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Rate of pseudophakic cystoid macular edema using intraoperative and topical nonsteroidal antiinflammatory drugs alone without steroids

Walter, Keith MD; Kauffman, Levi MD; Hess, Justin MD

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Journal of Cataract and Refractive Surgery: March 2020 - Volume 46 - Issue 3 - p 350-354
doi: 10.1097/j.jcrs.0000000000000062
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Cataract surgery patients have come to expect excellent vision following their procedures.1 However, the development of cystoid macular edema (CME) after cataract surgery is a common cause of reduced visual acuity.2 CME is thought to be the result of inflammation initiated by surgical trauma.1,3–5 Even in those cases in which postoperative CME is self-limiting, it can be a source of dissatisfaction to the patient and frustration for the surgeon and often results in added costs.6 Persistent cases often require additional follow-up visits and sometimes need additional treatments such as sub-Tenon or intravitreal injections. A review of 139 759 Medicare beneficiaries who underwent modern cataract surgery determined that total ophthalmic payments were 47% ($1,092) higher for those who developed postoperative CME compared with those who did not (P < .0001).7

Although the incidence of clinical CME associated with cataract extraction tends to be about 1% to 5% in patients with no risk factors, some studies have reported angiographic CME in up to 30% of patients undergoing cataract surgery.2,3,8–14 To decrease the rate of postoperative CME, corticosteroid eyedrops are routinely prescribed postoperatively by most cataract surgeons.15 Corticosteroid eyedrops have potential adverse effects such as steroid-induced ocular hypertension, delayed wound healing, and increased risk of infection. These agents require complex tapering regimens that can be burdensome for patients, which can lead to a high rate of noncompliance.16,17

Topical nonsteroidal antiinflammatory drugs (NSAIDs) have been used as an adjunct to corticosteroid drops to treat and prevent postoperative CME.4,5,15,18 Recently, an NSAID can also be delivered to the eye intraoperatively through an intracameral infusion of the phenylephrine 1%/ketorolac 0.3% solution (Omidria) during cataract surgery. Some surgeons have abandoned the use of topical corticosteroids in lieu of postoperative topical and intraoperative intracameral NSAIDs.15 This study assessed the rate of formation of clinical CME in patients treated with the intraoperative phenylephrine/ketorolac solution plus the postoperative NSAID bromfenac (BromSite) without the use of a topical corticosteroid and compared it with the published rates of CME in patients treated with various postoperative topical corticosteroids and a combination of corticosteroid/NSAID regimens.


The Institutional Review Board at Wake Forest Baptist Hospital (Winston-Salem, NC) approved this study. A retrospective chart review of the electronic medical records of adult patients who had undergone uneventful cataract surgery (Current Procedural Terminology [CPT] code 66984) was performed over a 2-year period from January 1, 2016, to December 31, 2017, by a single surgeon (KW). Patients who received the intraoperative phenylephrine 1%/ketorolac 0.3% solution and preoperative/postoperative bromfenac sodium and had at least 6 weeks of postoperative follow-up data were included.

Patients with a history of CME, diabetic macular edema, retinal vein occlusion, epiretinal membrane, vitreomacular traction, uveitis, or exudative age-related macular degeneration were excluded. In addition, patients were excluded if any corticosteroids were used in the postoperative phase or if follow-up was less than 6 weeks. Those who underwent combined procedures (eg, phacoemulsification/Descemet-stripping endothelial keratoplasty) and complex cataract extraction (CPT code 66982) were also excluded. Table 1 shows the characteristics of the patient population.

Table 1
Table 1:
Patient characteristics.

Follow-up appointments included a dilated fundus examination at 1 day, 1 to 3 weeks, and 4 to 6 weeks postoperatively. If corrected distance visual acuity was 20/30 or worse (ie, not 20/20 or 20/25) at the 4- to 6-week appointment period without a clear explanation, an optical coherence tomography (OCT) scan was obtained.

Experimental Treatments

Phenylephrine and ketorolac intraocular solution 1%/0.3% (Omidria) is approved by the U.S. Food and Drug Administration in addition to the irrigating solution during cataract surgery for maintaining the pupil size, for preventing intraoperative miosis, and for reducing postoperative ocular pain. The solution was administered at the beginning of surgery right after paracentesis to improve pupil dilation and to block prostaglandin release and was administered as a continuous infusion thereafter.

Topical bromfenac is approved for the treatment of postoperative inflammation and for the prevention of postoperative pain in patients undergoing cataract surgery. The use of bromfenac for the prevention of CME is currently considered to be off-label. All eyes in this study were treated with bromfenac (either BromSite 0.075% or Prolensa 0.07%) 2 days preoperatively and 28 days postoperatively using once-daily dosing.

All patients received intracameral moxifloxacin (moxifloxacin hydrochloride ophthalmic solution 0.5%) diluted 1:1 with a balanced salt solution (intraocular irrigating solution) unless contraindicated due to allergy.

Data Collection and Outcome Measures

Clinical CME was assessed during clinical examinations and confirmed using OCT. Cystoid macular edema was defined to be less than a 0.2 logarithm of the minimum angle of resolution improvement in corrected distance visual acuity compared with the preoperative potential visual acuity.19 The electronic record review was conducted using criteria of the CPT code (66984), a single surgeon (K.A.W.), and procedure dates from January 1, 2016, to December 31, 2017.


Overall, 824 patient records were reviewed. Of these, 320 were excluded, mostly because of inadequate follow-up, leaving 504 eyes included in the analysis.

