Effect of Intracameral Injection of Preservative Free, Fixed Concentration of Combined Mydriatic plus Anaesthetic Formulation on Corneal Endothelial Cell Count in Phacoemulsification

Introduction

Cataract surgery is the most commonly performed surgical procedure worldwide. There is good evidence to show that cataract extraction with intraocular lens implantation is one of the most beneficial procedures to improve a patient’s quality of life [1]. Adequate mydriasis is crucial for performing uneventful cataract surgery. Inadequate pupil dilation is associated with increased risk for intraoperative complications, including iris injury, incomplete removal of cortical and nuclear materials, and posterior capsule rupture [2].

Traditionally, surgeons use a combination of topical sympathomimetics (phenylephrine) and parasympatholytics (tropicamide, cyclopentolate) to achieve mydriasis before cataract surgery. In the context of ocular pharmacology, the bioavailability of topical medications has always been suboptimal. Only about 20% of a drop is retained in the cul- de-sac. The rapid turnover of the fluid in the tear reservoir of 16% per minute also reduces the amount of the drug [3]. This poor bioavailability not only leads to delay in the onset of mydriasis, but also causes cardiovascular side effects through systemic absorption via nasal mucosa [4].

Using intracameral mydriatics for cataract surgery avoids the issues of poor bioavailability, prolonged duration of action, and corneal epithelial toxicity associated with eyedrops. It also provides almost instant action. Intracameral dilation was first reported in 2003, with the use of non-preserved lidocaine hydrochloride 1.0% [5]. In the last few years, manufacturers all over the world have worked together, and currently there are 2 approved premade products for intracameral mydriasis: Omidria and Fydrane. Omidria is a commercially available FDA-approved combination drug product containing phenylephrine 1.0% and ketorolac 0.3%, a nonselective cyclooxygenase inhibitor approved for use during cataract surgery. This standardized premade combination represents a new treatment option for surgeons to address intraoperative miosis and postoperative ocular pain. Although patients still require topical dilating drops, this combination drug, used in the irrigating solution, has been shown to be effective in maintaining mydriasis [6]. Fydrane is the first commercially available intracameral mydriatic and anaesthetic mixture licensed for use during cataract surgery. It is comprised of a standardized combination of tropicamide 0.02%, phenylephrine 0.31%, and lidocaine 1.0%. First launched in Italy in 2016, this product is currently licensed for use in all 27 countries in the European Union [7]. The inclusion of lidocaine in Fydrane augments the effect of topical anaesthetic, producing better intraoperative anaesthesia. The anaesthetic agent in Fydrane is a response to a medical need suggested by the off-label use of IC anaesthetics to improve patient comfort intraoperatively. Traditional preoperative topical anaesthesia may be insufficient during surgery, especially during IOL insertion [8]. Previous studies have shown that 1% IC lidocaine does not cause endothelial cell toxicity. It induces serum concentrations of lidocaine that are below minimum detectable levels and it does not diffuse into the posterior segment (even with 500μL injection). An additional benefit is the mild mydriatic effect of IC lidocaine [9, 10].

Discussion

Fydrane is the first industrially manufactured and standardized mixture of mydriatics and anaesthetic used for injection in the anterior chamber to perform phacoemulsification. The active components, concentrations and volumes in the Fydrane formulation were based on the efficacy and safety of other IC formulations used for phacoemulsification cataract surgery [11, 12].

This randomized control clinical trial studied the effect of intracameral injection of, combined mydriatic (tropicamide 0.02%, phenylephrine 0.31%) and anaethetic (lidocaine 1.0%), Fydrane on corneal endothelial cell density during phacoemulsification. This was done in comparison with standard topical regimen (reference group) in which pupillary dilatation is achieved using topical drops preoperatively.

