In recent years, image-guided femtosecond laser treatment has been increasingly used in cataract surgery.1 The described benefits of this system include an exact sized anterior capsulotomy, an effective lens fragmentation, various types of corneal incisions, and new surgical techniques.2–5 Nevertheless, laser-induced miosis was reported after laser treatment in some cases. Smaller pupils can make cataract surgery more difficult and may lead to higher intraoperative complication rates.6
In a previous study, an increased level of prostaglandins was measured in the aqueous humor immediately after femtosecond laser treatment.7 These mediators of inflammation are most likely involved in miosis induction and are assumed to be released by the non-pigmented epithelial layer of the ciliary body.8 In a second study, we identified the anterior capsulotomy to be the main inducer of the prostaglandin release and not the more time- and energy-consuming lens fragmentation. It has been hypothesized that the ciliary body is irritated by laser spots in the aqueous humor via shockwaves or a temperature increase.9
Besides the optimization of the anterior capsulotomy settings, the application of nonsteroidal anti-inflammatory drugs (NSAIDs) appears to be an option to pharmacologically counter the prostaglandin release and thus prevent the intraoperative miosis.10 Therefore, the aim of this study was to evaluate whether the topical application of NSAIDs, before laser treatment, normalizes the prostaglandin levels in the anterior eye.
Patients and Methods
Aqueous humor samples were obtained from patients undergoing routine microincision cataract surgery or femtosecond laser-assisted cataract surgery, with and without topical NSAID pretreatment (Diclofenac Voltaren Ophtha sine; Novartis AG, Basel, Switzerland). Immediately after collection, the samples were stored until used at −80°C. The tenets of the Declaration of Helsinki were observed and approval by the local ethics committee was granted. Preoperative nuclear opalescence was estimated by one physician (TS) using a Haag Streit BQ 900 slit lamp (Haag-Streit, Bern, Switzerland) at maximum illumination using the Lens Opacities Classification System III.
Patients who were scheduled for cataract surgery on one eye and were willing to volunteer for the study after giving informed consent were randomly allocated to one of four groups. All patients had a significant cataract ranging from grades II to IV (Lens Opacities Classification System III nuclear opalescence grading score). A computerized random number generator was used to allocate the patients to the groups. One day prior to surgery, a corresponding envelope was opened by the surgeon. The pretreatment and the treatment were planned based on the group assignment.
Patients with coexisting ocular disease, history of inflammatory eye disease, previous ocular surgery or trauma, relevant corneal opacities, age-related macular degeneration, diabetic and hypertensive retinopathy, any kind of glaucoma, pseudoexfoliation, dilated pupil size smaller than 6 mm, rheumatic and metabolic diseases, age younger than 22 years, pregnancy, the use of NSAIDs or steroids in the past month, and participation in another clinical study were excluded.
Based on the above mentioned criteria, 75 patients were included in this prospective trial. The patients were randomly assigned to the following four groups:
Control group: Patients undergoing routine microincision cataract surgery.
Control plus NSAID group: Patients undergoing routine microincision cataract surgery with topical NSAID.
Femtosecond laser group: Patients undergoing femtosecond laser surgery.
Femtosecond laser plus NSAID group: Patients undergoing femtosecond laser treatment with topical NSAID.
Patients in the control plus NSAID group and femtosecond laser plus NSAID group were given the first NSAID drop at the time of their arrival and registration at the University Eye Hospital, Bochum, Germany (2 hours prior to surgery). One hour later, a second drop of the same drug was applied. Twenty minutes prior to surgery, the last drop of topical NSAID was applied in the operating area.
In the femtosecond laser group and femtosecond laser plus NSAID group, capsulotomy and lens fragmentation were performed with the Catalys Precision Laser System (Abbott Medical Optics, Santa Ana, CA). After docking with the non-applanating patient interface, the anterior segment of the eye was visualized by the integrated three-dimensional spectral-domain optical coherence tomography. The capsulotomy size was set to 4.9 mm with 4-µJ pulse energy (incision depth: 600 µm). The lens was segmented into quadrants and softened with a grid spacing of 300 µm with 10-µJ pulse energy. Corneal incisions were not performed in any of the cases. After undocking, the patient was swiveled under the operating microscope. Four to 5 minutes after undocking, a 1.2-mm paracentesis was made at the 11-o'clock position and approximately 100 µL of aqueous humor were collected with a syringe. The sample was immediately stored at −80°C. Subsequently, the lens was aspirated and an intraocular lens was implanted.
