Evidence-based Postoperative Care to Reduce the Risk of Ocular Inflammation

Cystoid macular edema (CME) was first described in the 1950s, correlating with the introduction and popularization of fluorescein angiography. Post-cataract CME was originally referred to as Irvine-Gass syndrome, after the physicians who first described it. The condition is characterized by late petalloid staining on fluorescein angiography, and macular thickening using optical coherence tomography (OCT).

In a recent retrospective review of 139 759 Medicare beneficiaries undergoing cataract surgery, an overall CME incidence of 1.95% was observed.¹ CME represents the leading cause of decreased vision following uncomplicated cataract surgery.

Patients who are predisposed to breakdown of their blood-ocular barrier are at increased risk of CME. There are a variety of risk factors for CME, such as ocular, vascular, or cardiovascular disease, uveitis, epiretinal membranes, vitreoretinal interface membranes, and retinitis pigmentosa.

Prevalence of Dry Eye Syndrome in the Cataract Population

As previously discussed, dry eye syndrome must be taken into consideration prior to ocular surgery, as it can have a significant impact on visual outcomes. A patient with pre-existing inflammation in the eye will be more susceptible to increased inflammation following the insult of surgery. The surgeon should look for signs of rosacea, which correlates with a high incidence of evaporative dry eye syndrome and should be treated prior to surgery.

In dry eye syndrome, tear hyperosmolarity leads to production of pro-inflammatory mediators. Inhibiting this process with the use of preoperative nonsteroidal anti-inflammaory drugs (NSAIDs) and “soft” steroids will not only alleviate dry eye syndrome, but will also reduce the risk of postoperative inflammation.

Postoperative Inflammation and Cataract Technique

Cataract surgery techniques are always changing, and there is considerable effort to determine the impact of these advances on outcomes, including postoperative inflammation. Angiographic evidence of CME was as high as 50% to 70% when intracapsular cataract extraction (ICCE) was the predominant surgical technique.² This incidence decreased to 20% to 30% with the evolution to extracapsular cataract extraction (ECCE) and phacoemulsification.³ With phacoemulsification, clinically significant CME with visual acuity <20/40 is present in <1% of patients following uncomplicated surgery. However, complications such as capsular rupture, vitreous loss, iris trauma, or intraocular hemorrhage increase the incidence of clinically significant CME to as high as 20%.⁴ Intraocular inflammation is more likely to occur in cases with hard cataracts, longer phacoemulsification time, and longer duration of surgery. Slit lamp and laser flare meter studies comparing phacoemulsification and ECCE have demonstrated significantly less inflammation in patients who undergo phacoemulsification with a return to baseline of 1 month compared to 2 months in patients who undergo ECCE.⁵

Etiology of Postoperative Inflammation

Postoperative inflammation occurs because the stress of ocular surgery increases the production of chemokines, prostaglandins (predominantly prostaglandin E₂), and other inflammatory mediators. This leads to the breakdown of the blood-ocular barrier, increase perifoveal capillary permeability, and subsequent accumulation of both intracellular and intraretinal fluid.

Surgical trauma breaks down cell membrane phospholipids (Figure 1). The enzyme phospholipase A₂ (PLA₂) converts these phospholipids into arachidonic acid. Corticosteroids block the conversion of phospholipids to arachidonic acid.⁶ Arachidonic acid can be converted to leukotrienes by lipoxygenase. This conversion to leukotrienes, which are chemotactic to white blood cells, contributes to inflammation. Arachidonic acid can also be converted to prostaglandins by enzymes known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), leading to inflammation. These enzymes are inhibited by NSAIDs.⁷

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NSAIDs

Topical NSAIDs are used for the management of postoperative CME following cataract surgery. They are also used for the prevention of postoperative CME and intraoperative miosis. Moreover, topical NSAIDs are also used for the reduction of pain and photophobia following keratorefractive surgery. However, for some NSAIDs this may represent an off-label use.

There are 4 topical ocular NSAIDs approved by the US Food and Drug Administration (FDA) for the treatment of postoperative inflammation after cataract surgery: diclofenac sodium ophthalmic solution 0.1%, ketorolac tromethamine ophthalmic solution 0.5%, nepafenac ophthalmic suspension 0.1%, and bromfenac ophthalmic solution 0.09%.^8–11 The available NSAIDs differ in terms of corneal permeability and bioactivation.¹¹ There are no published controlled studies comparing the efficacies of these agents. The FDA-approved dosing is 4 times daily for diclofenac and ketorolac. The approved dosing for nepafenac is 3 times daily beginning 1 day before surgery, while the approved dosing for bromfenac is twice daily, with no pre-dosing necessary.^8–11 With newer agents, further reductions in dosing can achieve zero cell and flare.¹²

