The Effect of Topical Apraclonidine on
`Subconjunctival Hemorrhage and Flap
`Adherence in LASIK Patients
`
`Ioannis M. Aslanides, MD, PhD; Nikolaos S. Tsiklis, MD; Efekan Ozkilic, MD; Efekan Coskunseven, MD;
`Ioannis G. Pallikaris, MD, PhD; Mirko R. Jankov, MD
`
`ABSTRACT
`
`PURPOSE: To determine whether the use of topical
`apraclonidine just before the LASIK procedure prevents
`subconjunctival hemorrhage and to study its effect on
`postoperative fl ap adherence.
`
`METHODS: Topical apraclonidine 0.125% was ran-
`domly applied to 1 eye of 66 myopic patients who
`underwent primary bilateral LASIK. Apraclonidine was
`instilled 1 hour prior to and 30 seconds before plac-
`ing the vacuum ring of the microkeratome, whereas the
`other eye served as control. Thirty minutes after the op-
`eration, all patients were examined by the surgeon to
`evaluate hyperemia and identify fl ap-related complica-
`tions (eg, slippage, dislocation, or fl ap folds). The size
`of subconjunctival hemorrhage was also evaluated on
`postoperative days 1 and 7. All 132 eyes in the study
`were examined after surgery to identify fl ap folds and/or
`their dislocation.
`
`RESULTS: In the apraclonidine group, 48 (72.8%) eyes
`had no hyperemia, 16 (24.2%) eyes had mild hyper-
`emia, 2 (3%) eyes had moderate hyperemia, and no
`(0%) eyes had severe hyperemia. In the control group,
`37 (56.1%) eyes had mild hyperemia, 21 (31.8%) eyes
`had moderate hyperemia, 1 (1.5%) eye had severe hy-
`peremia, and 7 (10.6%) eyes had no hyperemia. In the
`apraclonidine group, 44 (66.7%) eyes had no subcon-
`junctival hemorrhage (grade 0); grade 1 was present in
`19 (28.8%) eyes whereas grades 2 and 3 were present
`in 2 (3%) eyes and 1 (1.5%) eye, respectively. In the
`control group, 19 (28.8%) eyes showed grade 0, 13
`(19.7%) eyes had grade 1, and grades 2 and 3 were
`present in 20 (30.3%) eyes and 14 (21.2%) eyes, re-
`spectively. Chi-square test showed a highly signifi cant
`difference between the two groups (P⬍.001). No fl ap-
`related problems were reported in either group.
`
`CONCLUSIONS: Topical apraclonidine applied before
`LASIK surgery may prevent immediate postoperative
`hyperemia and prolonged subconjunctival hemorrhage
`by its alpha-mimetic vasoconstrictor effect without in-
`ducing fl ap adherence complication. [J Refract Surg.
`2006;22:585-588.]
`
`L aser in situ keratomileusis (LASIK) is a popular and
`
`relatively safe surgical procedure for the correction
`of myopia, hyperopia, and astigmatism.1 Although
`medical reasons are involved, many patients who seek LASIK
`surgery would like to free themselves from their glasses or
`contact lenses due to practical or cosmetic reasons. Thus,
`they want to see well from the fi rst postoperative day. How-
`ever, a number of patients have postoperative hyperemia and
`subconjunctival hemorrhage2-4 due to surgical manipulation,
`mainly because of the use of a vacuum ring during fl ap cre-
`ation. Although postoperative subconjunctival hemorrhage
`is considered a temporary cosmetic problem, a signifi cant
`degree of unnecessary anxiety and false alarm may arise in
`some patients in the immediate postoperative days.
`Apart from its well-described function among anti-glaucoma
`drugs,5 topical apraclonidine applied just before LASIK surgery
`may cause vasoconstriction5 of conjunctival vessels and thus re-
`duce the occurrence and severity of subconjunctival hemorrhage,
`as described with another vasoconstrictor, brominidine.6,7
`Proper adhesion between the corneal fl ap and stromal bed is
`mandatory after LASIK surgery to properly restore the corneal
`integrity, promote normal healing, and establish an adequate
`refractive outcome. Several fl ap complications that occur from
`poor fl ap adherence have been described,2,3 and there is con-
`troversial evidence that use of the vasoconstrictor brimonidine
`may increase the incidence of such complications.7
`The aim of this study is to analyze the effectiveness of topi-
`cal apraclonidine on decreasing conjunctival hyperemia and
`subconjunctival hemorrhage and its potential infl uence on
`fl ap adherence after LASIK surgery.
