- Email: [email protected]
Evaluation of a new preoperative ophthalmic solution
Evaluation of a new preoperative ophthalmic solution Takao Hirowatari,* MD; Kazuhiro Tokuda,* MD; Yuko Kamei,* MD; Yasunori Miyazaki†; Masao Matsubara,* MD, PhD ABSTRACT • RÉSUMÉ Background: Maximum mydriasis and corneal clarity during intraocular surgery are important to ensure operational safety. However, repeated instillation of mydriatic and anti-inflammatory ophthalmic solutions during surgery may affect compliance and may damage the corneal epithelium.We developed an ophthalmic solution containing tropicamide, phenylephrine hydrochloride and diclofenac sodium, and compared the properties and effect on corneal epithelial barrier function and on mydriasis of the solution and of its individual components. Methods: We developed the ophthalmic solution by mixing 10 mL of 0.5% tropicamide/0.5% phenylephrine, 10 mL of 5% phenylephrine and 10 mL of 0.1% diclofenac (TPD). We determined the stability of the chemicals in solution using high-performance liquid chromatography immediately, 1 week and 1 month after mixing. Corneal epithelial barrier function was assessed before and after instillation of the solutions in 26 eyes of 17 patients (5 with proliferative diabetic retinopathy or diabetic maculopathy, 8 with cataract and 4 with no eye disease).The fluorescent intensity was measured 10 times at the central cornea 30 minutes after instillation of 3 mL of 0.5% fluorescein solution and the average value calculated. Finally, the pupil diameter of 50 eyes of 38 patients undergoing cataract surgery was measured before and immediately after the operation. Results: No remarkable changes in the pH or pharmacologic activity of the TPD solution were observed at any time after mixing. In the patients with diabetic retinopathy or cataract, the increase in mean fluorescent intensity was significantly greater with the individual solutions than with the TPD solution (p < 0.01); there was no significant difference in mean fluorescent intensity in the subjects with no eye disease. No statistically significant difference in pupil diameter was observed between the eyes that received the TPD solution and those that received the individual solutions. Interpretation:TPD ophthalmic solution is simple to prepare and use.The TPD solution had a similar effect on mydriasis as the three individual solutions but was less destructive to the corneal epithelium.
From the Departments of *Ophthalmology and †Pharmacology, Daini Hospital, Tokyo Women’s Medical University, Arakawa-ku, Tokyo, Japan Originally received Nov. 4, 2003 Accepted for publication July 28, 2004 Presented in part at the Japanese Ophthalmological Society meeting held in Sendai, Japan, May 23–26, 2002
58
New preoperative solution—Hirowatari et al
Correspondence to: Dr. Takao Hirowatari, Department of Ophthalmology, Daini Hospital, Tokyo Women’s Medical University, 2-1-10 Nishi-Ogu, Arakawa-ku, Tokyo 116-8567, Japan; fax +81-3-3810-9817; [email protected] This article has been peer-reviewed. Can J Ophthalmol 2005;40:58–62
New preoperative solution—Hirowatari et al
Contexte : L’obtention d’une mydriase et d’une clarté cornéenne maximales pendant la chirurgie oculaire est importante pour assurer la sécurité de l’opération.Toutefois, l’instillation répétée de solutions ophtalmiques mydriatiques et anti-inflammatoires pendant la chirurgie peut affecter la concordance et endommager l’épithélium de la cornée. Nous avons développé une solution ophtalmique comprenant de la tropicamide, de l’hydrochlorure de phényléphrine et du sodium de diclofénac, et comparé les propriétés et l’effet de la solution et celui de chacun de ses composants sur la fonction protectrice de l’épithélium cornéen et sur la mydriase. Méthodes : Nous avons obtenu la solution ophtalmique en mélangeant 10 mL de tropicamide à 0,5 %/phényléphrine à 0,5 %, 10 mL de phényléphrine à 5 % et 10 mL de diclofénac à 0,1 % (TPD). Nous avons établi la stabilité des composants chimiques par chromatographie de haut rendement des liquides, immédiatement, une semaine et un mois après le mélange. La fonction protectrice de l’épithélium cornéen a été évaluée avant et après l’instillation des solutions dans 26 yeux de 17 patients (5 avec rétinopathie diabétique proliférante ou maculopathie