Pseudoexfoliation (PXF) syndrome is a hereditary systemic disorder of the extracellular matrix.1–3 The prevalence of this syndrome increases with age and varies in racial and ethnic populations.4–6 Pseudoexfoliation causes many ocular complications, such as elevated intraocular pressure (IOP), cataract formation, degeneration of corneal endothelial cells, and dehiscence of the lens zonular fibers.1–3,7,8 Specifically, progressive accumulation of the fibrillary extracellular matrix in the trabecular meshwork reduces the aqueous outflow and thus increases the IOP.9,10 When the IOP increases substantially, glaucomatous optic neuropathy develops at a high incidence.
Some studies reported that IOP increases markedly within 24 hours after cataract surgery in eyes with PXF syndrome.11–13 Levkovitch-Verbin et al.13 showed that the IOP elevation occurs within several hours after surgery. Furthermore, the short-term IOP elevation might be reduced with topical timolol maleate or bimatoprost.12,13 These studies provide little information regarding the longitudinal changes in IOP; however, the effectiveness of a topical antihypertensive agent has not been established. Furthermore, the optimal timepoint at which an antihypertensive agent should be administered to effectively prevent the short-term IOP elevation within 24 hours after surgery remains unclear.
The purposes of the present study were to examine the longitudinal changes in IOP after cataract surgery in eyes with PXF syndrome and to assess whether administering oral acetazolamide could effectively reduce the IOP elevation. In addition, we examined the appropriate time to administer the oral acetazolamide to prevent IOP elevation after cataract surgery.
Patients and methods
This study was a prospective randomized clinical study performed at the Hayashi Eye Hospital, Fukuoka, Japan, between October 2014 and June 2017. The Institutional Review Board/Ethics Committee of the Hayashi Eye Hospital prospectively approved the study protocol and all participants provided written informed consent after a detailed explanation of the nature of the study. This study was registered in the University Hospital Medical Information Network (UMIN000017556).
A clinical research coordinator screened all consecutive patients who were scheduled for admission to the Hayashi Eye Hospital to have cataract surgery. The major inclusion criteria were eyes with PXF syndrome that were to have phacoemulsification surgery with implantation of a single-piece hydrophobic acrylic intraocular lens (IOL) (SN60WF, Alcon Laboratories, Inc.), and eyes that were to have the first surgery by a single surgeon (M.Y.). Ophthalmologists used slitlamp microscopy (T.S., S.M., K.Y.) to determine the presence of PXF in the anterior ocular segment. Exclusion criteria were eyes with a pathology of the cornea, vitreous, or macula, planned extracapsular cataract extraction, eyes with lens luxation, eyes with a possible zonular dehiscence, a history of ocular inflammation or surgery, small pupillary diameter less than 4.0 mm after full mydriasis, patient refusal, and any anticipated difficulties with examination or analysis. Eyes with possible zonular dehiscence were defined as having a shallower anterior chamber depth (>0.2 mm) compared with the fellow eye. Eyes that had complicated surgery or eyes that had pupil enlargement procedures were also excluded. Patient enrollment was continued until 102 eyes of 102 patients were included.
The patients were randomly assigned to 1 of 3 groups the day before surgery as follows: (1) eyes that were scheduled to have administration of oral acetazolamide at 1 hour preoperatively (preoperative administration group), (2) eyes that were scheduled to have oral acetazolamide administration at 3 hours postoperatively (postoperative administration group), or (3) eyes that were not to have administration (no administration group). The coordinator generated a randomization code with equal numbers using random number tables and assigned each patient to 1 of the 3 groups. The coordinator informed a nurse who oversaw the oral acetazolamide administration about the group to which each patient had been assigned. The coordinator kept the assignment schedule concealed until all data were collected. The examiners, all staff other than the nurse in charge, surgeon, and data analyst, were unaware of the group to which the patients had been assigned.
Oral Acetazolamide Administration
Systemic or topical antihypertensive medications that had been used were suspended the day before surgery. The nurse in charge administered 500 mg of oral acetazolamide (Diamox) 1 hour before cataract surgery to patients in the preoperative administration group and administered the same dose of oral acetazolamide 3 hours after surgery to patients in the postoperative administration group.