The results of this clinical trial showed no statistical significance in the percentage of endothelial cell loss between (Fydrane group) in which mean percentage endothelial cell loss was (25.74%) and (reference group) (27.49%) with p value (0.595). The slightly higher endothelial cell loss in (reference group) is probably due to higher mean age in this group. In addition, we studied the ability of intracameral Fydrane to maintain adequate pupillary dilation throughout the phacoemulsification surgery to ensure safe surgery.

Our study showed that in Fydrane group all patients (100%) achieved adequate mydriasis after 30 seconds of injecting the intracameral drug with mean pupillary size (7.48±0.17) mm before capsulorhexis and maintained adequate mydriasis throughout the surgery with mean pupillary size (7.39±0.2) mm before IOL implantation. In Reference group, pupillary dilatation was maintained throughout the procedure in 12 cases (80%) with mean pupil size (7.9±0.3) mm. Intraoperative reduction in mydriasis occured in 3 cases (20%) reaching pupil size 5.5mm before IOL implantation which was probably caused by older patient’s age patients and consequently slightly harder nucleus. As the surgical time nucleus density and ultrasound time increase for any given surgical machine they cause tissue damage and which in turn causes release of prostaglandins leading to pupillary miosis. This can be prevented by preoperative topical NSAIDs (Non-Steroidal Anti-inflammatory Drugs).

Our results are in agreement with international phase III of prospective, randomized study of Labetoulle M, et al, [11] who compared the efficacy and safety of intracameral (IC) administration of 200μL of Fydrane at the beginning of cataract surgery just after the first incision to a standard topical regimen of one drop of tropicamide 0.5% and phenylephrine 10% repeated three times (reference group). Their study was done on 555 patients. Their study indicated that IC administration of Fydrane was safe intraoperatively and postoperatively up to 1 month. Endothelial cell loss observed in the Fydrane group was similar to the reference group [7].

Also, their study showed that In the Fydrane group, the rate of capsulorhexis performed without the use of additional mydriatics (or pupil-widening maneuvers) and with a pupil size of at least 6 mm just prior to capsulorhexis was very high (96.8%) and similar to the reference group. Surgeons found that IOL implantation was less challenging in the Fydrane group compared with the reference group with more cases of IOL implantation considered ‘slightly challenging’ or ‘challenging’ in the reference group (p=0.047). Once dilated, the pupil size remained stable in the Fydrane group with a mean size of approximately 7.50 mm from viscoelastic injection until the end of surgery [7].

Our results concur with Rudy M, et al, [13] who evaluated the safety and tolerability of a single intracameral administration of Fydrane with or without rinsing in experimental study using sixty pigmented rabbits. Rabbits received 100µL or 200µL of the combination product or a placebo (sodium chloride 0.9%) by intracameral injection. For the combination product, separate groups were included with and without rinsing after administration. From day 1day to 7days assessments included general clinical and ocular observations pupil diameter measurements and corneal assessments. Their study showed that rapid mydriasis, stable 24minutes after injection and returning to baseline levels by day 1 was induced in all groups that received the combination mydriatic and anesthetic drug. Rinsing had no effect [13].

They also reported that the combination product induced no adverse effects on the anterior or posterior segment of the eye (i.e., no increased corneal thickness and endothelial cell loss, no abnormalities in electroretinogram ERG). No toxic effects of the products were found on histological evaluation. So they reached a conclusion that the combination mydriatic and anesthetic drug administered to pigmented rabbits as a single intracameral injection at volumes of 100 µL and 200 µL was well tolerated with no ocular adverse effects and no effect on the corneal endothelium [13].

Ajay K, et al. [14] showed similar results to our study when they assessed the efficacy and safety of intracameral mydriatic solution containing 0.5% lignocaine and 0.001% epinephrine injected immediately after first entry into the anterior chamber (AC) as compared to preoperative topical mydriatics in patients undergoing manual small incision cataract surgery (MSICS) under peribulbar anesthesia in a study on 127 patients. Pupil sizes were measured serially, at six different junctures during surgery.