diabétique, 8 avec cataracte et 4 sans maladie oculaire). L’intensité de la fluorescence a été mesurée 10 fois au centre de la cornée 30 minutes après l’instillation de 3 mL de solution de fluorescéine à 0,5 %, puis on a calculé la valeur moyenne. Enfin, le diamètre de la pupille de 50 yeux chez 38 patients subissant la chirurgie de la cataracte a été mesuré avant et immédiatement après l’opération. Résultats : L’on n’a observé de modification notable du pH ou de l’activité pharmacologique de la solution TPD à aucun moment après le mélange. Chez les patients qui avaient une rétinopathie diabétique ou une cataracte, l’intensité moyenne de la fluorescence a augmenté significativement plus avec les solutions séparées qu’avec la solution TPD (p < 0,01); l’écart était peu important chez les personnes qui n’avaient pas de maladie oculaire. On n’a pas noté d’écart statistiquement important dans le diamètre de la pupille entre les yeux qui avaient reçu la solution TPD et ceux qui avaient reçu les solutions séparées. Interprétation : La solution ophtalmique TPD est simple à préparer et à utiliser. Elle a eu sur la mydriase des effets semblables à ceux des trois solutions appliquées séparément, mais s’est avérée moins destructrice pour l’épithélium cornéen.
M
aximum mydriasis and corneal clarity during intraocular surgery are important to ensure operational safety. Mydriatic and anti-inflammatory ophthalmic solutions need to be applied to both eyes many times to maintain mydriasis during surgery. Some eyes exhibit insufficient dilation on the day of surgery, or the dilation may decrease during the early phase of the operation. Repeated instillation can influence compliance, and chemicals such as antiseptics in ophthalmic solutions can damage the corneal epithelium. Superficial punctate keratitis sometimes appears before the operation. We developed an ophthalmic solution containing tropicamide, phenylephrine and diclofenac, and compared the properties and effect on corneal epithelial barrier function and on mydriasis of the solution and of its individual components.
METHODS Preparation of solution We prepared the ophthalmic solution using an aseptic technique at a clean bench. We loaded 10 mL of 0.5% tropicamide/0.5% phenylephrine hydrochloride (Mydrin-P, Santen Pharmaceutical Co. Ltd., Osaka) into syringe A and 10 mL of 5% phenylephrine hydrochloride (Neosynesin, Kowa Company Ltd., Nagoya, Japan) into syringe B. The two syringes were then connected with a fluid-dispensing connector (FDC1000, B. Braun Medical Inc., Bethlehem, Pa.), and the fluid in syringe B was introduced into syringe A. The contents of syringe A were then injected into syringe B. This process was repeated more than eight times to produce a uniform mixture. The contents were
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New preoperative solution—Hirowatari et al
then collected in syringe A, and syringe B was removed and replaced by syringe C, containing 10 mL of 0.1% diclofenac sodium (Diclod, Wakamoto Pharmaceutical Co. Ltd., Tokyo). The contents of syringes A and C were then mixed in the same manner. The resulting solution (0.17% tropicamide, 1.83% phenylephrine and 0.03% diclofenac) (TPD) was dispensed in aliquots of 2 mL into light-resistant bottles. The containers were stored at 10°C in the dark until use in the clinical trial.1 The ethics committee of Tokyo Women’s Medical University approved the production and clinical use of the ophthalmic solution. Informed written consent was obtained from every patient before enrolment in the trial.
bulbar conjunctiva and cornea were washed with 20 mL of BSS Plus (Alcon Laboratories, Inc.) to wash out the fluorescein within the tear fluid. The upper lid was everted and the tarsal conjunctiva washed, and the lower conjunctival sac was then washed again. Twenty minutes later the fluorescent intensity was measured 10 times at the central cornea and the average value calculated. The mean background fluorescent value was then subtracted2 to give the final value. At least 1 week later (to ensure repair of any corneal epithelial barrier damage caused by the TPD solution), we assessed corneal epithelial barrier function before and after instillation of tropicamide, phenylephrine and diclofenac individually, using the same procedure.
