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Immediate Postoperative Use of a Topical Agent to Prevent Intraocular Pressure Elevation After Pars Plana Vitrectomy With Gas Tamponade
Matthew S. Benz, MD;
Erika M. Escalona-Benz, MD;
Timothy G. Murray, MD;
Charles W. G. Eifrig, MD;
Daniel M. Yoder, MD;
Jeffrey K. Moore, MD;
Joyce C. Schiffman, MS
Arch Ophthalmol. 2004;122:705-709.
ABSTRACT
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Objective To determine whether a single topical aqueous suppressant applied immediately after pars plana vitrectomy with long-acting gas tamponade prevents intraocular pressure (IOP) elevation.
Methods Fifty patients who met the inclusion criteria and underwent pars plana vitrectomy with long-acting gas tamponade were randomized to receive a combination of timolol maleate and dorzolamide hydrochloride, long-acting timolol alone, dorzolamide alone, or placebo at the conclusion of surgery. The IOP was checked by a portable, handheld tonometer (Tono-Pen) at the conclusion of surgery and at 5 hours, 1 day, and 1 week after surgery.
Results There were no significant differences in IOP among the groups at the conclusion of surgery. The IOP at 5 hours after surgery (27.0 vs 17.4 mm Hg; P<.001) and 1 day after surgery (26.1 vs 19.9 mm Hg; P = .01) showed a statistically significant difference between the placebo and timolol-dorzolamide groups. The timolol-dorzolamide group showed greater IOP control than either the timolol alone or the dorzolamide alone groups at 5 hours (P = .04 for both).
Conclusion The use of a single topical aqueous suppressant (timolol-dorzolamide) given after pars plana vitrectomy with long-acting gas tamponade effectively prevents significant postoperative IOP elevation at 5 hours and 1 day after surgery.
INTRODUCTION
Pars plana vitrectomy is associated with a significant risk of postoperative elevation in intraocular pressure (IOP). Reasons for IOP elevation include significant intraocular inflammation, postoperative hyphema, and forward rotation of the ciliary body with anterior displacement of the lens-iris diaphragm secondary to intraocular tamponade with either silicone oil or intraocular gases.1 Fluorinated intraocular gases are used in many types of vitreoretinal surgery, most typically for postoperative tamponade of retinal breaks. Excessive expansion of an intraocular gas bubble can lead to postoperative IOP elevation, glaucomatous damage to the optic nerve, and even central retinal artery occlusion.2-4
Many vitreoretinal surgeons check the IOP postoperatively, and some routinely admit patients to the hospital for IOP monitoring. Other surgeons give aqueous suppressants (topical medications or oral or intravenous acetazolamide sodium) at the conclusion of surgery to those patients they believe will be most at risk of developing a postoperative elevation in IOP.
A previous study5 showed that the administration of multiple topical aqueous suppressants at the conclusion of pars plana vitrectomy with long-acting gas tamponade was effective in preventing significant IOP elevation in most patients. A separate study6 showed that intravenous acetazolamide was ineffective in reducing the risk of significant postoperative IOP elevation.
We designed and completed a prospective, randomized, controlled clinical trial to determine whether a single topical aqueous suppressant given immediately after surgery would prevent significant IOP elevation and to determine whether prophylactic use of such an agent would control postoperative IOP. We elected to evaluate the combination of 0.5% timolol maleate and 2% dorzolamide hydrochloride as the topical aqueous suppressant because of its proved efficacy, its rapid onset of action, and the additive effect of the combination medication compared with the concomitant administration of timolol and dorzolamide.7-8 In addition, we evaluated long-acting 0.5% timolol and 2% dorzolamide individually to determine whether either of these agents alone would produce a significant effect on postoperative IOP.
METHODS
The Institutional Review Board of the University of Miami School of Medicine approved this project. A prospective, randomized, controlled clinical trial was performed at the Bascom Palmer Eye Institute on the patients of 3 vitreoretinal surgeons (M.S.B., T.G.M., and C.W.G.E.); these patients underwent pars plana vitrectomy with long-acting gas tamponade, met inclusion and exclusion criteria, and consented to enroll in the study. The patients were 18 years or older and had an IOP on preoperative examination higher than 5 mm Hg and lower than 22 mm Hg. Exclusion criteria included a current or prior diagnosis of glaucoma, current use of a glaucoma medication, chronic or recurrent uveitis, a history of corticosteroid response, the presence or planned placement of an anterior chamber intraocular lens, a history of hypersensitivity to any of the study medications, obstructive airway disease, second- or third-degree heart block, or current use of tricyclic antidepressants. Patients were randomized preoperatively with a randomly permuted block scheme in which the block size varied between 1 and 4, with an equal number of patients randomized to each of the 4 treatment groups at the end of each block. After patient eligibility was determined, the examining physician called the Biostatistics Center, which assigned the patient to 1 of 4 treatment groups: (1) 0.5% timolol–2% dorzolamide (Cosopt; Merck & Co, Inc, Whitehouse Station, NJ), (2) 0.5% timolol gel-forming solution (Timoptic XE; Merck & Co, Inc), (3) 2% dorzolamide (Trusopt; Merck & Co, Inc), or (4) a placebo drop (artificial tears) (a combination of dextran 70 and hydroxypropyl methylcellulose [Tears Naturale II]; Alcon Laboratories, Inc, Fort Worth, Tex). The baseline characteristics of the treatment groups are given in Table 1.
