Effects of topical ketorolac tromethamine 0.45% on intraoperative miosis and prostaglandin E2 release during femtosecond laser–assisted cataract surgery

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ARTICLE

Effects of topical ketorolac tromethamine 0.45% on intraoperative miosis and prostaglandin E2 release during femtosecond laser–assisted cataract surgery Jong Hwa Jun, MD, PhD, Young-Sik Yoo, MD, Sung A. Lim, MD, Choun-Ki Joo, MD, PhD

Purpose: To determine the effects of topical 0.45% ketorolac tromethamine on intraoperative miosis and prostaglandin E2 (PGE2) release during femtosecond laser–assisted cataract surgery. Setting: Seoul St. Mary's Hospital, Seoul, Korea. Design: Prospective case series. Methods: The study comprised the following 3 groups: conventional cataract surgery without topical NSAIDs (conventional group); femtosecond laser–assisted cataract surgery with preoperative topical ketorolac tromethamine 0.45% (femtosecond NSAID group), and femtosecond laser–assisted cataract surgery without topical NSAIDs (femtosecond no-NSAID group). To measure the aqueous humor PGE2 concentration, a 100 mL aqueous humor sample was collected from the anterior chamber after femtosecond laser pretreatment. The PGE2 concentration was measured using an enzyme immunoassay.

V

arious studies have evaluated the usefulness of femtosecond laser–assisted cataract surgery. Precise evaluations of anterior segment structure via optical coherence tomography and ultrashort pulse energy emissions have yielded various surgical advantages.1,2 These are a precise capsulotomy, lower phacoemulsification energy, and concomitant astigmatic correction.2–7 Although these surgical advantages suggest promising innovations that compare with the development of the phacoemulsifier in the 1960s, their intraocular effects are still unknown. Among these, Bali et al.1 first reported intraoperative miosis after femtosecond laser–assisted cataract

Results: Topical ketorolac tromethamine 0.45% led to a significant reduction in intraoperative miosis in the femtosecond NSAID group compared with the femtosecond no-NSAID group (P < .001). Absolute and relative reductions in pupil area in the femtosecond NSAID group were significantly lower than in the femtosecond no-NSAID group (P Z .019 and P Z .007, respectively). The mean aqueous humor PGE2 concentrations were 893.60 pg/mL G 843.10 (SD) in the conventional group, 1911.43 G 1178.63 pg/mL in the femtosecond NSAID group, and 743.63 G 927.46 pg/mL in the femtosecond no-NSAID group (P < .001, conventional versus femtosecond NSAID and femtosecond NSAID versus femtosecond no NSAID; P > .05, conventional versus femtosecond NSAID). Conclusion: Preoperative topical ketorolac tromethamine 0.45% reduced miosis induced by femtosecond laser pretreatment and inhibited aqueous humor PGE2 elevation. J Cataract Refract Surg 2017; 43:492–497 Q 2017 ASCRS and ESCRS

surgery. Miosis is a major disadvantage of femtosecond laser–assisted cataract surgery versus conventional cataract surgery because miosis during the phacoemulsification procedure can substantially increase surgical complications.1,8–11 In a previous study,12 we found significant miosis after femtosecond laser pretreatment. Prostaglandin E2 (PGE2) release has been suggested as an underlying causative factor, although a precise mechanism has not been fully determined.13,14 In view of the significant miosis that occurs after femtosecond laser pretreatment, recent studies15–18 evaluated preventive regimens as well as the inhibition of PGE2 release into the aqueous humor when these regimens are used.

Submitted: August 12, 2016 | Final revision submitted: January 12, 2017 | Accepted: January 12, 2017 From the Department of Ophthalmology (Jun), Keimyung University School of Medicine, and Nune Eye Hospital (Lim), Daegu, the Catholic Institute for Visual Science (Yoo, Joo), and the Department of Ophthalmology and Visual Science (Joo), Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, South Korea. Supported by Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2016R1A6A1A03010528) and the NRF Grant funded by the Korea Government (2014R1A5A2010008). Presented in part at the 114th annual meeting of the Korean Ophthalmological Society, Kintex Koyang, South Korea, November 2015. Corresponding author: Choun-Ki Joo, MD, PhD, Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.