Mydriasis Properties of solution We determined the stability of each drug using highperformance liquid chromatography immediately, 1 week and 1 month after mixing. The detection wavelength was 254 nm for tropicamide and phenylephrine, and 279 nm for diclofenac. The mobile phase for tropicamide and phenylephrine was a mixture of methanol, water and acetic acid (60:39:1) containing 1.0 g of sodium 1-dodecanesulfonate in 1 L. The mobile phase for diclofenac was a mixture of sodium acetate–tetrabutyl ammonium test solution (pH 4.8) and acetonitrile (3:2).
Clinical variables Corneal epithelial barrier function Between June and August 2001, we assessed corneal epithelial barrier function before and after instillation of the TPD solution in 26 eyes of 17 patients at the Department of Ophthalmology, Daini Hospital, Tokyo Women’s Medical University. Five patients (10 eyes) (mean age 59.0 years [standard deviation (SD) 12.8 years]) had proliferative diabetic retinopathy or diabetic maculopathy, eight patients (8 eyes) (mean age 70.9 [SD 10.6] years) had cataracts, and four patients (8 eyes) (mean age 28.5 [SD 4.9] years) did not have eye disease. We assessed an area at the centre of the cornea measuring 0.15 mm by 0.3 mm. We measured background fluorescent intensity 10 times using a fluorophotometer (Anterior Fluorometer FL-500, Kowa Company Ltd.) focused on the cornea and took the average of the 10 measurements. Then 3 mL of 0.5% fluorescein solution (Fluorescite, Alcon Laboratories, Inc., Forth Worth, Tex.) was applied without contact to the eye near the lower conjunctival sac. Ten minutes later the lower tarsal conjunctiva, conjunctival sac,
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CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005
We assessed the effect of the solutions on mydriasis in 50 eyes of 38 patients ranging in age from 42 to 88 years (mean 72.4 [SD 8.5] years) who underwent cataract surgery between September 2001 and March 2002 and were followed for at least 3 months at Daini Hospital, Tokyo Women’s Medical University. Twentyfive eyes were randomly assigned to receive the TPD solution, and 25 eyes were randomly assigned to receive the three solutions containing the individual components. The assigned solution(s) was administered 120, 90, 60, 45, 30 and 15 minutes before surgery. Thus, the TPD solution was administered six times, and the solutions containing the individual components were administered 18 times, with at least 5 minutes between instillations. Two surgeons (M.M. and T.H.), who did not know which type of solution had been instilled, performed all the surgical procedures. Under 4% lidocaine eye drop anesthesia, all eyes underwent temporal clear-corneal incision, phacoemulsification, irrigation and aspiration (Series 20000 Legacy, Alcon Laboratories, Inc.) and implantation of an intraocular lens (AcrySof, Alcon Laboratories, Inc., or Acryfold, Hoya Corporation, Tokyo) in the capsule. No intraoperative complications were encountered. The surgeon and the surgeon’s assistant measured the horizontal pupil diameter using calipers before and immediately after the operation. We calculated the rate of miosis as (preoperative pupil diameter – postoperative pupil diameter) × 100/preoperative pupil diameter.
Statistical analysis We performed statistical analysis using Student’s t test for corneal epithelium barrier function and a paired t test for pupil diameter. The significance level was set at p < 0.05.
New preoperative solution—Hirowatari et al
RESULTS
Table 1—Properties and stability of an ophthalmic solution containing 0.17% tropicamide, 1.83% phenylephrine hydrochloride and 0.03% diclofenac sodium (TPD)
Properties of solution No remarkable changes in the pH or pharmacologic activity of the TPD solution were observed at any time after mixing (Table 1). The concentrations of the preservatives benzalkonium chloride and chlorobutanol in the TPD solution were one-third of those in the individual solutions.
