O R I G I N A L A R T I C L E
`
`Dilute Brimonidine to Improve Patient
`Comfort and Subconjunctival Hemorrhage
`After LASIK
`
`Theodore A. Pasquali, MD; Adam Aufderheide, MD; Jason P. Brinton, MD; Michele R. Avila, OD;
`Erin D. Stahl, MD; Daniel S. Durrie, MD
`
`ABSTRACT
`
`PURPOSE: To investigate whether dilute brimonidine
`(0.025%) reduces patient discomfort, subconjunctival
`hemorrhage, and injection after LASIK without a signifi -
`cant increase in the rate of fl ap complications or surgi-
`cal enhancements.
`
`METHODS: This randomized, double-blind, prospective
`study enrolled 180 patients (360 eyes) in a contralat-
`eral eye comparison of topical dilute brimonidine, nap-
`hazoline/pheniramine, or Systane Ultra (Alcon Labora-
`tories, Inc., Fort Worth, TX) administered shortly before
`LASIK for any indication. Patients were evaluated for
`subconjunctival hemorrhage, injection, and fl ap disloca-
`tion 1 hour and 1 day postoperatively. Patient question-
`naires measuring patient comfort and ocular symptoms
`were administered at these same follow-up visits. Pa-
`tients were examined for 3 months to determine similar
`outcomes for standard indices of safety, predictability,
`effi cacy, and enhancement rates.
`
`RESULTS: Scores of patient discomfort, subconjunctival
`hemorrhage, and injection were signifi cantly lower in
`eyes treated with dilute brimonidine at the 1 hour and
`1 day postoperative examinations. Refl oats for mild-
`fl ap edge wrinkling were required in 3 brimonidine eyes
`(2.5%), 1 naphazoline/pheniramine eye (0.8%), and no
`control eyes, but this difference did not reach statistical
`signifi cance (P = .18). There was no signifi cant differ-
`ence between eyes at 3 months in terms of visual acu-
`ity, refractive error, corrected distance visual acuity, or
`rate of enhancement.
`
`CONCLUSIONS: Use of dilute brimonidine before LASIK
`reduces subconjunctival hemorrhage and injection and
`improves patient comfort after surgery. Flap edge wrin-
`kling requiring refl oat may still be a complication with
`dilute brimonidine.
`
`[J Refract Surg. 2013;29(7):469-475.]
`
`O
`
`ne of the reasons that LASIK has become the domi-
`nant refractive procedure is that it involves signifi -
`cantly less postoperative patient discomfort than
`other keratorefractive procedures.1 Efforts have been made
`to improve comfort further, but they have not gained wide-
`spread adoption.2,3 In our experience, one means of improv-
`ing early postoperative patient comfort is the use of a single
`drop of dilute brimonidine (0.025%) prior to surgery.
`Use of brimonidine before lamellar procedures has been stud-
`ied for the reduction of subconjunctival hemorrhages that fre-
`quently occur due to the suction required for corneal applana-
`tion.4 Although these hemorrhages are temporary and without
`signifi cant visual consequence, reducing or eliminating them
`provides a more positive patient experience, avoids undue neg-
`ative psychological effects, and enhances aesthetic outcomes in
`the procedure with a signifi cant cosmetic component. Topical
`vasoconstrictors such as brimonidine,5-8 apraclonidine,9 phen-
`ylephrine,10 or combined naphazoline/pheniramine eye drops11
`help reduce postoperative subconjunctival hemorrhage, injec-
`tion, and hyperemia. However, the use of these medications
`has been avoided due to the possibility that they may increase
`the incidence of fl ap dislocations8 and the frequency of surgical
`enhancements.5 It remains controversial whether brimonidine
`increases the rate of fl ap dislocation; of two recent prospective
`contralateral eye studies investigating the use of brimonidine
`0.2% before LASIK, one demonstrated no increase in fl ap dis-
`location and the other demonstrated a 10.4% increase in the
`rate of fl ap dislocation.6,8 Another concern with the use of these
`medications is their effect on pupil size and shape,12-14 which
`could potentially interfere with pupil tracking.