0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.01.011

KETOROLAC 0.45% EFFECT ON INTRAOPERATIVE MIOSIS IN FEMTOSECOND-ASSISTED CATARACT SURGERY

In those studies, eyedrops comprising topical nepafenac and diclofenac, which are both nonsteroidal antiinflammatory drugs (NSAIDs), effectively reduced the concentration of PGE2 in the aqueous humor.15–18 However, whether the inhibition of PGE2 release by preoperative topical NSAIDs also prevents intraoperative miosis remains unknown. Therefore, in the current study, we evaluated the preventive effect of ketorolac tromethamine 0.45% eyedrops on the elevation of aqueous humor PGE2 concentration and its inhibitory effects on intraoperative miosis. PATIENTS AND METHODS This prospective comparative case series was approved by the Institutional Review Board (IRB), Catholic University of Korea (IRB #KC13DISI0534). The same board approved the collection of aqueous humor from each patient, and all patients provided written informed consent before surgery. All aspects of the study were performed in accordance with the tenets of the Declaration of Helsinki. Eyes of patients were randomly allocated to 1 of 3 groups as follows: conventional cataract surgery, femtosecond laser–assisted cataract surgery with NSAID pretreatment (femtosecond NSAID group), and femtosecond laser–assisted cataract surgery without NSAID pretreatment (femtosecond no-NSAID group). Patients were treated at the same institution (Seoul St. Mary's Hospital, Seoul, South Korea) between June 2014 and October 2015. Patients were excluded from the study if they had a history of intraocular surgery, a significant history of ocular trauma or surgery, or pseudoexfoliation syndrome; were using glaucoma medication; had ever had glaucoma surgery; or had preoperative zonular fiber weakness or poor pupil dilation. In addition, patients who had used systemic or topical steroids or NSAIDs within the previous 2 weeks or a systemic a1A-adrenoceptor antagonist (tamsulosin) were also excluded. Included cases were evaluated for patient age, sex, and laterality of surgery. The shifting time, defined as the time between femtosecond laser pretreatment termination and phacoemulsification initiation, was measured in each patient. Schultz et al.15 have reported that laser capsulotomy was solely related to PGE2 release; therefore, the capsulotomy diameter was compared between the 2 femtosecond groups. In addition, it has been reported that prostaglandin originating from the nonpigmented epithelium of the ciliary body19,20 as well as the pupil–capsulotomy distance are associated with PGE2 levels and miosis15; therefore, the study evaluated whether the pupil–capsulotomy distance was correlated with the PGE2 concentration in the aqueous humor. Surgical Technique All femtosecond laser pretreatments and phacoemulsification procedures were performed by the same experienced surgeon (C.-K.J.). In all patients, tropicamide 0.5%–phenylephrine 0.5% (Mydrin-P) was administered to patients 3 times in the 1 hour before surgery. When pupils did not dilate sufficiently (!5.0 mm), a dilating eyedrop was administered 1 or 2 more times. In the femtosecond NSAID group, ketorolac tromethamine 0.45% eyedrops (Acuvail) were administered 4 times during 1 hour before surgery because the time to maximum concentration in the iris–ciliary body after instillation of ketorolac 0.45% was 1 hour in an animal study21; no ketorolac tromethamine eyedrops were administered in the femtosecond no-NSAID group. After sufficient pupil dilation (R5.0 mm) was confirmed, femtosecond laser pretreatments were performed using the Catalys Precision laser system (Abbott Medical Optics, Inc.) in both femtosecond groups. All laser procedures and cataract surgeries were performed under topical anesthesia. In the femtosecond NSAID group, the capsulotomy size ranged from 4.5 to

