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Ophthalmology Management

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LASIK: A Breakthrough in Epithelial Protection

Buffering and cooling proparacaine has nearly eliminated epithelial damage in this practice. Here's how -- and why.

By: Brian R. Will, MD
Ophthalmology Management February 1, 2002

Patient Management
LASIK: A Breakthrough in Epithelial Protection
Buffering and cooling proparacaine has nearly eliminated epithelial damage in this practice. Here's how -- and why.
By Brian R. Will, M.D.

A few years ago, I performed LASIK on about 300 eyes a month. At least once a week, a patient would return with significant epithelial problems that required a contact lens and repeated visits to correct. It would take weeks for the patient's vision to return to normal -- and I had many more unhappy patients with epithelial problems than I would have liked.

Today, after extensive experimentation, we've discovered that increasing the pH and lowering the temperature of the proparacaine drops we use virtually eliminates most epithelial problems. I now perform almost twice as much LASIK each month, but I haven't had to treat a single case of "occult basement membrane disease" in the last 9 months.

A serious (but avoidable) problem

Many surgeons think of problems with the epithelium during LASIK as a minor issue, and one that simply has to be tolerated. My experience disagrees on both counts.

Epithelial defects or sloughing can have significant postoperative ramifications, especially if they involve the visual axis:

  • Immediate effects can include an increased risk of pain, inflammation and infection for the patient and difficulty in re-approximating the LASIK flap to the bed for the surgeon.
  • Postoperative problems can include ocular irritation, dry eye, recurrent erosions, epithelial ingrowth, increased frequency of flap microstriae, slow visual recovery, unstable intermediate refractions, unpredictable refractive endpoints and in- creased potential for flap "melt."

Traditionally, we've thought of damage to the epithelium during LASIK as being the result of multiple factors, possibly including ocular or corneal pathology such as dry eye or basement membrane disease, and diabetes or systemic disorders of the epidermis or collagen vascular system. However, by simply changing the way we use proparacaine, our practice has nearly eliminated epithelial problems.

The proparacaine factor

Proparacaine, the most widely used topical anesthetic in refractive surgery, is known to have an adverse effect on the stability of corneal epithelium. (For a detailed discussion of the biochemistry involved, see "The Chemistry of Proparacaine," on page 72.) When the cornea is subjected to a microkeratome pass, a vulnerable epithelium is a problem waiting to happen.

Because we were determined to uncover the reason for this problem, we investigated numerous possibilities. Through a process of trial and error -- and by noting changes in outcomes that accompanied changes in protocol (whether deliberate or accidental) -- we found that the negative effects of proparacaine disappear when the proparacaine used during LASIK in our practice:

  • has a pH of 6.5 ± 0.5 (proparacaine hydrochloride, commercially available as a 0.5% solution, can have a pH ranging from 4.0 to 6.0.)
  • is instilled in the eye at a temperature at the freezing point of proparacaine (32 degrees Fahrenheit)
  • is prepared fresh every day. (In our experience, attempting to reuse the drops leads to a reduction in the desired effect. In fact, if the drops are allowed to warm up as the day progresses, epithelial problems begin to rematerialize.)

Although much research still needs to be done, this protocol seems to be ideal for maximizing drug effect and permeability while maintaining an "epithelial-friendly" ocular environment.

Reaping the rewards

In addition to nearly eliminating epithelium-related complications, changing the way we manage proparacaine has eliminated a large measure of frustration experienced by patients and clinical staff alike. Improvements include:

  • fewer complaints of "stinging" when drops are instilled
  • improved subjective pain control during the microkeratome pass
  • virtual elimination of the "second eye" syndrome (patients complaining of much greater pain when operating on the second eye during bilateral LASIK)
  • noticeably fewer epithelial "tags" on flap relifts in patients previously treated with these drops
  • greater difficulty mechanically removing epithelium during PRK (an indication of increased epithelial stability)
  • enhanced "wettability" of the corneal surface both pre- operatively and immediately following surgery
  • improved maintenance of the hydrophilic mucous matrix on the ocular surface in the immediate post-op period
  • the ability to perform uneventful LASIK on patients with known basement membrane disease
  • a significant reduction in cases of epithelial ingrowth.