Their results showed Mean pupil size just before peribulbar block was 7.3 mm in topical group and 3.3mm in intracameral group (P<0.001). Mean pupil size in intracameral group increased to 7.3mm 30 s after injecting intracameral dilating solution. Mean pupil size in both groups progressively reduced reaching 5.5mm (topical group) and 6.2mm (intracameral group) just before intraocular lens implantation (P=0.001) and measured 5.1mm and 5.5mm respectively at the end of surgery (P=0.048). On first postoperative day there was no significant difference in distribution of corneal edema scores AC inflammation scores, and in median log MAR visual acuity between the two groups [14].

Chiambaretta F, et al. [15] also showed similar results to ours when they compared the effect of intracameral injection of combination of 2 mydriatics and 1 anesthetic to a standard topical regimen for cataract surgery in a prospective case series in which pupil size measurements were performed in 2 randomized studies (phase 2 and phase 3) which comprised 139 patients and 591 patients, respectively. After intracameral combination administration 95% of the pupil dilation was achieved within a mean of 28.6 seconds±4.6 (SD). At the beginning of capsulorhexis creation the mean pupil diameter was larger than 7.0mm in both groups. The intraoperative pupil diameter remained stable in the intracameral combination group and decreased in the topical group. The mean change in pupil size just before capsulorhexis to the end of surgery (just before cefuroxime injection) was 0.22±0.72mm and 1.67±0.98mm respectively. No clinically significant change in pupil diameter (change<1.0mm) occurred in the majority of the intracameral combination group (89.3%) compared with the topical group (26.8%) [15].

Gupta SK, et al. [16] also showed matching results with ours when they evaluated the role of intracameral irrigating solution (0.5% lignocaine+0.001% epinephrine) in initiating and maintaining the pupillary mydriasis during phacoemulsification and observe the effect of surgical time, nucleus density and ultrasound time on mydriasis during the procedure in a a prospective interventional case series on thirty patients underwent phacoemulsification under topical anesthesia. The pupil size increased from 2.1mm (Range 2-3.5mm SD±0.32) to 6.9 mm (range 5-9mm SD±1.02) in 30 seconds time after intracameral mydriatic solution delivery and was 7.0mm at the end of surgery. Duration of surgery grade of nucleus and ultrasound time had statistically insignificant effect on mydriasis [16].

Study Limitations

A drawback of our study is the small number of cases included. It does not study the other possible ocular side effects of Fydrane like posterior segment affection e.g. macular edema. It does not study the possible systemic adverse effects e.g. cardiovascular. This trial shows a 3weeks outcome which may not necessarily be indicative of longer- term outcomes. However, the aim of this study was to evaluate the safety of the Fydrane on endothelium and its mydriatic effect to determine its suitability for cataract surgery.

Based on this objective, we believe the 3 weeks period is appropriate for this evaluation because

• Postoperative follow-up by most cataract surgeons is 1 month;
• The potentially severe adverse effects of Fydrane (mostly toxicity on endothelial cells) were typically expected within days to weeks postoperatively;
• The long-term adverse effects of cataract surgery (i.e., retinal breaks and detachments) are related to the surgical procedure rather than to the products used preoperatively or intraoperatively. We recommend increasing the sample size and increasing the period of post-operative follow up to detect any other possible local and/or systemic adverse effects.

Summary and Conclusion

Fydrane is the first commercially available intracameral mydriatic and anaesthetic mixture licensed for use during cataract surgery; it is comprised of a standardized combination of tropicamide 0.02%, phenylephrine 0.31%, and lidocaine 1.0%. First launched in Italy in 2016 this product is currently licensed for use in all 27 countries in the European Union.

This study showed that intracameral injection of Fydrane is safe on corneal endothelium, as no statistically significant difference in the percentage of endothelial cell loss was found between Fydrane and standard topical regimen groups. It also showed that Fydrane is effective in maintaining pupillary dilatation throughout the surgery, avoiding intraoperative meiosis which may occur with the traditional pupil dilatation using topical mydriatics preoperatively.