The Combination of Corticosteroids and NSAIDs

Given the fact that NSAIDs and corticosteroids act at different steps in the inflammatory pathway, it is reasonable to speculate that they would be synergistic in the prevention and treatment of ocular inflammation. Several studies support this notion.^13-15 In a prospective, randomized, investigator-masked, multi-center clinical trial investigating the use of an NSAID in combination with a steroid, cataract surgery patients were randomized to 2 groups. One group received prednisolone acetate 1% QID, and the other group received prednisolone acetate 1% QID in combination with ketorolac 0.4% QID for 4 weeks postoperatively. Significantly less mean retinal thickness (P=.003) was observed through optical coherence tomography (OCT) analysis in patients receiving the combination of a steroid and an NSAID (<3.9 µ) compared to patients receiving only a steroid (<9.6 µ).¹⁴ Moreover, no definite/probable CME observed by OCT was found in patients receiving the combination of a steroid and an NSAID. In contrast, 6 steroid-only patients (2.4%) were observed to have probable/definite CME through OCT analysis (Figure 2).

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In the same study, possible CME was observed in 5.9% of patients receiving only a steroid, compared to 2.2% of patients receiving both the steroid and NSAID (Figure 2). Patients using ketorolac/prednisolone were significantly more likely to have <10 µm of retinal thickening than patients using steroid alone (73.6% vs 50.8%; P<.001). Contrast sensitivity was significantly improved in patients with <10 µm retinal thickening, compared to patients with >10 µm retinal thickening.¹⁴ In patients who develop acute CME, treatment with a combination of ketorolac and prednisolone was more effective compared to either agent alone. Patients treated with this combination were more likely to experience 2 lines of improvement in vision and faster time to resolution than patients treated with only 1 of the agents. These results strongly suggest that the combination of a steroid and an NSAID should be utilized in the prevention of inflammation following surgery.

Efficacy of Preoperative Dosing with NSAIDs

There is evidence suggesting that preoperative dosing with NSAIDs may have clinical benefit.¹⁶ In a study investigating whether preoperative dosing with ketorolac tromethamine 0.4% is effective, 100 patients

were randomized to 4 groups to receive either ketorolac for 3 days, 1 day, or 1 hour, or placebo before phacoemulsification. All treatment groups also received ketorolac 0.4% for 3 weeks postoperatively while the placebo group received vehicle. Results indicated that maintenance of pupil size was significantly better with 3-day dosing than 1-day dosing (P<.01), which was significantly better than 1-hour dosing or placebo (P<<.01). No patient who received ketorolac 0.4% preoperatively for 1 or 3 days developed CME, compared to 4% of patients who received ketorolac 0.4% 1 hour preoperatively and 12% of patients who received placebo. Moreover, 3-day and 1-day preoperative dosing of ketorolac reduced surgical time, phacoemulsification time and energy, and endothelial cell loss. Three-day and 1-day preoperative dosing also significantly improved visual acuity in the immediate postoperative period compared to that of 1-hour preoperative dosing or placebo. This improvement in postoperative visual acuity may correlate with the impact on miosis. NSAIDs do not have an effect on pre-existing ocular prostaglandins, making pretreatment with NSAIDs a reasonable option. These agents will inhibit the formation of endogenous prostaglandins, and would thus be more effective if implemented preoperatively.

Side Effects of Anti-inflammatory Treatments

NSAIDs

Side effects associated with topical NSAIDs include burning, stinging, corneal erosion, thinning, ulceration, and perforation. Delayed wound healing and increased susceptibility to infection may also be experienced with NSAIDs. The potentially sight-threatening side effects are

greater in patients who have complicated cataracts, corneal denervation, corneal epithelial defects, diabetes, ocular surface disease (including dry eye syndrome), rheumatoid arthritis, and have had repeat ocular surgeries. Longer and more frequent NSAID delivery also increases the risk of an adverse event. Ensuring that patients do not receive NSAIDs at doses that are administered too high or too frequently is important.

Corticosteroids

Side effects associated with corticosteroids include increased IOP, delayed wound healing, and increased susceptibility to infection. Utilization of a “soft” steroid such as loteprednol could be taken into consideration. As a “soft” steroid, loteprednol is inactivated when unbound, a property believed to minimize adverse events. Accordingly, there is evidence demonstrating that, unlike prednisolone acetate 1%, loteprednol is not associated with a statistically significant increase in IOP from baseline (Figure 3).^17,18 Loteprednol is associated with less potent anti-inflammatory action compared to prednisolone acetate.¹⁸ Nevertheless, when used in combination with an NSAID this is not a major concern.

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Summary

In summary, prospective, randomized, masked studies demonstrate a reduction of the incidence of CME and ocular inflammation with the perioperative use of topical NSAIDs and corticosteroids. The effects of these 2 agents appear to be synergistic, as they act at different points in the inflammatory cascade. Other inflammatory conditions that are prevalent in the cataract population, such as dry eye and rosacea, should be diagnosed and treated prior to surgery. Given the late onset of CME in capsular fibrosis, consideration of a 6 to 8 week treatment with a topical NSAID and a soft steroid should be considered, particularly in patients with risk factors for CME and in patients electing for premium IOL implantation, who will have greater expectations for immediate postoperative visual recovery.

References

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