ARTICLE
`
`Increased risk for flap dislocation
`with perioperative brimonidine use
`in femtosecond laser in situ keratomileusis
`
`Gonzalo Mun˜ oz, MD, PhD, FEBO, Ce´sar Albarra´n-Diego, OD, Hani F. Sakla, MD, PhD,
`Jaime Javaloy, MD, PhD
`
`PURPOSE: To determine whether brimonidine 0.2% minimizes the occurrence of subconjunctival
`hemorrhages without inducing postoperative flap complications in femtosecond laser in situ kera-
`tomileusis (LASIK).
`
`SETTING: Centro Oftalmolo´gico Marque´s de Sotelo and Hospital NISA Virgen del Consuelo, Valen-
`cia, Spain.
`
`METHODS: This prospective contralateral-eye interventional study evaluated consecutive patients
`who had bilateral simultaneous femtosecond LASIK for myopia (spherical equivalent [SE] range
`1.00 to 8.00 diopters) performed with an IntraLase femtosecond laser and a Visx Star 2 excimer
`laser. One eye of each patient received a single drop of brimonidine tartrate 0.2% (brimonidine
`group) and the other eye, a single drop of a balanced salt solution (control group).
`
`RESULTS: The study evaluated 136 eyes (68 patients). The difference in the incidence of subcon-
`junctival hemorrhages was statistically significantly lower in the brimonidine group (mean score
`2.24 G 1.96 [SD]) than in the control group (mean score 7.61 G 2.72) (P<.001). However, no
`eye in the control group and 7 eyes (10.4%) in the brimonidine group had a dislocated flap with
`folds on the first postoperative day (P
`.016). All eyes with dislocated flaps required surgical in-
`tervention. At 6 months, there was no significant difference between groups in the percentage of
`eyes achieving 20/20 or better uncorrected distance visual acuity, in the mean SE, or in the enhance-
`ment rate.
`
`CONCLUSIONS: Brimonidine prevented the formation of subconjunctival hemorrhages after femto-
`second LASIK but increased the risk for flap dislocation. Thus, surgeons are cautioned against the
`use of perioperative brimonidine to decrease hemorrhagic complications in femtosecond LASIK.
`
`J Cataract Refract Surg 2009; 35:1338 1342 Q 2009 ASCRS and ESCRS
`
`The ultrashort-pulse femtosecond laser has been used
`successfully in several types of corneal procedures
`including the creation of corneal flaps in laser in situ
`keratomileusis (LASIK),1 dissection of channels for
`intracorneal rings,2 and preparation of donor and
`host tissue for keratoplasty.3 As with any new tech-
`nique, using the femtosecond laser for LASIK flap cre-
`ation has advantages and disadvantages. A possible
`disadvantage of the femtosecond laser versus mechan-
`ical microkeratomes is that a longer period of suction is
`needed for the lamellar resection4; this may lead to an
`increased incidence of postoperative subconjunctival
`hemorrhages. Although from the surgeon’s perspec-
`tive subconjunctival hemorrhages may be considered
`a minor and temporary cosmetic problem,
`for
`
`a significant number of patients, the hemorrhages
`cause anxiety and false alarm in the immediate postop-
`erative period.5
`There have been attempts to decrease the incidence
`of subconjunctival hemorrhages through the use of
`drugs with vasoconstrictive effects, including brimo-
`nidine,6,7 apraclonidine,8,9 and phenylephrine.10 How-
`ever, there is controversial evidence that the use of
`perioperative vasoconstrictors may increase the inci-
`dence of flap complications caused by poor flap adher-
`ence. In a retrospective study, Walter and Gilbert7
`found a statistically significant increase in the inci-
`dence of a dislocated flap after LASIK with prophylac-
`tic brimonidine. However, another prospective study
`concluded that a2-agonists applied topically decrease
`
`1338
`
`Q 2009 ASCRS and ESCRS
`
`Published by Elsevier Inc.
`
`0886 3350/09/$
`
`see front matter
`
`doi:10.1016/j.jcrs.2009.03.029
`
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`RISK FOR FLAP DISLOCATION WITH BRIMONIDINE USE IN LASIK
`
`1339
`
`the incidence of subconjunctival hemorrhages after
`LASIK without increasing the risk for flap slippage.6
`In this study, we sought to determine whether bri-
`monidine 0.2% prevents or minimizes the occurrence
`of subconjunctival hemorrhages without
`inducing
`postoperative flap adherence complications after fem-
`tosecond LASIK.