An experienced surgeon (M.Y.) performed all the cataract surgeries. Each eye received a 2 mL sub-Tenon capsule injection of xylocaine 2.0%. A transconjunctival single-plane sclerocorneal incision was made using previously described surgical techniques.14 First, 2 side ports were made with a 0.6 mm slit knife approximately 45 degrees away from the main incision. Through a side port, a continuous curvilinear capsulorhexis was created using a 23-gauge capsulorhexis forceps. Then, a 2.2 mm single-plane incision was made in the sclera at approximately 1.5 mm posterior to the limbus with a stainless steel keratome. The keratome was moved forward through the sclera and cornea, and entered the anterior chamber at 0.5 mm anterior to the limbus. After hydrodissection, phacoemulsification of the nucleus and aspiration of the residual cortex was performed with the Constellation phacoemulsifier (Alcon Laboratories, Inc.). After the lens capsule was filled with sodium hyaluronate 1.0% (Hyaguard), the single-piece hydrophobic acrylic IOL was inserted into the capsule using a Monarch II injector with a D cartridge (Alcon Laboratories, Inc.). The ophthalmic viscosurgical device was thoroughly removed. Upon completion of the surgery, the side ports were hydrated and the anterior chamber was deepened with a balanced salt solution using a cannula. The IOP was measured using a rebound tonometer (Icare Tiolat, Icare Finland Oy). The IOP was adjusted to range between 15 mm Hg and 30 mm Hg by injecting a balanced salt solution or by removing anterior chamber fluid through a side port.
Patients in the 3 groups were evaluated for IOP, wound status and leaking, and flare intensity within 24 hours after surgery. The IOP was measured using the rebound tonometer 1 hour before surgery, at the conclusion of surgery, and at 1, 3, 5, 7, and 24 hours after surgery by experienced ophthalmic technicians. The same technician measured the IOP for each patient. The IOP measurement method using the rebound tonometer was described previously.15 The IOP measurements were repeated 3 times and the mean value was used for analysis. When any type of error sign was observed or when a discrepancy existed between 1 IOP reading and the other 2 IOP readings, the reading was abandoned and another measurement was obtained. The reliability and reproducibility of IOP measurements using the rebound tonometer have been verified.16–18
The wound state of the transconjunctival single-plane sclerocorneal incision was assessed 5 hours postoperatively using anterior segment optical coherence tomography (AS-OCT) (Casia, Tomey Corp.). The AS-OCT scans across the anterior ocular segment, including the main incision, and images the wound architecture. The presence of the 5 types of wound architectural features that exist was evaluated based on the classification system described by Calladine and Packard19 as follows: epithelial gaping, endothelial gaping, endothelial misalignment, local detachments of Descemet membrane, and loss of coaptation along the wound. Among the 5 features, the loss of coaptation is considered to represent incomplete wound closure. The wound length was also measured using the biometry incorporated in the AS-OCT. The Seidel test was performed under slitlamp microscopy 5 hours postoperatively by 3 ophthalmologists (T.S., S.M., K.Y.).
Flare intensity was measured using the flare meter (FC-1000, Kowa Co., Ltd.) 5 hours postoperatively. Corrected distance visual acuity (CDVA) was examined on decimal charts preoperatively and at 24 hours postoperatively. Decimal visual acuity was converted to the logarithm of the minimum angle of resolution scale for statistical analysis. Corneal astigmatism and the manifest refraction spherical equivalent (MRSE) were evaluated with an autorefractometer/keratometer (KR-7100, Topcon Corp.). The grade of nuclear opalescence was determined by the ophthalmologist according to the Lens Opacities Classification System III.20 During surgery, the surgery time, cumulative dissipated energy (CDE), and the total volume of irrigating solution used were recorded. Eyes with pseudoexfoliation glaucoma (PXG) had visual field sensitivity testing with a visual field analyzer (Humphrey Visual Field Analyzer, 30-2 program, Carl Zeiss Meditec AG) within 6 months before surgery. The IOP, AS-OCT, flare intensity, visual acuity, visual field sensitivity, and autokeratometer evaluations were performed by experienced ophthalmic technicians unaware of the purpose of the study.
The normality of the distribution of the data was evaluated by inspecting a histogram of the data. Because the IOP at several timepoints was not normally distributed, the IOP was converted to a logarithmic scale for statistical analysis and returned to the arithmetic scale for expression. The IOP at the completion of surgery was adjusted deliberately and therefore, excluded from the statistical analysis. Longitudinal changes in IOP in the 3 groups were assessed by comparing the mean logarithm IOP between each time interval pair using the paired t test with the Bonferroni adjustment for multiple comparisons. The mean IOP was compared between the 3 groups using a linear mixed model analysis. The linear mixed model treated the time interval as a categorical variable and the logarithm of preoperative IOP as a covariate (SAS Proc Mixed with Repeated statement and no Random statementA). To detect the interval after which the difference in IOP between the groups changed, this model introduced a time–hour interaction term between group and indicator variables to determine whether change occurred beyond the timepoint. The assessment of 3 model types—unstructured, compound symmetry, and autoregressive models—as a covariance structure based on the Akaike information criterionB showed that the unstructured model had the best fit. The Akaike information criterion was also calculated to detect the timepoint change between 3, 5, 7, and 24 hours after surgery. Based on the Akaike information criterion, the model in which intergroup difference changed at 5 hours after surgery was adopted. The preoperative value-adjusted means of the IOP were calculated from the model. The incidence of an IOP spike higher than 25 mm Hg or 30 mm Hg was compared between the 3 groups using the Kaplan-Meyer survival analysis. When a significant difference was detected between the 3 groups, the survival curves were also compared for each pair of groups.
