A Randomized Clinical Trial on Topical Ketorolac Administration Following Phaco-Surgery for Pseudoexfoliation Syndrome

INTRODUCTION

One in three blind people worldwide [1], particularly among the elderly [2], is blind due to cataracts, the most common cause of blindness worldwide. The front-line treatment strategy for cataracts is to replace the opacified intraocular lens (IOL) with an artificial crystalline lens via surgery [3] by multiple techniques, the most common of which is phacoemulsification [4]. In general, cataract surgery is safe and is associated with fewer serious complications, some of which are capsule rupture, retinal detachment, choroidal hemorrhage, and endophthalmitis. However, these adverse effects may lead to disturbed patient vision [5, 6].

A concomitant condition affecting the eyes is pseudoexfoliation syndrome (PEX), which weakens the zonular apparatus and capsule, increasing the risk of intraoperative and subsequent complications for those with it [7]. A distinct fibrillar substance that is deposited in the outer layer of the eye and other body segments is linked to this systemic condition. This condition raises the probability rate of anterior chamber inflammation (ACI), vitreous loss, lens dislocation, capsular phimosis, IOP spike, and corneal decompensation following surgery [8]." Accordingly, there is a need for further studies on this disease to reduce the risk of complications during and following phacoemulsification [9, 10]. According to specialists, experienced and skilled surgeons of phacoemulsification can eliminate the incidence rate of elevated adverse effects in eyes suffering from cataracts and PEX [11].

Another major complication following the cataract operation is inflammation, which can normally be prevented by prescribing post-operative eye drops, including NSAIDs (Non-Steroid Anti-Inflammatory Drugs) and steroids [12]. Various studies have examined and compared the effect of each of these two on post-operative adverse effects [12]. Based on the literature review, limited scientists examined the effect of NSAIDs in combination with steroids in subjects suffering from PEX following phacoemulsification regarding the cataract. Multiple studies reported significant positive effects for the combination of NSAIDs with steroids [13], while others found insignificant differences [14]. This controversy in different reports with various follow-up durations and types of NSAIDs/steroids used led us to investigate the impact of ketorolac eye drops in combination with topical steroids on post-surgical inflammation and anterior segment adverse effects in PEX patients.

MATERIALS AND METHODS

Patients with grade 3 cataracts with PEX and indications of phacoemulsification who were sent to the Hospital of Amir-al-Momenin in Rasht (Iran) between October 2016 and May 2019 were the subjects of the current endeavor. The research protocol, IRCT20160919029871N3, which was filed on the Iranian registry of clinical trials, was approved by the Guilan University of Medical Sciences Ethics Committee.

All patients were treated by the same ophthalmic surgeon. The OCCCGS (Oxford Clinical Cataract Classification and Grading System) was used to determine the cataract grade. The PEX was detected during slit lamp examination. An inclusion criterion was at least grade 3 cataracts with PEX and an indication of phacoemulsification. The exclusion criteria were hypersensitivity to any NSAIDs, ocular inflammation or trauma, chronic uncontrolled ocular or systemic disease, undergoing other cataract surgeries such as extracapsular or intracapsular techniques, history of oral, inhaled or locally taking NSAIDs a week before surgery or steroids by 2 weeks before surgery.

Patients were 
randomly allocated into the study group (topical ketorolac, additional to
 chloramphenicol and betamethasone) or the control group (chloramphenicol 
and betamethasone). Eligible patients were explained the research goals and methods and provided informed written consent to participate in the study voluntarily. Based on a 99% confidence interval and 90% test power, Coassin et al. [14] calculated the sample size to be 92. Forty-six patients in the study group and forty-six in the control group were removed from the trial because they did not receive a referral and did not cooperate.

The same surgeon performed standard phacoemulsification for all patients via a temporal incision (2.8 mm) and insertion of enVista® acrylic hydrophobic IOL in the lens capsule having 5-6mm-capsulorhexis. All patients underwent chloramphenicol (5%, Chlobiotic; Sina Company; Iran) plus betamethasone (0.1%, Chlobiotic; Sina Company; Iran) on the day after surgery every 4 hours two drops for each eye within 2 weeks and subsequently every 8 hours within 2 other weeks (a month in total). The research units were allocated into two groups by simple randomization, with a block size of 4 and a ratio of 1:1. Patients were blind to group allocation, and the study had a single-blinded design. These two and the ketorolac (study) group received ketorolac tromethamine (0.5%, Sinarolac, the same company) plus every 6 hours within 15 days.