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Table 1. Baseline Characteristics by Randomization Group*
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The patients underwent surgery for 1 of 3 diagnoses: rhegmatogenous retinal detachment with or without proliferative vitreoretinopathy, macular hole, or tractional retinal detachment. A standard 3-port pars plana vitrectomy was performed in all patients. On completion of an air-fluid exchange and closure of the superior sclerotomies, a mixture of long-acting gas was injected through the posterior infusion cannula while venting through a 27-gauge needle placed through the pars plana. A gas mixture, 50 mL, was instilled in this manner, ensuring a complete exchange of gas for air. Either perfluoropropane (C3F8) or sulfahexafluoride (SF6) was used, in minimally expansile or nonexpansile concentrations (C3F8, 14%-18%; or SF6, 16%-20%). The pure gases were diluted with filtered air to reach the anticipated concentrations. If the patients underwent general anesthesia, no nitrous oxide was administered.
After closure of the final sclerotomy, the IOP was checked with a portable, handheld tonometer (Tono-Pen; Mentor Ophthalmics, Norwell, Mass) with a sterile tip. If the IOP was lower than 10 or higher than 21 mm Hg, a gas mixture was either added or removed from the eye to bring the IOP between 10 and 21 mm Hg. After the IOP was confirmed by Tono-Pen to be between 10 and 21 mm Hg, the conjunctiva was closed. The eyes then received a subconjunctival injection with a combination antibiotic-corticosteroid, 0.25% scopolamine hydrobromide topically, and a combination of tobramycin sulfate and dexamethasone topically (Tobradex; Alcon Laboratories, Inc). According to randomization into 1 of the 4 groups, the patient then received 0.5% timolol–2% dorzolamide, 0.5% timolol gel-forming solution, 2% dorzolamide, or artificial tears before placement of a sterile patch and shield over the eye.
The IOP was checked by Tono-Pen in a masked fashion at 5 hours, 1 day, and 1 week after surgery by trained personnel. If the IOP was elevated at any measurement point, a standard treatment protocol was followed. We considered an IOP by Tono-Pen higher than 25 mm Hg to be elevated. For an IOP of 26 to 30 mm Hg, the patients received 0.2% brimonidine tartrate (Alphagan; Allergan, Inc, Irvine, Calif). For an IOP of 31 to 40 mm Hg, the patients received 2 of the following 3 medications: 0.5% timolol, 2% dorzolamide, or 0.2% brimonidine. For an IOP higher than 40 mm Hg, the patient underwent anterior chamber paracentesis.
Patient age and sex, diagnosis, lens status, and prior surgical procedures performed were recorded. The type of surgery performed and the occurrence of significant intraoperative complications were also documented. Outcome data collected included postoperative IOP measurements immediately after the surgery and 5 hours, 1 day, and 1 week after surgery.
Continuous baseline characteristics, such as age, were compared using t tests and an analysis of variance to test for differences among the treatment groups. Categorical variables, such as sex, were compared using  2 tests. Postoperative IOP measurements and change in IOP at 5 hours, 1 day, and 1 week after surgery were compared among treatment groups using an analysis of variance and t tests. Paired t tests were used to compare 5-hour, 1-day, and 1-week IOPs with immediate postoperative IOPs within treatment groups.
RESULTS
There were 52 eyes that met the inclusion and exclusion criteria and consented to participate in the study between September 1, 2001, and December 31, 2002. Two patients did not complete the study because of intraoperative reasons (use of air or silicone oil instead of long-acting gas). The 50 remaining patients were divided into 4 groups: (1) group 1 (n = 12), timolol-dorzolamide; (2) group 2 (n = 13), timolol alone; (3) group 3 (n = 13), dorzolamide alone; and (4) group 4 (n = 12), placebo. The mean age of the 50 participating patients was 57.6 years (range, 25-83 years). The diagnoses for which surgery was performed on the 50 patients were as follows: rhegmatogenous retinal detachment (with or without proliferative vitreoretinopathy), 40 (80%); macular hole, 5 (10%); and tractional retinal detachment, 5 (10%). There were no significant intraoperative complications, such as excessive hemorrhaging, in any of the study patients. According to the study protocol, patients with an IOP higher than 25 mm Hg at the 5-hour point received topical brimonidine: in group 1, 1 of 11 patients received brimonidine at the 5-hour point; in group 2, 2 of 13 patients received brimonidine; in group 3, 2 of 13 patients received brimonidine; and in group 4, 9 of 12 patients received brimonidine.
