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Figure 1.
Average intraocular pressure (IOP) after injection of viscoelastic substances into the anterior chamber. Error bars represent SDs.

Average intraocular pressure (IOP) after injection of viscoelastic substances into the anterior chamber. Error bars represent SDs.

Figure 2.
Average intraocular pressure (IOP; mean±SD) after injection of 10 U of hyaluronidase in the anterior chamber of right eyes, compared with injection of balanced saline solution in left eyes as control.

Average intraocular pressure (IOP; mean±SD) after injection of 10 U of hyaluronidase in the anterior chamber of right eyes, compared with injection of balanced saline solution in left eyes as control.

Figure 3.
Average intraocular pressure (IOP; mean±SD) after injection of viscoelastic substances (A, Healon; B, Healon GV; C, Viscoat; and D, Ocucoat) in both eyes. Right eyes were also injected with 10 U of hyaluronidase, whereas left eyes were injected with volumetrically equivalent doses of balanced saline solution as control.

Average intraocular pressure (IOP; mean±SD) after injection of viscoelastic substances (A, Healon; B, Healon GV; C, Viscoat; and D, Ocucoat) in both eyes. Right eyes were also injected with 10 U of hyaluronidase, whereas left eyes were injected with volumetrically equivalent doses of balanced saline solution as control.

Hyaluronidase Products Used in the Study Group*
Hyaluronidase Products Used in the Study Group*
1.
Mac Rae  SMEdelhauser  HFHyndiuk  RA  et al.  The effects of sodium hyaluronate, chondroitin sulfate, and methycellulose on the corneal endothelium and intraocular pressure. Am J Ophthalmol. 1983;95332- 341
2.
Glasser  DBMatsuda  MEdelhauser  HF A comparison of the efficacy and toxicity of and intraocular pressure response to viscous solutions in the anterior chamber. Arch Ophthalmol. 1986;1041819- 1824Article
3.
Dada  VKSindhu  NSachdev  M Postoperative intraocular pressure changes with use of different viscoelastic. Ophthalmic Surg. 1994;25540- 544
4.
Roberts  BPeiffer  RL Experimental evaluation of a synthetic viscoelastic material on intraocular pressure and corneal endothelium. J Cataract Refract Surg. 1989;15321- 326Article
5.
Raitta  CKommonen  BTarkkanen  A Effects of intracamerally or subconjunctivally injected cross-linked hyaluronic acid on the intraocular pressure and on the anterior segment of the rabbit eye. Acta Ophthalmol. 1988;66544- 551Article
6.
Barron  BABusin  MPage  CBergsma  DRKaufman  HE Comparison of the effects of Viscoat and Healon on postoperative intraocular pressure. Am J Ophthalmol. 1985;100377- 384
7.
Berson  FGPatterson  MMEpstein  DL Obstruction of aqueous outflow by sodium hyaluronate in enucleated human eyes. Am J Ophthalmol. 1983;95668- 672Article
8.
Hein  SRKeates  RHWeber  PA Elimination of sodium hyaluronate-induced decrease in outflow facility with hyaluronidase. Ophthalmic Surg. 1986;17731- 734
9.
Roden  LCampbell  PFraser  PLaurent  TCPertoft  HThompson  JN Enzymatic pathways of hyaluronan metabolism. Ciba Found Symp. 1989;14360- 76
10.
Grierson  ILee  VRAbraham  S A light microscopic study of the effects of testicular hyaluronidase on the outflow system of a baboon (Papio cynocephalus). Invest Ophthalmol Vis Sci. 1979;18356- 360
11.
Gotlieb  JLAntoszyk  ANHatchell  DLSaloupis  P The safety of intravitreal hyaluronidase. Invest Ophthalmol Vis Sci. 1990;312345- 2352
12.
Calder  IGSmith  VH Hyaluronidase and sodium hyaluronate in cataract surgery. Br J Ophthalmol. 1986;70418- 420Article
13.
Hutz  VWEckhardt  HBKohnen  T Comparison of viscoelastic substances used in phacoemulsification. J Cataract Refract Surg. 1996;22955- 959Article
14.
Mermoud  GBBaerveldt  GMinckler  DSLee  MBRao  NA Measurement of rabbit intraocular pressure with Tono-pen. Ophthalmologica. 1995;209275- 277Article
15.
Abrams  LSVitale  SJampel  HD Comparison of three tonometers for measuring intraocular pressure in rabbits. Invest Ophthalmol Vis Sci. 1996;37940- 944
16.
Stankiewicz  AGos  A Experimental depolymerization of hyaluronic acid in rabbit vitreous body. Klin Oczna. 1974;141005- 1010
Laboratory Sciences
September 1998