`
`PATIENTS AND METHODS
`Study Design
`This prospective contralateral eye interventional study
`evaluated consecutive patients who had bilateral simulta
`neous femtosecond LASIK for myopia ranging from 1.00
`to 8.00 diopters (D) of spherical equivalent (SE). Only pa
`tients with less than 1.00 D difference in SE between their 2
`eyes were included in the study. All the patients had a stable
`refractive history for more than 2 years. Written informed
`consent was obtained from all patients before surgery in ac
`cordance with the Declaration of Helsinki, and institutional
`review board approval was obtained from the hospital ethics
`committee.
`Preoperatively, patients had a complete ophthalmologic
`examination including manifest and cycloplegic refractions,
`uncorrected (UDVA) and corrected (CDVA) distance visual
`acuity measurements, computerized videokeratography,
`slitlamp biomicroscopy, Goldmann applanation tonometry,
`binocular indirect ophthalmoscopy, and ultrasonic pachy
`metry. Postoperative examinations were performed at 1, 3,
`and 7 days and 1, 3, and 6 months and included UDVA,
`CDVA, slitlamp evaluation, applanation tonometry, and
`corneal topography.
`One eye of each patient (right or left) was randomly as
`signed to treatment with a single drop of brimonidine
`tartrate 0.2% (Alphagan) approximately 5 minutes before
`surgery (brimonidine group). The other eye received a single
`drop of balanced salt solution (BSS) (control group).
`
`Surgical Technique
`The femtosecond laser technique for flap creation has been
`described.4,11 All surgeries were performed by the same sur
`geon (G.M.) using a 15 KHz IntraLase FS laser (IntraLase
`Corp.). Attempted flap thickness was 100 mm in all cases.
`The corneal stromal ablation was performed with a Visx
`Star 2 excimer laser (Abbott Medical Optics, formerly Ad
`vanced Medical Optics). After the ablation, the flap was
`
`Submitted: July 21, 2008.
`Final revision submitted: February 26, 2009.
`Accepted: March 12, 2009.
`
`From the Refractive Surgery Department, Centro Oftalmolo´gico
`Marque´s de Sotelo and Hospital NISA Virgen del Consuelo, Valen-
`cia, Spain.
`
`No author has a financial or proprietary interest in any material or
`method mentioned.
`
`Corresponding author: Gonzalo Mun˜oz, Centro Oftalmolo´gico Mar-
`que´s de Sotelo, Avenida Marque´s de Sotelo 5, Planta 2a, Puerta 5,
`46002 Valencia, Spain. E-mail: gon.munoz@ono.com.
`
`floated back in position using minimum irrigation with
`BSS. A wet surgical sponge was used to smooth the flap,
`properly align the flap, and ensure the flap had no visible
`folds. All flaps were allowed to dry for a minimum of 60 sec
`onds, and a striae test was performed to ensure proper flap
`adherence.
`All eyes were examined 30 minutes after surgery. Patients
`were instructed to wear protective eye shields and return the
`following day. Topical
`tobramycin dexamethasone eye
`drops were used every 2 hours for 3 days and then every 8
`hours for 4 days.
`The appearance of the flap with respect to the amount of
`subconjunctival hemorrhages and flap slippage/wrinkling
`was monitored using a slitlamp biomicroscope. Folds were
`defined as a series of parallel ridges in the flap that stained
`negatively with fluorescein. A dislocation was defined as
`folds accompanied by displacement of the flap edge from
`the edge of the lamellar cut of 0.5 mm or more (Figure 1).
`Subconjunctival hemorrhage was graded according to the
`number of involved quadrants (1 to 4) and size of the largest
`hemorrhage in each quadrant (1 to 3). A hemorrhage was
`considered small if it was less than 0.1 mm, medium if 0.1
`to 0.5 mm, and large if larger than 0.5 mm (Figure 2). Scores
`could range from 0 (no hemorrhages) to 12 (all quadrants af
`fected by large hemorrhages).
`
`Statistical Analysis
`Data from previous studies were used to calculate the
`sample size required to reach an appropriate statistical
`power. Walter and Gilbert7 found a 15.4% proportion of slip
`ped flaps using perioperative brimonidine versus 0% in
`a control group. Based on these data, it was calculated that
`48 eyes per group would yield a statistical power of 0.7
`with an a level of 0.05. The power of the study was increased
`by using a sample size of 68 eyes per group, which would
`theoretically yield a statistical power of 0.85.
