compared with control. There was also no difference in blood aqueous barrier permeability between lidocaine and control groups at 1 month.21 Many other experimental animal studies were performed looking at endothelial toxicity.7,16,25,30,31,35,36,38 Kim et al31 evaluated the in vitro effect of PF lidocaine 1% on the corneal endothelium of human and rabbit corneas perfused with either PF lidocaine 1% or control. After a 1-hour stabilization period with control fluid, the eyes were exposed to the drug or control for 15 minutes followed by a washout. Both human and rabbit corneas had transient, reversible edema during lidocaine perfusion that reversed after the control washout perfusion. Three human corneas were exposed to the lidocaine for 15 minutes followed by a 15-minute washout. A live cell-dead cell assay of the tissue showed no significant changes compared with controls. Kadonosono et al30 injected PF lidocaine in concentrations of 0.02%, 0.2%, and 2% intracamerally into one eye of rabbits and BSS in the fellow eye control. Continuous irrigation was performed for 10 minutes and the rabbits were sacrificed. Scanning electron microscopy revealed no abnormal findings in the eyes injected with either lidocaine 0.02% or 0.2% when compared with control, but the eyes
injected with lidocaine 2% showed irregular hexagonal endothelial cells and significant loss of microvilli. Similarly, Werner et al36 performed an in vitro study of rabbit cornea exposed to lidocaine 1%, lidocaine 5%, and a control of BSS. These were exposed for 20 minutes and then evaluated with trypan blue and alizarin red. Studies showed that none of the rabbit eyes had staining with trypan blue. There was no difference in cell loss, but the cells exposed to lidocaine 5% had more irregular shapes and borders. No long-term studies about the reversibility or changes due to pH and osmolarity were performed. A study done by Eggeling et al38 exposed porcine corneas to PF lidocaine hydrochloride at 1%, 5%, and 10% for 60 minutes. A small subset was exposed to lidocaine hydrochloride 1% only for 30 minutes to simulate the clinical situation. The study found that lidocaine 1% in contact with the endothelium for 30 minutes or 60 minutes in porcine corneas did not cause any significant corneal endothelial damage compared with the control. Significant corneal endothelial cell loss was observed with the lidocaine 5% and lidocaine 10% groups (P ⬍ 0.001 in both groups). Ohguro et al35 performed an in vivo study in cats. Intracameral 0.5% lidocaine was given along with sodium hyaluronate (0.25 ml), and no washout was performed. The eyes were evaluated clinically preoperatively and at 1, 4, and 7 days after drug delivery. Specular microscopy was also performed. The study found that the eyes injected with lidocaine had only mild edema and specular microscopic analysis revealed that the percentage of cell loss and percentage of hexagonal cells did not change significantly through the observational period. The percentage of hexagonal cells did tend to decrease at 7 days. Scanning electron microscopy was essentially normal in appearance after sacrifice at 7 days. While lidocaine is the most commonly used medication, some studies have also looked at bupivacaine. Anderson et al7 performed a double-masked randomized clinical study, which found no significant difference in pain between intracameral bupivacaine 0.5% and lidocaine 1%. They also performed a rabbit study in which corneal swelling was observed in rabbits exposed to bupivacaine 0.5% for 1 hour. Corneal changes, however, did not occur when the bupivacaine was diluted 1:1 with glutathione bicarbonate Ringer’s solution. Judge and co-authors25 found that intracameral injection of tetracaine hydrochloride 0.5% did not produce any significant corneal thickening in rabbits, but PF lidocaine hydrochloride 4%, bupivacaine hydrochloride 0.75%, and proparacaine hydrochloride 0.5% did produce significant thickening and opacification.
