R E D U C T I O N O F C O R N E A L E D E M A W I T H T O P I C A L

H Y P E R T O N I C A G E N T S

MALCOLM N . LUXENBERG, M . D , AND K E I T H GREEN, P H . D .

Baltimore, Maryland

Many types of therapy for the manage-ment of corneal edema are currently avail-able. This paper is concerned solely with evaluation of the use of topically applied hy-pertonic solutions, and no attempt will be made to discuss other forms of management.

Müller,1 using a 4 0 % glucose solution, and Cogan,2 5 using sodium chloride or glycerine solutions, were apparently the first to sug-gest topical use of hypertonic agents to re-duce corneal edema. Unfortunately, wide-spread use of these or similar agents did not take place for many years, probably because of difficulty in their application and discom-fort associated with their use.

This study was undertaken to evaluate ob-jectively reduction of corneal edema with the use of several readily available topically ap-plied hypertonic agents. A study of this type, to the best of our knowledge, has never been carried out in human eyes, in vivo.

MATERIALS AND METHODS

The patients used in this study were from the Eye Clinic of the USPHS Hospital and the Wilmer Eye Institute, Baltimore, Mary-land. Patients with chronic symptomatic cor-neal edema who were willing to use the vari-ous agents being tested and return for fre-quent detailed evaluation were included. It was difficult to find patients who were able to meet these criteria, and therefore, every compound (Table 1 ) could not be tested on each patient. A total of seven cases with cor-neal edema of varying etiology and severity were studied. The etiologies were: Fuchs'

From the W. K. Kellogg Foundation Laborato-ries, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Mary-land. Dr. Green was supported by USPHS Grant EY 00259 from the National Eye Institute.

Reprint requests to Malcolm N. Luxenberg, M.D, 2707 N. Flagler Drive, West Palm Beach, Florida 33407.

TABLE 1

HYPERTONIC AGENTS USED IN THIS STUDY LISTED

IN DECREASING ORDER OF EFFECTIVENESS

1. 5 % sodium chloride ointment containing petro-latum and wool fat (lanolin) (Muro Pharmacal Laboratories, Quincy, Massachusetts).

2. BP-E ocular. An experimental agent consisting of 5 % sodium chloride and 5 % glycerin in a buffered aqueous emulsion vehicle (prepared from the same formula as EKG-Sol, an electrocardiog-raphy electrode cream, by Burton, Parsons and Company, Inc., Washington, D. C ) .

3. 5 % sodium chloride with 5 % gum cellulose and 2% glycerin solution (Burris and Kemp Phar-macy, Baltimore, Maryland).

4. 30% sodium sulfacetamide solution in polyvinyl alcohol (Bleph-30, Allergan Pharmaceuticals, Irvine, California).

5. 5 % gum cellulose solution. 6. Corn syrup containing sucrose, dextrose, and

salt (Karo, Corn Products Company, Bayonne, New Jersey).

7. 0.9% methycellulose (4000 cps) with 5 % sodium chloride solution (Muro Pharmacal Laboratories, Quincy, Massachusetts).

dystrophy ( 3 cases), absolute glaucoma ( 1 case), herpes simplex keratitis ( 1 case), vit-reous touch following cataract surgery (1 case), and chemical injury with secondary glaucoma plus multiple surgical procedures ( 1 case).

A complete eye history and examination were obtained for each patient. All ocular medications except glaucoma drugs were stopped at least 4 8 hours before starting the trial agents.

Baseline studies of corneal thickness were then obtained for each patient using a Haag-Streit model 3 6 0 slit lamp with a pachometer attachment* All measurements were done by the same observer ( K . G . ) . Thickness could be measured to an accuracy of ± 1 0 u.. Three readings were taken on each cornea (nasal, central, and temporal), with the nasal and temporal readings being within 1 mm of the

847

848 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL. 1971

corneoscleral junction. A baseline was estab-lished for each region when the thickness measured at each of the three corneal loca-tions was the same on three consecutive read-ings taken 10 minutes apart.

Following this, each patient was started on one of the trial medications (Table 1) , with their order of use being randomized. Each trial medication was discontinued at least 48 hours before starting a new one. One drop (about 50 ml), in the case of liquids, or a "standard length" of approximately % inch for ointments was instilled in the inferior cul-de-sac. Measurements of the cornea, using the above described techniques, were then taken every 15 or 30 minutes until the thick-ness returned to baseline levels, unless the ef-fect lasted longer than 8.5 hours. Readings were discontinued after 180 minutes if there were no demonstrable effects.

