ARTICLE

Effects of topical diq

SubmittedFinal revisAccepted:

From theAichi Med(G. Miyak

CorresponFoundatio462-0825

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Pub

1682

uafosol pretreatmenton intraoperative corneal wetting

Goichiro Miyake, MD, Ichiro Ota, MD, Kensaku Miyake, MD, Masahiro Zako, MD, PhD,Masayoshi Iwaki, MD, PhD

: Oction sFebr

Depaical Ue, Ota

dingn, Mi, Jap

2014 A

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PURPOSE: To examine the effects of pretreatment with diquafosol 3.0% ophthalmic solution oncorneal surface wetting during cataract surgery with intraocular lens (IOL) implantation in casesof senile cataract.

SETTING: Shohzankai Medical Foundation, Miyake Eye Hospital, Nagoya, Japan.

DESIGN: Prospective randomized single-masked comparative study.

METHODS: Phacoemulsification and IOL implantation were performed in eyes with senile cataract.After a 2-week washout period, patients were randomly assigned to receive 1 drop of diquafosol3.0% ophthalmic solution or artificial tears 6 times daily for 4 weeks before surgery. The mainoutcome measure, termed the corneal wetting property, was the time between when a clear imageof the operating microscope light source appeared just after the corneal surface was irrigated with abalanced salt solution and the time at which that image began to blur.

RESULTS: The study enrolled 51 patients (76 eyes). The mean time to corneal wetting was 50.1secondsG 10.8 (SD) in the diquafosol group and 45.3G 9.2 seconds in the artificial tears group.The difference between the 2 groups was statistically significant (P<.029).

CONCLUSION: Four-week pretreatment with diquafosol 3.0% ophthalmic solution in patients withsenile cataract scheduled for cataract surgery with IOL implantation was effective in enhancing theintraoperative corneal surface wetting property, which suggests improved optical clarity duringsurgery.

Financial Disclosure: No author has a financial or proprietary interest in any material or methodmentioned.

J Cataract Refract Surg 2014; 40:1682–1688 Q 2014 ASCRS and ESCRS

The International Dry Eye Workshop (2007) states,“Dry eye is a multifactorial disease of the tear andocular surface that results in symptoms such as oculardiscomfort, visual disturbance, and tear film insta-bility with potential damage to the ocular surface.”1

Although many patients with dry eye are scheduled

ober 30, 2013.ubmitted: January 31, 2014.uary 2, 2014.

rtment of Ophthalmology (G. Miyake, Zako, Iwaki),niversity, Aichi, and Shohzankai Medical Foundation, K. Miyake), Miyake Eye Hospital, Nagoya, Japan.

author: Goichiro Miyake, MD, Shohzankai Medicalyake Eye Hospital, 3-15-68, Ozone, Kita-ku, Nagoyaan. E-mail: miyake@spice.or.jp.

SCRS and ESCRS

by Elsevier Inc.

for intraocular surgery, studies of how to managedry eye perioperatively are scarce.2,3

Management of dry eye in terms of intraoperativeoptical clarity during cataract surgery with intraocularlens (IOL) implantation is affected by many preopera-tive and intraoperative risk factors. These includeforced opening of the eyelid,4,5 aging,6,7 abnormalcircumstances induced by the operating microscope'slight and heat,8 preservatives in eyedrops,9 topicalanesthetics,10,11 and cleansing of the conjunctival sacand lid with povidone–iodine.12 These factors induceacute situations similar to dry eye that may result indisturbed homeostasis or integrity of the cornealepithelium as well as reduced optical clarity forsurgeons.

Recently, a significant amount of information on thepathophysiology of and therapy for dry eye hasbeen published.1,13,14 According to these studies, the

0886-3350/$ - see front matter

http://dx.doi.org/10.1016/j.jcrs.2014.02.035

1683TOPICAL DIQUAFOSOL AND INTRAOPERATIVE CORNEAL WETTING

essential factors in dry eye are the tear film and thecorneal and conjunctival epithelium. These 2 factorscomplement each other. The tear film covers theepithelium to maintain the epithelium's function, andthe epithelium secretes mucin and water to cleansethe tear film qualitatively and quantitatively. Damageto 1 of these 2 factors results in a cycle that induces dryeye. Based on this pathophysiology, treatment of dryeye has now shifted from prescribing artificial tearsto hydrate or lubricate the ocular surface to stimu-lating the epithelium to secrete aqueous tears ormucin.

