Intraocular dapiprazole for the reversal of mydriasis after extracapsular cataract extraction with intraocular lens implantation

Intraocular dapiprazole for the reversal of mydriasis after extracapsular cataract extraction with intraocular lens implantation Part II: Comparison with acetylcholine Francesco Ponte, M.D., Salvatore Cillino, M.D., Francesca Faranda, M.D., Francesco Casanova, M.D., Federico Cucco, M. D.

ABSTRACT Intraocular dapiprazole for reversing mydriasis during extracapsular cataract extraction with intraocular lens (IOL) implantation has been compared to intraocular acetylcholine. Ninety patients were enrolled in a double-blind study and divided into three groups of 30 eyes; each group received balanced salt solution (control), 0.25% dapiprazole, or 1% acetylcholine. Pupi11ary diameter recordings were performed immediately before and a few minutes after drug injection, and two, four and eight hours after surgery. Goldmann tonometry was performed the day before and 6 and 24 hours after surgery. Contact endothelial cell count was performed before and one and four months after surgery. The results indicated a slower starting but longer lasting effect with dapiprazole than with acetylcholine and a significant reduction of the postoperative intraoperative pressure rise with both drugs. No significant difference in reduction in the endothelial cell count was seen between dapiprazole and acetylcholine groups and the control group.

Key Words: acetylcholine , endothelial cell count, extracapsular cataract extraction, intraocular dapiprazole, intraocular lens implantation, intraoperative pressure, reversal of mydriasis

For a variety of reasons, many surgeons favor a reversal of mydriasis immediately after extracapsular cataract extraction (ECCE) with intraocular lens (IOL) implantation. These include verifying that the IOL is centered over the visual axis, that its haptics have cleared the iris, and that vitreous or capsular remnants have cleared the incision. Moreover, during at least 12 hours postoperatively, a miotic might also favorably affect transient intraocular pressure (lOP) elevation. Some long-acting (i.e., 6 to over 24 hours) parasympathomimetic miotics are currently used at the end of cataract surgery, both intracamerally, as 0.01% carbachol solution, and

topically, as 2% pilocarpine eyedrops. Although these agents accomplish the goals of postoperative miosis they also increase ocular vascular congestion, promote blood-aqueous barrier breakdown, and induce sphincter spasm,l all of which are presumably involved in the pathogenesis of synechial formation, cystoid macular edema (CME), and pupillary block. 2 ,3 For these reasons, most surgeons prefer another intraocular parasympathomimetic drug, 1% acetylcholine, which is characterized by rapid, short action, about ten minutes, thus avoiding the prolonged side effects of the other parasympathomimetics. Acetylcholine appears to be ideal for

Reprint requests to Salvatore Cillino, M.D., Clinica Oculistica, Policlinico, Via Liborio Giuffre 13, 90127 Palermo, Italy.

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the immediate requirements after ECCE with IOL implantation, but fails to achieve the aims of miotic treatment during the first several hours after surgery. For instance, it has been shown that, unlike carbachol, intraocular acetylcholine is not adequate to control lOP rise in ECCE patients 20 to 24 hours after surgery. 4 While previous experimental studies indicate that mammalian corneal endothelium tolerates intraocular acetylcholine injection,5,6 recent experimental and clinical studies demonstrate more marked endothelial damage by acetylcholine than by carbachol or pilocarpine in rabbit and human corneas. 7 - 9 Because of these problems, investigators have been studying the miotic effect of sympatholytic a-blocking agents. Intraocular dapiprazole has been clinically effective and well tolerated. 3 ,10 An in vitro study on rabbit corneas failed to reveal any endothelial toxicity after 15 minutes of 1 % dapiprazole perfusion. 9 In Part I of this study, we found that 0.25% intraocular dapiprazole was the optimum concentration in efficacy and safety and that its effect lasted for at least eight hours. Part II of the study compared pupillary diameter, corneal endothelial cell denSity, and lOP in eyes that received 0.25% dapiprazole or 1% acetylcholine intraocularly after ECCE and posterior chamber IOL implantation.