The various compounds used were ran-domly distributed among the patients. If a drug was noted to decrease corneal thick-ness, it was evaluated on at least six separate occasions. Agents not producing a reduction in corneal thickness were evaluated in the same manner at least four times.

Each drug was used four times a day for two weeks unless there were significant side effects or other factors necessitating its dis-continuance. Whenever the drug was stop-ped, another eye examination was made. The patient was questioned in detail about any side effects which might have been associated with the use of the drug. Specific questions were asked regarding irritation, pain, photo-phobia, foreign body sensation, and changes in vision. Visual acuity and external and slit-lamp examinations were performed, specifi-cally noting changes from the pretreatment evaluation. Each patient returned in no less than 48 hours after a drug was discontinued for another examination prior to starting a new medication.

RESULTS

The reduction in corneal thickness is ex-pressed as the percentage of decrease from

the original baseline thickness (initial thick-ness varied from 0.62 to 0.95 mm). The effi-cacy of each hypertonic agent in reducing corneal edema is illustrated in Figures 1 through 4. As shown in Figure 1, neither the Muro preparation of 0.9% methylcellulose and 5% sodium chloride, nor corn (Karo) syrup, nor 30% sodium sulfacetamide, nor 5% gum cellulose had any significant effect on corneal thickness. Figure 2 shows the effect of a 5% gum cellulose and 5% sodium chloride mixture, with a maximal reduction in corneal thickness of 9% between 45 and 60 minutes. This effect was short-lived how-ever, and thickness returned to the baseline in three hours.

The two most effective agents were BP-E ocular and the Muro 5% sodium chloride ointment. BP-E ocular (Fig. 3) caused a re-duction in thickness of at least 8% from 60 to 180 minutes after application, thereafter returning slowly to baseline thickness. Muro 5% sodium chloride ointment decreased cor-neal thickness by at least 12% from 45 to 480 minutes (seven hours), with a maximal reduction of over 20% between three to four hours after application. This agent proved to be the most effective both in amount of re-duction of corneal thickness and duration of effect.

In summary, the order of effectiveness of these agents in reducing corneal thickness is shown in Table 1.

In general, most agents used in this study were well tolerated. However, two patients complained of burning, irritation, or injec-tion with every substance tested. Every pa-tient complained of stinging and burning lasting four to five minutes when the 30% sodium sulfacetamide was instilled. This re-sponse (i.e., discomfort) is not unusual; Fenton7 showed that a 30% sodium sulface-tamide solution is markedly hypertonic and is approximately equal in tonicity to a 9% solution of sodium chloride. He also evalu-ated the effect of varying concentrations of sodium sulfacetamide on the normal human eye and found that when the concentration

VOL. 71, NO. 4 REDUCTION OF CORNEAL EDEMA 849

t 1 1 1 1 1 1 1 0 30 60 90 120 150 180

TIME cmiio Fig. 1 (Luxenberg and Green). Graph showing percentage reduction in corneal thickness, caused by four

osmotic agents, against time. T, C, and N refer to temporal, central, and nasal thickness, respectively. Each point is the mean ± SE of the number of determinations which is given in parenthesis after name of the agent employed.

850 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL, 1971

5% GUM CELLULOSE

5% NaCl

(BURRIS and KEMP)

- r —

180 — i — 210

time emir»

240

Fig. 2 with 5%

(Luxenberg and Green). Plot of reduction in corneal thickness caused by a mixture of 5% NaCl gum cellulose and 2% glycerine solution.

300 TIME cmin)

Fig. 3 (Luxenberg and Green). Graph showing percentage of reduction in corneal thickness caused by BP-E ocular plotted against time.

VOL. 71, NO. 4 REDUCTION OF C O R N E A L E D E M A 851

i — i — i — i — i — i — i — i i i—i I i — i — i — i — i — i — i — i — i O 60 120 180 240 300 360 420 480 540 600

TIME C min 3

Fig. 4 (Luxenberg and Green). Graph showing percentage of reduction in corneal thickness caused by 5% NaCl ointment plotted against time. Note that the scale on the ordinate is doubled compared to Figures 1-3.

reached 12.5%, pain was experienced by 95% of the subjects in his study.

