Effect of healon5 and 4 other viscoelastic substances on intraocular pressure and endothelium after cataract surgery1

Effect of Healon5 and 4 other viscoelastic substances on intraocular pressure and endothelium after cataract surgery Mike P. Holzer, MD, Manfred R. Tetz, MD, Gerd U. Auffarth, MD, Ru¨diger Welt, MD, Hans-Eberhard Vo¨lcker, MD ABSTRACT Purpose: To compare the ophthalmic viscoelastic device (OVD) Healon姞5 (sodium hyaluronate 2.3%) with 4 other commonly used OVDs during phacoemulsification and intraocular lens implantation in terms of influence on intraocular pressure (IOP) postoperatively and endothelial cells preoperatively and postoperatively. Setting: Department of Ophthalmology, Ruprecht-Karls-University Heidelberg, Germany. Methods: This clinical randomized prospective study, in which patients and observer were masked, comprised 81 eyes. Seventy-four eyes (mean patient age 71.2 years ⫾ 7.8 [SD]) completed all preoperative and 5 postoperative examinations. The OVDs used were OcuCoat姞 and Celoftal姞 (hydroxypropyl methylcellulose 2.0%), Viscoat姞 (sodium hyaluronate 3.0%– chondroitin sulfate 4.0%), Healon GV姞 (sodium hyaluronate 1.4%), and Healon5 (sodium hyaluronate 2.3%). Intraocular pressure was measured by standard Goldmann applanation tonometry preoperatively and 4 to 6 and 24 hours and 7, 30, and 90 days postoperatively. Endothelial cell counts were done preoperatively and 90 days postoperatively using a Pro/Koester WFSCM contact endothelial microscope. Exclusion criteria were IOP greater than 21 mm Hg at the preoperative examination, age younger than 40 years, significant corneal pathology, and a history or presence of uveitis or pseudoexfoliation syndrome. Results: All groups had increased IOP 4 hours postoperatively. The Healon5 group had the highest mean pressure (24.9 mm Hg) followed by the Viscoat group (23.6 mm Hg). The mean IOP in the other OVD groups was less than 22.1 mm Hg. These differences were not significant. Twenty-four hours postoperatively and at all subsequent examinations, mean IOP was below 20 mm Hg. The Healon5 group had the lowest mean endothelial cell loss (6.2%), significantly lower than in the other groups (P ⬍ .02). Conclusion: With all 5 OVDs, endothelial cell loss was found, with the lowest in the Healon5 group, and IOP was increased 4 to 6 hours postoperatively. After 24 hours, no significant increases in IOP were noted. J Cataract Refract Surg 2001; 27: 213–218 © 2001 ASCRS and ESCRS

© 2001 ASCRS and ESCRS Published by Elsevier Science Inc.

0886-3350/01/$–see front matter PII S0886-3350(00)00568-X

EFFECT OF HEALON5 ON IOP AND ENDOTHELIUM

A

stable anterior chamber is advantageous when performing cataract extraction by phacoemulsification combined with intraocular lens (IOL) implantation. To achieve stability, viscous substances are injected into the anterior chamber. The first use of ophthalmic viscoelastic devices (OVDs) in cataract surgery was described by Balazs et al. in 1972.1 The contents of currently used OVDs are based on hydroxypropyl methylcellulose (HPMC), chondroitin sulfate, or sodium hyaluronate. Depending on their biochemical and physical properties, OVDs can be classified into 2 subgroups: dispersive and cohesive.2,3 Dispersive OVDs commonly have a lower molecular weight and shorter molecular chains. In some cases, a longer aspiration time is required for complete removal of dispersive OVDs. Cohesiveness implies that the molecular chains are much longer and are strongly entangled. In general, removal of cohesive OVDs is relatively easy. Clinically, it appears as though all the OVD is aspirated in 1 or very few portions rather than multiple fractions of the anterior chamber filling. The most important function of OVDs during surgery is maintenance of the anterior chamber and protection of the corneal endothelium.3– 6 Several mechanisms of endothelial protection have been proposed. During phacoemulsification, OVDs protect against fluid movements and touch by particulate matter as well as against oxygen free radicals released during ultrasound. Sodium hyaluronate acts as a scavenger during phacoemulsification. Another protective effect may occur when the sodium hyaluronate binds to specific endothelial receptors. These hyaluronic acid binding sites are present on the corneal endothelium. Research shows that the binding affinity is dependent on the molecular weight of

