Documenta Ophthalmologica 81: 293-300, 1992. 9 1992 Kluwer Academic Publishers. Printed in the Netherlands.
The effect of Indomethacin, Diclofenac and Flurbiprofen on the maintenance of mydriasis during extracapsular cataract extraction KONSTANTINOS PSILAS, CHRIS K A L O G E R O P O U L O S , E M A N U E L LOUCATZICOS, IOANNIS ASPROUDIS & G E O R G E PETROUTSOS University Eye Clinic of Ioannina, Ioannina, Greece Accepted 9 July 1992
words: Diclofenac, Extracapsular cataract extraction (ECCE), domethacin, Surgically induced miosis (SIM) Key
Flurbiprofen, In-
Abstract. Surgically induced miosis (SIM) frequently occurs during extracapsular cataract
extraction (ECCE). A randomized clinical trial was performed to evaluate the effect of 3 nonsteroidal antiinflammatory drugs Indomethacin 1%, Diclofenac 0,1% and Flurbiprofen 0.03%, administered topically before ECCE, on the maintenance of mydriasis during surgery. The patients were grouped based on the type of NSAID given preoperatively in addition to the standard mydriatic agents: 46 patients in group A (Indomethacin), 40 patients in B (Diclofenac), 44 patients in C (Flurbiprofen) and 34 patients formed control group D (no NSAID was instilled). Horizontal pupillary diameter measurements were taken, using a caliper, immediately prior to surgery (step 0), after capsulotomy (step I), after expression of the lens nucleus (step II) and after irrigation-aspiration of the cortical remnants (step III). Differences in pupillary diameter between step 0 and the different surgical steps were used as indices of pupillary constrictions observed in the 4 groups. A significantly less pupillary constriction was found in groups A and C than in D between steps 0 and II (p = 0.01) and in groups A and C than in B and D between steps 0 and III (p = 0.001). Our results show that Indomethacin 1% and Flurbiprofen 0.03%, compared to Diclofenac 0.1% and no NSAID regime, are significantly more effective in maintaining mydriasis during cataract surgery. Abbreviations: NSAID-nonsteroidal
antiinflammatory drug; PGs-prostaglandins; C O cyclooxygenase; COls-cyclooxygenase inhibitors; SIM-surgically induced miosis; P D pupillary diameter; ECCE-extracapsular cataract extraction; PCIOL-Posterior chamber intraocular lens; L S D - linear significant difference
Introduction Intraoperative reduction of mydriasis in cataract surgery is a frequently occurring problem which hampers adequate anterior capsulotomy, complete removal of cortical remnants of the lens and the ease in the implantation of a posterior chamber intraocular lens (PCIOL). The clinical use of nonsteroidal antiinflammatory drugs (NSAIDs) in reducing the amount of surgically induced miosis (SIM) during ECCE and PCIOL implantation has been previously reported [1-6].
294 Several studies [7-9] performed on animal models have shown the effect of prostaglandins (PGs) and substance P on the iris sphincter. However, it has only recently been shown that substance P has a miotic effect on the human eye [Malfroy et al, unpublished data, presented at the 1989 ARVO Annual Meeting]. The mechanisms of action of autacoids involved in the SIM remain unclear. It has been suggested [10] that in the rabbit PGs have no miotic effect, although they may potentiate the miotic effects of other autacoids, such as substance P. The clinical use of cyclooxygenase inhibitors (COIs) could therefore be justified, since CO is an enzyme in the prostaglandin synthesis pathway [11]. This approach, however, cannot deduce the direct involvement of PGs in miosis induction in the human. Indomethacin, Flurbiprofen and Diclofenac are NSAIDs which inhibit the PG synthesis by inhibiting CO. The efficacy of Indomethacin and more recently of Flurbiprofen in the maintenance of mydriasis during ECCE is well documented [1, 2, 4, 6, 12, 13]. Diclofenac is however a new drug with a limited clinical reports [5]. The purpose of this study was to compare the efficacies of Indomethacin, 1%, Flurbiprofen 0.03% and Diclofenac 0.1% ophthalmic solutions in maintaining mydriasis during cataract surgery.