No significant objective changes in the conjunctiva were noted in any case in our study, and those present were of brief dura-tion. The 5% NaCl ointment is fairly solid in the tube but becomes fluid when exposed to body temperature. If too much of the ointment was used, it sometimes briefly de-creased vision and would also spill over the eyelids onto the face, creating a cosmetic problem. This difficulty was readily over-come by using smaller, but still effective, amounts of ointment. The 5% gum cellulose, 5% methylcellulose with 5% NaCl, 0.9% methylcellulose with NaCl, and corn syrup all caused some amount of sticking of the eyelids and lashes. This was probably due to the relatively high viscosity of these com-pounds. None of the patients were made worse with topical hyperosmotic agents, ex-

cept for the brief discomforts described herein.

Two patients had a dramatic, significant improvement in the treated eye which per-sisted over prolonged periods. In one case, vision improved from counting fingers at one to two feet to 20/100 after the use of 5% NaCl ointment. The second patient's vi-sion improved from 20/200 to 20/50 in the right eye, and from 20/200 to 20/100 in the left with topical hypertonic agents. When the treatment was discontinued, vision wors-ened. In three patients, the severity of the corneal disease precluded any significant im-provement in vision. In the remaining two patients, no change in vision was noted after treatment.

DISCUSSION

Many topical agents are said to reduce corneal edema,8 1 3 but duration of effect is

852 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL, 1971

often brief and side effects associated with their use have been many. However, there are definite benefits to be gained from this type of treatment and the present study was undertaken in order to try to find an agent or agents which would decrease corneal edema over a significant period of time with a minimum of side effects. EKG-Sol, which was apparently first used as a topical osmotic agent about 14 years ago by Dr. Max Fine,1 4

is now being used by many ophthalmologists because of good patient acceptability and re-duction of edema. However, it has never been prepared specifically for ophthalmic use. Therefore, an identical, but sterile, in-vestigational preparation (BP-E ocular) was developed for this study.

Three important treatment goals are the reduction of discomfort, improvement of vi-sion and prevention of secondary ulceration and infection of the cornea. Much of the dis-comfort associated with this disease is due to breakdown of epithelial bullae which then exposes the corneal nerve endings to irrita-tion, and predisposes the cornea to ulceration and infection. In addition, most of the de-crease in vision, except in advanced cases with stromal scarring, is due to irregular as-tigmatism on the anterior corneal surface produced by the epithelial edema.12 By re-ducing epithelial edema, topical hypertonic agents could offer benefit to the patient in all three of these areas.

Clinical evaluation of treatment is mainly subjective except for actual measurement of corneal thickness changes. Improvement in visual acuity and a decrease in symptoms are also important parameters, but are even more difficult to evaluate. Other objective means of evaluating change have been re-ported,1 0'1 5-1 8 but these are applicable only to isolated corneal buttons or animal eyes in the laboratory. In the present study, a decrease in corneal thickness was the main criterion for improvement.

Low concentrations of methylcellulose with NaCl were ineffective in reducing cor-neal thickness. Higher concentrations of me-thylcellulose, even without NaCl, were more

effective, and when NaCl was added, the effect was further enhanced. On the basis of these findings, it must be concluded that the vehicle plays an important role in holding the osmotic agent on the cornea.

Linn and Jones1 7 studied the rate of loss of vehicles from the corneal surface and found that even a 1% (4000 cps) solution of hydroxy-propyl-methylcellulose was retained for only 200 seconds. On the other hand, petrolatum was very effective and remained present long after instillation. It was not ex-creted, as were liquid substances, by closure of the eyelids forcing the agent down the lacrimal system. This evidence could explain the transient nature of the results found with liquid agents and also the retention on the cornea of the 5% sodium chloride oint-ment used in this study, as it contains petro-latum and wool fat. Droplets of oil could be seen on the corneal surface in the present study as long as seven hours after instillation of the ointment. The efficacy of this com-pound is probably related to its ability to re-main in the vicinity of the cornea for pro-longed periods. No other agent was as effec-tive in reducing thickness or in duration of effect. In one patient, the petrolatum :wool fat base of the ointment was evaluated alone (i.e., no sodium chloride was present). It produced a 10% reduction in corneal thick-ness and proved equally as long-lasting as the ointment containing sodium chloride. Thus, the ointment base proved a highly sig-nificant factor both in terms of amount of reduction of corneal thickness and duration of effect.