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5.8 mm and the pulse energy was set at 4.0 mJ with a depth of 600 mm. Lens fragmentation was segmented into quadrants with an 8 mJ/10 mJ (anterior/posterior) pulse energy, segmentation repetitions (n) of 4, and spacing (reg-soft/grid) of 500 mm/500 mm. The arcuate incision was performed with 5 mJ energy. The primary and secondary laser incisions were created with 6 mJ pulse energy. The spot spacing (horizontal/vertical) of the capsulotomy, lens fragmentation, and the arcuate, primary, and side-port incisions were 5 mm/10 mm, 10 mm/40 mm, 5 mm/10 mm, 4 mm/8 mm, and 3 mm/5 mm, respectively. The width/length of the primary incision and side-port incision were 2.3 mm/1.1 mm and 1.1 mm/1.1 mm, respectively. After completion of the entire laser emission procedure, each patient was transported to a day-surgery operation room. At the initiation of phacoemulsification in all 3 groups, approximately 70 to 100 mL of aqueous humor was aspirated using a 1.0 mL insulin syringe via a side-port incision. Each sample was abruptly frozen under liquid nitrogen and stored at
80 C until the PGE2 enzyme immunoassay was performed. The minimum volume required for the detection of PGE2 concentration is 150 mL; 2-fold dilution of aqueous humor was performed before enzyme immunoassay testing. The phacoemulsification procedure was performed using the Infiniti Vision System (Alcon Laboratories, Inc.) with the conventional technique. Pupil Area Measurement Assessments before and after femtosecond laser pretreatment were performed using a previously described method.12 Still images derived from video recordings of the femtosecond laser and phacoemulsification procedures were used after all surgeries were completed. The pupil area and capsulotomy area were measured using Image J software (National Institutes of Health).13 Using these factors, pupillary area was calculated using the following proportional equations for the pre-femtosecond pupil area (mm) and the pre-phacoemulsification pupil area (mm), respectively:  2 Laser area ðpupilÞ Diameter ðtargetÞ  p Laser area ðcapsulotomyÞ 2  2 Phaco area ðpupilÞ Diameter ðtargetÞ p Phaco area ðcapsulotomyÞ 2

Prostaglandin E2 Parameter Immunoassay In a pilot measurement of PGE2 concentration, higher levels of PGE2 were noted in some samples. The human PGE2 Parameter Assay Kit (R&D Systems, Inc.) was used to determine PGE2 concentrations (assay range 39 to 2500 pg/mL) in accordance with the manufacturer's protocol. After each sample was thawed, brief centrifugation was performed. Each sample was loaded into a 96-well assay plate, and the primary antibody solution was added. The plate was sealed and then incubated for 1 hour on an orbital shaker at 500 rpm. The PGE2 conjugate was added to each well, after which the plate was reincubated on the orbital shaker for 2 hours. Aspiration and repeated washing of the wells were performed, and the substrate solution was then added. Colorimetric changes were measured at 450 nM using a microplate reader (Versamax, Molecular Devices, LLC). Statistical Analyses A paired t test was used to compare pupil area reductions before and after femtosecond laser pretreatment. An independent t test was used to compare pupil area at the initiation of phacoemulsification in the 2 femtosecond groups. One-way analysis of variance was used to evaluate PGE2 levels in the aqueous humor in all groups. Pearson correlation coefficients were used to evaluate the statistical significance of relationships between pupil area reduction, patient age, capsulotomy–pupil margin distance, time Volume 43 Issue 4 April 2017

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from femtosecond laser pretreatment to phacoemulsification, and PGE2 concentration. A chi-square test was used to compare frequency parameters (eg, laterality of surgery and sex of patient). Statistical significance was defined as a P value less than 0.05. All statistical analyses were performed using SPSS statistical software (version 12.0, SPSS, Inc.).

femtosecond laser pretreatment was lower than in the femtosecond no-NSAID group (P Z .024, c2 test with Bonferroni correction, 2  2 comparisons between !5.5 mm and 5.5 to 7.0 mm; P value by c2 test with Bonferroni correction). Figure 1 shows the pupil diameter in both groups.

RESULTS The study comprised 90 eyes of 90 patients; each of the 3 groups comprised 30 eyes. The mean patient age was 67.13 years G 7.72 (SD) in the conventional cataract surgery group, 65.53 G 7.80 years in the femtosecond NSAID group, and 61.43 G 13.80 years in the femtosecond no-NSAID group. There was no statistically significant difference in mean age between the 3 groups (P Z .08). The distributions of laterality of surgery (right/left) were 11/19 in the conventional cataract surgery group, 12/18 in the femtosecond NSAID group, and 19/11 in the femtosecond no-NSAID group, and the sex distributions (male/female) were 7/23, 7/23, and 11/19, respectively. Neither the laterality of surgery distributions nor the sex distributions differed significantly between the 3 groups (P Z .106 and P Z .449, respectively). All enrolled patients had primary and arcuate incisions using the femtosecond laser, and side-port incisions for the use of the secondary instruments were performed in 16 of 30 patients in the femtosecond NSAID group and 13 of 30 patients in the femtosecond noNSAID group (c2 Z 0.601, P Z .438).