Materials and methods
One hundred and sixty-four (164) patients with senile cataract were included in our study. The following patients were excluded: those with a past history of anterior uveitis, herpetic keratouveitis, glaucoma, prior ocular surgery or trauma, those with iris atrophy as well as those receiving corticosteroids or antiglaucomatous eye drops or treated systemically with corticosteroids or NSAIDs. Patients who present diabetes mellitus and heart disease were also excluded from the trial. All 164 patients underwent uncomplicated ECCE and PCIOL implantation. Therefore, this total did not include six cases with intraoperative rupture of the posterior capsule and one case with intraoperative iris trauma. The ages of patients ranged from 50 to 89 years. Cases were randomized to receive one of the four preoperative treatments in addition to the routine mydriasis regime; ophthalmic solution 1% Indomethacin was instilled in 46 patients (group A), 0.1% Diclofenac in 40 patients (Group B), 0.03% Flurbiprophen in 44 patients (Group C). Patients in group D (34, Control) did not receive any NSAID. One drop of the assigned drug was instilled 4 times: at 3 hours, 2 hours, 1 hour and 30 minutes before surgery. Mydriasis was achieved by instillation of tropicamide 0.5% and phenylephrine 5% 5 times at equal intervals of 10 minutes, starting 1 hour before surgery.
295 Retrobulbar anaesthesia was carried out with a mixture of 0.5% bupivacaine hydrochloride and 2% lidocaine hydrochloride cum adrenaline in a ratio of 1"189 The surgery was performed by a group of ophthalmologists highly experienced in ECCE technique in order to avoid excessive intraoperative manipulation of the iris. In all cases the length of the operation uniformly did not exceed 30 minutes until the complete removal of lens cortical material. ECCE technique included the following steps: Through a corneoscleral puncture, made at the 12 o'clock position, a cystotome was inserted into the anterior chamber and a can-opener anterior capsulotomy was done. The anterior chamber was opened with scissors along a corneoscleral incision and lens nucleus was expressed. The lens cortical material was then removed using a manual irrigation-aspiration technique. Balanced salt solution (BSS) was used to irrigate lens remnants. No adrenaline solution was used during the operation. Sodium hyaluronate 1% (Healon) was used only after the complete removal of cortical material, just before IOL insertion, in order to facilitate the PCIOL implantation. Mydriasis was evaluated, before and during surgery, by measuring the pupillary diameters (PD) horizontally under operating-microscope visualization by means of a caliper with a 0.5 mm measuring scale. Surgeons were unaware of the randomized assigned treatment groups before and during surgery. PD measurements were taken preoperatively, just before conjuctival incision (step 0) and just after capsulotomy (step I), nucleus expression (step II) and complete removal of lens cortical material (step III). The data analysis was based on mydriasis loss during surgery. A loss of mydriasis was defined as the difference in horizontal PD between the initial measurement (step 0) and the measurements at the following steps I, II and III. Statistical analysis of data of mydriasis loss was carried out by means of parametric procedures: one-way analysis of variance and linear significant difference (LSD) multiple range analysis with 95 percent confidence limits. To ascertain randomization, the distribution of sex, iris colour, pseudoexfoliation, age and initial mydriasis (step 0), among the groups, was tested using either chi-square test or one-way analysis of variance.
Results
All of the following variables sex, iris colour and pseudoexfoliation were equally distributed among the groups (chi-square test; p > 0.05). The mean age (---standard deviation) of the patients was 70.8 -+-9.2 years in group A, 72.5 _+9 in group B, 72.8 --- 9.3 in group C and 72.7 --- 10.1 in group D. Just before conjuctival incision (step 0) mean (-+standard deviation)
296 horizontal pupillary diameters (in mm) were 8.08 -+ 0.96 (group A), 8.41 + 1.1 (group B), 7.95 + 1.08 (group C) and 8.47-+ 0.87 (group D). One-way analysis of variance showed that there were no significant differences among the groups with regard to mean age (F-ratio = 0.43, p-value: =0.72) and mean horizontal pupillary diameter at step 0 (Fratio = 2.42, p-value = 0.06). Mydriasis loss data of the 4groups during surgery are shown in Table 1. There were significant differences in mean decrease of horizontal PD among the groups at step II and step III (Table 1). LSD multiple range analysis for step II showed that in 2 homogeneous groups (A, C, B and B, D) the significant decrease in PD was observed when the values in groups A and C were compared against that in D. The mean SIM after nucleus expression was significantly smaller in Indomethacin group and Flurbiprofen group than in control group. The mean SIM in Diclofenac group was not significantly different from those of Indomethacin, Flurbiprofen or control group. For step III, multiple range analysis showed that in homogeneous groups A, C and B, D the significant decrease in PD was seen when groups A and C were compounded against