In this randomized clinical trial (RCT), a total of 101 eyes from 101 diabetic patients who were scheduled for cataract surgery at Torfeh Medical Center, Shahid Beheshti University of Medical Sciences were included. The study protocol was registered into www.clinicaltrial.gov with the RCT registration number NCT03551808.
The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences. All the study procedures were explained to all patients and a signed consent form was obtained from each patient before entry to the study.
Participants
Diabetic patients who were scheduled to undergo cataract surgery were included. All patients had controlled diabetes with fasting blood sugar (FBS) of 126 mg/dl or less and glycated hemoglobin A1c (HbA1c) of less than 7% at the time of study entry. Patients with glaucoma, uveitis, any previous intraocular surgery, any intravitreal injection in less than three months, macular laser photocoagulation in less than 6 months, presence of proliferative diabetic retinopathy (PDR) or any macular disease, cyclo-refraction of ≥±6 diopter (D), hazy media to obtain the high-quality images of the optical coherence tomography (OCT), baseline central macular thickness (CMT) ≥280µm excluded. Also, patients with any kind of intraoperative complications and those who lost to follow-up were excluded.
All the study subjects were interviewed to obtain demographic data as well as the patients' health and ocular history by an expert technician. All patients were ordered to perform the laboratory tests including FBS, creatinine, urea, and HbA1c at the time of study recruitment.
Participants were randomized using the permuted block randomization method in two groups. Cases were instructed to use ketorolac tromethamine 0.5% (Sinarolac®; Sina Darou, Tehran, Iran) eye drop three times daily one day before cataract surgery and continued it up to four weeks after the surgery, while the control group only received a placebo treatment (the preservative-free artificial tears ® (Sinalone ;Sina Darou, Tehran, Iran) which put into the drug container as same as the ketorolac eye drop). Postoperatively, betamethasone 0.1% (Betasonate®; Sina Darou, Tehran, Iran) eye drop was prescribed to all study subjects in both groups 4 times per day in the first week and it was gradually tapered to once a day in the fourth week. Also, chloramphenicol 0.5% (Cholobiotic®; Sina Darou, Tehran, Iran) eye drop was applied 4 times per day for one week after the surgery.
Comprehensive visual and ocular examinations were performed on all study subjects. Refractive error measurement was performed either by auto-refractometer (RM-8800; Topcon Medical, Oakland, NJ, USA) or retinoscope (HEINE BETA®200; Germany). BCVA was assessed using a Snellen E-chart at a distance of 6 meters by a trained optometrist. In addition, a biomicroscopic examination was performed to evaluate the anterior segment. Intraocular pressure was measured using the applanation tonometer (Goldmann applanation tonometer, Haag-Streit, USA). Fundus examination was conducted using an indirect ophthalmoscope through dilated pupil by a 78D lens to determine the stage of diabetic retinopathy according to the International classification. 24
Spectral-domain OCT (SD-OCT, Heidelberg Engineering OCT Spectralist, USA) was performed for all study subjects to measure the CMT. IOL power calculation was conducted using A-scan (ZEISS IOL Master 500; Germany) at the baseline examination. All ophthalmic examinations and cataract surgery were performed by an expert anterior segment ophthalmologist (HMR).
Surgical Technique
The procedure was performed under topical or general anesthesia, according to the patient’s condition, by a single anterior segment surgeon (HMR). After a 2.8 mm clear corneal incision, phacoemulsification was performed using the divide and conquer technique and the IOL was inserted in the capsular bag using the Monarch II injector and a C cartridge (Alcon Laboratories Inc., Fort Worth, TX, USA). After irrigation and aspiration, the anterior chamber was formed with the balanced salt solution. There was no wound leakage. Subconjunctival betamethasone (4 mg) and ceftazidime (100 mg) were injected, and the eyes were patched.
Follow-up Examinations
All patients were routinely examined the next day, one week, and one month after the surgery for possible surgical complications. Follow-up examinations including OCT imaging and BCVA measurement were conducted at the three-time points of 6, 12, and 24 weeks following the surgery for both cases and controls.
Randomization
All participants were randomly assigned into study groups of cases and controls using the permuted block randomization method with a random block length of 2, 4, 6, and 8. The randomization list was generated by a computer-based program and the details of the random sequence were concealed from researchers. Whenever a new patient entered into the study a new envelope (which contained the group for the order sequence of the patient) was opened and the group was revealed.
Blinding
Evaluation of outcomes was performed by a researcher who was uninformed about the group assignment. The study protocol and the type of treatment were concealed from our participants.
Sample Size
To have a power of 90% to detect a 30µm difference of CMT in 12 weeks, we needed 50 subjects in each group. It was based on the assumed standard deviation of 0.26 which was obtained in the pilot phase of this study. The probable attrition of up to 30% and type one error of 0.05 were also considered. Fifty-eight diabetic patients having the eligibility criteria were enrolled in each group due to overcoming the possible loss of follow-up.
Outcome Measures
The changes of CMT and BCVA at the three-time points of weeks 6, 12, and 24 compared to the baseline were considered as the primary outcome measures.
Statistical Analysis
The normal distribution of quantitative data was assessed by the Shapiro-Wilks test and Q-Q plot. To describe data, we used, mean and standard deviation, median and range, frequency and percentage. To compare the baseline variables between the two groups we used an independent t-test, Mann-Whitney test, chi-square test, and Fisher exact test. Evaluation of the variables’ changes in different follow-ups was performed using a linear mixed model. To compare the groups in different follow-ups we used Multivariate Analysis of Variance (MANOVA). All statistical analysis was performed using SPSS software Version 25 (IBM Corp. Armonk, NY). All tests were two-sided and P-value less than 0.05 was considered statistically significant.