Journal of Refractive Surgery

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Randomized Clinical Trial of Topical Sodium Hyaluronate After Excimer Laser Photorefractive Keratectomy

Kais Algawi, FRCS; Bengt Agrell, MSc; Michael Goggin, FRCSI

Abstract

ABSTRACT

BACKGROUND: Sodium hyaluronate (Healon) has been reported to promote corneal epithelial healing following severe eye burns in humans and rabbits. Endogenous hyaluronate has been shown to be significantly increased in the corneal tissue following extracapsular lens extraction, anterior segment trauma, and radial keratotomy. The authors report the use of topical sodium hyaluronate administration on the cornea of eyes which have been treated by photorefractive keratectomy for myopia.

METHODS: Forty eyes of 40 patients undergoing excimer laser photorefractive keratectomy for myopia were studied to evaluate the effect of topical sodium hyaluronate versus placebo (Healon buffer) instillation on pain and corneal epithelial healing in an observer blind randomized clinical trial.

RESULTS: There was no significant difference between patients whose eyes were treated with sodium hyaluronate and those treated with a placebo (Healon buffer), with regard to the amount of postoperative pain or the rapidity of corneal epithelial healing.

CONCLUSIONS: Topical sodium hyaluronate administration showed no effect on pain or corneal epithelial healing following photorefractive keratectomy in this study. [JRefìract Surg. 1995;11:42-44.]

Abstract

ABSTRACT

BACKGROUND: Sodium hyaluronate (Healon) has been reported to promote corneal epithelial healing following severe eye burns in humans and rabbits. Endogenous hyaluronate has been shown to be significantly increased in the corneal tissue following extracapsular lens extraction, anterior segment trauma, and radial keratotomy. The authors report the use of topical sodium hyaluronate administration on the cornea of eyes which have been treated by photorefractive keratectomy for myopia.

METHODS: Forty eyes of 40 patients undergoing excimer laser photorefractive keratectomy for myopia were studied to evaluate the effect of topical sodium hyaluronate versus placebo (Healon buffer) instillation on pain and corneal epithelial healing in an observer blind randomized clinical trial.

RESULTS: There was no significant difference between patients whose eyes were treated with sodium hyaluronate and those treated with a placebo (Healon buffer), with regard to the amount of postoperative pain or the rapidity of corneal epithelial healing.

CONCLUSIONS: Topical sodium hyaluronate administration showed no effect on pain or corneal epithelial healing following photorefractive keratectomy in this study. [JRefìract Surg. 1995;11:42-44.]

Sodium hyaluronate (Healon, Pharmacia, Monrovia, Calif) is a sterile non-pyrogenic viscoelastic preparation of highly purified noninflammatory, high molecular weight sodium hyaluronate. It is a transparent, viscous solution which has been used in intraocular surgery for more than 14 years in about 20 million patients.

Several surgical methods have been used to correct myopia during the past three decades,13 including excimer laser photorefractive keratectomy.4 However, the epithelial defect resulting from this procedure causes severe pain in most patients. Pain is a common complication of surgical procedures for myopia.5

Sodium hyaluronate has been reported as efficacious, in combined surgical and drug therapy, in promoting healing of the cornea in the treatment of severe eye burns.68 The effect of sodium hyaluronate on epithelial healing in corneal alkali wounds in rabbit eyes was confirmed in another study.9 Topical sodium hyaluronate application during penetrating keratoplasty has been speculated as promoting epithelial healing.10 Nishida et al11 demonstrated that sodium hyaluronate stimulates corneal epithelial migration in cultured rabbit cornea. Our study was conducted to investigate whether topical sodium hyaluronate application, following photorefractive keratectomy for myopia, has an effect on postoperative pain and epithelial healing.

MATERIALS AND METHODS

Forty eyes of 40 patients with myopia, 17 men and 23 women, were recruited from the Excimer Laser Clinic. Their ages ranged from 21 to 53 years (mean, 31 years). All patients were white except for one Asian. The distribution between treatment of right and left eyes was equal.

Each patient was given, prior to inclusion in the study, full and adequate verbal and written information regarding the objective of the study and possible risks involved. The patients were informed of their right to withdraw from the study at any time. Written informed consent was obtained from each patient prior to treatment.

Each patient was allocated for application of sodium hyaluronate (10 mg/ml sodium hyaluronate) or placebo (sodium hyaluronate buffer) after photorefractive keratectomy, according to a randomization computer program. Sodium hyaluronate (10 mg/ml) is dissolved in sodium hyaluronate buffer.

Table

Table 1Postoperative Pain in the Sodium Hyaluronate Group (Number of Eyes)Table 2Postoperative Pain in the Control Group (Number of Eyes)

Table 1

Postoperative Pain in the Sodium Hyaluronate Group (Number of Eyes)

Table 2

Postoperative Pain in the Control Group (Number of Eyes)

The syringes were filled with either solution and were marked with patient numbers to be issued consecutively. All syringes were packed in a similar manner. Neither the operator (M. O.K.), nor the observer (KA.) had access to the randomization list.

