Intracameral mydriatics in phacoemulsification surgery obviate the need for epinephrine irrigation

Authors


Björn Lundberg
Department of Clinical Sciences/ Ophthalmology
Umeå University Hospital
SE-901 85 Umeå
Sweden
Tel: + 46 90 785 24 23
Fax: + 46 90 13 34 99
Email: bjorn.lundberg@ophthal.umu.se

Abstract.

Purpose:  To evaluate the possibility of removing epinephrine from the irrigating solution in phacoemulsification surgery when using intracameral mydriatics (ICMs).

Methods:  We carried out a prospective, randomized, double-blinded study of 140 patients with age-related cataracts, scheduled for unilateral phacoemulsification. The first part of the study involved 90 patients divided into two groups. Patients in both groups were given 150 µl ICMs at the beginning of the procedure. In group 1, 0.6 µg/ml epinephrine was added to the irrigating balanced salt solution. No epinephrine was added to the irrigation solution used in group 2. The second part of the study involved 50 patients, all of whom were given topical mydriatics (TMs) and then similarly divided into two groups and treated as in the first study setting.

Results:  With ICMs, pupil sizes generally increased during the procedures. Remarkably, this increase was significantly greater without epinephrine (13 ± 19% versus 4 ± 14%; p = 0.02). In the TMs setting, pupil sizes decreased intraoperatively in both groups; significantly more without epinephrine (− 5 ± 4% versus − 12 ± 7%; p < 0.001).

Conclusions:  An irrigating solution without epinephrine can safely be used with ICMs. The increase in pupil size during the procedure is greater without epinephrine. This study also confirms earlier findings that epinephrine is beneficial when using TMs.

Introduction

Adequate mydriasis is required for any cataract procedure and is generally achieved by topical administration of anticholinergic and sympathomimetic mydriatic agents such as cyclopentolate and phenylephrine. Pupillary constriction during cataract surgery may increase the risk for complications, including iris damage, incomplete cortex removal, posterior capsule rupture, vitreous loss and dislocation of lens material (Goodman et al. 1989). Maintenance of mydriasis during the whole procedure is therefore crucial. This can be achieved in different ways: mechanically, such as with iris retractors (de Juan & Hickingbotham 1991), or pharmacologically, such as with topical non-steroidal anti-inflammatory drugs (NSAIDs) (Keates & McGowan 1984; Solomon et al. 1997) or with epinephrine (Duffin et al. 1983; Corbett & Richards 1994; Liou & Chen 2001).

Nowadays, preservative-free epinephrine in low concentrations is commonly used in the irrigating solution to maintain mydriasis. This practice avoids the problems encountered previously with epinephrine with a low pH and toxic preservatives (Slack et al. 1990), and no apparent side-effects have been noted (Fell et al. 1989; Liou & Yang 1998; Liou et al. 2002). However, as epinephrine is unstable in a solution with physiological pH, time-consuming repeated blending procedures are needed (Sweetman 2002).

We have developed a mydriatic regimen using intracameral mydriatics (ICMs), which we have demonstrated as safe and efficient for routine cataract surgery (Lundberg & Behndig 2003; Behndig & Eriksson 2004). At present, approximately 1000 packages of ICMs are prepared yearly by the Product and Laboratory Department of the Swedish Pharmacy (Apoteksbolaget AB, Umeå, Sweden). Roughly, this amount is sufficient for 5–10% of cataract surgeries performed each year in Sweden.

Contrary to events when using topical mydriatics (TMs), pupil size increases throughout a procedure with ICMs (Lundberg & Behndig 2003). The present study was therefore conducted to evaluate whether it is necessary to include epinephrine in the irrigating solution when using ICMs.

Materials and Methods

This prospective, randomized study was approved by the Research Ethics Committee of Umeå University, Umeå, Sweden. A total of 140 patients with age-related cataracts, all of whom were scheduled for unilateral phacoemulsification and intraocular lens (IOL) implantation, were asked to participate. Once they had given informed consent, they were randomly assigned to the various study groups.