`Statistical analysis was performed using SPSS for Win
`dows (version 15.0, SPSS, Inc). Differences in refractive
`data were analyzed by paired t tests. Differences in subcon
`junctival hemorrhage scores were compared using the Wil
`coxon signed rank test for mean values. The chi square test
`was used to compare the distribution of high scores and
`low scores for hemorrhages in both groups. The incidence
`of slipped flaps in both groups was compared using the
`McNemar test.
`
`Figure 1. Flap dislocation in a brimonidine treated eye.
`
`J CATARACT REFRACT SURG VOL 35, AUGUST 2009
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`1340
`
`RISK FOR FLAP DISLOCATION WITH BRIMONIDINE USE IN LASIK
`
`Figure 2. A large hemorrhage typically present in the area of suction
`ring placement in an eye not treated with brimonidine.
`
`Figure 3. Corneal dellen adjacent to a large nasal subconjunctival
`hemorrhage in an eye not treated with brimonidine.
`
`RESULTS
`By 6 months postoperatively, 1 patient was lost to fol-
`low-up, leaving 67 patients (134 eyes) in the analysis.
`The mean age of the 36 men (53.7%) and 31 women
`(46.3%) was 29.9 years G 6.0 (SD) (range 21 to 42
`years). Because this was a contralateral-eye study,
`there was no difference in age or sex between the bri-
`monidine group and the control group. There was
`no statistically significant difference in the preopera-
`tive mean SE between the brimonidine group (4.16
`G 1.88 D) and the control group (4.11 G 1.81 D)
`(P
`.451, paired t test).
`The use of perioperative brimonidine had a signifi-
`cant effect in preventing the formation of subconjunc-
`tival hemorrhages after femtosecond LASIK. The
`mean subconjunctival hemorrhage score was 2.24 G
`1.96 in the brimonidine group and 7.61 G 2.72 in the
`control group, a statistically significant difference
`(P!.001, Wilcoxon matched-pair test). The hemor-
`rhage score was 4 or lower (minimum to no subcon-
`junctival hemorrhages) in 57 eyes (85.1%) in the
`brimonidine group and 11 eyes (16.4%) in the control
`group. Clinically significant hemorrhages (scores
`R5) were present in 10 eyes (14.9%) in the brimonidine
`group and in 56 eyes (83.6%) in the control group
`(P!.001, chi-square test). Three eyes (4.5%) in the
`control group had corneal dellen adjacent to a large
`hemorrhage (Figure 3).
`No eye in the control group and 7 eyes (10.4%) in the
`brimonidine group had a dislocated flap with folds on
`the first postoperative day. The difference in the rate of
`dislocated flaps between groups was statistically sig-
`nificant (P
`.016, McNemar test). All eyes with dislo-
`cated flaps required surgical intervention to correct
`the abnormal flap appearance and improve visual
`
`function. One eye with a dislocated flap required
`retreatment for residual ametropia at the 6-month fol-
`low-up. There were no other complications (eg, epithe-
`lial ingrowth, flap striae, irregular astigmatism) in eyes
`with a dislocated flap at the 6-month follow-up.
`At 6 months, there were no significant differences
`between groups in the percentage of eyes achieving
`20/20 or better UDVA, in the mean SE, or in the en-
`hancement rate. Table 1 shows the results of the pri-
`mary procedure (ie, without enhancements) in both
`groups 6 months postoperatively.
`
`DISCUSSION
`Laser in situ keratomileusis has the shortest rehabilita-
`tion course of any corneal refractive surgical proce-
`dure.12 However, because of the use of the suction
`ring, some patients develop postoperative subconjunc-
`tival hemorrhages that may interfere with their return
`to a normal social or working life. A subconjunctival
`hemorrhage is not a significant complication for the re-
`fractive surgeon because it is self-limiting and does not
`affect vision or surgical outcomes. However, patients
`may perceive large subconjunctival hemorrhages as
`a serious intraoperative complication and may become
`alarmed about the surgical results. Large subconjuncti-
`val hemorrhages can preclude normal lubrication of
`the cornea, worsening the dry-eye condition typically
`present after LASIK. Some patients have LASIK shortly
`before important social events, and others prefer to
`keep their surgery private. In summary, there are med-
`ical, legal, and social reasons to search for a method to
`prevent subconjunctival hemorrhages after LASIK.
`Subconjunctival hemorrhage is a frequent finding
`after LASIK. Dada et al.5 report a 31% incidence
`of
`significant
`subconjunctival hemorrhages after
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`RISK FOR FLAP DISLOCATION WITH BRIMONIDINE USE IN LASIK
`
`1341
`
`Table 1. Results 6 months postoperatively.