Accepted for publication June 9, 2000. From the Departments of Ophthalmology, Humboldt University Berlin, Campus Virchow Klinikum, Berlin (Holzer, Tetz), and Ruprecht-Karls University Heidelberg, Heidelberg (Auffarth, Vo¨lcker), and the Eye Clinic Ludwigshafen, Ludwigshafen (Welt), Germany. None of the authors has a financial or proprietary interest in any material or method mentioned. Reprint requests to Manfred R. Tetz, MD, Department of Ophthalmology, Humboldt University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. 214

sodium hyaluronate; the higher the molecular weight, the stronger the binding.7–12 The compartmentalization of the anterior chamber during phacoemulsification may be one of the most important mechanical features that protect the eye. The best protection seems to occur when the OVD prevents continuous contact between the lens fragments and irrigation fluid on the corneal endothelium when phacoemulsification is occurring in the capsular bag or at the level of the capsulorhexis. Two OVDs that are most likely to be retained to a noticeable amount in the anterior chamber during phacoemulsification are Healon威5 (sodium hyaluronate 2.3%), a relatively new agent, and Viscoat威 (sodium hyaluronate 3.0%– chondroitin sulfate 4.0%). A possible drawback of the retentiveness of these OVDs is that the time required for their complete removal may affect endothelial cell loss.6 A potential complication of OVD use is a postoperative increase in intraocular pressure (IOP). This occurs when a significant amount of an OVD is left in the anterior chamber. The outflow of the aqueous humor from the anterior chamber is impeded, increasing IOP.13–16 This study compared Healon5 with 4 OVDs commonly used during phacoemulsification and IOL implantation. The influence on IOP and on preoperative and postoperative endothelial cells was evaluated.

Patients and Methods This randomized prospective clinical trial was performed at the Department of Ophthalmology, University of Heidelberg. Of the 81 eyes included, 74 completed all 6 scheduled examination visits. The results given are for these 74 eyes. The preoperative examination took place 1 to 5 days before surgery. Postoperative follow-up was at 4 to 6 and 24 hours and 7, 30, and 90 days. Intraocular pressure was measured by Goldmann applanation tonometry, and an endothelial cell count was done using a Pro/Koester WFSCM contact endothelial microscope. Exclusion criteria were age younger than 40 years, preoperative IOP greater than 21 mm Hg, glaucoma, marked corneal pathology, uveitis, and pseudoexfoliation syndrome. After the preoperative examination, patients were randomly assigned to 1 of 5 study groups based on the OVD used during phacoemulsification. The 5 OVDs

J CATARACT REFRACT SURG—VOL 27, FEBRUARY 2001

EFFECT OF HEALON5 ON IOP AND ENDOTHELIUM

were Healon GV威 (sodium hyaluronate 1.4%), Healon5, Viscoat, and OcuCoat威 and Celoftal威 (HPMC 2.0%). The number of patients in each group was 12, 19, 20, 15, and 15, respectively. At all examinations, the patient and observer were masked as to which OVD group the patient belonged. Because the OVDs have different biophysical behaviors (Table 1), the surgeon was not masked. The same surgeon (M.R.T.) performed all procedures using a standardized technique. A corneoscleral tunnel incision was made at 12 o’clock using a 2.5 mm phaco knife. Next, the OVD was injected into the anterior chamber. A capsulorhexis was created with a forceps. Hydrodissection was performed using balanced salt solution (BSS威). Phacoemulsification was done using a chopping technique (Nagahara phaco chopper) and a 1-handed irrigation/aspiration (I/A) tip with a 3.0 mm aspiration hole for cortex and OVD removal. The phaco machine was a Megatron威 (Geuder) and the phaco tip, a 30 degree Megatip威 (Geuder). The phaco and I/A settings were identical for all procedures. The incision was enlarged to 4.0 mm for implantation of a foldable IOL or to 6.0 mm for implantation of a poly(methyl methacrylate) IOL. Phacoemulification and removal times were documented when Healon5 or Viscoat was used because of the high retention of these OVDs. Statistical analysis was performed using the Kruskal–Wallis test.