Efficacy of Hyaluronidase in Reducing Increases in Intraocular Pressure Related to the Use of Viscoelastic Substances

Author Affiliations

From the Schepens Eye Research Institute, Harvard Medical School, Boston, Mass. Dr Harooni is now with the Department of Ophthalmology, State University of New York Health Science Center at Brooklyn, Brooklyn. The authors as well as the Schepens Eye Research Institute, Boston, Mass, do have a financial interest in the procedures described herein. The use of hyaluronidase in anterior chamber surgery is being considered for patent application by the Schepens Eye Research Institute and the authors.

Arch Ophthalmol. 1998;116(9):1218-1221. doi:10.1001/archopht.116.9.1218
Abstract

Objective  To evaluate the efficacy of hyaluronidase in preventing increases in intraocular pressure related to injections of hyaluronan-containing viscoelastic substances.

Methods  Twenty-five white rabbits were divided into 5 groups. In groups 1 through 4, 0.15 mL of aqueous humor was removed and replaced with 0.10 mL of a viscoelastic substance in both eyes. Additionally, 10 units of hyaluronidase (0.05 mL) was injected in the anterior chamber of the right eye, whereas the left eye was injected with a volumetrically equivalent dose of balanced saline solution. Viscoelastic substances tested were Healon and Healon GV (Pharmacia & Upjohn, Kalamazoo, Mich), Viscoat (Alcon Laboratories, Fort Worth, Tex), and Ocucoat (Storz Ophthalmics, Clearwater, Fla). In group 5, right eyes were injected with 10 units of hyaluronidase and the left eyes were treated with balanced saline solution.

Results  After injections of viscoelastic substance, intraocular pressure rose rapidly, reaching a peak at approximately 46 hours after injection and returning to preinjection levels within 24 hours. Hyaluronidase significantly decreased intraocular pressure when used with Healon, Healon GV, and Viscoat, but not with Ocucoat. When injected in the absence of viscoelastic, hyaluronidase appeared to decrease intraocular pressure, but this result was not statistically significant.

Conclusions  Injections of hyaluronidase into the anterior chamber of rabbits effectively prevent increases in intraocular pressure induced by hyaluronan-containing viscoelastic substances. This effect may be related to the ability of hyaluronidase to cleave hyaluronan moieties.

SODIUM HYALURONATE (NaHa), also known as hyaluronan, is a naturally occurring macromolecule found in many tissues, including the synovial fluid and vitreous body. Aqueous solutions of NaHa have viscoelastic properties. In addition to maintaining a deep anterior chamber during surgery and preventing sudden fluctuations in intraocular pressure, injections of NaHa into the anterior chamber have been shown to protect corneal endothelial cells.1,2 Injections of NaHa do not interfere with intraoperative visibility. For these reasons, NaHa has been used extensively in anterior segment surgery.

Because of the significant contribution of NaHa to eye surgery, several compounds have been developed that serve equivalent purposes. Some compounds are merely preparations of NaHa with different concentrations and molecular weights, whereas others combine NaHa with chondroitin sulfate. Others still use hydroxypropyl methylcellulose as a clear viscous substance.

Despite their advantages, the use of viscoelastic substances has been correlated with significant increases in intraocular pressure postoperatively.16 It is thought that retained NaHa blocks the outflow facility of the anterior chamber and prevents the egress of aqueous humor, thus leading to increases in intraocular pressure.7 Though transient, these increases can lead to significant ocular damage. Although strategies have been devised to minimize intraocular pressure elevations, including thorough washout of the anterior chamber at the end of surgery, routine use of antiglaucoma medicines postoperatively, and postoperative paracentesis, none is ideal.