The 20% reduction in corneal thickness caused by the 5% sodium chloride ointment is substantial, and this compound produced a marked subjective increase in visual acuity in two of the patients tested. Thus, osmotic withdrawal of fluid from the cornea with the use of topical hyperosmotic agents offers a suitable and practical clinical method of re-ducing corneal thickness and thereby in-creasing its transparency. B P - E ocular and 5% NaCl with 5% gum cellulose and 2% glycerin solution were less effective and the

VOL. 71. NO. 4 REDUCTION OF CORNEAL EDEMA 853

other agents tested were of no apparent clin-ical value. In this study, the agents which produced a thinning of the cornea also re-duced stromal as well as epithelial edema. Zucker1 9 showed in animal eyes that a 70% increase in stromal thickness may decrease vision by only 23% ; however, swelling be-yond this point markedly decreases corneal transparency. Hyperosmotic agents may therefore improve vision not only by dehy-dration of the epithelium but also by produc-ing changes in the stroma.

On the basis of this study, a trial of treat-ment with topical 5% NaCl ointment would seem to be warranted in indicated cases of corneal edema. The frequency of use should be varied depending on the individual pa-tient's needs. The benefits of some of the agents favorably reported in the literature have not been demonstrated in this study.

S U M M A R Y

The effect of topically applied hypertonic agents on the reduction of human corneal edema in vivo was studied. Seven commer-cially available compounds were evaluated with 5% sodium chloride ointment being the most effective. Other highly viscous agents were also effective, but to a lesser degree. The greater reduction of edema with the ointment and highly viscous agents, as com-pared to less viscous mixtures, is probably related to their prolonged retention on the cornea.

ACKNOWLEDGMENT

We thank Dr. Fritz Fraunfelder for his help and suggestions.

REFERENCES

1. Müller, H. K. : Die Entquellung der Hornhaut als therapeutische Massnahme. Klin. Mbl. Augen-heilk. 105:393, 1940.

2. Cogan, D. G. : Experimental production of so-called bullous keratitis. Arch. Ophth. 23:918, 1940.

3. Cogan, D. G. : Some practical considerations pertaining to corneal edema. Arch. Ophth. 25 :552, 1941.

4. Cogan, D. G., and Kinsey, V. E. : The Cornea, V. Physiologic aspects. Arch. Ophth. 28:661,1942.

5. Cogan, D. G. : Clearing of edematous corneas by glycerine. Am. J. Ophth. 26:551, 1943.

6. Maurice, D. M., and Giardini, A. A. : A simple optical apparatus for measuring the corneal thick-ness, and the average thickness of the human cor-nea. Brit. J. Ophth. 35:169, 1951.

7. Fenton, A. H. : Solutions of sulphacetamide sodium. Observations on tonicity and pH. Pharm. J. 166:6,1951.

8. Payrau, P., and Dohlman, C. H. : Medical treatment of corneal edema. Int. Ophth. Clin. 8:601, 1968.

9. Bietti, G. B , and Giraldi, J. P. : Topical os-motherapy of corneal edema. Measurement with new technical devices. Ann. Ophth. 1:40, 1969.

10. Donn, A. : Annual review. Cornea and sclera. Arch. Ophth. 75:261, 1966.

11. Stocker, F. W. : Clinical management of cor-neal dystrophies. In First World Congress on the Cornea. Washington, D.C, 1964. Washington, D.C, Butterworths, 1965, p. 133.

12. Dohlman, C. H.: Corheal edema and vascu-larization. In First World Congress on The Cornea. Washington, D.C, 1964. Washington, D.C, Butter-worths, 1965, p. 80.

13. Harris, J. E. : Factors influencing corneal hydration. Invest. Ophth. 1:151, 1962.

15. Honegger, H , Untersuchungen über die lokale Osmotherapie der Hornhaut, I. Quantitative experi-mentelle Untersuchungen über die osmotische Ent-quellung der Hornhaut. Klin. Mbl. Augenheilk. 141 : 582, 1962.

16. Zucker, B. B. : Hydration and transparency of corneal stroma. Arch. Ophth. 75:228, 1966.

17. Linn, M. L , and Jones, L. T. : Rate of lacri-mal excretion of ophthalmic vehicles. Am. J. Ophth. 65:76, 1968.