Ophthalmology Management

Preventing CME After Cataract Surgery
Topical NSAIDs reduce the risk of postoperative cystoid macular edema. But not all NSAIDs are alike. Here are some factors to consider.
By Robert W. Snyder, M.D., Ph.D., Tucson, Ariz.

When it comes to your patients' expectations about cataract surgery, the bar has been raised to new heights. Traditionally, patients expected a good result if they were diligent and followed their doctor's advice. Today, though, they expect new technology to deliver almost immediate visual recovery

As surgeons, we want to perform procedures that are flawless and hassle-free. We can use pharmaceutical agents to reduce the risks in surgery, speed recovery and minimize discomfort.

In this article, I'll point out that using nonsteroidal anti-inflammatory drugs (NSAIDs) is a potent way to avoid intraoperative miosis, postoperative inflammation, postoperative pain, cystoid macular edema (CME) and delayed wound healing. First, let's review the traditional pharmacology for cataract surgery.

How Surgical Trauma Induces Prostaglandins

Adapted from Robert Flach

Many surgeons learned to administer preoperative antibiotics and dilating drops, as well as an NSAID, such as flurbiprofen (Ocufen) or suprofen (Profenal), to prevent intraoperative miosis. Keeping a pupil dilated has proved to eliminate an important risk factor for capsule rupture. Postoperatively, surgeons give corticosteroids to reduce inflammation and antibiotics to prevent infection.

The topical NSAIDs ketorolac tromethamine 0.5% (Acular) and diclofenac sodium 0.1% (Voltaren) have an expanded role in many types of surgery, including cataract procedures. See "Appropriate Uses for NSAIDs" below.

NSAIDs are FDA-approved to reduce postoperative pain in refractive surgery. In cataract surgery, ketorolac and diclofenac are approved for reducing postoperative inflammation. They've been shown to reduce the risk of CME and are known to minimize intraoperative miosis when given preoperatively.

While post-op corticosteroids minimize cell/flare, they don't seem to inhibit intraoperative miosis. They have minimal analgesic effect and thus are not effective at controlling postoperative pain and photophobia. What's more, corticosteroids can reduce wound strength and cause steroid-induced glaucoma.

NSAIDs effectively block the production of prostaglandins. Surgical trauma releases cell membrane phospholipids, which in turn are converted to arachidonic acid. This acid becomes a substrate for two different enzymes, cyclo-oxygenase and lipoxygenase. Cyclo-oxygenase produces prostaglandins, which lead to a range of undesirable side effects. See "How Surgical Trauma Induces Prostaglandins."

Cyclo-oxygenase comes in two forms. COX-1 is constitutive and present in small levels, while COX-2 is inducible and quickly mobilized in response to trauma.

A basal level of prostaglandin is important for aqueous outflow and pupil constriction. Systemic COX-1 is important in the gastrointestinal tract for pH control and mucin production.

Induced by surgical trauma, COX-2 results in excess prostaglandins. These in turn cause pain, photophobia, breakdown of the blood-brain barrier and CME.

To block the production of prostaglandins during surgery, it's best to prevent the chain reaction by having therapeutic levels of the NSAID on board at the time of surgery. Calvin Roberts, M.D., and Michael Raizman, M.D., advocate starting NSAIDs four times a day, 3 days before surgery.

The FDA has approved both preservative-free ketorolac (Acular PF) and diclofenac to prevent postoperative pain in refractive surgery. Although not approved for this indication, they are probably effective in cataract surgery as well. Studies have found no differences in controlling postcataract cell/flare when comparing ketorolac or diclofenac to corticosteroids.

What's more, various studies reveal that NSAIDs decrease the incidence of CME in cataract surgery. Those studies include:

At the University of Arizona, we studied cataract patients in a randomized, single-masked trial. One eye received preoperative flurbiprofen and postoperative prednisolone acetate (Pred Forte). The other eye received ketorolac both pre- and postoperatively.

We found no difference in preventing intraoperative miosis and postoperative cell/flare. We concluded that ketorolac was effective as a single agent for use as an antimiotic and anti-inflammatory in cataract surgery. (Acular as a single agent for use as an antimiotic and anti-inflammatory in cataract surgery, Journal of Cataract and Refractive Surgery, August 2000, 26(8): 1225-7.)