Patients with diabetic retinopathy with proliferative changes, glaucoma medication with pilocarpine, a history of uveitis, previous intraocular surgery, previous eye trauma, malformations of the anterior segment, conditions where mechanical pupil dilatation was considered, only one functioning eye, signs of corneal disease, scheduled bilateral operations, ‘serious general disease’ or cognitive insufficiency were not included.

All patients were given three drops of tetracaine 1% at 5 mins prior to surgery. The first sample of 90 patients was divided into two groups. Group 1 was given 150 µl ICMs at the beginning of the procedure, which was performed using balanced salt solution (BSS) containing 0.6 µg/ml epinephrine as irrigating solution. Intracameral mydriatics contains 150 µl cyclopentolate 0.1%, phenylephrine 1.5% and xylocaine 1% without preservatives (Lundberg & Behndig 2003). It is administrated intracamerally through the side port via a syringe with a blunt cannula. Group 2 underwent the same procedure, but without epinephrine in the irrigating solution. The containers with irrigating solution were coded, so neither operating surgeon nor patient was aware of the treatment given.

The second sample of 50 patients were given TMs in all cases. Three drops each of cyclopentolate 1% and phenylephrine 10% were given at 15-min intervals. In addition, these patients received 150 µl preservative-free xylocaine 1% intracamerally at the beginning of the procedure. Group 1 was given irrigating solution with epinephrine and group 2 received irrigating solution without epinephrine.

All 140 procedures were performed by two surgeons (BL and AB), with equal distribution of cases. The standardized surgical technique has been detailed previously (Behndig & Lundberg 2002; Lundberg & Behndig 2003). Postoperatively, dexamethasone 0.1% was given three times daily for 3 weeks. No intraocular pressure (IOP)-reducing agents were given postoperatively except to patients with glaucoma, who continued with their regular drops.

In both the ICMs and TMs settings, the first 15 + 15 cases in each group (with and without epinephrine in the irrigating solution, respectively) were analysed as follows.

Preoperatively, and at 1 day and 1 month postoperatively, pupil size and central, nasal and temporal corneal thickness were measured with the Orbscan II® (Bausch & Lomb Surgical, Inc., San Dimas, CA, USA) (Yaylali et al. 1997; Marsich & Bullimore 2000). Central corneal endothelial photographs were taken with the Topcon SP-2000P specular microscope (Topcon Europe BV, Capelle a/d Ijssel, the Netherlands) preoperatively and at 1 month postoperatively. Corneal endothelial morphology was calculated from a central cluster of 55 cells from each photograph as previously detailed (Behndig et al. 2001). Apart from the endothelial cell count, the hexagon shape factor (HSF) (Behndig et al. 2001) quantifying the deviation from the ideal hexagonal cell shape, the degree of cell elongation (DE) and the coefficient of variation in cell size (CV) were calculated, and pre- and postoperative values were compared. Best corrected visual acuity (BCVA) was measured preoperatively and 1 month postoperatively, using the ETDRS-fast protocol (Klein et al. 1983; Camparini et al. 2001), and IOP was measured preoperatively and at 1 day and 1 month postoperatively with Goldmann applanation tonometry. Aqueous cells and flare were graded on scales of 0−5 and 0−4, respectively, preoperatively, and at 1 day and 1 month postoperatively. To rule out preoperative differences between the two groups, nuclear, anterior cortical and posterior cortical cataract was graded preoperatively using the Lens Opacities Classification System (LOCS) III protocol (Chylack et al. 1993). The presence of pseudoexfoliations was registered in all cases, as was iris colour (graded as blue, mixed or brown), age and sex. Intraoperatively effective phaco time (EPT), total surgical time and the quantity of irrigating solution used were recorded and the total amount of epinephrine given in each case was calculated.