Diquafosol ophthalmic solution, a relatively newmedication, is a dinucleotide and a purinoceptorP2Y2 agonist. Basic pharmaceutical studies indicatethat diquafosol acts on P2Y2 receptors on the ocularsurface, causing them to secrete aqueous tears andmucin by increasing the concentration of intracellularcalmodulin-dependent protein kinase II.15–17 In ani-mal studies, diquafosol was also found to affect theconjunctival epithelium or epithelial goblet cells,causing them to secrete tears or mucin to protect thecorneal epithelium and improve the corneal epithelialbarrier function.17–20

After experimental studies using animal models,17–20

the effects of diquafosol ophthalmic solution werestudied in human clinical cases with dry eye.21–24 Inthe present study, we report our preliminary findingsof pretreatment with diquafosol eyedrops to protectthe ocular surface during cataract surgery with IOLimplantation in eyes with risk factors for dry eye.4–12

The randomized single-masked active-controlled trialcompared the corneal wetting properties, whichimprove intraoperative optical clarity for the surgeon,between a group receiving diquafosol and a groupreceiving artificial tears.

PATIENTS AND METHODS

Consecutive cases diagnosed with bilateral or unilateralsenile cataract scheduled to have cataract surgery withIOL implantation at Miyake Eye Hospital from Marchto May 2013 were included in the study. Only patientswho gave written consent after they were given a fullexplanation of the study were enrolled. This study wasperformed in accordance with the Declaration ofHelsinki and the Japanese Ministry of Health, Labour,and Welfare and received approval from the InstitutionalReview Board, Shohzankai Medical Foundation, MiyakeEye Hospital.

Patients whose cataracts were not senile; who had glau-coma, diabetic mellitus, or uveitis; who were unable to ceasethe use of eyedrops because of other ocular disease; and whohad inadequate adherence using ophthalmic eyedrops wereexcluded from the study.

Patients scheduled for surgery at Miyake Eye Hospitalhave routine checkups duringwhich they complete a generaleye questionnaire that includes many questions about dry

J CATARACT REFRACT SURG -

eye taken from dry-eye studies in Japan.25 Patients in thisstudy were asked to complete this questionnairepreoperatively.

Protocol

This was a randomized single-masked active-controlledstudy to compare the effects of diquafosol 3.0% ophthalmicsolution (Diquas)with those of an artificial tear solution (My-tear) on intraoperative corneal wetting properties. Diquafo-sol tetrasodium 3.0% ophthalmic solution contains sodiumdiquafosol (30 mg/1 mL), dibasic sodium phosphate,sodium chloride, potassium chloride, sodium edetate hy-drate, a pH adjuster, and benzalkonium chloride. The artifi-cial tears contain sodium chloride, potassium chloride, driedsodium carbonate, dibasic sodium phosphate, boric acid,hydroxyethyl cellulose, and benzalkonium chloride. Usingthe envelope method, the controller and 1 author (M.Z.)divided the patients (not the eyes) randomly to the diquafo-sol group or the artificial tears group after a washout periodof 2 weeks. The patients received 4 weeks of pretreatmentbefore cataract surgery with IOL implantation. Patientsapplied 1 drop of their assigned ophthalmic solution 6 timesa day until the day before surgery and twice on the day ofsurgery.

Surgical Technique and Intraoperative CornealSurface Evaluation

Patients were given antibiotic eyedrops 3 times daily start-ing 3 days before surgery and nonsteroidal antiinflamma-tory eyedrops 3 times daily starting 1 day before surgery.Immediately before surgery, the eyelid and conjunctivalsac were cleansed using an iodine 8.0% solution.

One of 3 surgeons (G.M, I.O., K.M.) performed cataractsurgery with IOL implantation using an identical techniqueand topical anesthesia of lidocaine 4.0% ophthalmicsolution (Xylocaine). Briefly, under an operating micro-scope (OPMI Lumera T, Carl Zeiss Meditec AG), a cor-neoscleral incision of approximately 2.5 mm was created.After injection of an ophthalmic viscosurgical device(OVD) into the anterior chamber, a continuous curvilinearcapsulorhexis was created and phacoemulsification andaspiration were performed using a Constellation VisionSystem phaco unit (Alcon Laboratories, Inc.). The anteriorchamber was again filled with OVD through the sclerocor-neal incision, and 1 of several types of posterior chamberIOLs was implanted in the capsular bag using a posteriorchamber IOL injector. The operation time ranged from 5to 15 minutes.