`
`From Durrie Vision, Overland Park, Kansas (TAP, JPB, MRA, EDS, DSD); the
`Department of Ophthalmology, University of Kansas Medical Center, Kansas
`City, Kansas (AA, JPB, DSD); and Children’s Mercy Hospitals and Clinics,
`Kansas City, Missouri (EDS).
`
`Submitted: October 2, 2012; Accepted: March 12, 2013
`
`Dr. Durrie is a consultant for Alcon Laboratories, Inc. and Abbott Medical
`Optics. The remaining authors have no proprietary or financial interest in the
`materials presented herein.
`
`Correspondence: Daniel S. Durrie, MD, Durrie Vision, 5520 College Blvd.,
`Suite 201, Overland Park, KS 66211. E-mail: ddurrie@durrievision.com
`
`doi:10.3928/1081597X-20130617-05
`
`Journal of Refractive Surgery (cid:129) Vol. 29, No. 7, 2013
`
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`Dilute Brimonidine for LASIK Patients/Pasquali et al
`
`In designing this study, we hypothesized that an
`optimal dilution of brimonidine could reduce the rate
`of complications associated with full dose brimoni-
`dine while maintaining the benefi ts. We present a pro-
`spective, randomized, double-blind study comparing
`0.025% brimonidine, naphazoline/pheniramine, and
`control (artifi cial tears lubricant) to determine whether
`subconjunctival hemorrhage and injection can be min-
`imized effectively without increasing the risks of fl ap
`dislocation or need for enhancement. In addition, we
`evaluated the validity of our observation that dilute
`brimonidine is effective in reducing patient discomfort
`in the fi rst 24 hours after surgery, a fi nding that has not
`been previously reported.
`
`PATIENTS AND METHODS
`This prospective, randomized, double-blind, single-
`center clinical trial evaluated 180 patients (360 eyes)
`undergoing bilateral LASIK for refractive errors rang-
`ing from +6.00 to -12.00 diopters (D) sphere and up to
`-6.0 D of astigmatism. Inclusion criteria were a stable
`refraction for 1 year, an average central corneal thick-
`ness of at least 500 μm, and an otherwise healthy ante-
`rior segment. Written informed consent was obtained
`for all patients and the study was approved by an
`RCRC Independent Review Board.
`Eligible patients were examined preoperatively for
`measurement of corrected and uncorrected distance
`and near vision, cycloplegic and manifest refraction,
`pachymetry, corneal topography, and slit-lamp and
`fundus examinations. Pupil diameter was measured
`under mesopic conditions using an infrared pupillom-
`eter (Neuroptics, Irvine, CA) during the preoperative
`visit. Postoperatively, patients underwent an oph-
`thalmic evaluation at 1 hour, 1 day, 1 month, and 3
`months. All eyes were assessed according to standard
`criteria for satisfactory LASIK outcomes related to safe-
`ty, predictability, and effi cacy. Each patient was asked
`to complete a subjective questionnaire 1 hour and 1
`day postoperatively for self-evaluation of discomfort,
`irritation, burning, pain, and itching on a scale of 0
`(none) to 7 (severe). Subconjunctival hemorrhage and
`injection were evaluated by slit lamp at 1 hour and 1
`day postoperatively by a masked investigator using a
`grading scale of 0 (none) to 4 (severe) for each fi nding.
`Routine refraction and slit-lamp examinations were
`performed at the later postoperative visits.