Retinal Toxicity Retinal toxicity of intracameral lidocaine is another concern if it diffuses posteriorly to the retina. There have been anecdotal reports of patients losing light perception temporarily following intracameral anesthesia.9,29 Similarly, vision has been lost following an inadvertent intravitreal injection of lidocaine.33 Several in vitro experimental studies have suggested that lidocaine and/or bupivacaine may be toxic to the reti-
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Ophthalmology Volume 108, Number 9, September 2001 na.27,28,33,34 Mondragon and Frixione34 found that in vitro lidocaine may interfere with the dark adapting migration of screening pigments in crayfish photoreceptors and frog retinal pigment epithelial cells. The inhibition of dark adaptation was reversible and dependent on levels of calcium and sodium. Incubated chick retinas in vitro exposed to lidocaine (3 to 7 mM) for 30 minutes had a dose-dependent decrease in propagation, amplitude, and duration of the slow potential change of spreading depression. In a study by Grosskreutz et al,28 lidocaine was injected intravitreally in rats, and 1 week later the cells were evaluated histologically. Intravitreal lidocaine was toxic to the rat ganglion cells in a dosedependent fashion. This toxicity was blocked by nimodipine, which is a glutamate antagonist and seems to prevent neuronal death. The study also noted a dose-dependent toxicity to rat ganglion cells. Lower concentrations of lidocaine (0.5 mM and 1.0 mM) were nontoxic, but higher levels showed toxicity (2.0 mM, 6.0 mM, 12 mM). While no correlation can be made from in vitro rat cells to human in vivo cells, it is interesting to note that a 0.5 ml dose of lidocaine 1% distributed evenly in the human eye could produce a concentration of approximately 5 mM. While the above in vitro studies raise concern, other clinical6 and experimental32,33,37 studies have shown no long-term effect of the intracameral anesthetics on retinal cells. In the randomized clinical trial done by Anders et al,6 15 patients from both treatment (lidocaine 1% 0.15 ml) and control groups had ERGs evaluated preoperatively and 40 minutes postoperatively, as described above. There was a decrease of the b-wave amplitude 40 minutes postoperatively in both groups, but there was no significant change in the control versus the lidocaine group in terms of implicit time of amplitudes. Zemel et al37 evaluated the effect of intravitreal injections of lidocaine (5 mg and 10 mg) and bupivacaine (0.5 mg) in rabbits. Electroretinograms and visual evoked potentials (VEP) were performed 10 minutes following injection and 1 week later. Histopathology was also performed. The study found that intravitreal lidocaine 5 mg or 10 mg and bupivacaine 0.5 mg did not produce any ERG or VEP changes at the 1-week mark, and histopathology revealed normal histopathology in the lidocaine 5 mg and bupivacaine 0.5 mg group. The 10 mg group had structural changes only at the site of the injection. Other experimental studies also suggest that ERGs normalize in cats33 and rabbits32 following intravitreal injection of lidocaine. Liang et al32 injected 0.2 ml of lidocaine (2%, 1%, 0.5%, 0.25%) and bupivacaine (0.75%, 0.5%, 0.25%). No a-wave changes were noted and b-waves showed a dose-dependent decrease in amplitude and implicit time that normalized within 24 hours. No histological changes were noted at 1 week. In order to evaluate the pharmacodynamics of lidocaine, Anderson et al26 performed a laboratory study of uptake, washout, and metabolism of 1% lidocaine hydrochloride in the iris and ciliary body in the cornea of rabbits and humans. The authors reported that there is a rapid uptake of radiolabeled 1% lidocaine in the iris ciliary body tissue (50% to 60% in 5 minutes) and a rapid washout with a half-life of 8
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to 9 minutes. The corneal uptake and washout was also rapid and no lidocaine metabolites were detected. This study showed no difference between pigmented and nonpigmented eyes. Wirbelauer et al24 evaluated the systemic levels of lidocaine after intracameral injection of 0.5 ml of PF lidocaine 1%. The levels were measured at 1 minute, 2 minutes, 5 minutes, and 15 minutes after injection, and there was no detectable systemic level of lidocaine in the blood systems of the patients.
Conclusions Ten Level I randomized clinical trials have been performed to evaluate the effectiveness of intracameral anesthesia, primarily with PF lidocaine 1%. Several studies have indicated that the adjunct of intracameral anesthesia to topical drops provides increased patient comfort, particularly during iris manipulation, changes in the iris lens diaphragm, and IOL insertion. Studies that actually evaluated patient comfort during the surgery seemed to indicate that patients experienced more discomfort during certain portions of the surgery when placebo was used compared to intracameral anesthesia.9,12,13 Overall, however, the pain levels for both intracameral placebo and lidocaine were low because topical anesthesia alone is very effective. Four studies show no significant difference8,10,11,15 between intracameral anesthesia and intracameral BSS pain control except for the experience of increased light sensitivity from the microscope light and sensation of tissue manipulation. These studies may be limited in that the pain assessment was done in the recovery room at the end of surgery or on the first postoperative day. No long-term studies on corneal endothelial toxicity are available yet. Short-term studies seem to indicate that PF lidocaine 1% up to a dose of 0.5 ml is well tolerated by the corneal endothelium in the short term.12,13,18 This is corroborated by several animal studies where low-dose lidocaine is well tolerated.30,31,35 However, higher concentrations of lidocaine are indeed toxic to the corneal endothelium.30,36,38 There is some evidence of possible retinal toxicity, specifically of ERG changes following exposure to lidocaine or bupivacaine.27,28,33,34 Studies indicate that these changes are dose dependent32,37 and transient.6,32,38 Only the Anders et al6 study was done in the setting of a randomized clinical trial, and only 15 patients in each group were studied. Because of the small sample size, this study may have had inadequate power to detect clinically important differences.