`
`From VEIC - Vardinoyiannion Eye Institute of Crete, University of Crete,
`Greece (Aslanides, Tsiklis, Pallikaris, Jankov); World Eye Hospital, Istanbul,
`Turkey (Ozkilic, Coskunseven); and Instituto de Visão, Escola Paulista de
`Medicina, Universidade Federal de São Paulo, Brazil (Jankov).
`
`The authors have no proprietary interest in the materials presented herein.
`
`Correspondence: Ioannis M. Aslanides, MD, PhD, VEIC - Vardinoyiannion
`Eye Institute of Crete, University of Crete, PO Box 2208, 71003 Voutes,
`Heraklion Crete, Greece. Fax: 30 2810 394 653; E-mail: aslanides@med.uoc.gr
`or visioncare@mac.com
`
`Received: March 16, 2005
`
`Accepted: August 25, 2005
`
`Journal of Refractive Surgery Volume 22 June 2006
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`Apraclonidine and Flap Adherence/Aslanides et al
`
`PATIENTS AND METHODS
`Sixty-six consecutive patients (32 men and 34 wom-
`en, 132 eyes) who underwent primary bilateral LASIK
`in June 2004 for their refractive errors (myopia, astig-
`matism, and hyperopia) were included in this study.
`Mean spherical equivalent refraction was ⫺6.43⫾2.03
`diopters (D) (range: ⫺2.38 to ⫺10.63 D). Mean patient
`age was 33⫾11 years (range: 18 to 62 years).
`All procedures were performed by the same surgeon
`(I.M.A.), using an identical technique in all eyes regard-
`ing preoperative medication, use of microkeratome, fl ap
`manipulation, and drying time. The details of the tech-
`nique are as follows: one drop of proparacaine 0.5%
`(Alcaine; Alcon, Ft Worth, Tex) was instilled into each
`eye and the upper and lower lids were cleaned with
`povidone-iodine (Betadine; Lavipharm Hellas AE, Ath-
`ens, Greece). One additional drop of proparacaine was
`added to the operative eye immediately prior to the pro-
`cedure. A drape was used to retract the eyelashes, and a
`speculum was placed into the operative eye, while the
`fellow eye was occluded with an eye shield. Methylene
`blue (Visimark; Becton Dickinson & Co, Franklin Lakes,
`NJ) was used to mark the cornea in preparation for mak-
`ing the lamellar fl ap. A Moria M2 microkeratome (Moria
`Surgical, Antony, France) was used in manual mode to
`make a superiorly hinged fl ap in all 132 eyes. After the
`fl ap was made, the conjunctival fornix was dried using
`a surgical sponge (Murocel; Medtronic Solan, Jackson-
`ville, Fla). The fl ap was retracted back using a double-
`barrelled LASIK cannula (Moria Surgical). After laser
`ablation with the Allegretto Wave excimer laser (Wave-
`Light Laser Technologie AG, Erlangen, Germany), the
`fl ap was fl oated back into position with minimal irri-
`gation of balanced salt solution (BSS, Alcon) using the
`aforementioned cannula. A dry Murocel sponge was
`then used to absorb the excess moisture from beneath
`the fl ap, dry the periphery of the fl ap, and ensure a
`symmetric fl ap gutter. Subsequently, a wet sponge was
`used to smooth the fl ap and ensure its proper alignment
`with no visible folds. All fl aps were allowed to dry for
`1.5 minutes. The symmetry of the gutter was further
`evaluated by instilling a chalk white drop of predniso-
`lone acetate (Pred Forte; Allergan Pharmaceuticals Ltd,
`Westport, County Mayo, Ireland), which clearly demar-
`cated the exact outline of the gutter. A striae test was
`performed to ensure proper fl ap adherence by pressing
`the cornea just outside of the fl ap edge with a Murocel
`sponge to check whether striae outside the fl ap were in
`continuation with those inside the fl ap. All eyes were
`examined within 15 minutes after surgery. Patients
`were instructed to keep their eyes lightly closed, to wear
`protective eye shields at night, and return the following
`day for re-examination.
`
`586
`
`In addition to the previously described standard tech-
`nique, a drop of 0.125% topical apraclonidine (Iopidine;
`Alcon-Couvreur NV, Puurs, Belgium) was applied ran-
`domly (with a fl ip of a coin) to one eye of each patient 1
`hour prior to and 30 seconds before placing the vacuum
`ring of the microkeratome. In the control eye, a drop of
`sodium hyaluronate 0.18% (Vismed; TRB Chemedica
`AG, Haar/Munchen, Germany) was instilled.