Time after mixing Variable
Immediately
Colour
Colourless Colourless Colourless and clear and clear and clear 6.48 6.47 6.45
pH % survival Tropicamide Phenylephrine Diclofenac
Clinical variables Corneal epithelial barrier function Among the patients with diabetic retinopathy, two eyes of two patients exhibited abnormal fluorescent intensity values (normally 28.0 [SD 17.0] mg/mL) before instillation of the solutions. The increase in mean fluorescent intensity was significantly greater with the individual solutions than with the TPD solution (457.5 [SD 468.8] ng/mL vs. 100.6 [SD 235.7] ng/mL) (p < 0.01) (Table 2). Among the patients with cataract, one eye of one patient exhibited an abnormal fluorescein value before instillation. The increase in mean fluorescent intensity was significantly greater with the individual solutions than with the TPD solution (50.2 [SD 36.9] ng/mL vs. 20.6 [SD 15.9] ng/mL) (p < 0.05). In the subjects with no eye disease, there was no significant difference in mean fluorescent intensity between the TPD solution and the individual solutions.
100.0 100.0 100.0
1 wk
1 mo
100.0 98.4 97.8
99.4 97.8 101.9
Mydriasis The mean operating time was 9.96 (SD 3.6) minutes for the eyes that received the TPD solution and 9.92 (SD 4.8) minutes for the eyes that received the individual solutions. No complications, such as posterior capsule rupture, vitreous loss, wound leakage or cystoid macular edema, occurred during or after surgery in either group. The mean pupil diameter before surgery was 8.48 mm (SD 0.55 mm) in the TPD group and 8.68 mm (SD 0.58 mm) in the individual-solution group. The corresponding values after surgery were 8.04 mm (SD 0.79 mm) and 8.22 mm (SD 0.79 mm). Neither difference was significant. The rate of miosis was 5.3% (SD 5.6%) in the TPD group and 5.4% (SD 5.5%) in the individual-solution group, a nonsignificant difference.
Table 2—Corneal epithelial fluorescent intensity before and after instillation of the TPD solution and the solutions containing the individual components in patients with diabetic retinopathy, those with cataract and those with no eye disease Time; mean fluorescent intensity (and standard deviation), ng/mL TPD solution Patient group Diabetic retinopathy (n = 10 eyes) Cataract (n = 8 eyes) No eye disease (n = 8 eyes)
Before instillation
After instillation
Individual solutions Difference
141.9 (226.1) 242.4 (391.6) 100.6 (235.7) 27.8 (30.0) 5.4
(3.9)
48.4 (41.7) 10.6
(7.9)
20.6 (15.9) 5.2
(5.9)
Before instillation
After instillation
Difference
86.3 (127.3) 543.7 (455.0) 457.5 (468.8)* 36.1 (37.8) 9.2
(7.6)
85.8 (67.2) 18.0 (12.5)
50.2 (36.9)† 8.8
(6.9)
*p < 0.01 for difference between TPD group and individual-solution group. †p < 0.05 for difference between TPD group and individual-solution group.
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New preoperative solution—Hirowatari et al
INTERPRETATION
REFERENCES
The preparation and storage methods for the TPD ophthalmic solution were simple and easy to perform and did not require any special instruments. The stability of the chemicals in the solution was well preserved for up to 1 month when the solution was kept in the dark at 10°C. The use of the TPD solution was similar to that of the three individual solutions, but, of course, less time was required for instillation of the TPD solution. The TPD solution had a similar effect on mydriasis as the three individual solutions but was less destructive to the corneal epithelium. Preservatives such as benzalkonium chloride, chlorobutanol and diclofenac sodium are toxic to the corneal epithelium.3–6 The TPD solution enables the concentration of each preservative to be decreased. Therefore, intraocular visibility is improved during the operation, and postoperative corneal epithelial damage is reduced. Cataract surgery has progressed rapidly in recent years owing to the development of surgical instruments and improvements in surgical technique. As a result, the number of operations being performed is increasing. However, the preparations used before cataract surgery have not changed. We suggest that the use of a TPD ophthalmic solution may simplify and even improve the efficiency of surgical preparations. However, its stability during long-term storage must be further evaluated.