`Brimonidine tartrate ophthalmic solution 0.1% was
`compounded to 0.025% by an independent pharmacy
`in Overland Park, Kansas. Naphcon A (naphazoline
`hydrochloride 0.025%, pheniramine maleate 0.3%;
`Alcon Laboratories, Inc., Fort Worth, TX) and con-
`trol (Systane Ultra, polyethylene glycol 400 0.4%,
`
`470
`
`propylene glycol 0.3%; Alcon Laboratories, Inc.) are
`over-the-counter medications. All patients underwent
`bilateral surgery and were randomized to one of three
`regimens with 60 patients and 120 eyes each: (1) dilute
`brimonidine in one eye and control in the other eye,
`(2) naphazoline/pheniramine in one eye and control
`in the other eye, and (3) dilute brimonidine in one eye
`and naphazoline/pheniramine in the other eye. Five
`minutes prior to surgery, patients received one drop
`of the study medication according to the randomized
`group determination in addition to one drop of pro-
`paracaine and one drop of antibiotic.
`A fourth-generation IntraLase FS Laser (60 kHz;
`Abbott Medical Optics, Santa Ana, CA) was used to
`create the LASIK fl aps. Flap diameter was 8.5 mm and
`the intended fl ap thickness was 110 μm. A raster pat-
`tern was used with the hinge located in the superior
`position with raster energy of 1.2 mJ/spot and spot-
`line separation of 9 ⫻ 9 μm. The hinge angle was 50°
`and the side cut angle was 70° with pocket software
`enabled. Pupil size was measured under standard-
`ized light levels using the infrared pupillometer in the
`interim between fl ap creation and excimer ablation.
`All patients underwent vision correction performed
`with the same excimer laser (Allegretto Wave Eye-Q;
`WaveLight AG, Erlangen, Germany). All eyes received
`proparacaine 0.5% and tetracaine 0.5% drops during
`surgery. The goal of surgery was emmetropia or mono-
`vision of -0.75 to -1.50 depending on patient age and
`surgeon discretion.
`Immediately after surgery, patients received a fourth
`generation fl uoroquinolone antibiotic, prednisolone ac-
`etate 1%, and preservative-free artifi cial tears. Patients
`continued to use the antibiotic and steroid drops four
`times daily for 1 week and were encouraged to use the
`artifi cial tears frequently (every 15 to 30 minutes on the
`day of surgery, every 1 to 2 hours the day after surgery,
`tapering to six times daily with more frequent use if
`needed). Refl oats were performed in a procedure room
`with sterile technique and a microscope with the pa-
`tient in supine position. Determination of need for en-
`hancement was made at the 3-month postoperative visit
`at the surgeon’s discretion based on uncorrected vision
`and magnitude of refractive error. A data analysis soft-
`ware package (SAS, Cary, NC) was used to evaluate sta-
`tistical signifi cance. Results were analyzed by analysis
`of variance (ANOVA) with a Bonferroni correction test
`(alpha < .05, where alpha is a P value modifi ed for mul-
`tiple variable correction). The three treatment groups
`were also compared two by two (pairwise) to generate
`P values using the two-sample t test and P values were
`checked against the Bonferroni grouping to confi rm
`agreement. Fisher exact test was used to calculate P val-
`
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`Dilute Brimonidine for LASIK Patients/Pasquali et al
`
`TABLE 1
`Preoperative Patient Characteristics
`Brimonidine
`Naphazoline/Pheniramine
`Control
`120
`120
`120
`
`62
`58
`
`38.56 ± 10.64
`20 to 59
`
`-2.81 ± 3
`-9.25 to 2.5
`
`49
`71
`
`38.06 ± 11
`20 to 60
`
`-3.4 ± 2.44
`-9 to 3.5
`
`Characteristics
`No. of eyes
`Gender
` Male
` Female
`Age (y)
` Mean ± SD
` Range
`Sphere (D)
` Mean ± SD
` Range
`Cylinder (D)
`-0.95 ± 0.94
`-0.83 ± 0.83
`-1.06 ± 1.14
` Mean ± SD
`-5.5 to 0
`-5.5 to 0
`-5.75 to 0
` Range
`BN = dilute brimonidine vs naphazoline/pheniramine; BC = dilute brimonidine vs control; NC = naphazoline/pheniramine vs control; SD = standard deviation;
`D = diopters
`aP values listed for the three t test pairwise comparisons.
