October 2018

RESIDENTS

EyeWorld journal club
Review of “Effect of phenylephrine 1.0% ketorolac 0.3% injection on tamsulosin-associated intraoperative floppy iris syndrome”


by Kenneth Taubenslag, MD, Tigran Kostanyan, MD, Jennifer Lee, MD, Anagha Medsinge, MD, Siwei Zhou, MD, Leonid Zlotcavitch, MD, Ian Conner, MD, PhD,
and Evan Waxman, MD, PhD


Evan Waxman, MD, residency program director, UPMC Eye Center, University of Pittsburgh School of Medicine

Ian Conner, MD, associate residency program director, UPMC Eye Center, University of Pittsburgh School of Medicine


University of Pittsburgh Medical Center (UPMC) Eye Center residents; back row, from left: Tigran Kostanyan, MD, Leonid Zlotcavitch, MD, Jennifer Lee, MD, Kenny Taubenslag, MD;
front row, from left: Siwei Zhou, MD, Anagha Medsinge, MD

IFIS continues to vex cataract surgeons. This month, I invited the Pittsburgh residents to review a study on phenylephrine that appears in the September issue of JCRS.
—David F. Chang, MD,
EyeWorld journal club editor


Intraoperative floppy iris syndrome (IFIS), classically associated with alpha-1 adrenergic receptor antagonists such as tamsulosin, was first described by Chang and Campbell in 2005.1 IFIS is characterized by a triad of iris billowing, iris prolapse, and progressive intraoperative miosis, and has been shown to increase the risk of surgical complications, underscoring the importance of identifying safe and effective management strategies.2 Numerous interventions for the prevention and treatment of IFIS have been proposed including topical mydriatics and intracameral injections, modified incision construction and fluidic parameters, as well as iris hooks and Malyugin rings.

Study summary

Recently, phenylephrine 1.0%-ketorolac 0.3% (Omidria, Omeros, Seattle) was FDA-approved for intraoperative mydriasis in cataract surgery as well as postoperative pain.3 In the September issue of the Journal of Cataract & Refractive Surgery, Silverstein et al. evaluate the effect of Omidria on iris behavior in patients at risk for tamsulosin-associated IFIS.4 This is the first study to examine Omidria specifically for the prevention of IFIS, and the authors highlight its potential advantages in this context, namely its ease of use as an additive to irrigating solution, and its FDA approval. In this single-surgeon, prospective trial, 50 eyes of 50 men with a history of tamsulosin use were randomized in a 1:1 fashion to treatment and control groups. Both groups received preoperative topical 1.0% tropicamide and 2.5% phenylephrine for dilation. In the treatment group, 4.0 mL phenylephrine 1.0%-ketorolac 0.3% were added to the 500 mL irrigating solution prior to the start of cataract surgery. To be eligible for randomization, men had to have a history of prior or ongoing tamsulosin use and an indication for phacoemulsification without an additional, concomitant ophthalmic procedure. Exclusion criteria included diabetes, a previous ophthalmic diagnosis such as glaucoma or iris tears, a history of ocular trauma, current use of any ophthalmic medication other than artificial tears, and current use of any systemic medication known to affect pupil diameter, such as an opioid. Presence or absence of pseudoexfoliation and duration of tamsulosin use were not recorded.
The primary endpoints of the study included change in pupil diameter before and after cataract extraction and change in pupil diameter prior to cataract extraction and after intraocular lens implantation. Pupil diameter was measured from surgical videos using ImageJ software with a ruler reference. Additional primary endpoints were the rate of iris prolapse and iris billowing severity based on a novel, proposed iris billowing grading system. This new grading system assigns scores to the duration, frequency, and magnitude of iris billowing based on intraoperative video recordings taken from an endocyclophotocoagulation (ECP) probe. The study was double-masked in the sense that the patient and surgeon were masked to the study groups. However, it is not clear whether or not reviewers of the surgical videos from which the data were collected were blinded to the treatment. All parametric data were analyzed using student t-tests, and nonparametric data were analyzed with a chi-squared test.
After randomization, treatment and control groups had no statistical difference with respect to age, race or ethnicity, iris color, or cataract severity. In the Omidria group, mean pupillary diameter was significantly greater at all time points compared to the control group. Intraoperative pupillary constriction before and after cataract extraction averaged 0.38 ± 0.45 mm in the Omidria group compared to 1.23 ± 0.64 mm in controls (p<0.1). Mean pupillary constriction before cataract extraction and after lens implantation was 0.67 ± 0.44 mm in treated eyes compared to 1.67 ± 0.82 mm in controls (p<0.1). Iris prolapse was seen significantly more often in control eyes, occurring in 56% of cases compared to 12% in the treatment group. The control group also scored higher on the newly proposed iris billowing grading scale on average, though 60% of treated eyes still demonstrated what was characterized as moderate iris billowing. No surgical complications occurred in either study group.
There are no declared conflicts of interest, and Omeros did not sponsor the study. However, a search of Centers for Medicare and Medicaid Services (CMS) open payments data from 2015–2017 does show that Dr. Silverstein has been a paid consultant for Omeros, and the results should be interpreted in this context.