Seven millimeters of epithelium concentric with the constricted pupil was scraped using a beaver knife. All eyes were treated using 193-nanometer Summit Technology ExciMed UV 200 argon fluoride excimer laser. The diameter of the treatment zone was 5 mm with fluence of 180 mJ/cmp 2 and repetition rate of 10 Hz. A small amount of the test product was applied immediately after the laser treatment to the center of the cornea followed by the routine application of Maxitrol (Dexamethasone 0.1%, Neomycin sulphate 0.35% and polymyxin B sulphate 6000 iu per gram) eye ointment. A double eye pad was then placed over the treated eye.

The systemic analgesic, Solpadeine (paracetamol 500 mg, codeine phosphate 8 mg and caffeine 30 mg), was given postoperatively. Patients were advised to take analgesic tablets as needed and were also prescribed a sedative, Dalmane 30 mg (flurazepam), to be taken at nighttime.

The patients were assessed at 1, 2, 5, and 7 days postoperatively. At each visit, the patients were asked to reveal the degree of pain experienced which was recorded on a five-point scale (none, very mild, mild, moderate, or severe).

The Haag Streit 900 slit-lamp microscope was used to measure the diameter of the residual unhealed area of epithelium at each visit. The length of slit beams, at two directions, was measured using the incorporated beam length measure. This is compared to the initial denuded area at the time of treatment, which is usually a central 7.0 mm. Maxitrol ointment was applied topically to the operated eye by all patients four times per day during the first week.

Case Report Forms were computer-processed using a VAX-computer from Digital Equipment. The treatments were compared using Wilcoxon's rank sum test for categorical data, chi-square for binary data, and i-test for continuous data.

RESULTS

Most of the patients reported having moderate-tosevere pain at day 1, and none-to-mild pain at the day 2 visit. None of the patients had pain at the day 7 visit (Tables 1 and 2).

Six patients, two in the control group and four in the sodium hyaluronate group, received additional analgesic medication during the follow-up study period. There was no statistical difference regarding pain at any of the postoperative visits.

The median percentage of epithelium regrowth was 50 at the first postoperative visit and 100 at the third visit in the two groups. The estimated percentage of epithelial healing was not significantly different between the two groups at any of the visits.

At the third postoperative visit (5 days after laser surgery), four patients, two in the sodium hyaluronate group and two in the control group, failed to attend. Seven days after laser surgery, three patients in the control group did not attend.

No adverse event occurred during the 1-week follow-up period.

DISCUSSION

Pain occurring after photorefractive keratectomy is a significant side effect in most patients.12-14 It starts 2 to 3 hours after treatment, reaches a peak at 12 hours, and abates over a 24-hour period. Patients experience significant distress and discomfort and thus, some potential patients may decline this form of treatment. The cause of the pain is similar to that of a corneal abrasion and is the result of the mechanical removal of the epithelium which exposes the naked nerve endings. It has been postulated that prostaglandins may play a role in causing pain in the postoperative period. Topical prostaglandins inhibitors, therefore, are being tested in some centers, eg, topical diclofenac ( Voltarol).

Other therapies to control pain which have been attempted include bandage contact lenses,15 eye padding,13, 15,16 and topical cycloplegics.12,15 Systemic medications such as morphine, pethidene, Solpadeine, dextropropoxyphene with paracetamol (Distalgesic), or dihydrocodeine12,14,15 have also been suggested. These medications have been used in combination or separately. The effect of systemic treatment is quite limited in relieving local pain. However, a locally applied drug with rapid action and minimal, or no, systemic side effects could be useful, especially if the progress of the healing process is unaffected. We are currently investigating a new modality of alleviating pain by applying topical local anesthetics postoperatively.

Sodium hyaluronate has been used for years in intraocular surgery and has made a significant contribution to the safety and efficacy of surgery. Sodium hyaluronate has also been topically administered outside the eye. It produces a powerful lubricant and is believed to promote healing.9, 11 Reim6-8 has reported the use of sodium hyaluronate as part of a combined medical and surgical management of caustic and thermal eye injuries with satisfactory results. Fitzsimmons et al17 demonstrated that in rabbit eyes treated with excimer laser, hyaluronic acid (sodium hyaluronate) was produced in the corneal stroma during healing. Experimental work by Molander et al18, 20 showed in rabbits that endogenous hyaluronan (sodium hyaluronate) increased significantly in the corneal tissue following extracapsular lens extraction, anterior segment trauma, and radial keratotomy. These findings suggest a possible role of endogenous sodium hyaluronate in the healing of corneal tissue. Vinciguerra et al21 used topical 0.4% hyaluronic acid routinely in the immediate period following photorefractive keratectomy. In the study by Reim and Saric,8 antibiotic drops were applied to the chemically burned rabbit eye followed by sodium hyaluronate application. In our study, sodium hyaluronate was applied first to the laser-treated cornea followed by the application of Maxitrol ointment. This combination of sodium hyaluronate and ointment created a thick smear which perhaps did not allow for optimal penetration of the sodium hyaluronate. This lack of penetration could have contributed to our findings of no effect of sodium hyaluronate on corneal epithelial healing or pain following photorefractive keratectomy. Pain resulting from photorefractive keratectomy remains a universal problem despite the thousands of patients treated and the various local and systemic medications used.