1.
None of the authors has a financial interest in any of the products mentioned in this article.
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2.
3.
4.
5.
6.
Hirowatari T, Tokuda K, Kamei Y, Miyazaki Y, Matsubara M. Availability of TPD ophthalmic solution (mixture of Mydrin-P® solution, Neosynesin Kowa® solution, and Diclod® solution). Atarashii Ganka 2002; 19:107–9. Yokoi N, Kinoshita S. Clinical evaluation of corneal epithelial barrier function with the slit-lamp fluorophotometer. Cornea 1995;14:485–9. Hsu JKW, Johnston WT, Read RW, McDonnell PJ, Pangalinan R, Rao N, et al. Histopathology of corneal melting associated with diclofenac use after refractive surgery. J Cataract Refract Surg 2003;29:250–6. Hargrave S, Jung JC, Fini ME, Gelender H, Cather C, Guidera A, et al. Possible role of the vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis. Ophthalmology 2002;109:343–50. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal antinflammatory drugs. Ophthalmology 2001;108:936–44. Hashizume N, Saika S, Okada Y, Miyamoto T, Shimizu K, Ohnishi Y. Effects of antiinflammatory drugs on migration of the rabbit corneal epithelium. J Cataract Refract Surg 2001;27:1499–502.
Key words: tropicamide, phenylephrine hydrochloride, diclofenac sodium, ophthalmic solution, corneal epithelium, mydriasis
From the Departments of *Ophthalmology and †Pharmacology, Daini Hospital, Tokyo Women’s Medical University, Arakawa-ku, Tokyo, Japan Originally received Nov. 4, 2003 Accepted for publication July 28, 2004 Presented in part at the Japanese Ophthalmological Society meeting held in Sendai, Japan, May 23–26, 2002
58
New preoperative solution—Hirowatari et al
Correspondence to: Dr. Takao Hirowatari, Department of Ophthalmology, Daini Hospital, Tokyo Women’s Medical University, 2-1-10 Nishi-Ogu, Arakawa-ku, Tokyo 116-8567, Japan; fax +81-3-3810-9817; [email protected] This article has been peer-reviewed. Can J Ophthalmol 2005;40:58–62
New preoperative solution—Hirowatari et al
Contexte : L’obtention d’une mydriase et d’une clarté cornéenne maximales pendant la chirurgie oculaire est importante pour assurer la sécurité de l’opération.Toutefois, l’instillation répétée de solutions ophtalmiques mydriatiques et anti-inflammatoires pendant la chirurgie peut affecter la concordance et endommager l’épithélium de la cornée. Nous avons développé une solution ophtalmique comprenant de la tropicamide, de l’hydrochlorure de phényléphrine et du sodium de diclofénac, et comparé les propriétés et l’effet de la solution et celui de chacun de ses composants sur la fonction protectrice de l’épithélium cornéen et sur la mydriase. Méthodes : Nous avons obtenu la solution ophtalmique en mélangeant 10 mL de tropicamide à 0,5 %/phényléphrine à 0,5 %, 10 mL de phényléphrine à 5 % et 10 mL de diclofénac à 0,1 % (TPD). Nous avons établi la stabilité des composants chimiques par chromatographie de haut rendement des liquides, immédiatement, une semaine et un mois après le mélange. La fonction protectrice de l’épithélium cornéen a été évaluée avant et après l’instillation des solutions dans 26 yeux de 17 patients (5 avec rétinopathie diabétique proliférante ou maculopathie diabétique, 8 avec cataracte et 4 sans maladie oculaire). L’intensité de la fluorescence a été mesurée 10 fois au centre de la cornée 30 minutes après l’instillation de 3 mL de solution de fluorescéine à 0,5 %, puis on a calculé la valeur moyenne. Enfin, le diamètre de la pupille de 50 yeux chez 38 patients subissant la chirurgie de la cataracte a été mesuré avant et immédiatement après l’opération. Résultats : L’on n’a observé de modification notable du pH ou de l’activité pharmacologique de la solution TPD à aucun moment après le mélange. Chez les patients qui avaient une rétinopathie diabétique ou une cataracte, l’intensité moyenne de la fluorescence a augmenté significativement plus avec les solutions séparées qu’avec la solution TPD (p < 0,01); l’écart était peu important chez les personnes qui n’avaient pas de maladie oculaire. On n’a pas noté d’écart statistiquement important dans le diamètre de la pupille entre les yeux qui avaient reçu la solution TPD et ceux qui avaient reçu les solutions séparées. Interprétation : La solution ophtalmique TPD est simple à préparer et à utiliser. Elle a eu sur la mydriase des effets semblables à ceux des trois solutions appliquées séparément, mais s’est avérée moins destructrice pour l’épithélium cornéen.