Results The mean preoperative and postoperative IOP among groups did not differ significantly (P ⬎ .05). Four hours postoperatively, all groups had increased IOP. The highest mean values were in the Healon5 group (24.9 mm ⫾ 7.1 [SD]) and the Viscoat group (23.6 ⫾ 7.5 mm Hg). The mean IOPs at all examinations are shown in Table 2 and Figure 1. The Healon5 group had the lowest mean endothelial cell loss (– 6.2%) 90 days postoperatively. This was significantly lower than the means in the other 4 groups (P ⱕ .02). The results of the endothelial cell counts preoperatively and 90 days postoperatively are shown in Table 3 and Figure 2. Additional surgical procedures that were not part of the surgical protocol were performed in 3 groups: In the Healon5 group, 1 eye required an anterior vitrectomy because of a posterior capsule break. In 1 eye in the Viscoat group, Healon GV was used to maintain the anterior chamber. In the OcuCoat group, there was 1 zonular dehiscence requiring a capsular tension ring and an anterior vitrectomy and 2 cases in which Healon GV was used to maintain the anterior chamber.

Discussion Since the introduction of viscoelastic materials in ophthalmic surgery in 1972 by Balazs et al.,1 these substances have become increasingly important for intraocular procedures. The first commercially available

Table 1. Physical and biochemical properties of the OVDs. Property

Healon5

Healon GV

Viscoat

OcuCoat

Celoftal

Manufacturer

Pharmacia & Upjohn

Pharmacia & Upjohn

Alcon

Bausch & Lomb

Alcon

Ingredients per mL

23 mg NaHa

14 mg NaHa

1. 40 mg CDS 2. 30 mg NaHa

20 mg HPMC

20 mg HPMC

Source

Rooster combs

Rooster combs

1. Shark fin cartilage 2. Bacterial fermentation

Wood pulp

Wood pulp

Concentration (%)

2.3

1.4

1. 4 2. 3

2

2

Viscosity (mPas)

7 000 000

2 000 000

40 000

4000 ⫾ 1500

4000 ⫾ 1500

Molecular weight (dalton)

4 000 000

5 000 000

1. 22 500 2. ⬎500 000

⬎80 000

⬃80 000

Osmolarity (mOsm/L)

309

302

330

285 ⫾ 32

285 ⫾ 30

pH value

7.0–7.5

7.0–7.5

7.25 ⫾ 0.25

7.2 ⫾ 0.4

7.2 ⫾ 0.4

Storage (°C)

2–8

2–8

2–8

Room temp

Room temp

NaHa ⫽ sodium hyaluronate; CDS ⫽ chondroitin sulfate; HPMC ⫽ hydroxypropyl methylcellulose

J CATARACT REFRACT SURG—VOL 27, FEBRUARY 2001

215

EFFECT OF HEALON5 ON IOP AND ENDOTHELIUM

Table 2. Mean IOP over time. Postoperative Preoperative

4–6 Hours

24 ⴞ 4 Hours

7 ⴞ 2 Days

30 ⴞ 7 Days

90 ⴞ 10 Days

Healon5

14.5 ⫾ 2.7

24.9 ⫾ 7.1

15.7 ⫾ 4.1

13.5 ⫾ 2.6

12.9 ⫾ 2.8

14.1 ⫾ 2.9

Healon GV

16.0 ⫾ 3.3

21.6 ⫾ 4.5

17.1 ⫾ 7.8

13.3 ⫾ 2.6

13.1 ⫾ 2.0

13.4 ⫾ 3.3

Group

Viscoat

15.4 ⫾ 3.0

23.6 ⫾ 7.5

17.1 ⫾ 4.5

15.5 ⫾ 3.5

14.2 ⫾ 2.5

14.6 ⫾ 2.7

OcuCoat

16.7 ⫾ 3.3

22.1 ⫾ 7.4

19.2 ⫾ 4.2

13.9 ⫾ 3.8

13.9 ⫾ 2.8

12.4 ⫾ 3.0

Celoftal

16.5 ⫾ 3.1

21.5 ⫾ 7.1

19.4 ⫾ 3.6

12.9 ⫾ 2.9

13.6 ⫾ 3.0

12.0 ⫾ 2.0

Means ⫾ SD

Figure 1. (Holzer) Mean IOP over time.