Pupil size during the procedure was registered from video recordings. Firstly, the width of the blade of a 2.75-mm slit knife held over the incision site was measured directly on the monitor screen. Secondly, two perpendicular pupil diameters were measured from the same still picture. The pupil diameter, in mm, was calculated as the mean pupil diameter/blade width × 2.75, as previously detailed (Lundberg & Behndig 2003). Pupil size was determined before the first injection of the ophthalmic viscosurgical device (OVD) (T1), after the first OVD injection (immediately before performing the capsulorhexis; T2), before the second OVD injection (after phacoemulsification; T3), and after the second OVD injection (immediately before inserting the IOL; T4).

In four examinations, no corneal thickness data were obtainable. In the ICMs group, intraoperative pupil registrations before OVD injection at the end of the operation were incomplete in two cases and no pupil registration was obtainable in one case due to technical problems with the video recorder or inferior picture quality.

In the TMs group, pupil sizes at the end of the operation could not be measured in two cases for similar reasons.

Intraoperative pupil sizes were recorded in a total of 90 cases in the ICMs setting and 50 cases in the TMs setting. A binary logistic regression model was used to ascertain that no preoperative differences existed between the groups in terms of BCVA, IOP, pseudoexfoliations, iris colour, cataract classification, corneal endothelial cell count, pupil size, corneal thickness, age or sex. Mann–Whitney U-test was used for cells/flare data and Pearson bivariate correlation was used to assess the possible effect of differences in pseudoexfoliations. Student's two-tailed or paired t-test was used for all other statistical comparisons. A p-value of < 0.05 was considered statistically significant.

Results

In the ICMs setting, the pupil was significantly larger at the end of the operation (T3/T4) than at the beginning (T1/T2) in the non-epinephrine group (Table 1, Fig. 1). The increase in pupil size from T1 to T3 in the epinephrine group was also statistically significant (Table 1, Fig. 1), but, remarkably, the increase in pupil size in the ICMs cases was significantly larger without than with epinephrine (p = 0.02) (Table 2). In the TMs group, pupil sizes decreased significantly in both groups (Table 1, Fig. 2), but significantly more in the non-epinephrine group (p < 0.001) (Table 2).

Table 1.   Pupil sizes at different surgical time-points.
 Pupil size at T1 (mm)Pupil size at T3 (mm)p-valueChange in pupil size (%)*Pupil size at T2 (mm)Pupil size at T4 (mm)p-valueChange in pupil size (%)
  1. ICMs 0 = intracameral mydriatics, no epinephrine (n = 45); ICMs E = intracameral mydriatics, with epinephrine (n = 45); TMs 0 = topical mydriatics, no epinephrine (n = 25); TMs E = topical mydriatics, with epinephrine (n = 25).

  2. Pupil sizes were determined before the first injection of the ophthalmic viscosurgical device (OVD) (T1), after the first OVD injection (immediately before performing the capsulorhexis; T2), before the second OVD injection (after phacoemulsification; T3), and after the second OVD injection (immediately before inserting the IOL; T4).

  3. Change in pupil size represents the change from *T1 to T3 and from †T2 to T4.

ICMs 05.6 ± 1.36.2 ± 1.1< 0.00113 ± 196.2 ± 1.36.5 ± 1.10.0076 ± 16
ICMs E5.7 ± 1.05.9 ± 1.20.0494 ± 146.2 ± 1.06.2 ± 1.00.80 ± 10
TMs 07.7 ± 1.06.8 ± 1.2< 0.001 −  12 ± 77.9 ± 1.07.1 ± 1.1< 0.001 −  11 ± 5
TMs E7.9 ± 0.87.5 ± 0.8< 0.001 −  5 ± 48.1 ± 0.87.7 ± 0.9< 0.001 −  4 ± 5
Figure 1.

 Pupil sizes at different surgical time-points with intracameral mydriatics without epinephrine (ICM0, n = 45) and with epinephrine (ICME, n = 45) in the irrigating solution. Pupil sizes were determined before the first injection of the ophthalmic viscosurgical device (OVD) (T1), after the first OVD injection (immediately before performing the capsulorhexis; T2), before the second OVD injection (after phacoemulsification; T3), and after the second OVD injection (immediately before inserting the IOL; T4). Note that the increase in pupil size was significantly larger without than with epinephrine.