`
`Parameter
`
`Brimonidine Group
`
`Control Group
`
`P Value
`
`UDVA (logMAR)
`Mean G SD
`Range
`CDVA (logMAR)
`Mean G SD
`Range
`SE (D)
`Mean G SD
`Range
`Within G0.50 D of SE (%)
`UDVA R20/20 (%)
`Lost 1 line CDVA (%)
`Enhancement rate (%)
`Flap slippage (%)
`Minimum to no SCH (%)
`Clinically significant SCH (%)
`
`0.05 G 0.06
`0.00 to 0.30
`
`0.00 G 0.03
`0.08 to 0.10
`
`0.21 G 0.36
`C0.50 to 1.25
`82
`69
`4.5
`13.4
`10.4
`85.1
`14.9
`
`0.04 G 0.06
`0.00 to 0.22
`
`0.00 G 0.02
`0.08 to 0.05
`
`0.23 G 0.34
`C0.50 to 1.00
`81
`72
`3.0
`10.4
`0.0
`16.4
`83.6
`
`.148
`
`.152
`
`.743
`
`O.999
`.500
`O.999
`.500
`.016
`.001
`.001
`
`CDVA Z corrected distance visual acuity; SCH Z subconjunctival hemorrhages; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity
`
`bilateral simultaneous LASIK using the Hansatome
`microkeratome (Bausch & Lomb). The incidence of sig-
`nificant subconjunctival hemorrhages may be even
`higher with the femtosecond laser because longer pe-
`riods of suction are needed for flap creation.4
`Studies6,7 have shown that the use of perioperative
`brimonidine can significantly decrease the incidence
`of bleeding complications after LASIK. However,
`there are contradictory results on whether prophylac-
`tic use of brimonidine increases the incidence of flap
`dislocation or slippage. In a retrospective noncompar-
`ative interventional case-series study, Walter and
`Gilbert7 found a statistically significant increase in
`the incidence of dislocated flaps after LASIK with pro-
`phylactic brimonidine (15.4% versus 0%). They also
`report an increase in enhancement rates when perio-
`perative topical brimonidine was used. In contrast,
`a prospective double-masked single-surgeon study
`by Norden6 of 31 patients (61 eyes) who had LASIK
`with or without prophylactic brimonidine found no
`increase in flap dislocation or striae in eyes treated
`with brimonidine.
`The Walter and Gilbert7 study and our study found
`statistically significantly more flap dislocations in bri-
`monidine-treated eyes. However, Norden6 did not
`find an increased risk for flap slippage with preopera-
`tive brimonidine. Many reasons may account for this
`finding, including the timing of brimonidine adminis-
`tration, the anesthetic drop protocol before surgery,
`differences in flap architecture (eg, thickness, hinge lo-
`cation), the drying-time protocol, and postoperative
`use of lubricants or contact lenses. Walter and Gilbert7
`postulate that the increased flap dislocation in their
`
`study was caused by brimonidine-induced desicca-
`tion, possible ischemia due to vasoconstriction of the
`anterior ocular vessels, or direct toxicity of the drug
`to the endothelial pump. Given the anesthetic and des-
`iccating effects of brimonidine, copious postoperative
`lubrication seems essential to minimize flap slippage.
`Norden6 routinely instilled a lubricant gel into the
`eye to reduce friction between the upper lid and flap,
`whereas we did not use gel in our study. It is important
`to consider that the gel can insinuate itself into the la-
`mellar interface and cause inflammation.
`Although perioperative brimonidine significantly
`reduced the number and size of subconjunctival
`hemorrhages in the present study, our major finding
`was the increased incidence of flap dislocation and
`folds associated with the use of brimonidine. The in-
`cidence of dislocated flaps was statistically signifi-
`cantly higher in the brimonidine group than in the
`control group (10.4% versus 0%). A dislocated flap
`is a serious complication that can result in irregular
`astigmatism and loss of vision and requires prompt
`surgical correction. In our experience, the eyes with
`flap dislocation did not have any other complication,
`including flap striae, epithelial ingrowth, or irregular
`astigmatism, after flap repositioning. At the 6-month
`follow-up, the rate of enhancement in eyes with dis-
`located flaps was 14.3% (1 of 7 eyes), which is similar
`to the enhancement rate in all eyes treated with bri-
`monidine (13.4%). We acknowledge that 6 months is
`too short a period to calculate the enhancement rate
`because regression can occur after more than 1 year
`postoperatively; however, this is also true for eyes
`without flap dislocation.
`
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