There is evidence that decreases in intraocular pressure can be achieved enzymatically by means of hyaluronidase (Wydase; Wyeth Laboratories, Philadelphia, Pa).8 Hyaluronidase is currently used for subcutaneous and retrobulbar injections of local anesthetics to promote the diffusion of anesthetics. Hyaluronidase is a highly specific, naturally occurring enzyme that cleaves NaHa into disaccharide components, thus reducing both viscosity and molecular weight of NaHa.9 One study using baboon eyes showed an increase in outflow facility after instillation of hyaluronidase.10 Anterior- and posterior-chamber injections in animals as well as humans have strongly suggested that hyaluronidase is well tolerated in small doses.11,12

The above studies suggest a new method of controlling intraocular pressure by intraoperative injections of hyaluronidase. However, several questions remain to be answered regarding this treatment modality. Although studies have suggested that hyaluronidase can prevent a reduction in outflow facility, its effects on postinjection intraocular pressures have not been well documented. It is not known whether hyaluronidase merely blunts the zenith of intraocular pressure increases or actually prevents abnormal increases in pressure by keeping the trabecular meshwork free of NaHa. Neither has the effect of hyaluronidase on various preparations of NaHa, including the high–molecular-weight NaHa preparations (which are used with phacoemulsification techniques in cataract surgery) been studied, to our knowledge. It is the purpose of this study to provide data in an attempt to answer these unresolved questions. If anterior chamber injections of hyaluronidase are determined to be effective in eliminating intraocular pressure spikes, routine use of hyaluronidase in ocular surgery may significantly decrease complications related to postoperative intraocular hypertension.

MATERIALS AND METHODS

The viscoelastic substances and hyaluronidase used in this study are listed in Table 1. Hyaluronidase for intraocular injection was prepared by adding balanced saline solution to 150 U of lyophilized bovine testicular hyaluronidase (Wydase) to obtain a concentration of 10 U of hyaluronidase in 0.05 mL of fluid.

Twenty-five white New Zealand rabbits (weight, 2.0-3.4 kg) were included in this study. Throughout the study, the procedures in the Association for Research in Vision and Ophthalmology Statement on the Use of Animals in Ophthalmic and Vision Research were strictly adhered to. At the onset of the investigation, each eye of all rabbits was examined by slit-lamp biomicroscopy to exclude any preexisting abnormality.

Rabbits were anesthetized with intramuscular injection of a combination of ketamine hydrochloride (50 mg/kg) and 0.5 mL of chlorpromazine hydrochloride (100 mg/mL). Proparacaine hydrochloride 0.5% eyedrops were instilled into the conjunctival cul-de-sac 1 minute before injection. Preoperative intraocular pressures were measured by tonometry14,15 (Tono-pen XL; Mentor, Norwell, Mass) in each eye. The lids were held open with a wire speculum, and after the eyes were immobilized, a syringe fitted with a 30-gauge needle was inserted at the limbus into the anterior chamber and 0.15 mL of aqueous fluid was removed. Next, with a separate 30-gauge needle, 0.10 mL of viscoelastic substance was injected into the anterior chamber of the right eye. With the same needle, 0.05 mL of hyaluronidase (10 U) was injected in the anterior chamber of the same eye. The anterior chamber of the left eye, serving as control, was injected with an equivalent volumetric dose of the same viscoelastic substance (0.10 mL of viscoelastic and 0.05 mL of balanced saline solution). Rabbits were divided into 5 groups of 5 each. In group 5, the right eye was injected with 10 U of hyaluronidase (in 0.15 mL), and the left eye, serving as control, was injected with 0.15 mL of balanced saline solution.

Immediately after injections, rabbits were examined by biomicroscopy to evaluate possible ocular trauma caused by the injections. Intraocular pressures were measured immediately after injection. Tonometry was repeated at 1, 2, 4, 6, 8, 12, 24, and 48 hours after injection. Ocular examination was performed by means of slit-lamp biomicroscopy and indirect ophthalmoscopy to evaluate the anterior chamber, lens, vitreous, and retina. The data were analyzed statistically by 1- and 2-tailed 2-sample unequal variance Student t test.

At the completion of the study period, all rabbits were killed with a lethal dose of pentobarbital sodium (100 mg/kg given in the marginal ear vein).