Prevention of Aqueous Humor Prostaglandin E2 Elevation After Femtosecond Laser Pretreatment with Preoperative Topical Ketorolac Tromethamine 0.45%

Prevention of Intraoperative Miosis After Femtosecond Laser Pretreatment with Preoperative Topical Ketorolac Tromethamine 0.45%

The mean reduction in pupillary area after femtosecond laser pretreatment was significantly reduced by ketorolac tromethamine 0.45% pretreatment in femtosecond patients. However, the topical NSAID did not completely prevent the reduction in pupil area associated with femtosecond laser photodisruption. A substantial reduction in pupil area (mean 19.56%) was observed in the femtosecond NSAID group (Table 1). The mean pupil diameter after femtosecond laser pretreatment 5.78 G 1.02 mm (range 3.41 to 7.27 mm) in the femtosecond NSAID group and 6.50 G 0.65 mm (range 4.88 to 7.86 mm) in the femtosecond no-NSAID group. The frequency of clinically significant miosis in the femtosecond NSAID group (pupil diameter !5.5 mm) after

Femtosecond laser pretreatment induced significant PGE2 elevation in the aqueous humor compared with conventional cataract surgery. Topical NSAIDs prevented PGE2 elevation in the aqueous humor. In the femtosecond NSAID group, the mean aqueous humor PGE2 concentration was similar to that in the conventional cataract surgery group (Table 2 and Figure 2). Laser capsulotomy is a known factor for PGE2 release; there was no statistical difference between the 2 groups (mean capsulotomy diameter 5.15 G 0.18 and 5.14 G 0.13, respectively) (P Z .758). Correlations Between Factors and Aqueous Humor Prostaglandin E2 Level

Evaluation of the significance of correlations between patient age, pupil area reduction, capsulotomy–pupil margin distance, time from femtosecond laser pretreatment to phacoemulsification, and PGE2 concentration showed that patient age had no correlation with PGE2 concentration (r Z
0.023, P Z .889). In addition, there was no significant correlation between aqueous humor PGE2 concentration and the absolute reduction in pupil area (r Z 0.239, P Z .203) or relative reduction in pupil area (r Z 0.250, P Z .182). The mean shifting time was 68.37 G 21.52 minutes. The shifting time had no correlation with PGE2 concentrations (r Z 0.191, P Z .296). An evaluation of whether pupil– capsulotomy distance was correlated with aqueous humor PGE2 concentration, based on a predication that distance would be associated with PGE2 levels and miosis, found a low correlation that was not statistically significant (r Z 0.079, P Z .668). The mean pupil–capsulotomy distance was 0.97 G 0.23 mm. DISCUSSION A small pupil is one of the most challenging aspects of cataract surgery.11,22 Several studies11,23,24 reported that small

Table 1. Comparisons of estimated pupil area after femtosecond laser pretreatment with or without preoperative topical ketorolac tromethamine 0.45%. Mean ± SD Pupil Area (mm2) Ketorolac Pretreatment

Pre-Femto*

Pupil Reduction

Pre-Phaco

†

Absolute (mm2)

Relative (%)

P Valuez

No (n Z 30)

39.61 G 5.18

27.13 G 8.94

12.48 G 7.57

31.89 G 19.66

!.001

Yes (n Z 30)

40.95 G 4.47

33.02 G 6.25

8.20 G 6.15

19.56 G 13.83

!.001

.289

.005

.019

.007

d

P valuex

*Pupil area measured immediately before femtosecond laser pretreatment † Pupil area measured immediately before phacoemulsification z Paired t test x Independent t test

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Table 2. Comparisons of aqueous humor PGE2 levels by group. Group

Mean PGE2 (pg/mL) ± SD

Conventional (n Z 30)