Table 2.   Change in pupil size between different surgical time-points
 Mean difference without epinephrine
(mm)
Mean difference with epinephrine
(mm)
p-value
  1. Pupil sizes were determined before the first injection of the ophthalmic viscosurgical device (OVD) (T1), after the first OVD injection (immediately before performing the capsulorhexis; T2), before the second OVD injection (after phacoemulsification; T3), and after the second OVD injection (immediately before inserting the IOL; T4).

Difference in pupil size T1−T3 with ICMs0.6 ± 0.60.2 ± 0.70.02
Difference in pupil size T2−T4 with ICMs0.3 ± 0.70.0 ± 0.60.02
Difference in pupil size T1−T3 with TMs −  0.9 ± 0.4 −  0.4 ± 0.3< 0.001
Difference in pupil size T2−T4 with TMs −  0.9 ± 0.4 −  0.3 ± 0.4< 0.001
Figure 2.

 Pupil sizes at different surgical time-points with topical mydriatics, without epinephrine (TM0, n = 25) and with epinephrine (TME, n = 25) in the irrigating solution. Pupil sizes were determined before the first injection of the ophthalmic viscosurgical device (OVD) (T1), after the first OVD injection (immediately before performing the capsulorhexis; T2), before the second OVD injection (after phacoemulsification; T3), and after the second OVD injection (immediately before inserting the IOL; T4). Note that the pupils were significantly smaller without than with epinephrine at T3 and T4.

No significant difference in preoperative side-parameters was found between the two groups in the ICMs setting (overall statistics: p = 0.47). In the TMs group, significantly more patients with pseudoexfoliations received BSS without epinephrine (p = 0.046; overall statistics: p = 0.27). No significant correlation was found, however, between the presence of pseudoexfoliations and pupil size at the end of the operation or change in pupil size during the operation (p = 0.24 and p = 0.054, respectively).

We found no significant differences in perioperative parameters, such as operation time, the amount of irrigating solution used and effective phaco time between the groups. Furthermore, there were no differences in postoperative parameters, such as flare, corneal swelling and BCVA. Neither did endothelial parameters show any differences between the groups (Tables 3 and 4). The total dose of epinephrine administered was 87 ± 36 µg in ICMs patients and 76 ± 24 µg in TMs patients.

Table 3.   Selected parameters with intracameral mydriatics.
ParameterICMs with epinephrineICMs without epinephrinep-value
  1. Means ± standard deviations, except *median and interquartile ranges.

  2. P-values were calculated with Student's unpaired t-test, except †Mann–Whitney U-test.

  3. ICMs = intracameral mydriatics; BCVA = best corrected visual acuity.

Number of eyes45 (15)45 (15) 
Mean age (years)75 ± 976 ± 90.7
Mean surgical time (mins)9.7 ± 2.69.0 ± 1.90.4
Effective phaco time (EPT)7.1 ± 14.12.2 ± 2.50.2
BSS used (ml)146 ± 60131 ± 440.4
Change in BCVA (logMAR)1.8 ± 3.31.1 ± 2.50.5
Flare at day 1 (0–5)1.0 (2.0)*1.0 (1.0)*0.8
Cells at day 1 (0–4)1.0 (2.0)*1.0 (2.0)*0.7
Change in central corneal thickness at day 1 (%)9.0 ± 20.28.0 ± 8.50.09
Endothelial cell loss (%) −  4.7 ± 7.1 −  7.1 ± 15.50.6
Change in endothelial cell hexagonality (HSF)0.05 ± 0.20.07 ± 0.20.09
Change in endothelial cell elongation (DE) −  0.002 ± 0.020.008 ± 0.010.2
Change in endothelial cell polymegethism (CV)0.0001 ± 0.0080.003 ± 0.020.6
Table 4.   Selected parameters with topical mydriatics.
ParameterTMs with epinephrineTMs without epinephrinep-value
  1. Means ± standard deviations, except *median and interquartile ranges.