REFERENCES

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2. McDonald MB, Klyce SD, Suarez H, Kandarikis A, et al. Epikeratophakia for myopia correction. Ophthalmology. 1985;92:1417-1422.

3. Waring GO, Lynn MJ, Gelender H, Laibson RR, et al. Results of Prospective Evaluation of Radial Keratotomy (PERK) Study one year after surgery. Ophthalmology. 1985 ;92: 177-198.

4. Burrato L, Ferrari M. Excimer laser mtrastromal keratomileusis. Case reports. J Cataract Refract Surg. 1992;18:37-41.

5. Rashid ER, Waring GO. Complications of radial and transverse keratotomy. Surv Ophthalmol. 1989;34:73-106.

6. Reim M. A new treatment concept for severe caustic and thermal burns of the eyes. Klin Monatsbl Augenheilkd. 1990;196:1-5.

7. Reim M. A new treatment concept in severe caustic injuries and burns of the eye. Fortschr Ophthalmol. 1989;86:722-726.

8. Reim M, Saric D. Treatment of chemical burns of the anterior eye segment with macromolecular sodium hyaluronate (Healon). Vision and Visual Health Care. 1986;2:41-52.

9. Chung JH, Fagerholm P, Lindström B. Hyaluronate in healing of corneal alkali wound in rabbit. Exp Eye Res. 1989;48:569-576.

10. Reed DB, Hills JF, Mannis JM, Johnson CA. Corneal epithelial healing after penetrating keratoplasty using topical Healon versus balanced salt solution. Ophthalmic Surg. 1987;18:525-528.

11. Nishida T, Nakamura M, Mishima H, Otori T. Hyaluronan stimulates corneal epithelial migration. Exp Eye Res. 1991;53:753-758.

12. Gartry DS, Kerr Muir MG, Marshall J. Photorefractive keratectomy with Argon Fluoride excimer laser: a clinical study. J Refract Corneal Surg. 1991;7:420-435.

13. Seiler T, Wollensak J. Myopic photorefractive keratectomy with the excimer laser. One-year follow-up. Ophthalmology. 1991;98:1156-1163.

14. Seiler T, Kahle G, Kriegerowski M. Excimer laser (193 nm) myopic keratomileusis in sighted and blind human eyes. J Refract Corneal Surg. 1990;6:165-173.

15. McDonald MB, Frantz JM, Klyce SD, et al. Central photorefractive keratectomy for myopia. The blind eye study. Arch Ophthalmol. 1990;108:799-808.

16. Tengroth B, Epstein D, Fagerholm P, et al. Excimer laser photorefractive keratectomy for myopia. Clinical results in sighted eyes. Ophthalmology. 1993;100:739-745.

17. Fitzsimmons TD, Fagerholm P, Härfstrand A, Schenholm M. Hyaluronic acid in the rabbit cornea after excimer laser superficial keratectomy. Invest Ophthalmol Vis Sci. 1992;33:3011-3016.

18. Molander N, Ehinger B, Rolfsen W, et al. Histochemical identification of hyaluronan in the rabbit anterior segment during the healing period after extracapsular lens extraction. Acta Ophthalmol. 1993;71:336-346.

19. Molander N, Lindquist U, Lind ML, et al. Influence of anterior segment trauma on endogenous hyaluronan in the rabbit cornea and aqueous. European Journal of Implant and Refractive Surgery. 1993;5:121-127.

20. Molander N, Lindquist U, Stenevi U, et al. Influence of radial keratotomy on endogenous hyaluronan in cornea and aqueous humour. J Refract Corneal Surg. 1993;9:358-365.

21. Vinciguerra P, Bottoni F, Zenoni S, De Molfetta V. Excimer laser for the treatment of high myopia (area photoablation). Invest Ophthalmol Vis Sci. 1991;32(suppl):997.

Table 1

Postoperative Pain in the Sodium Hyaluronate Group (Number of Eyes)

Table 2

Postoperative Pain in the Control Group (Number of Eyes)

10.3928/1081-597X-19950101-11

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