Because age, corneal astigmatism, MRSE, flare intensity, and continuous variables other than IOP and visual acuity were normally distributed, these were compared between groups using the 1-way analysis of variance. Categorical variables were compared between groups using the chi-square goodness of fit test. When a significant difference between groups was detected, the difference between each group pair was compared using the unpaired t test for continuous variables, and the chi-square or Fisher exact test for categorical variables with the Bonferroni adjustment for multiple comparisons. Differences with a P value less than 0.05 were considered statistically significant.
Of the 102 eyes of 102 patients, 6 eyes (5.9%) were lost to follow-up: Three eyes required a complicated surgery, 2 eyes had pupil enlargement procedures, and reliable IOP measurement could not be performed in 1 eye. Accordingly, 96 eyes completed all scheduled examinations and were included in analysis. Because only the nurse in charge administered the oral acetazolamide to all patients, the examiners, surgeon, other nurses, and data analyst were not aware of the group to which each patient had been assigned.
Table 1 shows baseline characteristics and surgical outcomes of the patients in the 3 groups. The mean age, ratio of men and women, ratio of left eyes and right eyes, corneal astigmatism, MRSE, CDVA, nuclear opalescence grade, surgical duration, CDE, and volume of irrigation solution used did not differ significantly between groups.
Eight eyes (25.0%) in the preoperative administration group, 10 eyes (31.3%) in the postoperative administration group, and 9 eyes (28.1%) in the no administration group had PXG; the incidence of eyes with glaucoma was not significantly different between the 3 groups (P = .857). Table 2 shows the antiglaucoma medications taken by the patients until 1 day preoperatively. The number and type of antiglaucoma medications prescribed before surgery did not differ significantly between the 3 groups. The mean deviation and pattern standard deviation of the visual field analyzer program in the last examination before surgery also did not differ significantly between the 3 groups.
Longitudinal Changes in IOP and Comparison of IOP Between Groups
In the no administration group, the mean IOP at 3, 5, and 7 hours after surgery was significantly higher than the IOP before surgery or at 24 hours after surgery (P ≤ .006) (Table 3), indicating significant IOP elevation at 3, 5, and 7 hours after surgery. In the preoperative administration group, the mean IOP 3 hours after surgery was significantly higher than the IOP at 1 hour postoperatively (P = .003). In the postoperative administration group, the mean IOP 3 hours after surgery was significantly higher than the IOP before surgery or at 1, 5, and 7 hours after surgery (P ≤ .001), and the IOP at 1, 3, 5, and 7 hours was significantly higher than the IOP at 24 hours (P ≤ .002), indicating that the elevated IOP was attenuated at 5 hours or later.
The mean IOP was not significantly different between groups before surgery and at the completion of surgery. Using the linear mixed model 1 hour and 3 hours after surgery, the mean IOP was significantly lower in the preoperative administration group than in the postoperative administration group or no administration group (P ≤ .001; Figure 1). At 5, 7, and 24 hours after surgery, the IOP was significantly lower in the preoperative and postoperative administration groups than in the no administration group (P ≤ .005).
Incidence of Marked Intraocular Pressure Spike
An IOP spike higher than 25 mm Hg occurred in 2 eyes (6.3%) in the preoperative administration group, 8 eyes (25.0%) in the postoperative administration group, and 13 eyes (40.6%) in the no administration group; the survival curve was significantly better in the preoperative administration group than in the postoperative and no administration groups (P ≤ .034; Figure 2). An IOP spike higher than 30 mm Hg did not occur in the preoperative administration group; however, it did occur in 1 eye (3.1%) in the postoperative administration group and in 4 eyes (12.5%) in the no administration group.
Wound States and Flare Intensity
The mean incision length was 1.7 mm ± 2.3 (SD) in the preoperative administration group, 1.8 ± 2.6 mm in the postoperative administration group, and 1.8 ± 2.3 mm in the no administration group; the mean length was not significantly different between groups (P = .177). The frequency of the 4 wound architectural features (epithelial gaping, endothelial gaping, endothelial misalignment, and local detachment of Descemet membrane) did not differ significantly between groups (Table 4). Loss of coaptation along the stromal tunnel was not detected in any eye. The Seidel test was negative in all eyes. The mean flare intensity was 34.9 ± 22.2 mg/dl in the preoperative administration group, 30.9 ± 15.7 mg/dl in the postoperative administration group, and 28.4 ± 12.9 mg/dl in the no administration group; the flare intensity did not differ significantly between groups (P = .337).
