Cataracts are the leading cause of blindness globally and as of 2002, they accounted for approximately 50% of all surgical cases.1 Age-related cataracts affect more than 22 million people in the United States, and it is estimated that this number will rise to 30 million by 2020.2 As a consequence, cataract surgery is the most common surgical procedure performed in the world.3
Maintaining mydriasis during cataract surgery is essential for ensuring patient safety and the efficiency of the surgical procedure.4,5 Pupil constriction during or before removal of the lens greatly increases the difficulty of surgery, despite recent advancements in modern cataract surgery. Small decreases in the pupil diameter exponentially reduce the viewing portal for the surgeon, and diameters smaller than 6.0 mm have been associated with multiple increased risks, such as posterior capsule tears, retained cortex and lens fragments, iris damage, and vitreous loss.5–7
Before and during cataract surgery, pupil dilation is accomplished with topical or intracameral administration of various mydriatics.8–10 Topical administration to achieve and maintain pupil dilation often requires preoperative administration of multiple doses, which is cumbersome for the patient and perioperative personnel.9,10 In addition, topical agents can be washed out of the eye after administration, limiting their efficacy.11,12 Furthermore, prostaglandin formation from intraoperative iris manipulation and surgical trauma is a well-known and previously described cause of miosis during cataract surgery.13
Use of the femtosecond laser in cataract surgery has increased over the past decade as surgeons have gained greater experience with the technology.14 These lasers are combined with computer-controlled optical delivery systems to create precise incisions without extraneous damage to surrounding tissues.15 The benefits of using a femtosecond laser in surgery include a more precise and consistent capsulotomy, reduced phacoemulsification time, and reduced complications16,17; however, a drawback is increased prostaglandin release in the eye before the first surgical instrument is introduced.18,19 This can, and often does, increase pupil miosis before cataract extraction, making surgery more complicated.20
Intraoperative management of pupils is often needed when preoperative measures are not enough to maintain proper dilation. In cases in which the pupil is not as responsive to mydriatics or when complications such as intraoperative floppy-iris syndrome arise, the surgeon might have to use mechanical devices to maintain adequate mydriasis. Pupil expansion devices, in particular the Malyugin ring (MicroSurgical Technology), are widely used. However, the ring is not a first-line method for several reasons. Understandably, mechanical devices add to surgical time, which is often associated with an increased risk for complications from prolonged stress to the ocular tissue.21 Also, mechanical devices can physically injure the iris, further increasing prostaglandin release. Worse, they can cause hyphema, iris atrophy, or both. Specific to femtosecond cataract cases, the diminished pupil can interfere with safe insertion of the expansion device and can often rip the premade capsule, risking a rupture. Given the advantages and drawbacks of pupillary expansion rings, they are usually reserved for patients with suboptimum pupil sizes of 6.0 mm or less at the beginning of manual cataract surgery.
Phenylephrine 1.0% and ketorolac 0.3% intraocular solution (Omidria) contains an α-1 adrenergic receptor agonist and nonselective cyclooxygenase inhibitor. The U.S. Food and Drug Administration (FDA) has approved Omidria for use in adults and children.A It is added to the irrigation solution during cataract surgery to prevent intraoperative miosis and to reduce postoperative ocular pain by inhibiting prostaglandin release.B The purpose of this study was to determine whether compared with epinephrine, the use of phenylephrine and ketorolac would reduce surgical time and the need for pupil expansion devices during FLACS.
Patients and methods
This retrospective cohort study analyzed data from patients having FLACS at Wake Forest Baptist Eye Center, Winston-Salem, North Carolina, USA. In the first group of consecutive patient series, epinephrine 1 μg/mL was used in the irrigation solution. In the second group of consecutive patient series, phenylephrine 0.1%–ketorolac 0.3% was used at a concentration of 4 mL added to 500 mL ocular irrigation solution.
Patients were included if they had cataract surgery using the femtosecond laser and had complete preoperative and postoperative follow-up data. All procedures were performed between January 2015 and November 2016. All patients were given topical bromfenac 2 days before surgery. The same surgeon (K.A.W.) performed all cataract procedures using the same femtosecond laser (Catalys, Johnson & Johnson Vision Care, Inc.) and the same operative conditions. The surgeon was proficient with the femtosecond laser and had performed more 1000 femtosecond laser–assisted cataract procedures before the start of the study.