The 3 surgeons evaluated the corneal surface wettingproperty without knowledge of which pretreatment wasapplied by evaluating eyes at a relatively early stage ofsurgery, at which time there was no OVD in the conjunctivalsac; this was done to avoid the influence of the OVD on thewetting property of the cornea.26–28 To prevent possible lighttoxicity of the operating microscope to the retina during theevaluation, the power of the operating microscope light wasreduced to 20% and 3 light-source images on the corneawereconfirmed under�12magnification. The starting point of theevaluation was immediately after a balanced salt solutionwas instilled on the corneal surface because at that point, 3light sources of the operatingmicroscope were clearly visibleon the corneal surface (Figure 1, left) and the surgeon wasable to carefully observe the image. The endpoint was the

VOL 40, OCTOBER 2014

Figure 1. Example demonstrating actual measurement of intraoperative corneal surface wetting property. Left: Corneal surfaces at the startingpoint of measurement. Right: Corneal surfaces at the endpoint of measurement. In this case, the duration of measurement 1 (top), 2 (center), and 3(bottom) was 42 seconds, 38 seconds, and 41 seconds, respectively. The mean value (40 seconds) was considered to be the duration.

1684 TOPICAL DIQUAFOSOL AND INTRAOPERATIVE CORNEAL WETTING

moment the 3 lights began to blur (Figure 1, right). After thisprocedure was repeated 3 times, the mean time taken fromthe starting point to the endpoint was calculated and usedas the indicator of the corneal surface wetting property.The duration was measured using a time recorder on a

J CATARACT REFRACT SURG -

videotape that was simultaneously used to film the surgery.A technician noted the time on the time recorder whenthe surgeon indicated with a hand sign the starting pointand the endpoint. The results were analyzed by 1 of theauthors (M.I.).

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1685TOPICAL DIQUAFOSOL AND INTRAOPERATIVE CORNEAL WETTING

Statistical Analysis

Statistical analysis was performed and the sample wascalculated using JMP software (version 10.0, SAS Institute),and the sample distribution checked using the Shapiro-Wilk test. In a sample size of 76 eyes, the power wasfound to be 55.4%. The distribution was found to be notnormal.

A P value less than 0.05% was considered statistically sig-nificant. The values are shown as the mean G SD. The pa-tients' demographics were analyzed using the chi-squaretest, the t test, and the Fisher direct probability measuretest. The incidence of symptoms was analyzed using theFisher direct probability measure test. The corneal wettingproperty was analyzed using the Wilcoxon rank-sum test.Statistical analysis was performed using JMP version 10.0(SAS Institute, Inc.).

RESULTS

The study enrolled 53 patients (80 eyes). Of these, 2patients (4 eyes) dropped out of the study beforesurgery because of an unwillingness to comply withpretreatment in 1 case and because of an unwilling-ness to have the surgery in the other case. Thus, 51patients (76 eyes) completed the study, 24 (38 eyes)in the diquafosol group and 27 (38 eyes) in the artifi-cial tear group. There was no statistically significantdifference in sex, age, or surgeon between the 2groups (Table 1).

Table 2 shows the incidence of symptoms assessedusing the questionnaire and the number of patientswho completed the questionnaire. Therewas no signif-icant difference in the incidence of symptoms betweenthe 2 groups.

Figure 2 shows the results of the intraoperativecorneal wetting property (in seconds). The meantime to corneal wetting was 50.1 seconds G 10.8(SD) in the diquafosol group and 45.3 G 9.2 secondsin the artificial tears group. This difference was statis-tically significant (P!.029).

Table 1. Patient demographics.

ParameterDiquafosolGroup

ArtificialTears Group

PValue

Mean age (y) G SD 74.8 G 9.0 71.7 G 6.0 .1627Sex* .5780

Female 11 10Male 13 17

Surgeon† .8894K.M 2 3G.M 21 21I.O 15 14

*Number of patients†Number of eyes

J CATARACT REFRACT SURG -

DISCUSSION

During the preoperative and intraoperative periods ofcataract surgery with IOL implantation, several riskfactors can induce dry eye. These include forcedopening of the eyelids,4,5 aging,6,7 abnormal circum-stances induced by the operating microscope lightand heat,8 preservatives in eyedrops,9 topical anes-thetics,10,11 and cleansing of the conjunctival sac andlid with povidone–iodine.12 Damage to the cornealand conjunctival epithelium and decreased stabilityof the tear film are core mechanisms of dry-eye for-mation, and inflammation and the osmolality oftear fluid have also been suggested as causes.1,13,14

The preoperative and intraoperative risk factorsmight affect these elements in dry eye. Diquafosolwas found to be effective in preventing damage tothe corneal and conjunctival epithelium anddecreased stability of the tear fluid in experimentaland human dry-eye studies.17–24 The present studycompared diquafosol and artificial tears, using thecorneal wetting property as the indicator of intra-operative dry-eye symptoms. We found that pretreat-ment with diquafosol was effective in reducing therisk for dry eye. This indicates that enhanced intra-operative ocular surface wetting intentionallyinduced by balanced salt solution irrigation with di-quafosol is a worthwhile topic for discussion phar-macologically, optically, and clinically.