We've also noted other improvements:

  • In those rare cases in which epithelial defects still occur, the healing time is reduced to hours or days instead of the weeks often experienced with our previous regimen.
  • Topical anesthetics can be instilled in the eye with near impunity, so we don't have to instill eye drops minutes or seconds before surgery. This is a real asset, especially if laser maintenance or patient-related concerns cause a surgical delay.
  • We haven't seen any cases of recurrent erosions or "occult" basement membrane disease to date.
  • We've been able to reduce the waiting time for flap adherence to the stromal bed from 2 minutes to less than 60 seconds. This has reduced the adverse effects of flap dehydration and improved OR efficiency.

Another step toward problem-free LASIK

Chilling and buffering the proparacaine isn't our only strategy for protecting the epithelium. We work to condition the health of the epithelial layer through tear supplements and dietary modifications preoperatively. We also strive to improve the quantity and quality of the aqueous phase of the patient's tear film. (The buffering capacity of the tear film is essential to prevent excessive impact by the proparacaine.) Nevertheless, it's clear that the dramatic change in our epithelial outcomes is primarily the result of the change in our proparacaine protocol.

Seeing the difference this change has made has convinced us that epithelial problems only appear to be "unavoidable." If you perform LASIK, I urge you to try managing proparacaine this way. Whatever the biochemical explanation turns out to be, the benefits for you and your patients are clear.

Brian R. Will, M.D., is president and chief executive officer of Will Vision & Laser Centers in Vancouver, Wash. He's certified by both the American Board of Ophthalmology and the American Board of Eye Surgeons, and he's served as a project director for the International Institute for Advanced Laser Surgery.

-- Brian R. Will, M.D.

 

The Chemistry of Proparacaine

Although we don't know exactly how proparacaine produces its anesthetic effect, we do know that its chemical and biological mechanisms are affected dramatically by both the pH and temperature of the solution.

DESTABILIZING MECHANISMS

Proparacaine may destabilize the adhesion complex or hemidesmosomes that attach the epithelium to Bowman's membrane in a number of ways:

K Phase transition temperature. Cell membranes typically are in either a gel state or a "liquid crystal" state (loosely analogous to a liquid or solid state) depending on the ambient temperature. Adding a chemical to the mix may alter the temperature at which the membrane shifts from one phase to the next, just as adding salt to water lowers the temperature at which it freezes.

Research suggests that proparacaine molecules affects cell membrane fluidity and stability by entering the cell membrane and shifting the phase transition temperature of the phospholipid bilayer. As a result, topically applied proparacaine may cause cell membranes exposed to the solution to shift from the normal gel to the liquid crystal phase.

In a neuron, this phase shift probably impairs neuronal impulse transmission and thus produces the anesthetic effect. However, in the phospholipid bilayer of normal corneal epithelial cells, this could dramatically affect the stability of the cell membrane, which becomes extremely leaky and unstable when it's passing through its specific phase transition temperature. It could also turn the membrane into a mixture of "islands" of gel phase phospholipid and liquid crystal phospholipid, making the cell membrane matrix vulnerable to rupture.

K The transmembrane protein connection. A destabilized cell membrane may allow the transmembrane proteins that make up the hemidesmosome to become unstable, disrupting the attachment of the cell to the type VII collagen anchoring fibrils.

K Collagen fiber crosslinking. Positively charged proparacaine molecules can react with the negatively charged carboxyl groups that crosslink the type VII collagen anchoring fibrils (which connect the transmembrane proteins with Bowman's membrane). This reduces collagen crosslinking and further destabilizes the hemidesmosomal complex.