Study endpoints were total operative time and the number of patients who required use of a pupillary expansion ring (Malyugin ring) to maintain mydriasis during the surgical procedure.
Data were manually extracted from patient medical and surgical records at the clinic and compiled in an Excel spreadsheet (Microsoft Corp.) in a prespecified format with all personal identifying information removed. Descriptive statistics were generated for demographics, baseline characteristics, use of pupil expansion devices, and total operative time for phenylephrine–ketorolac versus epinephrine. Comparisons between treatments were performed with a t test for continuous variables and chi-square or Mann-Whitney test for binary or categorical variables using a 2-sided significance level of 5%.
Data were collected from 200 patients, 100 in each treatment group. At baseline, the mean age was approximately 70 years old and was similar between the epinephrine group and phenylephrine–ketorolac group (Table 1). In addition, the mean baseline pupil size, measured by optical coherence tomography before the femtosecond laser was armed, was similar in both groups. There were no statistically significant demographic differences between the 2 treatment groups.
The mean operative time was statistically significantly shorter in the phenylephrine–ketorolac group than in the epinephrine group (P = .007) and remained so after patients from both groups who required a pupil expansion device were excluded (Table 2). Significantly fewer patients in the phenylephrine and ketorolac than in the epinephrine group (P = .009) required a pupil expansion device to maintain mydriasis during the procedure (Table 2).
This study found that the use of phenylephrine 1.0%–ketorolac 0.3% (Omidria) produced significant benefits over epinephrine by reducing the mean operative time of FLACS and by reducing the proportion of patients who required a pupil expansion device (Malyugin ring). These findings suggest that the side effects of femtosecond laser–associated release of prostaglandins and the resulting smaller pupil can be counteracted with the addition of intracameral phenylephrine–ketorolac. These findings are relevant because maintaining mydriasis and preventing miosis during cataract surgery are essential to a safer and more efficient procedure.
In randomized controlled studies of patients having cataract surgery with lens replacement or refractive lens exchange,22,23 phenylephrine–ketorolac maintained intraoperative mydriasis and reduced postoperative ocular pain better than a placebo. In another study,24 it was also better than phenylephrine alone and than ketorolac alone in preventing miosis. Although the registration clinical trials resulting in the 2014 FDA approval of Omidria showed the benefits of phenylephrine and ketorolac, surgical time and use of pupil expansion devices were not study endpoints and post hoc analysis of surgical time did not reach statistical significance. Therefore, real-world studies such as the present one and those by Bucci et al.,25 Rosenberg et al.,26 and Visco27 were performed to assess surgical time and the use of pupil expansion devices in controlled environments using phenylephrine–ketorolac versus the standard of care.
Bucci et al.25 reported that during conventional phacoemulsification, patients receiving phenylephrine–ketorolac required fewer pupil expansion devices than those in a control group (n = 915 versus n = 1004), with expansion devices used in 2.95% of phenylephrine–ketorolac patients and 7.87% of control patients (P < .001). The control patients received nothing in the irrigation solution or, at the physician’s discretion, received epinephrine as a supplemental bolus injection. Bucci et al. also found that fewer pupil expansion devices were used in patients who were treated with a femtosecond laser and given phenylephrine–ketorolac (n = 149 [0%]) than in patients receiving epinephrine (n = 151 [2.6%]). Rosenberg et al.26 also reported shorter surgical times by patient age quartile for phenylephrine–ketorolac versus epinephrine and a reduced need for pupil expansion devices. Finally, in a study of high-risk patients, Visco27 reported a significantly lower rate of iris fixation ring use in an intracameral phenylephrine–ketorolac group than in an intracameral epinephrine group (0% versus 50%; P = .0034) and significantly shorter surgical times by 2.9 minutes (P = .0068) in the phenylephrine–ketorolac group. Similarly, our current study showed a 14% reduction in surgical time and an 83% reduction in the use of expansion devices with the administration of phenylephrine–ketorolac. We believe that we are the first to report this benefit in FLACS.