viscoelastic substance, Healon, made cataract surgery safer and easier.17 Healon and Healon5 contain sodium hyaluronate at different concentrations. Healon GV has an altered molecular weight. Since the 1980s, other OVDs with different or additional contents have become commercially available. Based on their physical and biochemical properties, Arshinoff2,3 classified them into 2 groups— cohesive and dispersive—with an emphasis on their intraocular behavior. Most OVDs contain sodium hyaluronate (Healon GV, Healon5), HPMC (OcuCoat, Celoftal), chondroitin sulfate, or a mixture of sodium hyaluronate and chondroitin sulfate (Viscoat). Since Kelman introduced the phacoemulsification technique of cataract extraction, protecting the endothelium from particulate matter and/or free radicals formed during the procedure has become important. Before OVDs, air or a balanced saline solution was used to maintain space in the anterior chamber. However, protection of the endothelium was poor, resulting in significant endothelial cell loss. Because of their viscosity, 216

OVDs provide better anterior chamber maintenance and endothelial protection than air or saline, decreasing endothelial cell loss.18,19 In this study, we performed central endothelial cell counts preoperatively and 90 days postoperatively. The Oxford Cataract Treatment and Evaluation Team examined more than 300 eyes after cataract surgery, evaluating among other things endothelial cell loss for 4 years postoperatively. The team found an increase in endothelial cell loss depending on the postoperative period.20 These results suggest that an endothelial cell count should be performed at least 90 days postoperatively (as in our study), when cell reorganization and loss have stabilized. Several studies have compared OVDs and their influence on endothelial cell loss following surgery.21–28 Some dispersive OVDs are thought to protect the endothelium better than cohesive OVDs. We did not confirm this in our study. In fact, the lowest mean cell loss (6.2% ⫾ 6.5%) was in the Healon5 group and the highest, in the OcuCoat group (16.7% ⫾ 10.8%). OcuCoat contains HPMC and has dispersive characteristics. Viscoat, another dispersive agent, yielded a cell loss of 15.4% ⫾ 9.1%. Some cell loss with the dispersive OVDs may have been a result of the extended times needed to remove them. The study protocol required complete removal of the OVDs after surgery. Because of the physical and biochemical properties of dispersive OVDs and their tendency to adhere to the endothelium, such substances (eg, Viscoat) take longer to remove. In this study, we used Arshinoff’s rock ’n roll technique29 to remove the OVDs (G.U. Auffarth, MD, “Evaluation of Different Removal Techniques of a High-Viscosity Viscoelastic,” presented at the Symposium on Cataract, IOL and Re-

J CATARACT REFRACT SURG—VOL 27, FEBRUARY 2001

EFFECT OF HEALON5 ON IOP AND ENDOTHELIUM

Table 3. Endothelial cell loss preoperatively and 90 days postoperatively. Endothelial Cells (cells/mm2) Preoperative

90 ⴞ 10 Days Postoperative

Mean Loss Absolute Value

Mean Loss Relative Value (%)

Healon5

2355 ⫾ 333

2214 ⫾ 372

140.7 ⫾ 132.5

6.2 ⫾ 6.5

Healon GV

2192 ⫾ 243

1957 ⫾ 308

235.0 ⫾ 157.7

10.9 ⫾ 7.5

Viscoat

2384 ⫾ 381

2032 ⫾ 461

351.7 ⫾ 176.3

15.4 ⫾ 9.1

Group

OcuCoat

2275 ⫾ 271

1899 ⫾ 351

376.7 ⫾ 248.8

16.7 ⫾ 10.8

Celoftal

2197 ⫾ 370

1896 ⫾ 220

301.4 ⫾ 198.2

12.9 ⫾ 6.2

Means ⫾ SD

Figure 2. (Holzer) Mean endothelial cell loss 90 days postoperatively.