`
`55
`65
`
`38.24 ± 10.38
`20 to 60
`
`-3.4 ± 2.44
`-9 to 3.5
`
`P (BN, BC, NC)a
`
`.24, .53, .58
`
`.72, .81, .89
`
`.88, .10, .09
`
`.07, .38, .32
`
`ues for fl ap dislocation rates (a categorical comparison).
`Using the reported rate of 1%15,16 for the occurrence of
`fl ap dislocation in LASIK with femtosecond laser, pow-
`er analysis determined that this study had 80% power
`to detect an increase of 0.06 (6%) in the rate of disloca-
`tion (GraphPad StatMate, San Diego, CA). Data are pre-
`sented as mean ± standard deviation. P values less than
`.05 were considered signifi cant.15,16 Refractive outcome
`measures were calculated according to the standardized
`graphs as originally defi ned by Waring.17
`
`RESULTS
`The study included 360 eyes from 180 patients.
`There were no statistically signifi cant differences be-
`tween the groups in terms of preoperative characteris-
`tics (Table 1). One hundred sixty-two patients (90%)
`completed 3 months of follow-up examinations. All
`patients completed at least 1 day of follow-up, which
`was suffi cient for inclusion in the analysis of fl ap dis-
`location, slit-lamp parameters (subconjunctival hem-
`orrhage and injection), and patient questionnaires.
`However, only patients with 3 months of follow-up
`were able to be included in the analysis of visual out-
`comes and frequency of enhancements.
`At 3 months, there were no signifi cant differences be-
`tween eyes in the percentage achieving 20/20 (logMAR
`0.00) or better uncorrected visual acuity (for the respec-
`tive target distance), mean spherical equivalent, mean
`absolute error, corrected distance visual acuity (CDVA),
`or in the enhancement rate (Table 2). Mean absolute er-
`ror is calculated as the absolute value of the difference
`
`Journal of Refractive Surgery (cid:129) Vol. 29, No. 7, 2013
`
`between the postoperative manifest refraction (spheri-
`cal equivalent) and the target refraction. Refractive out-
`comes for each group are reported in Figure 1.
`The use of dilute brimonidine or naphazoline/phe-
`niramine signifi cantly reduced the amount of injection
`and subconjunctival hemorrhage 1 hour postopera-
`tively when compared to control (Figure 2), with dilute
`brimonidine demonstrating a greater amount of reduc-
`tion than naphazoline/pheniramine (P ⭐ .006 for all
`pairwise comparisons for both parameters). In terms of
`incidence, only 10% of dilute brimonidine eyes were
`graded as having greater than “trace” subconjunctival
`hemorrhage versus 24% of the naphazoline/phenira-
`mine eyes and 93% of control eyes. At the 1-day follow-
`up visit, dilute brimonidine and naphazoline/phenira-
`mine continued to show a marked benefi t in reducing
`subconjunctival hemorrhage when compared to control
`(P < .001 for both comparisons) (Figure 2), with dilute
`brimonidine exhibiting lower scores than naphazoline/
`pheniramine (0.17 ± 0.43 vs 0.34 ± .016, P =.01). How-
`ever, by the 1-day follow-up visit, injection scores were
`no different between treatment groups (ANOVA P = .32
`with P ⭓ .16 for all pairwise comparisons).