A retrospective study design was appropriate for this study because it became apparent that the use of phenylephrine–ketorolac during FLACS greatly improved the safety and benefits for our patients and the drug became available at our facility for every cataract surgery procedure. A randomized trial would not be considered ethical by our institutional review board given the proven benefits of Omidria in previous studies and our experience. Given the retrospective nature and that pupil size is not routinely recorded throughout surgery, we cannot comment or analyze whether the pupils maintained mydriasis in the phenylephrine–ketorolac study group. However, we strongly suspect this to be the case given the lack of mechanical devices used and the reduction in surgical time when phenylephrine–ketorolac was used. A single center with an experienced surgeon provided consistency for the procedure and technique. One advantage of this retrospective analysis is that these data reflect actual clinical practice and are not influenced by the required restrictions of a controlled study protocol. In addition, potential bias was likely further reduced by this study’s objective endpoints of operative time, preoperative pupil diameter, and use of pupil expansion devices as well as by the fact that the study design was conceived of only after Omidria became available and routinely used for more than a year at our institution. The large proportion of patients treated with phenylephrine–ketorolac is another strength of this study.
In conclusion, the data from this clinical practice retrospective study show that compared with epinephrine, phenylephrine 1.0%–ketorolac 0.3% significantly reduces FLACS time and the use of pupil expansion devices. The reduction in surgical time was significant even when cases requiring a pupil expansion device in either study arm were eliminated. This likely indicates hesitancy in decision-making, technique, or possibly both in cases that did not receive a mechanical or chemical aid in pupil management. Future studies assessing the effects of phenylephrine 1.0%–ketorolac 0.3% on acute and chronic complication rates and cost-benefit analyses are warranted.
What Was Known
- Effective mydriasis and prevention of miosis are essential for successful outcomes in cataract surgery.
- Femtosecond laser–assisted surgery has increased prostaglandin levels and, subsequently, the risk for inflammation and miosis.
- Intracameral administration of phenylephrine and ketorolac is indicated for maintaining pupil size by preventing intraoperative miosis and for reducing postoperative pain.
What This Paper Adds
- Compared with epinephrine, intracameral phenylephrine 1.0%–ketorolac 0.3% reduced operative time and obviated the need for pupil expansion devices in patients having femtosecond laser–assisted cataract surgery.
1. Resnikoff S, Pascolini D, Etya’Ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ
2. Gollogly HE, Hodge DO, St. Sauver JL, Erie JC. Increasing incidence of cataract surgery: Population-based study. J Cataract Refract Surg
3. Trikha S, Turnbull AMJ, Morris RJ, Anderson DF, Hossain P. The journey to femtosecond laser-assisted cataract surgery: new beginnings or false dawn? Eye
4. Narendran N, Jaycock P, Johnston RL, Taylor H, Adams M, Tole DM, Asaria RH, Galloway P, Sparrow JM. The Cataract National Dataset electronic multicentre audit of 55 567 operations: risk stratification for posterior capsule rupture and vitreous loss. Eye
5. Hashemi H, Seyedian MA, Mohammadpour M. Small pupil and cataract surgery. Curr Opin Ophthalmol
6. Guzek JP, Holm M, Cotter JB, Cameron JA, Rademaker WJ, Wissinger DH, Tonjum AM, Sleeper LA. Risk factors for intraoperative complications in 1000 extracapsular cataract cases. Ophthalmology
7. Goldman JM, Karp CL. Adjunct devices for managing challenging cases in cataract surgery: capsular staining and ophthalmic viscosurgical devices. Curr Opin Ophthalmol
8. Fraunfelder FT, Scafidi AF. Possible adverse effects from topical ocular 10% phenylephrine. Am J Ophthalmol
9. Hejny C, Edelhauser HF. Surgical pharmacology: intraocular solutions and drugs used for cataract surgery. Buratto L, Werner L, Zanini M, Apple D, editors. Phacoemulsification; Principles and Techniques. 2nd ed. Thorofare NJ: Slack; 2003: pp. 230-236.