fractive Surgery, San Diego, California, USA, April 1995). Since Viscoat, OcuCoat, and Celoftal are dispersive agents, it took longer to remove them. We also measured the removal time and the ultrasound time for Viscoat and Healon5. It took significantly less time to completely remove the Healon5 than to remove the Viscoat (P ⬍ .001); however, the ultrasound times were not significantly different. The longer removal time for the Viscoat may have caused trauma, damaging the corneal endothelium and leading to greater cell loss than with Healon5. The U.S. Food and Drug Administration recommends complete removal of all OVDs from the eye at the end of surgery. Several methods to shorten OVD removal time are being studied, including Tetz and Holzer’s30,31 2-compartment technique. If the OVD is not removed completely, IOP can increase postoperatively. Because of their viscosity, OVDs can obstruct the trabecular meshwork and the

canal of Schlemm.6 Highly viscous OVDs such as Healon GV and Healon5 can cause significant IOP increases. In our study, we found a moderate increase in mean IOP with all viscoelastic substances. Four hours postoperatively, the highest mean IOP was in the Healon5 group, followed by Viscoat, OcuCoat, Healon GV, and Celoftal, although the differences were not statistically significant. At 24 hours, all mean IOPs were less than 20 mm Hg. At 7, 30, and 90 days, mean IOPs were close to preoperative values. In 3 eyes (2 with HPMC and 1 with Viscoat), the anterior chamber became shallow and the OVD could not overcome the increased posterior vitreous pressure. Therefore, the more viscous Healon GV was used as an adjunct. In conclusion, no severe postoperative complications such as a high IOP rise were observed with any OVD. However, endothelial cell loss was significantly lower with the viscoadaptive Healon5.

References 1. Balazs EA, Freeman MI, Klo¨ti R, et al. Hyaluronic acid and replacement of vitreous and aqueous humor. Mod Prob Ophthalmol 1972; 10:3–21 2. Arshinoff S. Dispersive and cohesive viscoelastic materials in phacoemulsification. Ophthalmic Pract 1995; 13: 98 –104 3. Arshinoff S. The physical properties of ophthalmic viscoelastics in cataract surgery. Ophthalmic Pract 1991; 9:81– 86 4. Arshinoff S. The physical properties of ophthalmic viscoelastics in cataract surgery. Proceedings National Ophthalmic Speakers Program. Montreal, Canada, Medicopea, 1992 5. Hu¨tz WW, Eckhardt HB, Kohnen T. Comparison of viscoelastic substances used in phacoemulsification. J Cataract Refract Surg 1996; 22:955–959

J CATARACT REFRACT SURG—VOL 27, FEBRUARY 2001

217

EFFECT OF HEALON5 ON IOP AND ENDOTHELIUM

6. Dick B, Schwenn O, Pfeiffer N. Classification of viscoelastic substances for ophthalmologic surgery. Ophthalmologe 1999; 96:193–211 7. Madsen K, Schenholm M, Jahnke G, Tengblad A. Hyaluronate binding to intact corneas and cultured endothelial cells. Invest Ophthalmol Vis Sci 1989; 30:2132– 2137 8. Stenevi U, Gwin T, Ha¨rfstrand A, Apple D. Demonstration of hyaluronic acid binding to corneal endothelial cells in human eye-bank eyes. Eur J Implant Refract Surg 1993; 5:228 –232 9. Madsen K, Stenevi U, Apple D, Ha¨rfstrand A. Histochemical and receptor binding studies of hyaluronic acid and hyaluronic binding sites on corneal endothelium. Ophthalmic Pract 1989; 7:92–97, 119 –120 10. Ha¨rfstrand A, Molander N, Stenevi U, et al. Evidence of hyaluronic acid and hyaluronic acid binding sites on human corneal endothelium. J Cataract Refract Surg 1992; 18:265–269 11. Ha¨rfstrand A, Stenevi U, Schenholm M, et al. Sodium hyaluronate on the corneal endothelium. Implant Ophthalmol 1990; 4:83– 87 12. Holst A, Rolfsen W, Svensson B, et al. Formation of free radicals during phacoemulsification. Curr Eye Res 1993; 12:359 –365 13. Storr-Paulsen A. Analysis of the short-term effect of two viscoelastic agents on the intraocular pressure after extracapsular cataract extraction. Sodium hyaluronate 1% vs hydroxypropyl methylcellulose 2%. Acta Ophthalmologica 1993; 71:173–176 14. Henry JC, Olander K. Comparison of the effect of four viscoelastic agents on early postoperative intraocular pressure. J Cataract Refract Surg 1996; 22:960 –966 15. Kohnen T, von Ehr M, Schu¨tte E, Koch DD. Evaluation of intraocular pressure with Healon and Healon GV in sutureless cataract surgery with foldable lens implantation. J Cataract Refract Surg 1996; 22:227–237 16. Probst LE, Hakim OJ, Nichols BD. Phacoemulsification with aspirated or retained Viscoat. J Cataract Refract Surg 1994; 20:145–149 17. Miller D, Stegmann R. Use of Na-hyaluronate in anterior segment eye surgery. Am Intra-Ocular Implant J 1980; 6:13–15 18. Musch DC, Meyer RF, Sugar A, Soong HK. Endothelial rejection following penetrating keratoplasty using Healon or BSS. Cornea 1990; 9:305–311 19. Alpar JJ. Use of Healon in different cataract surgery techniques: endothelial cell count study. Ophthalmic Surg 1987; 18:529 –531