Table 1. Cases treated with intraocular miotics. Age (Yr ± SD)

Malel Female

1 (control)

30

68.1±1D.2

16/14

2 (0 .25% dapiprazole)

30

67.5± 9.1

14116

3 (1 % acetylcholine)

30

70. 1± 6.5

17/13

postoperative examiners knew the intraocular substance used in each case. Table 1 shows the clinical data of the patients, whose mean age was 68.6 years. The groups were comparable in age, sex, and cardiovascular diseases. Cases with systemic and/or ocular diseases other than cataracts that may have affected the results, such as diabetes or uveitis, were not enrolled in the study. All patients had ECCE with IOL implantation performed by the same surgeon and by the method described in Part I. Pupillary diameter measurements were performed at similar times using the method described (Part I). Goldmann tonometry was performed the day before and 6 and 24 hours after surgery. Central corneal endothelial cell examination was performed using a Konan automatic contact specular microscope, producing immediate prints. A cell count was carried out before and one and four months after surgery. The clinical follow-up lasted four months in all cases (see Part I). Statistical data analysis was based on Student's t-test and Mann-Whitney U test if nonparametric values were considered.

SUBJECTS AND METHODS Ninety patients (90 eyes) admitted to the hospital for cataract surgery were randomly assigned to three groups. Data from the first two groups were presented in Part I. Group 1 and Group 2 included the cases in which balanced salt solution (BSS Plus®) and 0.25% dapiprazole, respectively, were injected after IOL implantation. The third group (Group 3), which was not presented, included cases in which 0.3 ml of commercially available intraocular 1% acetylcholine (Miochol®) was used . Neither the surgeon nor the

Number of Eyes

Group

RESULTS Table 2 and Figure 1 show the mean pupillary diameter in the three groups before and during the first eight hours after anterior chamber irrigation with different solutions. No significant difference between the three groups existed before irrigation.

Table 2. Mean pupillary diameter in millimeters (± SD) before and after miotic irrigation. Time After Anterior Chamber Irrigation 2 Hours 4 Hours

Before Irrigation

After Wound Closure

1 (control)

6.7 ± 0.7

6.7 ± 0.8*

6.7 ± 0.7*

6.2 ± 0.8*t

6.0 ± 0.9*

2 (0 .25% dapiprazole)

6.5 ± 0.8

5.1 ± 0.9t

4.8 ± 0.8

4.8 ± 0.7

4.7 ± 0.8

3 (1 % acetylcholine)

6.9 ± 1.0

4.3 ± l.lH

5.6 ± l.2H

5.5 ±

Group

*p < .01 relative to other three groups

tP < .01 relative to previous value tP < .05 relative to the corresponding dapiprazole (Group 2) value 786

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1.1*

8 Hours

5.3 ± l.Ot

7

6

Fig . 1. 5

(Ponte) Mean pupillary diameter hefi)re and after intraocular miotic irrigation. TO = before irrigation (after IOL implantation); Tl = after wound closure.

4 ~---------------------------------------------------

TO

T1

-

2h

CONTROL

4h

8h

~ ACETYLCHOLINE

After wound closure Groups 2 and 3 exhibited a significant reduction in diameter; this was significantly greater (P < .05) in the acetylcholine group (Group 3). No variation was seen in Group 1. Two hours after surgery there was still a significant difference between the mean pupillary diameter of dapiprazole (Group 2) and acetylcholine cases (Group 3). However, now the acetylcholine eyes exhibited a larger pupil than measured at wound closure, while pupils in the dapiprazole cases became smaller. Two hours later the difference between Groups 2 and 3 was nearly the same, while eight hours after surgery the difference between them was reduced although still significant. The relationship between the mean pupillary diameter in Group 1 (control) and in the groups in which a miotic was used was similar to that described in Part I. The intraocular pressure values are shown in Table 3 and Figure 2. The preoperative lOP values were comparable in the three groups. Similarly, the increased lOP values in the three groups at the sixth hour after surgery did not significantly differ by Student's t-test. On the contrary, the mean percentage lOP increase was significantly higher in Group 1 (control) than in the groups in which a miotic was used. Twenty-four hours after surgery the lOP values had almost returned to normal in all three groups . Table 4 and Figure 3 show the mean corneal endothelial cell density before and one and four months after surgery. A significant reduction in endothelial cell population was seen in all groups one month after surgery, and another slight, not significant, reduction was seen at the fourth month. The final mean decrease did not significantly diffe r J CATARACT