Table 1 provides baseline characteristics, such as age, sex, study eye, lens status, and history of prior surgery, for each of the 4 treatment groups. It also includes diagnosis and preoperative IOPs taken in the clinic at enrollment in the trial. The treatment groups were similar, with no statistically significant differences.
Table 2 provides the postoperative IOP course, with P values comparing IOP outcomes among the 4 treatment groups.
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Table 2. The IOP Measurements at Indicated Points
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With timolol alone, dorzolamide alone, and placebo, there was a statistically significant IOP increase at the 5-hour postoperative point (P = .01, P = .001, and P<.001 by paired t test, respectively). This IOP increase persisted at 1 day for these treatment groups (P = .01, P<.001, and P<.001, respectively). There was no statistically significant (P = .91) IOP increase with timolol-dorzolamide. It was also true that patients treated with timolol or dorzolamide alone had less of an IOP increase at the 5-hour point than patients treated with placebo (P = .02 and P = .009 by t test, respectively).
Figure 1 graphically shows the mean IOP in the 4 treatment groups at the immediate postoperative, 5-hour, 1-day, and 1-week points.
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Mean intraocular pressure (IOP) measurements at indicated time points. Dorzolamide was administered as dorzolamide hydrochloride.
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Table 3 provides the number and percentage of patients in each treatment group with an IOP higher than 25 mm Hg at 5 hours and 1 day postoperatively. When comparing timolol-dorzolamide with placebo, there was a statistically significant difference in the likelihood of an IOP higher than 25 mm Hg at the 5-hour point and a trend toward significance at the 1-day point.
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Table 3. Incidence of IOP Elevation (>25 mm Hg) at the 5-Hour and 1-Day Points*
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COMMENT
Numerous researchers2-3,9-11 have reported previously on the incidence of postoperative IOP elevation after pars plana vitrectomy with long-acting gas tamponade. When used in vitreoretinal surgery, these long-acting gases are typically diluted to a minimally or nonexpansile concentration, usually 18% to 20% for SF6 and 14% to 18% for C3F8. However, there is clear evidence that the IOP can be significantly elevated after surgery. The risk of IOP elevation after injection of SF6 has been reported to range from 6.1% to 67%,3, 9 while the risk of IOP elevation after injection of C3F8 has been reported to range from 18% to 59%.10-11 While the maximum size of the long-acting gas bubble is not reached until 24 to 48 hours for SF612 and 72 to 96 hours for C3F8,13-14 the most rapid rate of volume increase occurs within 5 to 8 hours.15 For this reason, many vitreoretinal surgeons monitor IOP at approximately 5 hours after surgery, as we do on our service. Treatment of elevated postvitrectomy IOP is usually accomplished medically via aqueous suppressants, although invasive procedures such as anterior chamber paracentesis may occasionally be necessary.
Prophylactic treatment of elevated postvitrectomy IOP has been proposed and studied before. The use of intravenous acetazolamide during surgery has been shown to be ineffective,6 while the combined use of multiple topical aqueous suppressants has been shown to be effective in the prevention of postvitrectomy IOP elevation.5 In the present study, we investigated whether a single topical aqueous suppressant would be sufficient to prevent significant postvitrectomy IOP elevation. We believed that the use of a single agent would be more practical in the prophylactic treatment of IOP elevation in this setting.
We chose to evaluate the combination of timolol-dorzolamide because it was the single topical aqueous suppressant with the greatest IOP-lowering effect during the critical 5- to 8-hour postoperative period.7 In addition, we investigated the effectiveness of timolol and dorzolamide used separately. Combination timolol-dorzolamide has been shown previously to be more effective than monotherapy with either timolol or dorzolamide.16 Although timolol and dorzolamide alone showed a significant treatment effect at the 5-hour point when compared with placebo, this treatment effect was significantly less than that of the combination of timolol-dorzolamide at the 5-hour point. In patients with no medical contraindications, a combination topical medication, such as timolol-dorzolamide, is preferred for decreasing the risk of an elevated IOP after pars plana vitrectomy with use of a long-acting gas tamponade.