Discussion

Overall this is a strong study supporting the efficacy of phenylephrine 1.0%-ketorolac 0.3% for reducing signs of IFIS in patients with a history of tamsulosin use. The study was adequately powered, and the authors demonstrated a significant reduction in intraoperative miosis and iris prolapse with Omidria. Strengths of the study also include its prospective and randomized design. The study was not adequately powered to detect a difference in complication rates between treatment and control groups. In theory, as IFIS has been associated with increased rate of surgical complications, use of Omidria in patients with a history of tamsulosin use should reduce the risk of iris trauma, retained cortex, and posterior capsular rupture; however, a much larger study would be necessary to confirm or refute this hypothesis.2 Additionally, as only patients on tamsulosin were studied, the results cannot be extrapolated to patients on other medications implicated in IFIS such as other alpha-blockers, antipsychotics, or saw palmetto.
The study puts forth its novel iris billowing grading scale based on ECP probe recordings as an aid to future research on IFIS. Higher scores in the control group support the validity of the grading scale. However, the grading scale has not yet been shown to correlate with any other outcomes such as intraoperative miosis or surgical complications. Additionally, the study does not state how many reviewers scored the videos and therefore does not address intra- and inter-reader scoring variability. Additional work is necessary before such a grading system is adopted in the cataract community as a meaningful outcome metric.
One weakness of the paper is the discussion’s handling of alternative approaches to pupil management. For example, the authors characterize the Malyugin ring as “somewhat” effective in IFIS, while at least one prior study demonstrated excellent efficacy in maintaining pupillary diameter.5 The discussion claims that epi-Shugarcaine has been shown to make no difference in the reduction of IFIS. However,
the single paper cited to make this claim is a retrospective series where the presence of IFIS was deduced from operative reports, raising concern for recall bias.6 A number of other historical methods for managing IFIS are also omitted from the discussion. For example, topical atropine with or without or intracameral epinephrine has been shown to be efficacious in several small series.7,8 With a number of available options for managing IFIS, a more interesting study would have compared Omidria to a stronger control group. Even the addition of a topical preoperative NSAID, which is standard practice for many surgeons, to both treatment and control arms would have made a more compelling case for intracameral phenylephrine-ketorolac. A head-to-head comparison comparing Omidria to the only other FDA-approved addition to irrigating solution for intraoperative mydriasis, adrenaline, would also be a welcome addition to the literature. Though this study does support the efficacy of Omidria in the prevention of tamsulosin-associated IFIS, it brings us no closer to determining the optimal management for this increasingly common phenomenon, which is all the more problematic when considering the cost of Omidria.
Until December 31, 2017, Omidria cost approximately $465.00 per single-patient use vial and had pass-through payment status from CMS. However, pass-through status has since expired. Omeros offers a facility reimbursement for the difference between cost and insurance coverage as well as a patient assistance program for patients without insurance or with government insurance; still, the cost and administrative burden of enrolling patients may affect surgeon utilization.

References

1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg. 2005;31:664–73.
2. Haridas A, et al. Intraoperative floppy iris syndrome (IFIS) in patients receiving tamsulosin or doxazosin—a UK-based comparison of incidence and complication rates. Graefes Arch Clin Exp Ophthalmol. 2013;251:1541–5.
3. Hovanesian JA, et al. 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;41:2060–8.
4. Silverstein SM, et al. Effect of phenylephrine 1.0%-ketorolac 0.3% injection on tamsulosin-associated intraoperative floppy iris syndrome. J Cataract Refract Surg. 2018;44:1103–1108.
5. Chang DF. Use of Malyugin pupil expansion device for intraoperative floppy-iris syndrome: results in 30 consecutive cases. J Cataract Refract Surg. 2008;34:835–41.
6. Chen AA, et al. Pharmacologic prophylaxis and risk factors for intraoperative floppy-iris syndrome in phacoemulsification performed by resident physicians. J Cataract Refract Surg. 2010;36:898–905.
7. Bendel RE, Phillips MB. Preoperative use of atropine to prevent intraoperative floppy-iris syndrome in patients taking tamsulosin. J Cataract Refract Surg. 2006;32:1603–5.
8. Masket S, Belani S. Combined preoperative topical atropine sulfate 1% and intracameral nonpreserved epinephrine hydrochloride 1:4000 [corrected] for management of intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2007;33:580–2.

Contact information

Connor
: connerip@upmc.edu
Waxman: waxmane@upmc.edu

Review of “Effect of phenylephrine 1.0% ketorolac 0.3% injection on tamsulosin-associated intraoperative floppy iris syndrome” Review of “Effect of phenylephrine 1.0% ketorolac 0.3% injection on tamsulosin-associated
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