DAPIPRAZOLE

in the three groups. No cases of uveitis or corneal decompensation were found during the four month follow-up. One case of clinical CME was found in the acetylcholine group. DISCUSSION Our data showed that the effect of dapiprazole and acetylcholine on pupillary diameter after ECCE with posterior chamber IOL implantation was similar but not identical. The former produced a relatively mild, slowly increasing and long-lasting miosis, whereas the latter caused a strong, fast and transient one. These findings can be explained if we recall that mydriatic agents such as tropicamide and phenylephrine maintain their effect for at least six hours. l Acetylcholine, by directly stimulating the neuromuscular parasympathetic junction , can rapidly overcome the mydriatic effect, but only transiently because of the presence of uveal cholinesTable 3. Mean lOP (mm Hg ± SD) before and after surgery. Postoperatively 6 Hours 24 Hours

Group

Preoperatively

1 (control)

14.84 ± 2.97 21.74 ± 10.0.'3* 1.5.63 ± 5.72 [41.1 ± 39.8lt

2 (dapiprazole)

15 .88 ± 2.72 19.00 ± 6.97* 16.26 ± 4.13 [16.4 ± 23.0J

15.11 ± 2.97 18.00 ± 5.71* 16.01 ± 3.62 3 [17.1 ± 18.6] (acetylcholine)

*p < tP <

.05 relative to preoperative value .05 relati\'e to other two grollps' vallies In brackets, mean % lOP increase ± SD

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25

20

Fig. 2. 15

(Ponte) 1'.lean intraocular pressllre before and after surge ry.

10 L--------------------------------------------------

Before

6 hours

CONTROL

24 hours

~ ACETYLCHOLINE

DAPIPRAZOLE

terases . Dapiprazole, however, progressively and firmly antagonizes phenylephrine at adrenergic receptor sites to produce a long-lasting mydriasis reversal (see Part I). Both dapiprazole and acetylcholine reduce the well-known postoperative lOP rise at the sixth hour after surgery, which is one of the maximum risk times. l l It is unclear how acetylcholine can produce such a persistent effect on lOP, which contrasts with the transient miotic action. Perhaps the strong trabecular meshwork stretching is responsible for this finding, which has been confirmed by others.l 1 The final corneal endothelial cell loss in our cases, 7.6%, agrees with data in the literature.l 2 - 14 Moreover, we found a slight decrease between the first and the fourth month control. In ECCE with posterior chamber intercapsular IOL implantation, cell loss stabilizes within three months, without Significant changes in polymegathism (cell area Table 4. Mean endothelial cell density (cell/mm 2 ± SD) in the three groups.

Group

Preoperatively

Postoperatively 1 Month 4 Months

CONCLUSIONS

1 (control)

2,219 ± 230

2,035 ± 247*

2,005 ± 242 [7.2 ± 5.4]t

2 (dapiprazole)

2,295 ± 355

2,125 ± 281*

2,103 ± 278 [7.8 ± 3.3]t

3 2,391 ± 229 (ace tylcholine)

2,213 ± 262*

2,196 ± 24R [8.0 ± 3.81 t

*p < .05 relative to preoperative value t Not significant relative to each other group In hrackets, mean % cell loss relative to preoperative vallie 788

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variations) and pleomorphism (% hexagonal cells). 15 We found that neither dapiprazole nor acetylcholine significantly influenced endothelial cell loss in cases in which no miotic was used (Group 1). Our clinical data confirm the experimental safety of dapiprazole for the corneal endothelium. 9 Our findings for acetylcholine contrast with recent literature data. In fact, it has been shown that an in vitro perfusion for 15 minutes significantly alters the rabbit cornea hydration state if acetylcholine or pilocarpine is used rather than dapiprazole. 9 At 30 days after surgery, endothelial cell area (which is related to cell density) shows a significant increase if intraocular 1% acetylcholine is used, whereas no significant increase is found with external 2% pilocarpine eyedrops. S We should emphasize that the in vitro conditions are not completely comparable to the in vivo ones because of the rapid hydrolysis and washout of the small injected quantity (0.3 ml) of miotic in the latter case. We can only hypothesize that the quantity of acetylcholine injected by the authors in that study, 1 ml, was relatively more toxic than the 0.3 ml we used. Further studies are needed to clarify this point.