  2. P-values were calculated with Student's unpaired t-test, except †Mann–Whitney U-test.

  3. TMs = topical mydriatics; BCVA = best corrected visual acuity.

Number of eyes25 (15)25 (15) 
Mean age (years)73 ± 1178 ± 70.1
Mean surgical time (mins)7.9 ± 1.17.9 ± 1.31.0
Phaco total EPT3.4 ± 2.91.7 ± 1.30.06
BSS used (ml)126 ± 40123 ± 340.8
Change in BCVA (logMAR)0.5 ± 0.30.4 ± 0.20.1
Flare at day 1 (0–5)0.0 (1.0)*0.0 (1.0)*1.0
Cells at day 1 (0–4)1.0 (1.0)*1.0 (1.0)*0.9
Change in central corneal thickness at day 1 (%)18 ± 2413 ± 110.5
Endothelial cell loss (%) −  16.6 ± 17.2 −  13.1 ± 15.70.6
Change in endothelial cell hexagonality (HSF)0.07 ± 0.20.24 ± 0.30.07
Change in endothelial cell elongation (DE)0.007 ± 0.020.01 ± 0.020.4
Change in endothelial cell polymegethism (CV)0.005 ± 0.10.02 ± 0.030.3

Discussion

We have shown here that adding epinephrine to the irrigating solution does not contribute to preserving pupil size during phacoemulsification cataract surgery using ICMs. On the contrary, a greater pupil enlargement is achieved with ICMs without epinephrine in the irrigating solution than with epinephrine. The exact mechanisms behind this finding are not known, but the dilator muscle in the iris has mainly α-adrenergic and few β-adrenergic receptors. Phenylephrine is more potent in stimulating α-receptors than epinephrine. The response occurs in reverse order for β-receptors (Mishima 1982). When phenylephrine is injected into the anterior chamber, the adrenergic receptors become occupied, but when epinephrine enters the eye it may gradually compete with phenylephrine and take over some of the receptors. Being a weaker dilator, epinephrine may thus lead to a smaller pupil.

The differences in pupil sizes become less pronounced after injection of OVD, as the OVD acts as an unspecific pupil dilator.

When ICMs are given in the present dosage, the amount of phenylephrine is about 26 times the quantity of epinephrine (2250 µg : 87 µg), but much of the phenylephrine is likely to be washed out at the beginning of the operation, whereas epinephrine is continuously administered.

Pupil sizes generally decreased in the TMs setting, with or without epinephrine, but the difference between the epinephrine and non-epinephrine groups was clearly significant, with greater constriction without epinephrine. It has been suggested that the well known phenomenon of intraoperative pupil constriction is mediated via the release of prostaglandins by mechanical stimulation of the iris (Duffin et al. 1982); this study confirms that epinephrine is necessary when using TMs (Gimbel 1989; Corbett & Richards 1994; Liou & Yang 1998).

This study was not designed to compare pupil sizes between TMs and ICMs. This has been studied previously (Lundberg & Behndig 2003) and these earlier findings of smaller pupil sizes with ICMs were confirmed in the present study. The smaller pupil size achieved with ICMs, however, has been demonstrated not to have any negative clinical effects (Behndig & Eriksson 2004). Clinically, with ICMs, if the pupil is sufficiently large at the beginning of the procedure, it is likely to remain sufficiently large. A pupil that enlarges during surgery, even if it is smaller, may even be more comfortable to work with than a larger pupil that is contracting, especially if this holds true for longer, more complicated procedures. In the present study, operation times were generally short, but another study aimed at evaluating pupil constriction or dilatation with ICMs and TMs in longer procedures is ongoing.

Finally, we conclude that ICMs, which represent a secure and efficient alternative to TMs in routine phacoemulsification surgery, may potentially simplify cataract surgery procedures as ICMs obviate the need for epinephrine in irrigating solution.

Acknowledgement

These findings were presented in part at the annual Swedish Medical Congress, Älvsjö, December 2005.

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