`Thirty minutes postoperatively, severity of hyper-
`emia of both eyes was detected by an independent ob-
`server (N.S.T.) in a double-blind manner and classifi ed
`as follows: grade 0, no hyperemia; grade 1, mild; grade 2,
`moderate, and grade 3, severe. The size of subconjuncti-
`val hemorrhage was detected on the fi rst postoperative
`day. The size of the subconjunctival hemorrhage was
`classifi ed by slit-lamp examination as follows: grade 0,
`no hemorrhage present; grade 1, ⬍1 mm (micro-hemor-
`rhage); grade 2, between 1 and 3 mm (moderate hemor-
`rhage); and grade 3, ⬎3 mm (macro-hemorrhage).
`The appearance of the fl ap with respect to folds and
`dislocations was carefully monitored using slit-lamp
`microscopy immediately after (⬍15 minutes) and on
`the day after the surgery (24 hours). Folds were defi ned
`as a series of parallel ridges in the fl ap that were best
`seen with retro-illumination and stained negatively
`with fl uorescein. A dislocation was defi ned as folds ac-
`companied by ⭓0.5-mm displacement of the fl ap edge
`from the edge of the lamellar cut.
`Postoperatively, patients were prescribed sodium
`fl urbiprofen 0.03% (Ocufl ur, Allergan) drops 4 times
`a day for 2 days, dexamethasone 0.1% and tobramy-
`cin 0.3% (Tobradex, Alcon) drops 4 times a day for
`2 weeks, and Vismed drops initially hourly and then
`when necessary for 1 month thereafter.
`Statistical analysis was performed using a chi-square
`test, and P⬍.01 was considered statistically signifi cant.
`For this statistical test, the expected frequency could
`not be ⬍5 in ⬎20% of cells,8 therefore the values for
`moderate and severe hyperemia were combined for the
`purpose of statistical evaluation.
`
`RESULTS
`
`VASOCONSTRICTIVE EFFECTS
`In the apraclonidine group, 48 (72.8%) eyes had no
`hyperemia, 16 (24.2%) eyes had mild hyperemia, and 2
`eyes (3%) had moderate hyperemia. No eye had severe
`hyperemia. In the control group, 37 (56.1%) eyes had
`mild, 21 (31.8%) eyes moderate, and 1 (1.5%) eye had
`severe hyperemia. Seven (10.6%) eyes did not have
`any hyperemia (Fig 1). Chi-square test revealed a sig-
`nifi cant difference between the two groups (P⬍.001).
`Concerning the subconjunctival hemorrhage, in the
`
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`Apraclonidine and Flap Adherence/Aslanides et al
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`Figure 1. Conjunctival hyperemia in eyes
`with apraclonidine versus control.
`
`Figure 2. Subconjunctival hemorrhage in
`eyes with apraclonidine versus control.
`
`apraclonidine group, 44 (66.7%) eyes had no subcon-
`junctival hemorrhage (grade 0), and grade 1 was pres-
`ent in 19 (28.8%) eyes, whereas grades 2 and 3 were
`present in 2 (3%) eyes and 1 (1.5%) eye, respectively.
`In the control group, 19 (28.8%) eyes were grade 0, 13
`(19.7%) eyes were grade, and grades 2 and 3 were pres-
`ent in 20 (30.3%) eyes and 14 (21.2%) eyes, respective-
`ly (Fig 2). A signifi cant difference was noted between
`the two groups using the chi-square test (P⬍.001).
`
`FLAP ADHERENCE AND OTHER EFFECTS
`No eye had any fl ap complications in the postopera-
`tive course, including fl ap adherence problems. All eyes
`in the apraclonidine group had a slight upper eyelid re-
`traction, which was not present the following day.
`
`DISCUSSION
`Although LASIK is sometimes performed for medi-
`cal reasons (eg, correction of anisometropia), it is per-
`formed mostly for cosmetic purposes. After LASIK
`surgery, most patients experience subconjunctival
`hemorrhage due to surgical manipulation and the use
`of the vacuum ring during fl ap creation. Because it is
`
`a self-limited and temporary complication, most sur-
`geons do not consider subconjunctival hemorrhage a
`problem. Many patients, however, despite prior coun-
`seling, perceive this as an untoward effect rather than
`just a cosmetic problem. Patients may be alarmed and
`worried about the surgical outcome, although it usu-
`ally resolves spontaneously within 2 to 3 weeks; this
`condition may persist even longer in some cases.