B and D. The mean SIM after removal of cortical material was significantly smaller in Indomethacin group and Flurbiprofen group than in Diclofenac and control groups. A smaller SIM was observed in Diclofenac group than in control group but this difference was not significant. The mean SIM for each group at different steps of surgery is shown in Figure 1. According to Table 1 and Figure 1 the larger part of SIM (from the start of the operation) in all groups took place preceding the irrigation-aspiration of cortical lens material, i.e. after nucleus expression (step II), although between steps II and III there also was a further but of a relatively lesser degree of SIM. In addition, it is important to note that in control group there is a consistently larger decrease of PD, after nucleus expression and cortical material removal, than in Diclofenac group. However, this difference is relatively reduced at step lII, at which the difference between the Table I. Decreases in PD (mean _+SD; mm) after capsulotomy (step I), nucleus removal (step II) and cortical material removal (step III) in 164 patients subjected to different NSAID treatments* in addition to the standard mydriatic regime
Steps
I II III
Groups (number of patients)
One way analysis of variance
A(46)
B(40)
C(44)
D(34)
F-ratio
p-value
0.60 -+ 0.53 1.32 -+ 0,8 2.23 +- 0.96
0.67 -+ 0.53 1.66 --- 1.08 2.77 -+ 1.24
0.78 -+ 0.72 1,56 -+ 1.06 2,25 -+ 1.1
0.68 -+-0.6 2.11 -+ 1.24 3.11 -+ 1.16
0.61 3.81 5.71
0.6 0.01 0.001
P D - p u p i l l a r y diameter; S D - s t a n d a r d deviation; N S A I D - n o n s t e r o i d a l antiinflammatory drug. Group A: Indomethacin; Group B: Diclofenac; Group C: Flurbiprofen; Group D: no NSAID.
297
31
Mean PD d e c r e a s e
(Rim)
f
/ //
o ~'oup A o 6roup B 9 ~roup C
-,Group D
ur
0
j
0
I
II
J
III
Fig. 1. Mean pupiUary diameter (PD) decrease in the Indomethacin (A), Diclofenac (B), Flurbiprofen (C) and control group (D) at the different steps of the operation: (I) after capsulotomy, (II) after nucleus expression, and (III) after cortical material removal.
mean SIM in Diclofenac group and that in either Indomethacin or Flurbiprofen group is significant (Table 1, Figure 1). The distributions of PD decrease for all groups after complete removal of cortical material are shown in Table 2; the majority of cases in group A and C experienced PD decreases no more than 2 ram, while in group B and D experienced decreases more than 2 ram. Table 2. Frequency distribution of decreases in PD at step III for groups receiving NSAID and for control group (in %)
PD decreases (mm) >4 >3-4 >2-3 > 1-2 ~
The effect of Indomethacin, Diclofenac and Flurbiprofen on the maintenance of mydriasis during extracapsular cataract extraction KONSTANTINOS PSILAS, CHRIS K A L O G E R O P O U L O S , E M A N U E L LOUCATZICOS, IOANNIS ASPROUDIS & G E O R G E PETROUTSOS University Eye Clinic of Ioannina, Ioannina, Greece Accepted 9 July 1992
words: Diclofenac, Extracapsular cataract extraction (ECCE), domethacin, Surgically induced miosis (SIM) Key
Flurbiprofen, In-
Abstract. Surgically induced miosis (SIM) frequently occurs during extracapsular cataract
extraction (ECCE). A randomized clinical trial was performed to evaluate the effect of 3 nonsteroidal antiinflammatory drugs Indomethacin 1%, Diclofenac 0,1% and Flurbiprofen 0.03%, administered topically before ECCE, on the maintenance of mydriasis during surgery. The patients were grouped based on the type of NSAID given preoperatively in addition to the standard mydriatic agents: 46 patients in group A (Indomethacin), 40 patients in B (Diclofenac), 44 patients in C (Flurbiprofen) and 34 patients formed control group D (no NSAID was instilled). Horizontal pupillary diameter measurements were taken, using a caliper, immediately prior to surgery (step 0), after capsulotomy (step I), after expression of the lens nucleus (step II) and after irrigation-aspiration of the cortical remnants (step III). Differences in pupillary diameter between step 0 and the different surgical steps were used as indices of pupillary constrictions observed in the 4 groups. A significantly less pupillary constriction was found in groups A and C than in D between steps 0 and II (p = 0.01) and in groups A and C than in B and D between steps 0 and III (p = 0.001). Our results show that Indomethacin 1% and Flurbiprofen 0.03%, compared to Diclofenac 0.1% and no NSAID regime, are significantly more effective in maintaining mydriasis during cataract surgery. Abbreviations: NSAID-nonsteroidal
antiinflammatory drug; PGs-prostaglandins; C O cyclooxygenase; COls-cyclooxygenase inhibitors; SIM-surgically induced miosis; P D pupillary diameter; ECCE-extracapsular cataract extraction; PCIOL-Posterior chamber intraocular lens; L S D - linear significant difference
Introduction Intraoperative reduction of mydriasis in cataract surgery is a frequently occurring problem which hampers adequate anterior capsulotomy, complete removal of cortical remnants of the lens and the ease in the implantation of a posterior chamber intraocular lens (PCIOL). The clinical use of nonsteroidal antiinflammatory drugs (NSAIDs) in reducing the amount of surgically induced miosis (SIM) during ECCE and PCIOL implantation has been previously reported [1-6].
