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Effects of topical diquafosol pretreatment on intraoperative corneal wetting

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

Author Information
Journal of Cataract & Refractive Surgery: October 2014 - Volume 40 - Issue 10 - p 1682-1688
doi: 10.1016/j.jcrs.2014.02.035
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Abstract

The International Dry Eye Workshop (2007) states, “Dry eye is a multifactorial disease of the tear and ocular surface that results in symptoms such as ocular discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.”1 Although many patients with dry eye are scheduled for intraocular surgery, studies of how to manage dry eye perioperatively are scarce.2,3

Management of dry eye in terms of intraoperative optical clarity during cataract surgery with intraocular lens (IOL) implantation is affected by many preoperative and intraoperative risk factors. These include forced opening of the eyelid,4,5 aging,6,7 abnormal circumstances induced by the operating microscope’s light and heat,8 preservatives in eyedrops,9 topical anesthetics,10,11 and cleansing of the conjunctival sac and lid with povidone–iodine.12 These factors induce acute situations similar to dry eye that may result in disturbed homeostasis or integrity of the corneal epithelium as well as reduced optical clarity for surgeons.

Recently, a significant amount of information on the pathophysiology of and therapy for dry eye has been published.1,13,14 According to these studies, the essential factors in dry eye are the tear film and the corneal and conjunctival epithelium. These 2 factors complement each other. The tear film covers the epithelium to maintain the epithelium’s function, and the epithelium secretes mucin and water to cleanse the tear film qualitatively and quantitatively. Damage to 1 of these 2 factors results in a cycle that induces dry eye. Based on this pathophysiology, treatment of dry eye has now shifted from prescribing artificial tears to hydrate or lubricate the ocular surface to stimulating the epithelium to secrete aqueous tears or mucin.

Diquafosol ophthalmic solution, a relatively new medication, is a dinucleotide and a purinoceptor P2Y2 agonist. Basic pharmaceutical studies indicate that diquafosol acts on P2Y2 receptors on the ocular surface, causing them to secrete aqueous tears and mucin by increasing the concentration of intracellular calmodulin-dependent protein kinase II.15–17 In animal studies, diquafosol was also found to affect the conjunctival epithelium or epithelial goblet cells, causing them to secrete tears or mucin to protect the corneal epithelium and improve the corneal epithelial barrier function.17–20

After experimental studies using animal models,17–20 the effects of diquafosol ophthalmic solution were studied in human clinical cases with dry eye.21–24 In the present study, we report our preliminary findings of pretreatment with diquafosol eyedrops to protect the ocular surface during cataract surgery with IOL implantation in eyes with risk factors for dry eye.4–12 The randomized single-masked active-controlled trial compared the corneal wetting properties, which improve intraoperative optical clarity for the surgeon, between a group receiving diquafosol and a group receiving artificial tears.

Patients and methods

Consecutive cases diagnosed with bilateral or unilateral senile cataract scheduled to have cataract surgery with IOL implantation at Miyake Eye Hospital from March to May 2013 were included in the study. Only patients who gave written consent after they were given a full explanation of the study were enrolled. This study was performed in accordance with the Declaration of Helsinki and the Japanese Ministry of Health, Labour, and Welfare and received approval from the Institutional Review Board, Shohzankai Medical Foundation, Miyake Eye Hospital.

Patients whose cataracts were not senile; who had glaucoma, diabetic mellitus, or uveitis; who were unable to cease the use of eyedrops because of other ocular disease; and who had inadequate adherence using ophthalmic eyedrops were excluded from the study.

Patients scheduled for surgery at Miyake Eye Hospital have routine checkups during which they complete a general eye questionnaire that includes many questions about dry eye taken from dry-eye studies in Japan.25 Patients in this study were asked to complete this questionnaire preoperatively.

Protocol

This was a randomized single-masked active-controlled study to compare the effects of diquafosol 3.0% ophthalmic solution (Diquas) with those of an artificial tear solution (Mytear) on intraoperative corneal wetting properties. Diquafosol tetrasodium 3.0% ophthalmic solution contains sodium diquafosol (30 mg/1 mL), dibasic sodium phosphate, sodium chloride, potassium chloride, sodium edetate hydrate, a pH adjuster, and benzalkonium chloride. The artificial tears contain sodium chloride, potassium chloride, dried sodium carbonate, dibasic sodium phosphate, boric acid, hydroxyethyl cellulose, and benzalkonium chloride. Using the envelope method, the controller and 1 author (M.Z.) divided the patients (not the eyes) randomly to the diquafosol group or the artificial tears group after a washout period of 2 weeks. The patients received 4 weeks of pretreatment before cataract surgery with IOL implantation. Patients applied 1 drop of their assigned ophthalmic solution 6 times a day until the day before surgery and twice on the day of surgery.