893.60 G 843.10

Femtosecond (n Z 30) Ketorolac given Ketorolac not given

743.63 G 927.46 1911.43 G 1178.63

Ketorolac Z ketorolac tromethamine 0.45%; PGE2 Z prostaglandin E2

Figure 1. Classification of patients according to pupil diameter after femtosecond laser pretreatment (ketorolac tromethamine 0.45%
Z femtosecond laser pretreatment without topical ketorolac tromethamine 0.45%; ketorolac tromethamine 0.45%C Z femtosecond laser pretreatment with topical ketorolac tromethamine 0.45%; NSAID Z nonsteroidal antiinflammatory drug).

pupils were associated with increased serious complications, posterior capsule rupture, dropped lens nucleus, iris damage, and cystoid macular edema during phacoemulsification. Although the exact complications potentially arising from a small pupil occurring after uneventful femtosecond laser pretreatment in cataract surgery are not known, it is reasonable to expect that increases in the aforementioned complications might be associated with the small pupil. To improve the stability of surgical outcomes after femtosecond laser–assisted cataract surgery, including capsulotomy, effective phaco time, intraocular lens centration, and refractive

Figure 2. Mean aqueous humor PGE2 levels in the 3 study groups (Conventional Z conventional cataract surgery; Femtosecond(
) Z femtosecond laser pretreatment without topical ketorolac tromethamine 0.45%; Femtosecond(C) Z femtosecond laser pretreatment with topical ketorolac tromethamine 0.45%; PGE2 Z prostaglandin E2).

results, issues related to intraoperative miosis should be further studied with regard to the causative mechanisms and potential solutions should be explored.3–5,7 Schultz et al.14 suggested that elevated prostaglandin is the main cause of pupillary constriction; however, they were unable to ascertain which procedures of femtosecond laser–assisted cataract surgery were associated with its elevations. Yet in their follow-up study,15 they suggested that laser capsulotomy is strongly associated with PGE2 elevation. They hypothesized that lower pulse energy and reduced incision depth during capsulotomy are important for the prevention of miosis because vibrations or shockwaves delivered to the ciliary body might be the main trigger of PGE2 release.15,18–20 They also postulated that combining the procedure with NSAID pretreatment might contribute to the prevention of PGE2 elevation.16 In another study,18 NSAID pretreatment effectively inhibited PGE2 release into the anterior chamber. However, it remains to be determined whether pretreatment with NSAIDs effectively inhibits the reduction of the pupil area. In addition, the relationship between NSAID pretreatment and changes in PGE2 concentration has not been fully evaluated. With regard to pharmacokinetics, ketorolac tromethamine 0.45% is effectively delivered to aqueous humor or the iris–ciliary body after administration, and maximum concentrations were observed within 1 hour in rabbits.25 On this basis, we administered ketorolac 0.45% eyedrops 1 hour before surgery in an effort to ensure that similar and effective amounts of the NSAID were delivered to the aqueous humor or iris tissue of each patient. In our study, the NSAID eyedrops reduced the absolute or relative reduction in the pupillary area compared with eyes not receiving it. However, a paired t test analysis of the pupillary area before and after femtosecond laser pretreatment revealed that there was still a reduction in pupillary area of nearly 20% with NSAID medication. In addition, a small proportion of patients showed clinically significant miosis (a pupil diameter of less than 5.5 mm, data not shown). Thus, further studies investigating the use of eyedrops or medication strategies to prevent miosis are required. We also evaluated the changes in PGE2 levels with and without topical NSAID pretreatment. As reported by Shultz et al.,14,15 femtosecond laser pretreatment induced significant PGE2 release into the aqueous humor. In addition, topical NSAID pretreatment on the day of surgery effectively reduced PGE2 to levels comparable to those associated with conventional phacoemulsification without femtosecond laser pretreatment. In another study, pretreatment with Volume 43 Issue 4 April 2017