In the control group and control plus NSAID group, a 1.2-mm paracentesis was created in the same manner, before routine cataract surgery was performed. Identical to the femtosecond laser groups, approximately 100 µL of aqueous humor were collected and immediately stored at −80° C. After manual capsulorhexis and phaco-emulsification, an intraocular lens was implanted.
All samples from the four groups were measured at the same time by the same investigator with the same standard preparation to avoid inter-user or plate variability. Prostaglandin concentrations (total prostaglandin) were determined using a commercially available enzyme immunoassay kit (Cayman Chemicals, Ann Arbor, MI) according to the manufacturer's instructions.7,9 Measurements were performed using a microplate reader (AESKU Reader with Gen5 ELISA Software; AESKU.Diagnostics, Wendelsheim, Germany).
Statistical analyses were performed using a commercial statistical software package (Statistica V12; Statsoft, Tulsa, OK). The groups were compared by analysis of variance followed by Tukey post-hoc test. Data are presented as mean ± standard error of the mean as well as mean ± standard deviation.
In total, 75 aqueous humor samples were analyzed. There was no difference between the groups with regard to age or cataract density (Table 1). No intraoperative complication occurred during the laser treatment (the femtosecond group and femtosecond plus NSAID group) or during the manual opening of the eye (the control group and control plus NSAID group).
Similar to a previous study by our group, a higher prostaglandin level was measured in aqueous humor from patients in the femtosecond group (294.4 ± 66.5 pg/mL) compared to the control group (109.6 ± 32.0 pg/mL; P = .007).
In both surgical groups, NSAID pretreatment led to decreased prostaglandin levels (Figure 1). Hence, the lowest prostaglandin concentrations were measured in the control and femtosecond laser groups that were pre-treated with NSAID (control plus NSAID group: 63.9 ± 19.5 pg/mL; femtosecond plus NSAID group: 65.3 ± 13.2 pg/mL). No significant difference was found between the control plus NSAID group and femtosecond plus NSAID group (P = .99). The highest prostaglandin concentration was measured in the femtosecond laser group, whereas levels were significantly lower in the femtosecond laser plus NSAID group (P = .0009) and control group (P = .0007).
Mean aqueous humor prostaglandin levels in the control, control plus nonsteroidal anti-inflammatory drugs (NSAID), femtosecond laser, and femtosecond laser plus NSAID groups. Values are presented as mean ± standard error of the mean (SEM) and mean ± standard deviation (SD). ** = P < .01; *** = P < .001.
Laser-assisted capsulotomy induces an immediate prostaglandin release in the aqueous humor, which can lead to an intraoperative miosis and associated complications.7,9,11 This study is the first to describe a short-term protocol to avoid this phenomenon. Prostagladins are highly active mediators for inflammation and pain.12 In the eye, they are synthesized from arachidonic acid by the cyclooxygenase (COX-1 homeostatic; COX-2 inducible).13 Most likely, the release occurs in the non-pigmented epithelial layer of the ciliary body.8 In the literature, enzyme suppression was described after routine cataract surgery by local instillation of NSAIDs.14,15 For commercially available NSAIDs, the measured time to peak concentration was described to be within the first hours after application.16 Therefore, an easy adoptable protocol with three drops at the day of surgery was developed. The total prostaglandin concentrations after NSAID application was the lowest in the femtosecond plus NSAID group and control plus NSAID group. Levels were even lower than the control group. As measured in previous studies, femtosecond laser treatment without NSAIDs leads to a significant increase in prostaglandin levels.7,9 However, the measured mean concentration was minimally lower than in the previous studies. Potentially, the updated software version and capsulotomy settings reduced the release slightly. The time-dependence of the prostaglandin release was not investigated in the study. A higher release for a period of time appears to be likely in the femtosecond laser group. Therefore, the pupil contraction rate might increase without NSAID pretreatment, if the time between laser treatment and manual part of the surgery extends. With the used protocol the incidence during a period of time might also be lower, because the COX is regularly inhibited for several hours.16 Furthermore, penetration of prostaglandins into the posterior part of the eye was not investigated and should be the aim of future studies.
The protocol we used has proven to be effective in blocking the laser-induced prostaglandin release and has great potential to avoid intraoperative miosis in a daily use routine set-up.