The combined effect of these factors is a decreased attachment of the corneal epithelium to Bowman's membrane, making it more susceptible to damage during the microkeratome pass.

RETURNING TO STABILITY

Given the biochemical mechanisms described above, the dramatic reduction in epithelial damage when the proparacaine is chilled and buffered could be explained as follows:

A Lowering the temperature of the solution may solve the problem of cell membranes being in a mixture of gel and liquid crystal states by moving the entire phospholipid domain of the epithelial cell membrane to a single phase. This would reduce cell membrane fluidity and instability in the hemidesmosome complex during the microkeratome pass.

The lower temperature may also reduce the rate at which positively charged proparacaine molecules react with type VII collagen carboxyl groups, preserving more collagen crosslinking.

A In order to interact with the cell membrane, the proparacaine molecules must be ionized. Altering the pH changes the number of ionized molecules that are available to enter the cellular membrane and alter its fluid characteristics. Fewer ionized molecules also means less interference with collagen anchoring fibril crosslinking, helping to stabilize the hemidesmosome.

 

-- Thomas Claringbold, D.O.

LASEK and the Epithelium

"Protect the epithelium!" The phrase has become a mantra for refractive surgeons, and for good reason: Disruptions in the epithelium during laser-assisted in situ keratomileusis (LASIK) can cause delayed visual recovery and increased pain, and possibly diffuse lamellar keratitis (DLK). Not surprisingly, most LASIK surgeons take precautions to protect the epithelium.

For surgeons like me who perform primarily laser-assisted sub-epithelial keratectomy (LASEK), the epithelium presents an interesting dichotomy. The structure, function and physical properties of the epithelium make it possible for LASEK to work, yet we do little during the procedure to protect it.

For example, minimizing the use of proparacaine preoperatively not only does nothing to alter recovery but actually makes flap elevation more difficult. Liberal use of anesthetic drops prior to the procedure helps to weaken epithelial-stromal adhesions and facilitates LASEK flap creation.

Intraoperatively, no special steps are taken to protect the epithelium other than making sure the flap is safely outside the ablation zone. After the flap is replaced, we bathe the epithelium with chilled balanced salt solution, mainly to decrease postoperative discomfort.

Actually, for the LASEK surgeon, preserving the epithelium is much more important than protecting it. Histopathological studies have demonstrated that the epithelial cells closest to the stroma remain viable after LASEK, making the procedure more than just "modified PRK." However, the alcohol solution used to create the flap does devitalize the most superficial layers, causing a delayed visual recovery -- at least compared to LASIK.

I'm aware of two steps a surgeon can take to reduce the loss of epithelium during LASEK:

Make sure the epithelium is as healthy as possible before the procedure. I have my LASEK patients use a dry-eye supplement containing a mix of omega-6 fatty acids and mucin (HydroEye by Science Based Health) once daily, starting 2 weeks before surgery and continuing for 1 week after LASEK. The flaps in these patients seem stronger and more pliable during surgery and re-epithelialize up to 24 hours sooner postoperatively.

Use the "butterfly" technique. Paolo Vinciguerra, M.D., of Milan, Italy, has developed a "butterfly" technique to create the LASEK flap. He makes a central, linear incision and then spreads the two "wings" of the incision with a speculum. Reports indicate that this variation can decrease alcohol exposure time by as much as 66%. Also, because this technique doesn't use the standard circular incision, it doesn't disrupt the physiologic radial pathways of the epithelial stem cells from the limbus to the center of the cornea. In theory, this should facilitate healing.

Ultimately, the key to preserving epithelium during LASEK, and therefore decreasing recovery time, is the development of a better solution than ethyl alcohol to use when creating the epithelial flap. Early work with enzymatic solutions that cleave hemidesmosomes and preserve the epithelial cells appear promising. Progress in this area, combined with benefits already seen with LASEK -- including fewer flap complications, less dry eye and fewer higher-order aberrations -- may help make LASEK the procedure of choice for more refractive surgeons.

 

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