We used the Tono-Pen to measure IOP because it has several advantages in the current setting. The Tono-Pen is portable and requires no other instrumentation, facilitating its use in the operating room, the recovery room, and the clinic. The latex tip of the Tono-Pen can be sterilized for use during surgery, and the Tono-Pen is accurate even with an irregular corneal epithelium. Although the Tono-Pen has been shown to be similarly accurate to Goldmann applanation tonometry for eyes with an IOP within the physiologic range, some reports17-19 have indicated that it overestimates low pressures and underestimates high pressures.
In gas-filled eyes, the compressible nature of the gas leads to underestimation of the IOP by the typical indentation methods of tonometry. In 1990, Lim et al18 found that the Tono-Pen significantly underestimates IOP at pressures of 30 mm Hg or higher, averaging 12.1 mm Hg below the true IOP as measured by manometry. In 1993, Badrinath et al19 expanded on these findings, compared IOP measurements with the Tono-Pen with manometric pressure, and reported a calibration curve for use of the Tono-Pen to measure IOP in gas-filled eyes that had undergone vitrectomy. Patients with a Tono-Pen pressure of 25 mm Hg had an IOP by manometry of 30.77 mm Hg, and those with a Tono-Pen pressure of 30 mm Hg had an IOP by tonometry of 36.73 mm Hg. We believe the Tono-Pen is an easy and relatively accurate means of measuring IOP in patients after vitrectomy and that it was the best way to measure IOP in this clinical trial. We considered a Tono-Pen IOP reading of 25 mm Hg or higher significant, because it corresponds to a true IOP of greater than 30 mm Hg.18-19 In addition, Mittra et al5 previously reported similar results using multiple topical aqueous suppressants, and they similarly considered a Tono-Pen measurement of an IOP higher than 25 mm Hg as a significant elevation.
In their study, Mittra et al5 showed that the use of multiple topical aqueous suppressants after pars plana vitrectomy with long-acting gas tamponade was effective in reducing the incidence of significant IOP elevation after surgery, with a significant increase in IOP defined as 25 mm Hg or higher. They also showed that the treated eyes did not on average have a significant increase in IOP during the critical 6-hour postoperative period while control eyes had a significant increase in IOP (an average 8–mm Hg increase) during the early postoperative period. In the present study, we demonstrated similar results in a prospective, randomized, controlled clinical trial with the use of a single topical aqueous suppressant (timolol-dorzolamide). We showed that eyes treated with timolol-dorzolamide had no difference between the IOP measured immediately postoperatively and at the 5-hour postoperative point. However, control eyes that received placebo at the end of surgery had a mean 12–mm Hg increase in IOP at the 5-hour postoperative point and the IOP was still elevated at 1 day (P<.001 for both).
This prospective, randomized, controlled clinical trial shows that 0.5% timolol–2% dorzolamide given immediately after pars plana vitrectomy with long-acting gas tamponade can reduce the likelihood of IOP elevation higher than 25 mm Hg (9% in group 1 vs 75% in group 4; P = .006) at the 5-hour postoperative point. This decreases the risk of visual loss secondary to an elevated IOP, decreases the likelihood of patient discomfort, and reduces the need for further therapy, including invasive procedures such as anterior chamber paracentesis. The use of a single topical agent rather than multiple agents simplifies the treatment process, eliminating the need for multiple drops and the potential for washout of drops placed one after the other.
With the trend toward outpatient vitreoretinal surgery, there is a desire to avoid altogether postoperative monitoring of IOP during the first night after surgery. Our results show that 0.5% timolol–2% dorzolamide applied immediately after pars plana vitrectomy with long-acting gas tamponade helps to avoid IOP elevation in many patients. Vitreoretinal surgeons can be confident that most of their postoperative patients can avoid the dangers associated with an elevated IOP during the early postoperative period. Surgeons may still want to check the IOP at the 5-hour point, especially in patients with a history of an elevated IOP after surgery or a history of glaucoma or when using a concentration of gas with more expansile qualities than used in the present study.
AUTHOR INFORMATION
Corresponding author and reprints: Matthew S. Benz, MD, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin, Mail Stop NC-205, Houston, TX 77030 (e-mail: mbenz{at}bcm.tmc.edu).
Submitted for publication June 4, 2003; final revision received October 8, 2003; accepted October 29, 2003.
This study was supported, in part, by an unrestricted research grant from Research to Prevent Blindness, New York, NY.
We thank Merck & Co, Inc, for providing the medications used in this study.
From the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla (Drs Benz, Escalona-Benz, Murray, Eifrig, Yoder, and Moore and Ms Schiffman); the Cullen Eye Institute, Baylor College of Medicine, Houston, Tex (Drs Benz and Escalona-Benz); and Retina Associates, PC, Raleigh, NC (Dr Eifrig). The authors have no relevant financial interest in this article.
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