10. Lundberg B, Behndig A. Intracameral mydriatics in phacoemulsification cataract surgery. J Cataract Refract Surg
11. Katsev DA, Katsev CC, Pinnow J, Lockhart CM. Intracameral ketorolac concentration at the beginning and end of cataract surgery following preoperative topical ketorolac administration. Clin Ophthalmol
12. Waterbury LD. Alternative drug delivery for patients undergoing cataract surgery as demonstrated in a canine model. J Ocul Pharmacol Ther
13. Malyugin BE. Recent advances in small pupil cataract surgery. Curr Opin Ophthalmol
14. Donaldson KE, Braga-Mele R, Cabot F, Davidson R, Dhaliwal DK, Hamilton R, Jackson M, Patterson L, Stonecipher K, Yoo SH. for the ASCRS Refractive Cataract Surgery Subcommittee. Femtosecond laser–assisted cataract surgery. J Cataract Refract Surg
15. Nagy Z, Takacs A, Filkorn T, Sarayba M. Initial clinical evaluation of an intraocular femtosecond laser in cataract surgery. J Refract Surg
16. Abell RG, Kerr NM, Vote BJ. Toward zero effective phacoemulsification time using femtosecond laser pretreatment. Ophthalmology
17. Scott WJ, Tauber S, Gessler JA, Ohly JG, Owsiak RR, Eck CD. Comparison of vitreous loss rates between manual phacoemulsification and femtosecond laser–assisted cataract surgery. J Cataract Refract Surg
18. Schultz T, Joachim SC, Kuehn M, Dick HB. Changes in prostaglandin levels in patients undergoing femtosecond laser-assisted cataract surgery. J Refract Surg
19. Schultz T, Joachim SC, Szuler M, Stellbogen M, Dick HB. NSAID pretreatment inhibits prostaglandin release in femtosecond laser-assisted cataract surgery. J Refract Surg
20. Schultz T, Joachim SC, Stellbogen M, Dick HB. Prostaglandin release during femtosecond laser-assisted cataract surgery: main inducer. J Refract Surg
21. Grob SR, Gonzalez-Gonzalez LA, Daly MK. Management of mydriasis and pain in cataract and intraocular lens surgery: review of current medications and future directions. Clin Ophthalmol
22. Lindstrom RL, Loden JC, Walters TR, Dunn SH, Whitaker JS, Kim T, Demopulos GA, Tjia K. Intracameral phenylephrine and ketorolac injection (OMS302) for maintenance of intraoperative pupil diameter and reduction of postoperative pain in intraocular lens replacement with phacoemulsification. Clin Ophthalmol
. 2014;8:1735-1744. erratum 2015; 9:181.
23. Hovanesian JA, Sheppard JD, Trattler WB, Gayton JL, Malhotra RP, Schaaf DT, Ng E, Dunn SH. Intracameral phenylephrine and ketorolac during cataract surgery to maintain intraoperative mydriasis and reduce postoperative ocular pain: integrated results from 2 pivotal phase 3 studies. J Cataract Refract Surg
. 2015;41:2060-2068. erratum, 2016; 42:951.
24. Donnenfeld ED, Whitaker JS, Jackson MA, Wittpenn J. Intracameral ketorolac and phenylephrine effect on intraoperative pupil diameter and postoperative pain in cataract surgery. J Cataract Refract Surg
25. Bucci FA Jr, Michalek B, Fluet AT. Comparison of the frequency of use of a pupil expansion device with and without an intracameral phenylephrine and ketorolac injection 1%/0.3% at the time of routine cataract surgery. Clin Ophthalmol
26. Rosenberg ED, Nattis AS, Alevi D, Chu RL, Bacotti J, LoPinto RJ, D’’Aversa G, Donnenfeld ED. Visual outcomes, efficacy, and surgical complications associated with intracameral phenylephrine 1.0%/ketorolac 0.3% administered during cataract surgery. Clin Ophthalmol
27. Visco D. Effect of phenylephrine/ketorolac on iris fixation ring use and surgical times in patients at risk of intraoperative miosis. Clin Ophthalmol
Dr. Walter is a consultant to Omeros Corp. None of the other authors has a financial or proprietary interest in any material or methods mentioned.
Other Cited Material
B. Omeros Corp. Omidria®
(phenylephrine and ketorolac intraocular solution) 1%/0.3% [package insert]. 2017, Omeros Corp., Seattle, WA, Available at: http://www.omeros.com/pipeline/ophtha.htm