Only 2 eyes developed CME, providing a rate of 0.0040 (0.4%; 95% CI: 0.0005 to 0.0143) (Table 2). Of the 2 patients who developed CME, one returned to 20/20 by postoperative month 3. The other had a chronic intraretinal cyst that may have been pre-existing. However, the patient's vision improved to 20/25 after 6 months.

Table 2
Table 2:
Incidence of clinical CME.


The dual NSAID combination of intraoperative phenylephrine 1%/ketorolac 0.3% solution was administered intracamerally, and perioperative topical bromfenac was effective in limiting the rate of clinically significant pseudophakic CME in our cohort of patients. Our CME rate of 0.40% was below the historical published rates in patients using traditional topical corticosteroids with or without topical NSAIDs (Table 1). The historical incidence of clinical CME after cataract surgery using postoperative topical corticosteroids typically ranges from 1% to 5% in clinical studies, even in patients having no risk factors.2,3,8,10–14,19 Grzybowski et al. have provided an excellent review of pseudophakic CME, including factors associated with increased risk of the condition.2 The results from these reports underscore the need for effective inflammation prophylaxis for all cataract surgery patients, whether or not they have risk factors.

Although ocular corticosteroids are widely used to prevent postoperative inflammation and CME, they do have some drawbacks, such as increased intraocular pressure, delayed wound healing, and increased risk of infection.20,21 In addition, corticosteroid regimens require a complex tapering schedule with which few elderly patients can comply.17 Noncompliance or even a rapid tapering can result in rebound inflammation.22 Generic substitution for suboptimal formulations of corticosteroid is common and can further affect outcomes.23 Thus, minimizing corticosteroid use may provide benefits to many of our patients.

A Cochrane review by Juthani et al., based on 4 randomized controlled trials that reported CME at 1 month, reported evidence that patients treated with an NSAID alone without a steroid might have a lower risk of developing CME compared with patients treated with a corticosteroid alone (relative risk 0.26, 95% CI 0.17 to 0.41).21 However, the European Society of Cataract and Refractive Surgeons' Prevention of Macular Edema after Cataract Surgery Study Group found a CME incidence of 3.6% when using bromfenac alone, 4.5% with dexamethasone alone, and 1.5% with the combination of both (overall P = .043) within 12 weeks of surgery.19 Our low incidence of CME without a topical steroid supports the Cochrane analysis, providing a benefit and, at the same time, reducing the burden of topical drops for patients after cataract surgery.21,24 Of the 2 patients in our study who had CME, one was diabetic giving a 1.1% CME rate (n = 1 of 95 diabetic patients). This is still considerably lower than the reported CME rate of 2.9% in diabetics undergoing modern cataract surgery.6

Topical NSAIDs are well known to decrease the incidence of CME after cataract surgery.4,21,25 However, their use has been limited by many surgeons because topical ocular NSAIDs have been associated with punctate keratitis, corneal ulceration, or even corneal melting.20,22 Katsev et al. have shown that topical ketorolac, even when applied 4 times daily for the 2 days before surgery, is nearly undetectable in the anterior chamber immediately after cataract surgery despite adequate levels being detected before surgery.26 Intracameral ketorolac has no known adverse reactions with the cornea or other ocular structures.27 This NSAID delivered intracamerally in the phenylephrine/ketorolac 1.0%/0.3% combination has been shown to suppress cyclooxygenase-1 and cyclooxygenase-2 enzymes for at least 10 hours after cataract surgery in an animal model.27 Therefore, beyond its miosis prevention benefits, phenylephrine 1%/ketorolac 0.3% solution may be a reasonable substitute for corticosteroids and perhaps even for topical NSAIDs in preventing postoperative inflammation in cataract surgery. Further prospective randomized studies are warranted to elicit whether the phenylephrine 1%/ketorolac 0.3% solution would be beneficial in preventing CME either alone or with other antiinflammatory agents.

Our study is limited by its retrospective nature, lack of OCT analysis on every patient, and limited follow-up in our comanaged patients. The CME rate may appear lower than it was in actuality, as we only obtained OCT on patients with unexplained vision of 20/30 or worse. There may have been patients who developed CME but maintained vision of 20/25 or even 20/20; however, we consider this level to be clinically insignificant. As far as possible selection bias in our comanaged patients is not included in the analysis, we believe strongly that the 500+ patients we did follow clinically had excellent results using the intracameral phenylephrine 1%/ketorolac 0.3% solution and perioperative topical bromfenac without the use of a steroid.

We believe that the combination of intraoperatively delivered phenylephrine 1%/ketorolac 0.3% intraocular solution and perioperative topical bromfenac offers an effective alternative to topical corticosteroids and to combinations of corticosteroids and NSAIDs for limiting the occurrence of clinically significant pseudophakic CME. The CME rate observed in this study was below the published historical values from studies with either topical corticosteroid or a combination of corticosteroid/NSAID regimens, indicating that dual (intraoperative and perioperative) NSAID treatment alone may be adequate to minimize CME after cataract surgery and allow surgeons to discontinue the use of a topical steroid when using the intracameral phenylephrine 1%/ketorolac 0.3% solution.


  • Topical corticosteroids and nonsteroidal antiinflammatory drugs have commonly been used to prevent inflammation and cystoid macular edema after cataract surgery; however, each of these treatments has drawbacks.


  • The use of a combination of intraoperative phenylephrine 1%/ketorolac 0.3% solution with perioperative bromfenac may limit the occurrence of clinically significant pseudophakic cystoid macular edema after cataract surgery without the drawbacks of topical corticosteroids.

The authors would like to acknowledge Julie Crider, PhD, for medical writing/editing contributions. Writing support was funded by Omeros Corporation.


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