After ECCE with posterior chamber IOL implantation, 0.25% dapiprazole was effective in producing a persistent miosis without side effects for the postoperative clinical course and the corneal endothelium. Moreover, the drug reduced the transient postoperative lOP increase . Similarly, 1% acetvlcholine was safe for the endothelium and reduced the lOP increase. However, the miotic effect was transient and was overcome by the

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Fig . 3.

CONTROL

D

DAPIPRAZOLE

Before surgery

1 month after

(Ponte) Mean endothelial cell density hefiH'e ,md after surgery.

ACETYLCHOLINE

D

4 months after

persistent pharmacological mydriasis. It did not, therefore, satisfy all the requirements for a miotic agent during the first few postoperative hours. REFERENCES 1. Havener WHo Ocular Pharmacology. St Louis. CV Mosbv, 1978; 218-328 2. Apple DJ, Mamalis N. Loftfield K. et al. Complications of intraocular lenses. A historical and histopathological review. Sur\' Ophthalmol 1984: 29:1-,54 .3. Gall enga PE . r-.lastropasqua L, Lobefalo L,Mancini A. Uso intraope ratorio de l dapiprazolo. Nota preliminare. Proc Symp Aspctti Oftalmologici. XXVI Giornate tl-led Inte rnaz, Vibn , Vale ntia, 1986: 53-56 4. McKinzie J\V, Boggs MB Jr. Comparison of postoperative intraocular pressures after use of Miochol and Miostat. J Cataract Refi'act Surg 1989; 15: 185-190 5. Vaughn ED. Hull OS. Green K. Effect of intraocular miotics on corneal endothe lium. Arch Ophthalmol 1978: 96:1897-1900 6. Olson RI, Kolodner H. Riddle P, Escapini H Jr. Commonly used intraocular medications and the corneal endothelium. Arch Ophthalmol 1980; 98:2224-2226 I. Yee R\V, Edelhause r HF, Comparison of intraocular acetylcholine and carboch,,1. J Cataract Refract Surg 1986; 12:18-22

8. Menchini U, Scialdone A, Fantaguz:li S. et al. Clink'al evaluation of the effect of acetvlcholine on the corneal endothelium. J Cataract Refract 'Surg 1989; 15:421-424 9. Cerulli L, Ricci F, Pocobelli A. et al. Intraocular miotics and corneal endothelium. an in viti'll study. Ital J Ophthalmol 1989; III:121-1 30 10. Prosdoeimo G , De Marco D. Intraocular dapiprazole to reve rse mydriasis during extracapsular cataract extraction (letter). Am J Ophthalmol 1988; 105:321-322 II. Hollands RH, Drance SM, Schulzer M. The effect of acetylcholine on early postoperative intraocular pressure . Am J Ophthalmol 1987: 103:749-753 12. Azen SP, Hurt A, Steel 0 , et al. Effects of the Shearing poste rior chamber intraocular lens o n the corneal endothelium. Am J Ophthalmol 1983; 95:798-802 1.3. Liesegang TJ. Bourne WM, I1strup OM. Short- and longterm endothelial cell loss associated with cataract ext raction and intraocular lens implantation. Am J Ophthalmol1984; 97:32-39 14 . Bourne WM, Liesegang TJ. Waller RR, I1strup OM . The effect of sodium h yaluronate on endnthelial cell damage during extracapsul ar cataract extraction and posterior chamber lens implantation. Am J Ophthalmol 1984: 98: 759-762 1.5. !\'Iatsuda M, Miyake K. Inaha M . Lon g-term corneal endothelial changes afte r intraocular lens implantation, Am J Ophthalmol 19i18; 105:248-252

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