- Corcoran KJ. Macroeconomic landscape of refractive surgery in the United States. Curr Opin Ophthalmol. 2015;26:249–254. doi:10.1097/ICU.0000000000000159 [CrossRef]
- Schultz T, Joachim SC, Tischoff I, Dick HB. Histologic evaluation of in vivo femtosecond laser-generated capsulotomies reveals a potential cause for radial capsular tears. Eur J Ophthalmol. 2015;25:112–118. doi:10.5301/ejo.5000484 [CrossRef]
- Conrad-Hengerer I, Hengerer FH, Schultz T, Dick HB. Effect of femtosecond laser fragmentation on effective phacoemulsification time in cataract surgery. J Refract Surg. 2012;28:879–883. doi:10.3928/1081597X-20121116-02 [CrossRef]
- Nagy ZZ, Filkorn T, Takács AI, et al. Anterior segment OCT imaging after femtosecond laser cataract surgery. J Refract Surg. 2013;29:110–112. doi:10.3928/1081597X-20130117-05 [CrossRef]
- Dick HB, Schultz T. Primary posterior laser-assisted capsulotomy. J Refract Surg. 2014;30:128–133. doi:10.3928/1081597X-20140120-09 [CrossRef]
- Artzen D, Lundstrom M, Behndig A, Stenevi U, Lydahl E, Montan P. Capsule complication during cataract surgery: case-control study of preoperative and intraoperative risk factors: Swedish Capsule Rupture Study Group report 2. J Cataract Refract Surg. 2009;35:1688–1693. doi:10.1016/j.jcrs.2009.05.026 [CrossRef]
- Schultz T, Joachim SC, Kuehn M, Dick HB. Changes in prostaglandin levels in patients undergoing femtosecond laser-assisted cataract surgery. J Refract Surg. 2013;29:742–747. doi:10.3928/1081597X-20131021-03 [CrossRef]
- Maihöfner C, Schlötzer-Schrehardt U, Gühring H, et al. Expression of cyclooxygenase-1 and -2 in normal and glaucomatous human eyes. Invest Ophthalmol Vis Sci. 2001;42:2616–2624.
- Schultz T, Joachim SC, Stellbogen M, Dick HB. Prostaglandin release during femtosecond laser-assisted cataract surgery: main inducer. J Refract Surg. 2015;31:78–81. doi:10.3928/1081597X-20150122-01 [CrossRef]
- Dick HB, Gerste RD, Schultz T. Laser cataract surgery: curse of the small pupil. J Refract Surg. 2013;29:662. doi:10.3928/1081597X-20130920-01 [CrossRef]
- Roberts TV, Lawless M, Bali SJ, Hodge C, Sutton G. Surgical outcomes and safety of femtosecond laser cataract surgery: a prospective study of 1500 consecutive cases. Ophthalmology. 2013;120:227–233. doi:10.1016/j.ophtha.2012.10.026 [CrossRef]
- Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007;67:1291–1308. doi:10.2165/00003495-200767090-00004 [CrossRef]
- Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004;18:790–804. doi:10.1096/fj.03-0645rev [CrossRef]
- Bucci FA Jr, Waterbury LD. Aqueous prostaglandin E(2) of cataract patients at trough ketorolac and bromfenac levels after 2 days dosing. Adv Ther. 2009;26:645–650. doi:10.1007/s12325-009-0042-5 [CrossRef]
- Bucci FA Jr, Waterbury LD. Prostaglandin E2 inhibition of ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% in patients undergoing phacoemulsification. Adv Ther. 2011;28:1089–1095. doi:10.1007/s12325-011-0080-7 [CrossRef]
- Walters T, Raizman M, Ernest P, Gayton J, Lehmann R. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg. 2007;33:1539–1545. doi:10.1016/j.jcrs.2007.05.015 [CrossRef]
|Group (No. of Patients)||Age (Mean ± SD)||Sex (Male/Female)||Eye (Right/Left)||Cataract Stage (Mean ± SD)|
|Control (20)||73.3 ± 10.3||7/13||11/9||3.7 ± 0.7|
|Control plus NSAID (20)||69.3 ± 8.0||8/12||8/12||3.5 ± 0.7|
|Femtosecond laser (18)||71.2 ± 9.1||11/7||10/8||3.4 ± 0.7|
|Femtosecond laser plus NSAID (17)||74.7 ± 8.4||11/6||10/7||3.6 ± 0.5|