The recorded demographic profiles of the participants were age and gender. The patients were examined at 1, 3, 7, and 30 days and 6 months postoperatively. The main results were tests of the anterior and posterior segments, such as IOP, ACI, and BCVA (Best Corrected Visual Acuity). At 1, 3, 7, and 30 days following surgery, ACI was assessed using slit-lamp examination data on cell counts and flare categorization. Based on the protein level, the number of individuals with this complication was calculated and ranged from 0 to 4. The working group of Standardization of Uveitis Nomenclature [15] classified the cases as follows: 0 represents none, 1+ represents faint, 2+ represents moderate (lens and iris details clear), 3+ represents marked (lens and iris details hazy), and 4+ represents intense (plasmoid or fibrin aqueous). Through the Snellen chart, Goldman Applanation Tonometry and BCVA were used to calculate the IOP, which was then reported using Log MAR.

The slit lamp test was used to examine the degree of ACO (Anterior Capsule Opacification) and PCO (Posterior Capsule Opacification) six months following surgery. The results were scored from 0 to 4. In terms of PCO, grade 0 (none) denotes the absence of any PCO, grade 1 (trace) denotes the presence of a few discrete epithelial pearls, grade 2 (mild) denotes the presence of several discrete epithelial pearls, grade 3 (moderate) denotes the presence of many coalescent epithelial pearls, and grade 4 (severe) denotes the presence of thick sheets [16]. When it comes to the ACO, grade 0 (clear) denotes a transparent anterior capsule, grade 1 denotes opacification on the capsulorhexis's edge, grade 2 denotes occasionally diffuse and moderate opacification with capsular folding, grade 3 denotes intense opacification with capsular folding, and grade 4 denotes constriction (phimosis) of the capsulorhexis opening with a diameter of less than a mm. The same anterior segment surgeon (M.A.) performed all examinations of the research units and surgical protocols and follow-up examinations.

The medications of those undergoing prostaglandin analogs to treat glaucoma were substituted with another anti-glaucoma agent. The excluded ones were the subjects with intraoperative adverse effects like vitreous loss and posterior capsule rupture and the patients requiring systemic NSAIDs or corticosteroids because of severe inflammatory responses after surgery.

Statistical Analysis

Data were described as percentage frequency and mean (± SD or standard deviation). Numerical data between the two groups were compared using the Mann-Whitney test or t-test, and the normality of the data was evaluated using the Kolmogorov-Smirnov test. Fisher's exact and Chi-square tests were used to compare the classified data between the two groups. The impact of time was evaluated using ANOVA repeated measurements or Friedman's test, an analogous non-parametric test. To perform a pairwise comparison for significant differences, we used Tukey's post hoc test. The SPSS21 program was used to analyze the data (Armonk, NY: IBM Corp.; IBM Corp., 2012). P<0.05 was regarded as the statistically significant threshold.

RESULTS AND DISCUSSION

Forty-six (46) patients participated in the study group (with ketorolac), and 42 patients in the control group (without ketorolac). Table 1 presents the participants' demographic characteristics. The two groups were homogenous for the average age, age distribution, and gender (P>0.05).

^* Results of Fisher's exact test of independent samples of t-test; The Chi-squared test findings

According to the BCVA test data (Table 2), there was no significant difference in this regard between the groups at the intervals measured (P>0.05), and the Friedman test data displayed the significant impact of time (P<0.001) and a better post-operative BCVA in both groups (P<0.001). Comparison of mean differences in BCVA values between pre- and post-operative status (Table 2) revealed a significant improvement on days 3 and 7 postoperatively (both P = 0.022), whereas not on months 1 and 6 postoperatively (P> 0.05).

^*The Mann-Whitney U test results

According to the IOP test results (Table 3), there was no difference in this regard between the two groups at any of the intervals measured (P>0.05). Hence, the Friedman test results revealed a significant impact of time (P<0.001) and a better post-operative IOP in both groups (P<0.001). Comparison of mean differences in IOP values between pre- and post-operative status (Table 2) revealed significant IOP values in the study group on month 1 after surgery (P=0.027) but not in other time points (P> 0.05).

^*The Mann-Whitney U test results

Based on the categorization of cell count and flare at 3, 7, and 30 days postoperatively, Table 4 illustrates the considerable differences in ACI distributions between the two groups. Higher degrees of inflammation were more frequently seen in the controls. The Friedman test results showed that time significantly impacted groups (P<0.001). There were also important differences between the two groups seven (P<0.001) and one (P<0.001) days after surgery, one month (P<0.001) and one day (P<0.001), and one month (P<0.001) and three days (P<0.001) after surgery, and between those two groups.

^* The Fisher's exact test results; the Chi-square test findings; all values are given as No. (%)

Based on Table 5, the two groups had an important difference in PCO (P=0.002) and ACO (0.001), and the study group experienced no ACO grades 3 and 4 and PCO grade 3.

^* Following Fisher's exact test, the findings were: the Chi-square test findings; all values are given as No. (%)