The findings of the present study showed that IOP elevation occurs within 24 hours after phacoemulsification surgery in eyes with PXF syndrome. Specifically, this short-term IOP elevation was prominent within 3 to 7 hours after surgery with a peak of 5 hours in eyes that did not receive an antihypertensive medication. When oral acetazolamide was administered 1 hour before surgery, the IOP elevation was attenuated throughout the 24-hour follow-up. When acetazolamide was administered 3 hours after surgery, the IOP elevation was attenuated at 5 hours after surgery or later. These findings suggest that oral acetazolamide administration just before surgery was more effective for preventing short-term IOP elevation than that administered after surgery in eyes with PXF syndrome.
Survival analysis showed that the occurrence of IOP spikes higher than 25 mm Hg was significantly decreased in eyes that received oral acetazolamide 1 hour before surgery compared with eyes that received acetazolamide 3 hours after surgery or eyes that did not receive acetazolamide. Furthermore, extensive IOP spikes higher than 30 mm Hg did not occur when oral acetazolamide was administered 1 hour before surgery, whereas 12.5% of the eyes that did not receive acetazolamide had an IOP spike higher than 30 mm Hg. Thus, short-term IOP spikes after cataract surgery were prevented by administrating oral acetazolamide 1 hour before surgery.
Wound states determined using the AS-OCT did not differ significantly between the 3 groups. In addition, the flare intensity was also not different between the groups. Only the eyes in which the surgery was uneventful using a standard phacoemulsification technique were included in the analysis. Accordingly, the intergroup difference in the wound states and degree of postoperative inflammation were not considered to affect the results of IOP elevation in the present study. It is conceivable, however, that more extensive IOP spikes might occur when the zonular dehiscence is more severe and special surgical techniques need to be performed, including pupil enlargement or transscleral fixation of the IOL.
Several studies11–13 found that the IOP markedly increases immediately after cataract surgery in eyes with PXF syndrome. Levkovitch-Verbin et al.13 reported that the IOP elevation occurs within several hours after surgery and this IOP elevation could be reduced with the use of topical timolol maleate 0.5% at the conclusion of surgery. Takmaz et al.12 found that a marked IOP spike was prevented by the use of topical bimatoprost. Because these studies provided little information regarding the longitudinal changes in IOP, however, the optimal time for administering the antihypertensive medication was not clarified. The present study showed that oral acetazolamide administration just before surgery was more effective for preventing the short-term IOP elevation than administration at several hours after surgery. Oral acetazolamide reduces IOP within 2 to 6 hours after administration with a peak at 4 hours.21 Accordingly, oral acetazolamide administration just before surgery can effectively prevent the immediate IOP elevation in eyes with PXF that occurs within 3 to 7 hours after cataract surgery.
A limitation of the present study is that we could not show whether the prevention of the short-term IOP spike by the oral acetazolamide attenuates optic nerve damage. Among the eyes enrolled in the present study, however, 30% had PXG. We believe that it is safer to prevent the immediate IOP spike, specifically for eyes with glaucoma.
In conclusion, short-term IOP elevation occurred within 3 to 7 hours after cataract surgery with a peak at 5 hours in eyes with PXF syndrome. When oral acetazolamide was administered 1 hour before surgery, the IOP elevation was reduced throughout the 24-hour follow-up. When acetazolamide was administered 3 hours after surgery, the IOP elevation was reduced by 5 hours after surgery or later. Thus, oral acetazolamide administration just before surgery was effective for preventing short-term IOP elevation. The most effective type of antihypertensive medication for reducing the IOP elevation, however, remains unclear. Further studies are necessary to compare the prophylactic effects against IOP elevation between various types of antihypertensive medications.
What Was Known
- Previous studies found that IOP markedly increases shortly after cataract surgery in eyes with PXF syndrome.
- This short-term IOP elevation might be reduced with topical timolol maleate or bimatoprost, although the exact time course of IOP elevation was unclear.
What This Paper Adds
- Short-term IOP elevation occurred within 3 to 7 hours after cataract surgery with a peak at 5 hours in eyes with PXF syndrome.
- Oral acetazolamide administered 1 hour before surgery significantly reduced this short-term IOP elevation within the 24 hours after surgery, whereas oral acetazolamide administered 3 hours after surgery significantly reduced the IOP elevation by 5 hours after surgery and later.
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None of the authors has a financial or proprietary interest in any material or method mentioned.
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