`According to questionnaire responses, patients who
`received dilute brimonidine or naphazoline/phenira-
`mine were markedly more comfortable and less symp-
`tomatic than those who received control 1 hour post-
`operatively in terms of discomfort, irritation, burning,
`pain, and itching scores (P < .01 for all symptom score
`comparisons), whereas scores for dilute brimonidine and
`naphazoline/pheniramine were not statistically different
`
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`Dilute Brimonidine for LASIK Patients/Pasquali et al
`
`TABLE 2
`Surgical Outcomes at 3 Months
`Brimonidine
`Naphazoline/Pheniramine
`108
`107
`
`81
`-0.07 ± 0.12
`-0.30 to 0.30
`
`27
`0.07 ± 0.13
`-0.10 to 0.40
`
`0.24 ± 0.25
`0 to 1.38
`
`87
`-0.06 ± 0.12
`-0.30 to 0.40
`
`20
`0.08 ± 0.16
`-0.20 to 0.40
`
`0.29 ± 0.30
`0 to 1.88
`
`Characteristic
`No. of eyes
`UDVA (logMAR) for distance corrected eyes
` No.
` Mean ± SD
` Range
`UNVA (logMAR) for near corrected eyes
` No.
` Mean ± SD
` Range
`MAE (D)
` Mean ± SD
` Range
`CDVA (D)
`-0.10 ± 0.08
`-0.11 ± 0.08
`-0.10 ± 0.09
` Mean ± SD
`-0.30 to 0.20
`-0.30 to 0.20
`-0.30 to 0.20
` Range
`.80, 1.0, .80
`8 (7.4%)
`9 (8.4%)
`8 (7.4%)
`Enhancements (eyes)
`BN = dilute brimonidine vs naphazoline/pheniramine; BC = dilute brimonidine vs control; NC = naphazoline/pheniramine vs control; UDVA = uncorrected
`distance visual acuity; SD = standard deviation; UNVA = uncorrected near visual acuity; MAE = mean absolute error; D = diopters; CDVA = corrected distance
`visual acuity
`aP values listed for the three t test pairwise comparisons.
`
`Control
`108
`
`82
`-0.07 ± 0.12
`-0.30 to 0.40
`
`26
`0.07 ± 0.11
`-0.10 to 0.30
`
`0.28 ± 0.30
`0 to 1.50
`
`P (BN, BC, NC)a
`
`.54, .83, .40
`
`.82, .88, .72
`
`.26, .36, .84
`
`.80, .87, .66
`
`Figure 1. The standard graphs for reporting refractive surgery adapted to present the outcomes for the three groups.
`
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`Dilute Brimonidine for LASIK Patients/Pasquali et al
`
`B
`A
`Figure 2. Slit-lamp findings (A) 1 hour and (B) 1 day postoperatively for each medication. Error bars represent confidence intervals. The Y axis values
`represent the graded scoring system, 0 for no findings and 4 for severe. Naph/Phen = naphazoline/pheniramine
`
`A
`
`B
`
`Figure 3. Questionnaire results (A) 1 hour and (B) 1 day postoperatively. The Y axis values represent the patient response scoring scale, where 1
`represents most comfort/no symptoms and 7 represents most discomfort/worst symptoms. B = dilute brimonidine, N = naphazoline/pheniramine, C
`= control
`
`(P > .23 for all symptom score comparisons). One day
`postoperatively, symptom scores for discomfort, burning,
`pain, and itching (Figure 3) were statistically similar for
`the three treatment groups (ANOVA P > .09 for these four
`symptoms). Irritation scores 1 day postoperatively for
`eyes treated with control were signifi cantly higher when
`compared to scores for dilute brimonidine eyes (P = .047)
`and naphazoline/pheniramine eyes (P = .01); however,
`there was no difference between dilute brimonidine and
`naphazoline/pheniramine treatments (P = .63).
`Mild-fl ap edge wrinkling occurred in three (2.5%)
`of the dilute brimonidine eyes and one (0.8%) of the
`naphazoline/pheniramine eyes with no instances (0%)
`in the control group. This difference did not reach sta-
`tistical signifi cance (P = .18, Fisher exact test). Two
`eyes were refl oated at 1 day and two eyes at 1 hour. No
`eyes experienced fl ap dislocations.