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KETOROLAC 0.45% EFFECT ON INTRAOPERATIVE MIOSIS IN FEMTOSECOND-ASSISTED CATARACT SURGERY

topical nepafenac 0.1% the day before femtosecond laser–assisted cataract surgery effectively reduced total prostaglandin intracameral level to even lower than that of the total prostaglandin concentration in conventional cataract surgery.18 In our results, topical NSAID pretreatment on the day of surgery inhibited both aqueous humor PGE2 and significant miosis after femtosecond laser pretreatment. However, we did not observe a significant correlation between aqueous humor PGE2 concentration and a reduction in pupillary area. Thus, unknown factors might induce pupil constriction and these factors are not blocked or reversed by NSAID pretreatment. Therefore, the sampling timepoint of aqueous humor would induce a discrepancy in measured PGE2 concentrations and a reduction in pupillary area. Furthermore, there are interpersonal disparities between baseline PGE2 concentrations and PGE2 release induced by femtosecond laser irradiation. Further studies are needed to assess the underlying mechanisms. The PGE2 concentrations in the present study were much higher than those reported in previous studies.14–17,26 The femtosecond laser machine and ambulatory operating room are located in separate spaces; however, both femtosecond laser pretreatment and phacoemulsification are performed by the same surgeon. Therefore, femtosecond laser pretreatment of 3 or 4 patients is usually performed simultaneously. Then, the surgeon will move to the operating room and perform phacoemulsification sequentially. Therefore, the time between the 2 procedures is long in some cases. Patients having femtosecond laser pretreatment waited a mean of 68.37 G 21.52 minutes before phacoemulsification could be performed. During this time, PGE2 was likely released from the intraocular tissues into the anterior chamber aqueous humor, resulting in higher levels and a larger standard deviation of PGE2 concentrations than in the previous studies. In addition, our dilation regimen entailed a relatively weaker concentration of sympathomimetics and parasympatholytics, and this might have resulted in the differences between the results in the current study and the results of Schultz et al.14–16 This would suggest that the time between laser treatment and phacoemulsification should be minimized and that higher concentrations of dilating agents are favorable for preventing miosis in femtosecond laser–assisted cataract surgery. In addition, several differences in the experimental procedures, from collection of aqueous humor samples to detection of PGE2 using an enzyme immunoassay kit, might account for the higher levels of PGE2 in our study. We stored aqueous humor samples after snap freezing using liquid nitrogen. Because of this, our samples might have been less degraded than the samples in previous studies. Also, different enzyme immunoassay kits would show different levels of PGE2. Comparison of our results with those in previous studies is further complicated because the recent studies reporting an elevated aqueous humor PGE2 concentration and its blockage by NSAIDs each used different procedures for the application of NSAID eyedrops and other pretreatment methods. In addition, 1 study that evaluated PGE2 concentration after Volume 43 Issue 4 April 2017

femtosecond laser pretreatment and prevention by NSAID eyedrops showed similarly high concentrations of PGE2 and similar standard deviations without NSAID eyedrop administration before femtosecond laser pretreatments.18 One limitation of this study is the short period between NSAID pretreatment and femtosecond laser pretreatment. Although we based our protocol on a previous animal study of ketorolac tromethamine, aqueous humor concentration of ketorolac could be insufficient to prevent miosis. In addition, even though the NSAID achieved the maximum concentration in the aqueous humor, the long shifting time between femtosecond laser pretreatment and manual surgery could have induced a greater release of prostaglandins into the anterior chamber. In conclusion, the reduction in pupil area and PGE2 elevation were inhibited by preoperative topical ketorolac tromethamine 0.45% administered 1 hour before femtosecond laser pretreatment. However, the NSAID eyedrop pretreatment did not prevent pupil constriction completely. Future studies should evaluate which NSAID is more effective and what timing is efficient in preventing pupil constriction. In addition, further study is needed to determine additional factors associated with intraoperative miosis.

WHAT WAS KNOWN  Femtosecond laser pretreatment can induce intraoperative miosis.  Femtosecond laser pretreatment induces PGE2 release into the aqueous humor, although the precise mechanisms remain unclear.

WHAT THIS PAPER ADDS  Topical ketorolac tromethamine 0.45% significantly reduced the degree of intraoperative miosis after femtosecond laser pretreatment.  Topical ketorolac tromethamine 0.45% inhibited the elevation of PGE2 levels in the aqueous humor.

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Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned.

First author: Jong Hwa Jun, MD, PhD Department of Ophthalmology, Keimyung University School of Medicine, Daegu, South Korea

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