Surgical Technique and Intraoperative Corneal Surface Evaluation

Patients were given antibiotic eyedrops 3 times daily starting 3 days before surgery and nonsteroidal antiinflammatory eyedrops 3 times daily starting 1 day before surgery. Immediately before surgery, the eyelid and conjunctival sac were cleansed using an iodine 8.0% solution.

One of 3 surgeons (G.M, I.O., K.M.) performed cataract surgery with IOL implantation using an identical technique and topical anesthesia of lidocaine 4.0% ophthalmic solution (Xylocaine). Briefly, under an operating microscope (OPMI Lumera T, Carl Zeiss Meditec AG), a corneoscleral incision of approximately 2.5 mm was created. After injection of an ophthalmic viscosurgical device (OVD) into the anterior chamber, a continuous curvilinear capsulorhexis was created and phacoemulsification and aspiration were performed using a Constellation Vision System phaco unit (Alcon Laboratories, Inc.). The anterior chamber was again filled with OVD through the sclerocorneal incision, and 1 of several types of posterior chamber IOLs was implanted in the capsular bag using a posterior chamber IOL injector. The operation time ranged from 5 to 15 minutes.

The 3 surgeons evaluated the corneal surface wetting property without knowledge of which pretreatment was applied by evaluating eyes at a relatively early stage of surgery, at which time there was no OVD in the conjunctival sac; this was done to avoid the influence of the OVD on the wetting property of the cornea.26–28 To prevent possible light toxicity of the operating microscope to the retina during the evaluation, the power of the operating microscope light was reduced to 20% and 3 light-source images on the cornea were confirmed under ×12 magnification. The starting point of the evaluation was immediately after a balanced salt solution was instilled on the corneal surface because at that point, 3 light sources of the operating microscope were clearly visible on the corneal surface (Figure 1, left) and the surgeon was able to carefully observe the image. The endpoint was the moment the 3 lights began to blur (Figure 1, right). After this procedure was repeated 3 times, the mean time taken from the starting point to the endpoint was calculated and used as the indicator of the corneal surface wetting property. The duration was measured using a time recorder on a videotape that was simultaneously used to film the surgery. A technician noted the time on the time recorder when the surgeon indicated with a hand sign the starting point and the endpoint. The results were analyzed by 1 of the authors (M.I.).

Figure 1
Figure 1:
Example demonstrating actual measurement of intraoperative corneal surface wetting property. Left: Corneal surfaces at the starting point 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.

Statistical Analysis

Statistical analysis was performed and the sample was calculated 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 was found to be 55.4%. The distribution was found to be not normal.

A P value less than 0.05% was considered statistically significant. The values are shown as the mean ± SD. The patients’ demographics were analyzed using the chi-square test, the t test, and the Fisher direct probability measure test. The incidence of symptoms was analyzed using the Fisher direct probability measure test. The corneal wetting property 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, 2 patients (4 eyes) dropped out of the study before surgery because of an unwillingness to comply with pretreatment in 1 case and because of an unwillingness to have the surgery in the other case. Thus, 51 patients (76 eyes) completed the study, 24 (38 eyes) in the diquafosol group and 27 (38 eyes) in the artificial tear group. There was no statistically significant difference in sex, age, or surgeon between the 2 groups (Table 1).

Table 1
Table 1:
Patient demographics.

Table 2 shows the incidence of symptoms assessed using the questionnaire and the number of patients who completed the questionnaire. There was no significant difference in the incidence of symptoms between the 2 groups.

Table 2
Table 2:
Symptoms assessed by the questionnaire.

Figure 2 shows the results of the intraoperative corneal wetting property (in seconds). The mean time to corneal wetting was 50.1 seconds ± 10.8 (SD) in the diquafosol group and 45.3 ± 9.2 seconds in the artificial tears group. This difference was statistically significant (P<.029).