`Topical apraclonidine has a vasoconstrictive5 effect
`due to its alpha-mimetic action and is used for glauco-
`ma treatment. Vajpayee et al9 determined that interface
`hemorrhage during LASIK surgery may affect visual per-
`formance. Topical apraclonidine may prevent interface
`hemorrhage and therefore prevent its possible deteriora-
`tive effect on postoperative course and visual outcome.
`Before LASIK, instillation of one drop of apraclonidine
`may prevent hyperemia and subconjunctival hemorrhage
`by its vasoconstrictive effect on conjunctival vessels.
`Topical apraclonidine also has an ocular hypo-
`tensive effect and is used in glaucoma treatment as
`0.125% to 0.5% drops due to its partial agonistic effect
`on alpha-2 adrenergic receptors.
`As more speculations arise from glaucoma special-
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`Apraclonidine and Flap Adherence/Aslanides et al
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`ists about potential barotrauma damage on the optic
`nerve head during suction in LASIK surgery, apra-
`clonidine might be an additional protection factor in
`our everyday surgical routine. Because the perfusion
`pressure equals the systemic blood pressure minus the
`intraocular pressure (IOP), when apraclonidine is ap-
`plied just 30 seconds before LASIK surgery, its vaso-
`constrictive effect begins prior to vacuum ring appli-
`cation. However, as its antiglaucomatous effect does
`not take place until 1 hour later with the peak at 3 to
`5 hours,5 one drop was also applied 1 hour prior to
`the surgery. This has another potentially benefi cial
`effect on the eye, as it may decrease the risk of post-
`traumatic IOP peak (barotrauma) after the surgery.
`McCarty et al,10 on the other hand, found that the use
`of brimonidine prior to LASIK did not affect the struc-
`ture or function of the optic nerve, and that the altera-
`tion in corneal birefringence after excimer laser abla-
`tion may explain the reduction in direct retinal nerve
`fi ber layer measures without the concomitant change
`in ratio measures. However, as this surpasses the scope
`of our study, we suggest further clinical studies focus-
`ing on the numerous variables involved in the optic
`nerve head perfusion be carried out to clarify this hy-
`pothesis.
`Norden6 conducted a double-masked study and con-
`cluded that topical brimonidine before LASIK surgery
`may decrease the amount of subconjunctival hemor-
`rhage and hyperemia due to LASIK surgery. Our study
`confi rms the hypothesis that alpha-agonists applied
`topically, in our case apraclonidine, may signifi cantly
`decrease hyperemia and subconjunctival hemorrhage
`after LASIK surgery.
`In all cases, eyes treated with apraclonidine had
`upper lid retraction in the early postoperative period
`due to stimulation of the upper lid Muller muscle by
`the alpha-mimetic action of apraclonidine. Left eyes
`in which apraclonidine was applied had upper lid
`retraction and less hyperemia; however, right eyes
`without apraclonidine had relatively ptotic and more
`hyperemic appearance. The difference in appearance
`revealed signifi cant cosmetic disparity between the
`two eyes.
`Topical apraclonidine may lead to ocular and der-
`matologic allergic reactions5 in chronic use as in glau-
`coma treatment. Therefore, it should not be used for a
`long period of time to prevent hyperemia, otherwise
`rebound effect may occur.5 In this study, we did not
`detect any allergic reaction due to topical apracloni-
`dine. This may be due to the single use of the drug.
`Walter and Gilbert7 concluded that topical brimoni-
`
`dine application before LASIK surgery may lead to an
`increase in abnormal fl ap adhesion. Their conclusion
`was based on a retrospective non-controlled study of
`39 eyes, which we believe is an inadequate study type
`and too small a number of eyes for such a conclusion.
`In our prospective, randomized, controlled study with
`three times the number of eyes, no fl ap adhesion com-
`plications occurred in the eyes that received apracloni-
`dine.
`There are several hypotheses regarding the topical
`infl uence of alpha-2 agonistic effect, such as a direct
`lubricant impact, a desiccation or ischemic effect of
`the anterior segment due to anterior ocular vessels con-
`striction, and/or direct toxic effect to the endothelial
`cells.7 However, we tend to agree with Norden6 that a
`simpler reason, such as excess moisture on the bed and
`insuffi cient fl ap stroking, may be responsible for the
`poor fl ap adherence described previously.
`Topical apraclonidine before LASIK surgery may
`prevent early postoperative hyperemia and subcon-
`junctival hemorrhage without adverse effects on the
`fl ap adherence.
`
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