Recommendations Straight topical anesthesia appears to be effective for the appropriately selected patient population. Surgeons may elect to use intracameral anesthesia for incremental pain control in patients who cannot be adequately managed with topical alone. Topical anesthesia with supplemental intracameral anesthesia offers rapid visual rehabilitation and,
American Academy of Ophthalmology 䡠 Ophthalmic Technology Assessment depending on individual surgeon’s circumstances, a potential reduction in length of room turnover time compared to retrobulbar or peribulbar anesthesia. Appropriate patient selection is important when using intracameral anesthesia. Patient cooperation, anticipated duration of surgery, possibility of complications, axial length, and anticoagulation status of the patient are some factors to consider when choosing whether or not to use this type of anesthesia. It is recommended that the minimal amount and concentration of intracameral anesthesia be used based on the surgeon’s surgical technique and patient needs. Preservative-free lidocaine 1% in doses of 0.1 ml to 0.5 ml has not been associated with short-term problems in patients, but experimental studies suggest that higher concentrations may be associated with corneal endothelial toxicity. Most reports studied lidocaine that was injected directly into the aqueous humor (compared with using lidocaine solution for hydrodissection, for example), but the optimal timing and placement of administration has not been studied. While the short-term studies seem to indicate safety, there are still many unknowns, including the long-term effect on the corneal endothelium, the possible toxicity
relating to posterior diffusion of the anesthetics through an intact posterior capsule and zonules, and the effect of administering multiple doses. Intracameral bupivacaine in cataract surgery is not as well studied as lidocaine. Bupivacaine 0.5% or 0.75% may be more toxic to the corneal endothelium than 1% lidocaine. An advantage over lidocaine has not been established, suggesting that 1% lidocaine may be a more reasonable choice.
Future Research Long-term studies in humans still need to be done to evaluate corneal endothelial toxicity. Additional short-term and long-term human retinal studies are also required to ensure that intracameral anesthesia is indeed safe. Additional questions to be answered include: ● ● ● ●
Specifically, how does intracameral compare to retrobulbar or peribulbar anesthesia? Which method of anesthesia do patients prefer? What is the ideal timing and placement of intracameral anesthesia? What is the cost-effectiveness of different anesthesia strategies?
Preparation was coordinated by the Ophthalmic Technology Assessment Committee Anterior Segment Panel. Original Draft by: Ophthalmic Technology Assessment Committee Anterior Segment Panel
Edited by: Managing Editors:
Approved by:
Carol L. Karp, MD, OTAC Anterior Segment Panel Michael D. Wagoner, MD, Chair Reginald G. Ariyasu, MD, PhD Deborah S. Jacobs, MD Terry A. Cox, MD, Methodologist Susan Garratt Flora Lum, MD Nancy Collins, RN, MPH Margo Leslie Board of Trustees, June 10, 2001
*Proprietary Interests N N N N N N N N N
*Proprietary interests stated Category
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Financial interest in equipment, process, or product presented. Such interest in potentially competing equipment, process, or product. Financial interest in a company or companies supplying the equipment, process, or product presented. Such interest in a potentially competing company. Compensation received within the past 3 years for consulting services regarding the equipment, process, or product presented. Such compensation received for consulting services regarding potentially competing equipment, process, or product. Examples of compensation received include: 1. Retainer 2. Contract payments for research performed 3. Ad hoc consulting fees 4. Substantial nonmonetary perquisites 5. Contribution to research or research funds 6. Contribution to travel funds 7. Reimbursement of travel expenses for presentation at meetings or courses 8. Reimbursement of travel expenses for periods of direct consultation No financial interest. May be stated when such interests might falsely be suspected.
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Ophthalmology Volume 108, Number 9, September 2001
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