Figure 2
Figure 2:
Corneal wetting property by group (* = statistically significant).

Discussion

During the preoperative and intraoperative periods of cataract surgery with IOL implantation, several risk factors can induce dry eye. These include forced opening of the eyelids,4,5 aging,6,7 abnormal circumstances induced by the operating microscope light and heat,8 preservatives in eyedrops,9 topical anesthetics,10,11 and cleansing of the conjunctival sac and lid with povidone–iodine.12 Damage to the corneal and conjunctival epithelium and decreased stability of the tear film are core mechanisms of dry-eye formation, and inflammation and the osmolality of tear fluid have also been suggested as causes.1,13,14 The preoperative and intraoperative risk factors might affect these elements in dry eye. Diquafosol was found to be effective in preventing damage to the corneal and conjunctival epithelium and decreased stability of the tear fluid in experimental and human dry-eye studies.17–24 The present study compared diquafosol and artificial tears, using the corneal wetting property as the indicator of intraoperative dry-eye symptoms. We found that pretreatment with diquafosol was effective in reducing the risk for dry eye. This indicates that enhanced intraoperative ocular surface wetting intentionally induced by balanced salt solution irrigation with diquafosol is a worthwhile topic for discussion pharmacologically, optically, and clinically.

Diquafosol is a dinucleotide derivative and exhibits purinoceptor P2Y2 receptor agonist activity.29 In general, the P2Y2 receptor agonist exists in the cell membranes and activates phospholipase C, leading to various physiologic reactions. The P2Y2 receptor gene exists at the conjunctival epithelium, corneal epithelium, and the goblet cells of the corneal epithelium of the ocular surface.30 The P2Y2 receptor agonists, including diquafosol, are reported to stimulate secretion of water and mucin onto the ocular surface.15–17 Mucin is widely distributed in the mucous tissues of the body; it moistens mucous membranes and prevents the mucous tissues from damage. Decreased mucin on the ocular surface has been suggested as a pathogen of dry eye and a short tear-film breakup time (TBUT), which leads to a type of dry eye often seen clinically.31–33 These reports indicate that mucin clinically works with aqueous tears to maintain the corneal wetting property. Both increased tear and mucin secretion contribute to an enhanced wetting property. A situation similar to dry eye induced intraoperatively and the related changes on the corneal surface wetting property are nonphysiologic, iatrogenic, and acute phenomena. In such situations, the time it takes the solution used for irrigation to dry on the ocular surface can be presumed to reflect the amount of mucin secreted.

The definition of dry eye, revised in 2006, lists visual disturbance and ocular discomfort as the main subjective symptoms.1 With dry eye, the stability of tear fluid is reduced and a change the TBUT or in tear-film thickness occurs, significantly influencing the ocular optics.34–36 Other studies report aberrations37 as well as abnormalities in the surface regularity index and surface asymmetry index detected by corneal topography in cases of dry eye.38 Diquafosol ophthalmic solution is reported to prevent these visual function disturbances.24 The above studies discuss the relationship between visual function and dry eye from the perspective of patients and suggest that an improved intraoperative corneal wetting property improves the surgeon’s intraoperative optical clarity by reducing the need to frequently irrigate the field with a balanced salt solution. Previous studies26–28 of corneal wetting properties compared the efficacy of several OVDs and balanced salt solution, which were administered intraoperatively. They found the former to be more efficacious than the latter.

In Japan, the incidence of dry eye in the elderly population is reported to be as high as 73.5%.25 Thus, our finding that pretreatment with diquafosol enhances intraoperative corneal wetting properties is clinically relevant because the majority of patients who have cataract surgery with IOL implantation are elderly. Our results are promising and relevant because of the paradigm shift in the management of dry eye from simply lubricating and hydrating the ocular surface with artificial tears to strategies that stimulate natural production of tears and improve ocular surface homeostasis.1,13,14 Our findings also indicate that this type of pretreatment prevents intraoperative iatrogenic dry eye and reduces the frequency of irrigation with a balanced salt solution. Additional studies are needed to determine whether this type of medication has an influence on corneal surface integrity and the visual rehabilitation process during the early postoperative period.

What Was Known

  • There are a few studies comparing the efficacy of OVDs with that of balanced salt solution to maintain intraoperative corneal wetting properties.

What This Paper Adds

  • Topical diquafosol improved intraoperative corneal wetting properties.

References

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