`The 3-month outcomes for the four eyes requiring
`refl oat due to fl ap wrinkling are presented in Table 3.
`All four eyes had 20/25 or better visual acuity and all
`corrected eyes had 20/20 or better visual acuity at their
`last follow-up visit with no loss of CDVA. None of the
`eyes demonstrated more than 0.50 D difference in sphere
`or cylinder between the target and achieved refractive
`outcome. One additional refl oat was performed 5 days
`postoperatively due to diffuse lamellar keratitis in a
`
`Journal of Refractive Surgery (cid:129) Vol. 29, No. 7, 2013
`
`TABLE 3
`Outcomes at 3 Months of Patients With Mild
`Flap Edge Wrinkling Successfully Refloated
`Medication
`UDVA
`Sphere
`Cylinder
`CDVA
`Nephazoline/pheniramine
`20/20
`0.50
`0.00
`20/20
`Brimonidine
`20/20
`-0.25
`-0.25
`20/20
`Brimonidine
`20/20
`0.00
`0.00
`20/20
`Brimonidine
`20/25
`-0.50
`0.00
`20/20
`UDVA = uncorrected distance visual acuity; CDVA = corrected distance visual
`acuity.
`Visual acuity is in Snellen equivalent.
`
`naphazoline/pheniramine group eye. The diffuse lamel-
`lar keratitis was likely related to an epithelial defect that
`developed after surgery unrelated to the study medica-
`tion. The refl oat was not included in the analysis because
`it was not related to fl ap dislocation or wrinkling.
`There were no instances of pupil size adversely affect-
`ing the ability of the laser software to accurately track
`pupil locations during the treatment in any of the eyes.
`
`DISCUSSION
`It is believed that brimonidine can destabilize fl ap
`adherence by adversely affecting corneal reepithe-
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`Dilute Brimonidine for LASIK Patients/Pasquali et al
`
`lialization and endothelial cell function (the latter
`disrupting the negative intrastromal corneal pressure
`gradient responsible for early fl ap adherence).18 Some
`studies have found no increase in the risk of fl ap com-
`plications with use of brimonidine,6,7 whereas other
`studies have reported an incidence of fl ap dislocation
`varying from 10% to 36%.5,8 We did not encounter
`any frank fl ap dislocations in 120 eyes treated with
`dilute brimonidine. There was a small trend toward
`fl ap wrinkling in these eyes, although this did not meet
`statistical signifi cance. Our study had power to detect
`a 6% difference. To detect a 1.5% or smaller difference
`in the rate of fl ap dislocation (baseline rate of 1% to
`2%15,16 versus 2.5% among brimonidine eyes in this
`study), a sample size of 2,000 or more eyes would be
`required. Enlarging our study to meet this number was
`not feasible.
`Flap dislocation is a concern because of long-
`term visual consequences if not addressed appro-
`priately; however, with prompt management these
`consequences are greatly mitigated. In a study using
`full dose brimonidine, the seven eyes that required
`refl oats for fl ap dislocation did not experience any
`further complications such as fl ap striae, epithelial in-
`growth, or irregular astigmatism as of 6 months post-
`operatively.8 We experienced no further complications
`after performing refl oats in the four eyes in our study
`with fl ap edge wrinkles and these eyes showed excel-
`lent visual outcomes and no loss of lines of CDVA.
`Even though refl oating the fl ap was uncomplicated
`and those eyes requiring refl oats went on to have excel-
`lent outcomes, the signifi cance of refl oats should not
`be minimized. Refl oats are an additional procedure,
`requiring extra time for healing and follow-up, and
`may produce anxiety and discomfort. These potential
`consequences are important to consider given that we
`are seeking to increase patient comfort and minimize
`the social and psychological impact of subconjuncti-
`val hemorrhage. Even a potential and small increase
`(1.5%) in the rate of refl oats may still be too great for
`some surgeons.