M
aximum mydriasis and corneal clarity during intraocular surgery are important to ensure operational safety. Mydriatic and anti-inflammatory ophthalmic solutions need to be applied to both eyes many times to maintain mydriasis during surgery. Some eyes exhibit insufficient dilation on the day of surgery, or the dilation may decrease during the early phase of the operation. Repeated instillation can influence compliance, and chemicals such as antiseptics in ophthalmic solutions can damage the corneal epithelium. Superficial punctate keratitis sometimes appears before the operation. We developed an ophthalmic solution containing tropicamide, phenylephrine and diclofenac, and compared the properties and effect on corneal epithelial barrier function and on mydriasis of the solution and of its individual components.
METHODS Preparation of solution We prepared the ophthalmic solution using an aseptic technique at a clean bench. We loaded 10 mL of 0.5% tropicamide/0.5% phenylephrine hydrochloride (Mydrin-P, Santen Pharmaceutical Co. Ltd., Osaka) into syringe A and 10 mL of 5% phenylephrine hydrochloride (Neosynesin, Kowa Company Ltd., Nagoya, Japan) into syringe B. The two syringes were then connected with a fluid-dispensing connector (FDC1000, B. Braun Medical Inc., Bethlehem, Pa.), and the fluid in syringe B was introduced into syringe A. The contents of syringe A were then injected into syringe B. This process was repeated more than eight times to produce a uniform mixture. The contents were
CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005
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New preoperative solution—Hirowatari et al
then collected in syringe A, and syringe B was removed and replaced by syringe C, containing 10 mL of 0.1% diclofenac sodium (Diclod, Wakamoto Pharmaceutical Co. Ltd., Tokyo). The contents of syringes A and C were then mixed in the same manner. The resulting solution (0.17% tropicamide, 1.83% phenylephrine and 0.03% diclofenac) (TPD) was dispensed in aliquots of 2 mL into light-resistant bottles. The containers were stored at 10°C in the dark until use in the clinical trial.1 The ethics committee of Tokyo Women’s Medical University approved the production and clinical use of the ophthalmic solution. Informed written consent was obtained from every patient before enrolment in the trial.
bulbar conjunctiva and cornea were washed with 20 mL of BSS Plus (Alcon Laboratories, Inc.) to wash out the fluorescein within the tear fluid. The upper lid was everted and the tarsal conjunctiva washed, and the lower conjunctival sac was then washed again. Twenty minutes later the fluorescent intensity was measured 10 times at the central cornea and the average value calculated. The mean background fluorescent value was then subtracted2 to give the final value. At least 1 week later (to ensure repair of any corneal epithelial barrier damage caused by the TPD solution), we assessed corneal epithelial barrier function before and after instillation of tropicamide, phenylephrine and diclofenac individually, using the same procedure.