Diquafosol is a dinucleotide derivative and exhibitspurinoceptor P2Y2 receptor agonist activity.29 Ingeneral, the P2Y2 receptor agonist exists in the cellmembranes and activates phospholipase C, leadingto various physiologic reactions. The P2Y2 receptorgene exists at the conjunctival epithelium, cornealepithelium, and the goblet cells of the corneal epithe-lium of the ocular surface.30 The P2Y2 receptor

Table 2. Symptoms assessed by the questionnaire.

Symptom

Number of Patients

DiquafosolGroup

(24 Patients)

Artificial TearGroup

(27 Patients)P

Value

Blurred vision 20 23 1.000Fatigue 16 18 1.000Irritation 12 13 1.000Dryness 7 6 .749Foreign-bodysensation

5 4 .718

Hyperemia 4 5 1.000Pain 2 0 .217Burning sensation 0 1 1.000Frequent blinking 1 0 .471

VOL 40, OCTOBER 2014

Figure 2. Corneal wetting property by group (* Z statisticallysignificant).

1686 TOPICAL DIQUAFOSOL AND INTRAOPERATIVE CORNEAL WETTING

agonists, including diquafosol, are reported to stim-ulate secretion of water and mucin onto the ocularsurface.15–17 Mucin is widely distributed in themucous tissues of the body; it moistens mucousmembranes and prevents the mucous tissues fromdamage. Decreased mucin on the ocular surfacehas been suggested as a pathogen of dry eye and ashort tear-film breakup time (TBUT), which leadsto a type of dry eye often seen clinically.31–33 Thesereports indicate that mucin clinically works withaqueous tears to maintain the corneal wetting prop-erty. Both increased tear and mucin secretioncontribute to an enhanced wetting property. Asituation similar to dry eye induced intraoperativelyand the related changes on the corneal surface wet-ting property are nonphysiologic, iatrogenic, andacute phenomena. In such situations, the time ittakes the solution used for irrigation to dry on theocular surface can be presumed to reflect the amountof mucin secreted.

The definition of dry eye, revised in 2006, listsvisual disturbance and ocular discomfort as themain subjective symptoms.1 With dry eye, the stabil-ity of tear fluid is reduced and a change the TBUT orin tear-film thickness occurs, significantly influencingthe ocular optics.34–36 Other studies report aberra-tions37 as well as abnormalities in the surface regular-ity index and surface asymmetry index detected bycorneal topography in cases of dry eye.38 Diquafosolophthalmic solution is reported to prevent thesevisual function disturbances.24 The above studiesdiscuss the relationship between visual function anddry eye from the perspective of patients and suggestthat an improved intraoperative corneal wetting

J CATARACT REFRACT SURG -

property improves the surgeon's intraoperative opti-cal clarity by reducing the need to frequently irrigatethe field with a balanced salt solution. Previousstudies26–28 of corneal wetting properties comparedthe efficacy of several OVDs and balanced saltsolution, which were administered intraoperatively.They found the former to be more efficacious thanthe latter.

In Japan, the incidence of dry eye in the elderly pop-ulation is reported to be as high as 73.5%.25 Thus, ourfinding that pretreatment with diquafosol enhancesintraoperative corneal wetting properties is clinicallyrelevant because the majority of patients who havecataract surgery with IOL implantation are elderly.Our results are promising and relevant because ofthe paradigm shift in the management of dry eyefrom simply lubricating and hydrating the ocularsurface with artificial tears to strategies that stimulatenatural production of tears and improve ocular surfacehomeostasis.1,13,14 Our findings also indicate that thistype of pretreatment prevents intraoperative iatro-genic dry eye and reduces the frequency of irrigationwith a balanced salt solution. Additional studies areneeded to determine whether this type of medicationhas an influence on corneal surface integrity and thevisual rehabilitation process during the early postop-erative period.

VO

WHAT WAS KNOWN

� There are a few studies comparing the efficacy of OVDswith that of balanced salt solution to maintain intraopera-tive corneal wetting properties.

WHAT THIS PAPER ADDS

� Topical diquafosol improved intraoperative cornealwetting properties.

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First author:Goichiro Miyake, MD

Department of Ophthalmology, AichiMedical University, Aichi, Japan