`Against this small, potential risk, we found signifi -
`cant benefi ts to using brimonidine. In particular, we
`measured decreases in patient reported levels of dis-
`comfort, irritation, burning, pain, and itching, with
`symptom scores among control eyes nearly double
`those of the medicated eyes 1 hour after surgery. Pre-
`vious studies6,7 have focused on the reduction in sub-
`conjunctival hemorrhage but have not recognized this
`benefi t for patients. Our study is also different from
`previous studies in that only a fraction of the brimoni-
`dine dose (1/8) was required for the same dramatic re-
`duction in the rate (93% vs 10%) and severity (average
`
`474
`
`score of 1.6 vs 0.2) of subconjunctival hemorrhage
`(control vs brimonidine, respectively). Many surgeons
`believe that subconjunctival hemorrhage is of little or
`no importance given that it is self-limited and has no
`effect on visual outcomes. Still, patients may perceive
`a subconjunctival hemorrhage as a stark red sign that
`“something went wrong,” as a bad outcome, or as an
`impediment to returning to normal social life or work.4
`Concern about these factors and about the overall pa-
`tient experience is important for an elective procedure
`that depends on a positive patient experience.
`We found general equivalency between groups in
`refractive outcomes at 3 months as demonstrated in
`the standard graphs for reporting refractive outcomes
`(Figure 1). Although 3 months is a short period for
`evaluation of refractive outcomes, the main ques-
`tions in our study regarded early differences in patient
`comfort and cosmesis. Visual outcomes were closely
`monitored to ensure that there were no major refrac-
`tive differences between the drops early after surgery
`that might indicate an unforeseen risk or benefi t, with
`the likelihood that any major refractive difference re-
`sulting from a single drop of medication at the time of
`surgery would manifest by 3 months.
`As part of this analysis, we found no differences
`between groups in frequency of enhancement. The
`possibility of increased rates of enhancement in eyes
`treated with brimonidine was fi rst observed in a small
`retrospective study, which, as the authors of that study
`point out, was meant merely to report observations and
`prompt further studies to the signifi cance of the obser-
`vations.5 In the studies that followed, no randomized
`prospective evidence was found to suggest that brimo-
`nidine increased the enhancement rate at all.6-8 We be-
`lieve that a 3-month follow-up period is not suffi cient
`for evaluating enhancement rate when regression can
`occur over longer time periods. We reason that one
`drop of a dilute medication used once before surgery
`is unlikely to have an effect on healing after 3 months,
`so if there were a dichotomy between the groups it is
`likely we would have observed it by that time. In ad-
`dition, none of the eyes with mild fl ap edge wrinkling
`required enhancements, so if refl oats predispose eyes
`to needing enhancement the rate of this predisposition
`is small and was not detectable in our study.
`Surgeons carefully weigh the risks of fl ap complica-
`tions against the benefi ts of using brimonidine. We be-
`lieve these are not mutually exclusive: by reducing the
`strength of brimonidine, the same level of benefi t can
`be garnered at a fraction of—and possibly even with-
`out—the risk. Our study further demonstrated another
`important point that has not been made or evaluated
`previously: dilute brimonidine makes for a more com-
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`fortable patient experience. This is another dimension
`of the benefi t to this therapy that should be considered
`when deciding whether to use dilute brimonidine be-
`fore surgery.
`
`AUTHOR CONTRIBUTIONS
`Study concept and design (EDS, DSD); data collection (TAP, JPB,
`MRA, EDS, DSD); analysis and interpretation of data (TAP, AA, JPB,
`MRA, EDS, DSD); drafting of the manuscript (TAP, AA); critical revi-
`sion of the manuscript (TAP, JPB, MRA, EDS, DSD); statistical exper-
`tise (MRA); supervision (JPB, DSD)
`
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`Journal of Refractive Surgery (cid:129) Vol. 29, No. 7, 2013
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