Mydriasis Properties of solution We determined the stability of each drug using highperformance liquid chromatography immediately, 1 week and 1 month after mixing. The detection wavelength was 254 nm for tropicamide and phenylephrine, and 279 nm for diclofenac. The mobile phase for tropicamide and phenylephrine was a mixture of methanol, water and acetic acid (60:39:1) containing 1.0 g of sodium 1-dodecanesulfonate in 1 L. The mobile phase for diclofenac was a mixture of sodium acetate–tetrabutyl ammonium test solution (pH 4.8) and acetonitrile (3:2).
Clinical variables Corneal epithelial barrier function Between June and August 2001, we assessed corneal epithelial barrier function before and after instillation of the TPD solution in 26 eyes of 17 patients at the Department of Ophthalmology, Daini Hospital, Tokyo Women’s Medical University. Five patients (10 eyes) (mean age 59.0 years [standard deviation (SD) 12.8 years]) had proliferative diabetic retinopathy or diabetic maculopathy, eight patients (8 eyes) (mean age 70.9 [SD 10.6] years) had cataracts, and four patients (8 eyes) (mean age 28.5 [SD 4.9] years) did not have eye disease. We assessed an area at the centre of the cornea measuring 0.15 mm by 0.3 mm. We measured background fluorescent intensity 10 times using a fluorophotometer (Anterior Fluorometer FL-500, Kowa Company Ltd.) focused on the cornea and took the average of the 10 measurements. Then 3 mL of 0.5% fluorescein solution (Fluorescite, Alcon Laboratories, Inc., Forth Worth, Tex.) was applied without contact to the eye near the lower conjunctival sac. Ten minutes later the lower tarsal conjunctiva, conjunctival sac,
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CAN J OPHTHALMOL—VOL. 40, NO. 1, 2005
We assessed the effect of the solutions on mydriasis in 50 eyes of 38 patients ranging in age from 42 to 88 years (mean 72.4 [SD 8.5] years) who underwent cataract surgery between September 2001 and March 2002 and were followed for at least 3 months at Daini Hospital, Tokyo Women’s Medical University. Twentyfive eyes were randomly assigned to receive the TPD solution, and 25 eyes were randomly assigned to receive the three solutions containing the individual components. The assigned solution(s) was administered 120, 90, 60, 45, 30 and 15 minutes before surgery. Thus, the TPD solution was administered six times, and the solutions containing the individual components were administered 18 times, with at least 5 minutes between instillations. Two surgeons (M.M. and T.H.), who did not know which type of solution had been instilled, performed all the surgical procedures. Under 4% lidocaine eye drop anesthesia, all eyes underwent temporal clear-corneal incision, phacoemulsification, irrigation and aspiration (Series 20000 Legacy, Alcon Laboratories, Inc.) and implantation of an intraocular lens (AcrySof, Alcon Laboratories, Inc., or Acryfold, Hoya Corporation, Tokyo) in the capsule. No intraoperative complications were encountered. The surgeon and the surgeon’s assistant measured the horizontal pupil diameter using calipers before and immediately after the operation. We calculated the rate of miosis as (preoperative pupil diameter – postoperative pupil diameter) × 100/preoperative pupil diameter.
Statistical analysis We performed statistical analysis using Student’s t test for corneal epithelium barrier function and a paired t test for pupil diameter. The significance level was set at p < 0.05.
New preoperative solution—Hirowatari et al
RESULTS
Table 1—Properties and stability of an ophthalmic solution containing 0.17% tropicamide, 1.83% phenylephrine hydrochloride and 0.03% diclofenac sodium (TPD)
Properties of solution No remarkable changes in the pH or pharmacologic activity of the TPD solution were observed at any time after mixing (Table 1). The concentrations of the preservatives benzalkonium chloride and chlorobutanol in the TPD solution were one-third of those in the individual solutions.