218

20. Oxford Cataract Treatment and Evaluation Team. Longterm corneal endothelial cell loss after cataract surgery; results of a randomized controlled trial. Arch Ophthalmol 1986; 104:1170 –1175 21. Lane SS, Naylor DW, Kullerstrand LJ, et al. Prospective comparison of the effects of Ocucoat, Viscoat, and Healon on intraocular pressure and endothelial cell loss. J Cataract Refract Surg 1991; 17:21–26 22. Rafuse PE, Nichols BD. Effects of Healon vs Viscoat on endothelial cell count and morphology after phacoemulsification and posterior chamber lens implantation. Can J Ophthalmol 1992; 27:125–129 23. Guthoff R, Wendl U, Bo¨hnke M, Winter R. Endothelzellschu¨tzende Wirkung hochvisko¨ser Substanzen in der Kataraktchirurgie. Ophthalmologe 1992; 89:310 –312 24. Koch DD, Liu JF, Glasser DB, et al. A comparison of corneal endothelial changes after use of Healon or Viscoat during phacoemulsification. Am J Ophthalmol 1993; 115:188 –201 25. Probst LE, Nichols BD. Corneal endothelial and intraocular pressure changes after phacoemulsification with Amvisc Plus and Viscoat. J Cataract Refract Surg 1993; 19: 725–730 26. Dick HB, Kohnen T, Jacobi FK, Jacobi KW. Long-term endothelial cell loss following phacoemulsification through a temporal clear corneal incision. J Cataract Refract Surg 1996; 22:63–71 27. Ravalico G, Tognetto D, Baccara F, Lovisato A. Corneal endothelial protection by different viscoelastics during phacoemulsification. J Cataract Refract Surg 1997; 23: 433– 439 28. Schmidl B, Mester U, Anterist A. Intraindividueller Vergleich zweier Viskoelastika unterschiedlicher Viskosita¨t und Moleku¨lgro¨␤e (Healon GV, Provisc) bezu¨glich des Hornhautendothelschutzes bei Phakoemulsifikation an Risikoaugen mit cornea guttata. Ophthalmologe 1998; 95(suppl):48 20. Arshinoff SA. Rock ’n roll removal of Healon GV. Proceedings National Ophthalmic Speakers Program. Ottawa, Canada, Medicopea, 1997 30. Tetz MR, Holzer MP. Two compartment technique to remove ophthalmic viscosurgical devices. J Cataract Refract Surg 2000; 26:641– 643 31. Tetz MR, Holzer MP. Healon5: clinical performance and special removal technique (TCT technique). In: Buratto L, Giardini P, Bellucci R, eds, Viscoelastics in Ophthalmic Surgery. Thorofare, NJ, Slack, 2000; 401– 404

J CATARACT REFRACT SURG—VOL 27, FEBRUARY 2001