RESULTS

Figure 1 summarizes the average changes of intraocular pressure in control (left) eyes treated with various viscoelastic substances (groups 1-4). Intraocular pressure increased within 1 hour after anterior chamber injection of viscoelastic and reached a peak at approximately 46 hours after injection. Intraocular pressure gradually decreased to approximate preinjection levels at about 24 hours after injection. An increase in intraocular pressure occurred with all of the viscoelastic substances evaluated. Healon GV appeared to have the most profound increase in intraocular pressure (P<.05 at 2, 4, and 6 hours after injection) compared with other viscoelastics.

Figure 2 represents the intraocular pressures obtained after 10 U of hyaluronidase was injected in the anterior chamber of the right eye (group 5). Compared with control (left eye), intraocular pressures appeared to decrease modestly. These results were statistically significant only at 4 (P=.02) and 48 (P=.01) hours after injection.

Figure 3 summarizes the results of intraocular pressure changes when Healon, Healon GV, Viscoat, and Ocucoat were used in the presence (hyaluronidase-treated right eye) and absence (control left eye) of hyaluronidase. Differences in intraocular pressure between the treated and control eyes were assessed by the unequal paired Student t test. In all except the Ocucoat group (Figure 3, D), intraocular pressure was significantly lower in the hyaluronidase-treated right eye. In the Ocucoat group, intraocular pressure was lower in the hyaluronidase-treated eyes, but this result was not statistically significant.

COMMENT

Increases in intraocular pressure related to viscoelastic substances used as surgical aids have been extensively studied.16 Shortly after injection of a viscoelastic substance into the anterior chamber, intraocular pressure increases rapidly. In rabbits, approximately 6 to 12 hours after injection, intraocular pressure approaches a zenith and begins to decline. Within 12 to 24 hours after injection, intraocular pressure stabilizes to preinjection levels. Our study is in general agreement with previously published results, indicating that intraocular pressure reaches maximum values approximately 6 to 8 hours after injection and returns to preinjection pressures within 24 hours after injection.6 This time-dependent increase in pressure appears to be generally independent of the type of viscoelastic used.

The mechanism of viscoelastic-related intraocular pressure rise is not clearly understood. It has been shown that outflow facility is significantly decreased with anterior chamber injections of NaHa, correlating with increases in intraocular pressure.12 Increased resistance to flow of aqueous humor is thought to occur in the endothelial meshwork, a region with the highest concentrations of NaHa.3 It is thought that viscoelastic substances bind in this region, where the resistance to aqueous flow is highest, and "clog" the trabecular canals. Thus, aqueous humor meets increased resistance across the endothelium of trabecular meshwork, causing an increase in intraocular pressure.9 If this hypothesis is correct, then hyaluronidase, which cleaves NaHa into its disaccharide components (thus reducing both the molecular weight and viscosity), should prevent such a block in outflow facility. Moreover, hyaluronidase should have no effect on blockage of outflow facility caused by viscoelastic substances unrelated to NaHa, such as hydroxypropyl methylcellulose. We have demonstrated that some viscoelastic-related increases in intraocular pressure can be prevented with concomitant use of hyaluronidase. This occurs with all NaHa-containing viscoelastics. We have also shown that hyaluronidase appears to be ineffective in reducing intraocular pressures when hydroxypropyl methylcellulose is used. These results agree well with previous studies, demonstrating the ability of hyaluronidase to prevent the blocking of outflow facility by NaHa.7,8 These results support the notion that pressure-reducing effects of hyaluronidase are related to its ability to cleave NaHa moieties.

The trabecular meshwork's extracellular matrix contains glycosaminoglycans including NaHa, which are believed to line the trabecular canals and contribute to overall resistance to flow.12 Studies have demonstrated that perfusion of the trabecular meshwork with hyaluronidase results in decreases in intraocular pressure.9 Our study demonstrates that anterior chamber injections of hyaluronidase alone have only a modest effect in decreasing intraocular pressure. Therefore, it appears that the effects of hyaluronidase in preventing viscoelastic-related pressure spikes are at least in part related to the degradation of injected NaHa rather than native trabecular NaHa molecules. However, that hyaluronidase has a pressure-lowering effect independent of its ability to cleave the injected NaHa cannot be ruled out.

Despite earlier disappointment with intravitreal injections of hyaluronidase,16 there is considerable evidence that intraocular injections of testicular hyaluronidase appear to be safe.11 Calder and Smith12 used up to 750 U of hyaluronidase in human patients after cataract surgery and reported no adverse effects. In this study, there was no evidence of ocular toxic effects from use of 10 U of hyaluronidase. Nevertheless, more extensive studies may be necessary to establish the intraocular safety of hyaluronidase.