Corneal Wound Healing Rate After Photoablative Keratectomy with Commercially Available NSAIDs

In prescribing NSAIDs to control CME after cataract surgery, keep in mind that not all NSAIDs are the same. You should consider relative analgesic potency, anesthetic effect, penetration and toxicity, as well as side effects in making your choice.

As mentioned earlier, you'll also consider COX-1 and COX-2 activity. Flurbiprofen (Ocufen) and suprofen (Profenal), for instance, do not inhibit COX-2 very well, and they have poor penetration. Also, the FDA has approved only ketorolac and diclofenac for inflammation control after cataract surgery.

I have used NSAIDs in more than 98% of my cataract surgery cases for roughly the last 4 years without problems. However, they can delay epithelial healing. Keep this in mind when managing patients with significant dry eye, rheumatoid arthritis, advanced diabetes, or those who are susceptible to epithelial erosions and healing problems.

Studies of epithelial defects in rabbits where the basement membrane has been removed by excimer laser indicate that both ketorolac and diclofenac delay corneal wound healing somewhat; there's no statistical difference between either drug. (See "Corneal Wound Healing Rate After Photoablative Keratectomy with Commercially Available NSAIDs.")

Preservative-free ketorolac has less epithelial delay than ketorolac or diclofenac and is preferred for refractive surgery. I recommend using it four times a day for up to 24 hours, and I try to minimize the duration of use for this indication.

Despite what I believe is a good track record and my personal experience of safe use, there was an "outbreak" of corneal melts involving NSAIDs that the American Society of Cataract and Refractive Surgery (ASCRS) evaluated by survey in 1999.

More than 800 surgeons who responded to that survey found nearly 200 cases of epithelial and corneal problems associated with NSAID use, including corneal melts. This led the ASCRS to issue an alert on NSAID use.

Most of these corneal melts were associated with diclofenac or diclofenac with multiple medications. Some 84% were with diclofenac and 54% with generic diclofenac. Ultimately, generic diclofenac was taken off the market.

In contrast, ketorolac as a single agent seems to have a long track record of safety. I have continued to use it without problems, and it's been effective in reducing intraoperative miosis, minimizing inflammation and CME and reducing discomfort. I am aware of the potential for problems, however, and will discontinue the drug if I see signs of epithelial erosions. (I've had to discontinue this drug three or four times in 4 years.)

Recurring CME Resolved

This case shows the value of postoperative ketorolac tromethamine 0.5% (Acular). The patient had phacoemulsification complicated with endophthalmitis postoperatively caused by Staphylococcus epidermidis.

The appropriate intravitreal antibiotics cleared the infection, but the patient's condition required a second procedure to release adhesions between the intraocular lens and the iris. His postoperative vision was compromised to roughly 20/80 by cystoid macular edema (CME), which responded to topical ketorolac and prednisolone acetate (Pred Forte).

When these were discontinued, the CME returned and then resolved again after a course of ketorolac q.i.d. The patient now sees well with a visual acuity of 20/25 and is relatively happy.

NSAIDs may cause irritation when applied. In 1999, I helped conduct a study on patient comfort in a randomized comparison of ketorolac, preservative-free ketorolac and diclofenac. One of these agents was applied to one or the other eye of 35 volunteers, who scored their symptoms at 5 and 60 minutes.

For both burning and stinging, the study found no difference between ketorolac or diclofenac. Volunteers reported less burning and stinging with preservative-free ketorolac. But they reported no significant difference in aching, light sensitivity and foreign body sensation with any of the three. In my experience, you can reduce irritation by refrigerating the bottle of NSAID.

Research suggests that brand-name NSAIDs (Acular and Voltaren) are effective for treating postoperative CME in cataract surgery. What's more, a combination of topical NSAID and Pred Forte is superior to either one alone in treating CME if it should occur (Topping, T. M., et al. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema. Ophthalmology 1072034-8; discussion 2039 Nov. 2000).

In my experience and studies, Acular provides a "one bottle" solution for cataract surgery. Besides preventing postoperative CME, it prevents intraoperative miosis and postoperative inflammation, and it minimizes postoperative discomfort.

In essence, it provides a triple threat. It prevents CME, minimizes post-op discomfort and keeps the pupil dilated during surgery.

Dr. Snyder is a clinical professor and the head of the Department of Ophthalmology at the University of Arizona College of Medicine in Tucson.