The Efficient Ophthalmologist

Spreading the World on a Spreading Agent

The benefit in writing a column under such a broad heading is that it provides me with a wide berth to discuss topics both scientific and business in nature. This column is dedicated to the (re)education of our use of hyaluronidase — its function, derivation, history, risks, and the next-generation products now available to our specialty.

A Primer on Hyaluronidase

Hyaluronidase is an enzyme that degrades hyaluronan and, though used in many disciplines in medicine, has been employed in peri- and retro-bulbar blocks in ophthalmology for more than 60 years. It was first introduced by Dr. W. S. Atkinson in 1949 for use with local anesthetics. Its purpose is to quickly and efficiently aid in spreading the fluid with which it is mixed—for our purposes, the anesthetic block—in order to use less volume of fluid, decrease the risk of periocular pressure rise and to provide a more complete and rapid onset of akinesia and anesthesia.

Since it's origin, hyaluronidase has been derived from only two sources: bovine (bull) and ovine (sheep) testes, ground up and synthesized into a concentrated form that is dosed in “units” of product. Yes, that's right, we have been injecting testicular product around our patients' eyes all this time. Who knew? Certainly not I. That is, until I was recruited to lead a study with the first recombinant human-derived product, rHuPH20 (Hylenex from Halozyme Therapeutics) in 2011. More on this later.

No bull. Hylenex is the first ophthalmic spreading agent made using pure Human DNA recombinant hyaluronidase, eliminating inconsistencies found with bull testes.

Quality and Safety Issues

The issues surrounding animal-derived hyaluronidase are many. With the exception of Vitrase (Ista Pharmaceuticals), which is derived from sheep testes, no hyaluronidase product is subject to the FDA's stringent criteria. Therefore, concentration and consistency of product, contaminants and other non-medicinal components of delivered product, and the sources of the animal protein material are all over the board, as the study demonstrated via gel electrophoresis (SDS-PAGE technique), Western blot analysis, and measurement of active drug concentration. As a result, patients have been unknowingly exposed to notable risk of significant hypersensitivity reaction with potentially dire consequences.

An inquiry made to the FDA Adverse Events Reporting System (AERS) revealed dozens of AEs associated with the use of animal-derived hyaluronidase. They included periorbital edema, erythema, chemosis, itch and pain, proptosis, angioedema, “frozen globe,” elevated IOP, vision loss and blindness. Further, since the removal of bovine-derived Wydase from the market in 1999, other products have come and gone, either due to supply shortages or concerns about product purity.

This explains why most hyaluronidase is supplied by compounding pharmacies, which opens a new can of worms. Compounded products are not subject to FDA mandates. That means issues of purity, contamination, concentration, and source of material are completely unregulated. Only two states — Missouri and North Carolina — have laws that demand the registration of adverse events that compounded medicines cause, so adverse events go largely unreported.

Much of the raw protein material comes from China and other countries abroad, and can often contain melamine as a protein filler (also used in dog food to “bulk up” the protein content). An example seen in systemic use is in heparin containing melamine sourced from China, which has been reported to cause certain AEs in specific treated patients.

Animal-derived proteins have been associated with transmissible spongiform encephalopathy (TSE), better known as prion disease, Jacob-Crutzfeld and “mad cow” disease. This potential risk is so significant that in 2003 the World Health Organization (WHO) issued a strong warning against such sources of protein product and recommended use of another source of material if at all possible.

A Safe New Spreading Agent

With the disclosure that I do consult for the parent company, Halozyme Therapeutics, though derive no other financial benefit as a result, I want to introduce you to the first and only source of human DNA recombinant hyaluronidase, Hylenex, which has been shown to be 140-200 times more pure than its animal-derived counterparts.

To date, there have been no reported cases of hypersensitivity reaction to this product in ophthalmic use. It is FDA-regulated and approved, and we are using it in our ASC. By serendipity, in 2011 I cared for a 34-year-old woman from India who vaguely reported having had an allergic reaction to “something in the anesthetic” given to her before cataract surgery. She had required a corneal transplant. We administered a routine 6-cc peribulbar block that contained our standard animal-derived hyaluronidase and I witnessed an immediate allergic reaction comprised of the findings mentioned earlier, and IOP of 52 mm Hg. No globe perforation occurred and, thankfully, the patient responded to conservative treatment with no aberrant sequelae, though the graft was canceled. I realize, in retrospect, a handful of patients out of thousands of blocks have experienced similar reactions, which I attributed to a shallow orbit or volume overload, who were likely cases of hypersensitivity reactions.

How does this relate to becoming a more efficient ophthalmologist, which is, after all, the purpose of this column? Simple. When we have access to superior products, our everyday procedures will be safer and more predictable. We can eliminate most unexpected, time-consuming and troubling incidents. As highly trained practitioners, we are comfortable with the skills we possess. What bothers us most are unanticipated events with causes difficult to discern. With the advent of Hylenex, we can ensure a higher level of predictability and safety in our routine surgical procedures.

A Change Worth Considering

In closing, I recommend that you inquire about the source of the hyaluronidase used in the blocks for your patients when required, whether you operate in a hospital-based facility or ASC. I suggest educating the purchasers of the center's products and, because we now have a safer option, request they switch to a human-derived source of this material. OM

Steven M. Silverstein, MD, FACS, is a cornea-trained comprehensive ophthalmologist in practice at Silverstein Eye Centers in Kansas City, Mo. He invites comments. His e-mail is ssilverstein@silversteineyecenters.com.