294 Several studies [7-9] performed on animal models have shown the effect of prostaglandins (PGs) and substance P on the iris sphincter. However, it has only recently been shown that substance P has a miotic effect on the human eye [Malfroy et al, unpublished data, presented at the 1989 ARVO Annual Meeting]. The mechanisms of action of autacoids involved in the SIM remain unclear. It has been suggested [10] that in the rabbit PGs have no miotic effect, although they may potentiate the miotic effects of other autacoids, such as substance P. The clinical use of cyclooxygenase inhibitors (COIs) could therefore be justified, since CO is an enzyme in the prostaglandin synthesis pathway [11]. This approach, however, cannot deduce the direct involvement of PGs in miosis induction in the human. Indomethacin, Flurbiprofen and Diclofenac are NSAIDs which inhibit the PG synthesis by inhibiting CO. The efficacy of Indomethacin and more recently of Flurbiprofen in the maintenance of mydriasis during ECCE is well documented [1, 2, 4, 6, 12, 13]. Diclofenac is however a new drug with a limited clinical reports [5]. The purpose of this study was to compare the efficacies of Indomethacin, 1%, Flurbiprofen 0.03% and Diclofenac 0.1% ophthalmic solutions in maintaining mydriasis during cataract surgery.
Materials and methods
One hundred and sixty-four (164) patients with senile cataract were included in our study. The following patients were excluded: those with a past history of anterior uveitis, herpetic keratouveitis, glaucoma, prior ocular surgery or trauma, those with iris atrophy as well as those receiving corticosteroids or antiglaucomatous eye drops or treated systemically with corticosteroids or NSAIDs. Patients who present diabetes mellitus and heart disease were also excluded from the trial. All 164 patients underwent uncomplicated ECCE and PCIOL implantation. Therefore, this total did not include six cases with intraoperative rupture of the posterior capsule and one case with intraoperative iris trauma. The ages of patients ranged from 50 to 89 years. Cases were randomized to receive one of the four preoperative treatments in addition to the routine mydriasis regime; ophthalmic solution 1% Indomethacin was instilled in 46 patients (group A), 0.1% Diclofenac in 40 patients (Group B), 0.03% Flurbiprophen in 44 patients (Group C). Patients in group D (34, Control) did not receive any NSAID. One drop of the assigned drug was instilled 4 times: at 3 hours, 2 hours, 1 hour and 30 minutes before surgery. Mydriasis was achieved by instillation of tropicamide 0.5% and phenylephrine 5% 5 times at equal intervals of 10 minutes, starting 1 hour before surgery.
295 Retrobulbar anaesthesia was carried out with a mixture of 0.5% bupivacaine hydrochloride and 2% lidocaine hydrochloride cum adrenaline in a ratio of 1"189 The surgery was performed by a group of ophthalmologists highly experienced in ECCE technique in order to avoid excessive intraoperative manipulation of the iris. In all cases the length of the operation uniformly did not exceed 30 minutes until the complete removal of lens cortical material. ECCE technique included the following steps: Through a corneoscleral puncture, made at the 12 o'clock position, a cystotome was inserted into the anterior chamber and a can-opener anterior capsulotomy was done. The anterior chamber was opened with scissors along a corneoscleral incision and lens nucleus was expressed. The lens cortical material was then removed using a manual irrigation-aspiration technique. Balanced salt solution (BSS) was used to irrigate lens remnants. No adrenaline solution was used during the operation. Sodium hyaluronate 1% (Healon) was used only after the complete removal of cortical material, just before IOL insertion, in order to facilitate the PCIOL implantation. Mydriasis was evaluated, before and during surgery, by measuring the pupillary diameters (PD) horizontally under operating-microscope visualization by means of a caliper with a 0.5 mm measuring scale. Surgeons were unaware of the randomized assigned treatment groups before and during surgery. PD measurements were taken preoperatively, just before conjuctival incision (step 0) and just after capsulotomy (step I), nucleus expression (step II) and complete removal of lens cortical material (step III). The data analysis was based on mydriasis loss during surgery. A loss of mydriasis was defined as the difference in horizontal PD between the initial measurement (step 0) and the measurements at the following steps I, II and III. Statistical analysis of data of mydriasis loss was carried out by means of parametric procedures: one-way analysis of variance and linear significant difference (LSD) multiple range analysis with 95 percent confidence limits. To ascertain randomization, the distribution of sex, iris colour, pseudoexfoliation, age and initial mydriasis (step 0), among the groups, was tested using either chi-square test or one-way analysis of variance.