Time after mixing Variable
Immediately
Colour
Colourless Colourless Colourless and clear and clear and clear 6.48 6.47 6.45
pH % survival Tropicamide Phenylephrine Diclofenac
Clinical variables Corneal epithelial barrier function Among the patients with diabetic retinopathy, two eyes of two patients exhibited abnormal fluorescent intensity values (normally 28.0 [SD 17.0] mg/mL) before instillation of the solutions. The increase in mean fluorescent intensity was significantly greater with the individual solutions than with the TPD solution (457.5 [SD 468.8] ng/mL vs. 100.6 [SD 235.7] ng/mL) (p < 0.01) (Table 2). Among the patients with cataract, one eye of one patient exhibited an abnormal fluorescein value before instillation. The increase in mean fluorescent intensity was significantly greater with the individual solutions than with the TPD solution (50.2 [SD 36.9] ng/mL vs. 20.6 [SD 15.9] ng/mL) (p < 0.05). In the subjects with no eye disease, there was no significant difference in mean fluorescent intensity between the TPD solution and the individual solutions.
100.0 100.0 100.0
1 wk
1 mo
100.0 98.4 97.8
99.4 97.8 101.9
Mydriasis The mean operating time was 9.96 (SD 3.6) minutes for the eyes that received the TPD solution and 9.92 (SD 4.8) minutes for the eyes that received the individual solutions. No complications, such as posterior capsule rupture, vitreous loss, wound leakage or cystoid macular edema, occurred during or after surgery in either group. The mean pupil diameter before surgery was 8.48 mm (SD 0.55 mm) in the TPD group and 8.68 mm (SD 0.58 mm) in the individual-solution group. The corresponding values after surgery were 8.04 mm (SD 0.79 mm) and 8.22 mm (SD 0.79 mm). Neither difference was significant. The rate of miosis was 5.3% (SD 5.6%) in the TPD group and 5.4% (SD 5.5%) in the individual-solution group, a nonsignificant difference.
Table 2—Corneal epithelial fluorescent intensity before and after instillation of the TPD solution and the solutions containing the individual components in patients with diabetic retinopathy, those with cataract and those with no eye disease Time; mean fluorescent intensity (and standard deviation), ng/mL TPD solution Patient group Diabetic retinopathy (n = 10 eyes) Cataract (n = 8 eyes) No eye disease (n = 8 eyes)
Before instillation
After instillation
Individual solutions Difference
141.9 (226.1) 242.4 (391.6) 100.6 (235.7) 27.8 (30.0) 5.4
(3.9)
48.4 (41.7) 10.6
(7.9)
20.6 (15.9) 5.2
(5.9)
Before instillation
After instillation
Difference
86.3 (127.3) 543.7 (455.0) 457.5 (468.8)* 36.1 (37.8) 9.2
(7.6)
85.8 (67.2) 18.0 (12.5)
50.2 (36.9)† 8.8
(6.9)
*p < 0.01 for difference between TPD group and individual-solution group. †p < 0.05 for difference between TPD group and individual-solution group.
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New preoperative solution—Hirowatari et al
INTERPRETATION
REFERENCES
The preparation and storage methods for the TPD ophthalmic solution were simple and easy to perform and did not require any special instruments. The stability of the chemicals in the solution was well preserved for up to 1 month when the solution was kept in the dark at 10°C. The use of the TPD solution was similar to that of the three individual solutions, but, of course, less time was required for instillation of the TPD solution. The TPD solution had a similar effect on mydriasis as the three individual solutions but was less destructive to the corneal epithelium. Preservatives such as benzalkonium chloride, chlorobutanol and diclofenac sodium are toxic to the corneal epithelium.3–6 The TPD solution enables the concentration of each preservative to be decreased. Therefore, intraocular visibility is improved during the operation, and postoperative corneal epithelial damage is reduced. Cataract surgery has progressed rapidly in recent years owing to the development of surgical instruments and improvements in surgical technique. As a result, the number of operations being performed is increasing. However, the preparations used before cataract surgery have not changed. We suggest that the use of a TPD ophthalmic solution may simplify and even improve the efficiency of surgical preparations. However, its stability during long-term storage must be further evaluated.
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None of the authors has a financial interest in any of the products mentioned in this article.
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Key words: tropicamide, phenylephrine hydrochloride, diclofenac sodium, ophthalmic solution, corneal epithelium, mydriasis