The ability of hyaluronidase to prevent increases in intraocular pressure provides a method of preventing viscoelastic-related postoperative pressure spikes. This enzyme can conceivably be instilled in the anterior chamber at some point after NaHa-containing viscoelastic has been used during anterior segment surgery. This enzyme can possibly also obviate the need to completely evacuate the viscoelastic after surgery. While further study is necessary to establish the safety and efficacy of hyaluronidase in anterior segment surgery, this enzyme appears to hold promise in decreasing viscoelastic-related complications.

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Article Information

Accepted for publication April 20, 1998.

This study was supported in part by grant EY00327 from the National Eye Institute, National Institutes of Health, Bethesda, Md.

Corresponding author: Mark Harooni, MD, c/o Miguel Refojo, DSc, Schepens Eye Research Institute, 20 Staniford St, Boston, MA 02114 (e-mail: sunyretina@aol.com).

References
1.
Mac Rae  SMEdelhauser  HFHyndiuk  RA  et al.  The effects of sodium hyaluronate, chondroitin sulfate, and methycellulose on the corneal endothelium and intraocular pressure. Am J Ophthalmol. 1983;95332- 341
2.
Glasser  DBMatsuda  MEdelhauser  HF A comparison of the efficacy and toxicity of and intraocular pressure response to viscous solutions in the anterior chamber. Arch Ophthalmol. 1986;1041819- 1824Article
3.
Dada  VKSindhu  NSachdev  M Postoperative intraocular pressure changes with use of different viscoelastic. Ophthalmic Surg. 1994;25540- 544
4.
Roberts  BPeiffer  RL Experimental evaluation of a synthetic viscoelastic material on intraocular pressure and corneal endothelium. J Cataract Refract Surg. 1989;15321- 326Article
5.
Raitta  CKommonen  BTarkkanen  A Effects of intracamerally or subconjunctivally injected cross-linked hyaluronic acid on the intraocular pressure and on the anterior segment of the rabbit eye. Acta Ophthalmol. 1988;66544- 551Article
6.
Barron  BABusin  MPage  CBergsma  DRKaufman  HE Comparison of the effects of Viscoat and Healon on postoperative intraocular pressure. Am J Ophthalmol. 1985;100377- 384
7.
Berson  FGPatterson  MMEpstein  DL Obstruction of aqueous outflow by sodium hyaluronate in enucleated human eyes. Am J Ophthalmol. 1983;95668- 672Article
8.
Hein  SRKeates  RHWeber  PA Elimination of sodium hyaluronate-induced decrease in outflow facility with hyaluronidase. Ophthalmic Surg. 1986;17731- 734
9.
Roden  LCampbell  PFraser  PLaurent  TCPertoft  HThompson  JN Enzymatic pathways of hyaluronan metabolism. Ciba Found Symp. 1989;14360- 76
10.
Grierson  ILee  VRAbraham  S A light microscopic study of the effects of testicular hyaluronidase on the outflow system of a baboon (Papio cynocephalus). Invest Ophthalmol Vis Sci. 1979;18356- 360
11.
Gotlieb  JLAntoszyk  ANHatchell  DLSaloupis  P The safety of intravitreal hyaluronidase. Invest Ophthalmol Vis Sci. 1990;312345- 2352
12.
Calder  IGSmith  VH Hyaluronidase and sodium hyaluronate in cataract surgery. Br J Ophthalmol. 1986;70418- 420Article
13.
Hutz  VWEckhardt  HBKohnen  T Comparison of viscoelastic substances used in phacoemulsification. J Cataract Refract Surg. 1996;22955- 959Article
14.
Mermoud  GBBaerveldt  GMinckler  DSLee  MBRao  NA Measurement of rabbit intraocular pressure with Tono-pen. Ophthalmologica. 1995;209275- 277Article
15.
Abrams  LSVitale  SJampel  HD Comparison of three tonometers for measuring intraocular pressure in rabbits. Invest Ophthalmol Vis Sci. 1996;37940- 944
16.
Stankiewicz  AGos  A Experimental depolymerization of hyaluronic acid in rabbit vitreous body. Klin Oczna. 1974;141005- 1010
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