Results
All of the following variables sex, iris colour and pseudoexfoliation were equally distributed among the groups (chi-square test; p > 0.05). The mean age (---standard deviation) of the patients was 70.8 -+-9.2 years in group A, 72.5 _+9 in group B, 72.8 --- 9.3 in group C and 72.7 --- 10.1 in group D. Just before conjuctival incision (step 0) mean (-+standard deviation)
296 horizontal pupillary diameters (in mm) were 8.08 -+ 0.96 (group A), 8.41 + 1.1 (group B), 7.95 + 1.08 (group C) and 8.47-+ 0.87 (group D). One-way analysis of variance showed that there were no significant differences among the groups with regard to mean age (F-ratio = 0.43, p-value: =0.72) and mean horizontal pupillary diameter at step 0 (Fratio = 2.42, p-value = 0.06). Mydriasis loss data of the 4groups during surgery are shown in Table 1. There were significant differences in mean decrease of horizontal PD among the groups at step II and step III (Table 1). LSD multiple range analysis for step II showed that in 2 homogeneous groups (A, C, B and B, D) the significant decrease in PD was observed when the values in groups A and C were compared against that in D. The mean SIM after nucleus expression was significantly smaller in Indomethacin group and Flurbiprofen group than in control group. The mean SIM in Diclofenac group was not significantly different from those of Indomethacin, Flurbiprofen or control group. For step III, multiple range analysis showed that in homogeneous groups A, C and B, D the significant decrease in PD was seen when groups A and C were compounded against B and D. The mean SIM after removal of cortical material was significantly smaller in Indomethacin group and Flurbiprofen group than in Diclofenac and control groups. A smaller SIM was observed in Diclofenac group than in control group but this difference was not significant. The mean SIM for each group at different steps of surgery is shown in Figure 1. According to Table 1 and Figure 1 the larger part of SIM (from the start of the operation) in all groups took place preceding the irrigation-aspiration of cortical lens material, i.e. after nucleus expression (step II), although between steps II and III there also was a further but of a relatively lesser degree of SIM. In addition, it is important to note that in control group there is a consistently larger decrease of PD, after nucleus expression and cortical material removal, than in Diclofenac group. However, this difference is relatively reduced at step lII, at which the difference between the Table I. Decreases in PD (mean _+SD; mm) after capsulotomy (step I), nucleus removal (step II) and cortical material removal (step III) in 164 patients subjected to different NSAID treatments* in addition to the standard mydriatic regime
Steps
I II III
Groups (number of patients)
One way analysis of variance
A(46)
B(40)
C(44)
D(34)
F-ratio
p-value
0.60 -+ 0.53 1.32 -+ 0,8 2.23 +- 0.96
0.67 -+ 0.53 1.66 --- 1.08 2.77 -+ 1.24
0.78 -+ 0.72 1,56 -+ 1.06 2,25 -+ 1.1
0.68 -+-0.6 2.11 -+ 1.24 3.11 -+ 1.16
0.61 3.81 5.71
0.6 0.01 0.001
P D - p u p i l l a r y diameter; S D - s t a n d a r d deviation; N S A I D - n o n s t e r o i d a l antiinflammatory drug. Group A: Indomethacin; Group B: Diclofenac; Group C: Flurbiprofen; Group D: no NSAID.
297
31
Mean PD d e c r e a s e
(Rim)
f
/ //
o ~'oup A o 6roup B 9 ~roup C
-,Group D
ur
0
j
0
I
II
J
III
Fig. 1. Mean pupiUary diameter (PD) decrease in the Indomethacin (A), Diclofenac (B), Flurbiprofen (C) and control group (D) at the different steps of the operation: (I) after capsulotomy, (II) after nucleus expression, and (III) after cortical material removal.
mean SIM in Diclofenac group and that in either Indomethacin or Flurbiprofen group is significant (Table 1, Figure 1). The distributions of PD decrease for all groups after complete removal of cortical material are shown in Table 2; the majority of cases in group A and C experienced PD decreases no more than 2 ram, while in group B and D experienced decreases more than 2 ram. Table 2. Frequency distribution of decreases in PD at step III for groups receiving NSAID and for control group (in %)
PD decreases (mm) >4 >3-4 >2-3 > 1-2 ~
