Miotics After Modern Cataract Surgery Are History

Abstract

Purpose:

The aim of this study was to investigate the usefulness of a long-acting miotic (physostigmine) after phacoemulsification in preventing peripheral anterior synechiae (PAS), lens dislocation, and high postoperative intraocular pressure.

Methods:

This was a prospective randomized controlled trial of 400 patients (400 eyes) scheduled for phacoemulsification. Patients were randomly assigned either to receive a single application of physostigmine ointment directly after phacoemulsification or not. The main outcome measures were the change of intraocular pressure (IOP) before and after surgery, number of extra outpatient clinic visits within 4 weeks postoperatively, verbal rating pain scale (VRS), status of the angle by gonioscopy, and best corrected visual acuity (BCVA).

Results:

There was no significant difference in IOP and BCVA between both groups. There were more patients who reported a VRS score of more than 3 in the physostigmine group (P=0.021). PAS or (anterior) lens dislocation was not observed.

Conclusion:

In eyes without co-morbidity, the routine use of physostigmine ointment has lost its rationale.

Introduction

Worldwide, opacification of the lens is the major cause of visual impairment, and currently the only treatment option is surgery. The improvement of surgical techniques has made cataract surgery an ambulatory procedure.^1,2 These developments seem to justify the question whether certain traditional procedures, such as the postoperative administration of miotics such as physostigmine, are obsolete.

Physostigmine, also known as eserine, is a reversible acetylcholine esterase inhibitor. By increasing the concentration of acetylcholine at cholinergic transmission sites, receptors are continuously stimulated, causing muscle spasms.^3,4 Physostigmine has been used in the treatment of glaucoma, myasthenia gravis, and Alzheimer disease and to reverse the effect of certain overdoses of drugs.^3,5

Physostigmine was introduced in ophthalmology in 1877 to treat glaucoma by Laquer.⁶ Local application to the eye induces miosis by contraction of the musculus sphincter pupillae; this together with the contraction of the ciliary muscle facilitates outflow of the aqueous.³ Furthermore, a change in the blood–aqueous barrier reduces the inflow of aqueous humour.⁷ Both reactions reduce the intraocular pressure (IOP).⁴ After application of physostigmine, miosis becomes manifest within a few minutes and lasts for 24–72 h.⁸ Because the pupil is reduced to pinpoint size, most patients putatively attain good initial postoperative visual acuity. In cataract surgery, this pupil effect of miotics was used to prevent intraocular lens (IOL) dislocation, and it is believed that the effect of pulling the iris away from the chamber angle and incisions prevents the development of peripheral anterior synechiae (PAS).⁸ PAS alter the anterior chamber anatomy by adhesion of iris and trabecular meshwork; this may impede aqueous outflow and cause an inflammatory reaction.

Local, postoperative administration of physostigmine ointment was the traditional procedure in The Rotterdam Eye Hospital to prevent IOL dislocation and PAS. The use of such a miotic has been drastically reduced in our hospital as well as elsewhere, because many ophthalmologist no longer believe it to be of any advantage, although this has never been substantiated by solid evidence. Furthermore, physostigmine may have undesirable effects, such as muscular twitches,⁹ brow ache,³ and the good initial vision, which usually disappears after 2–3 days, may lead to an increase of visits of outpatients because they experience a reduction of vision. In view of the (still-continuing) developments in cataract surgery, the use of postoperative miotics may have lost its rationale altogether.

In this study, the usefulness of physostigmine ointment 1% (magistral formulation) after cataract surgery by phacoemulsification was evaluated with respect to the prevention of lens dislocation, development of PAS, and reduction of IOP.

Materials and Methods

Four hundred Caucasian patients (400 eyes) having phacoemulsification with IOL implantation at The Rotterdam Eye Hospital between February, 2007, and June, 2009, were recruited. Exclusion criteria were: mature, brunescent, or posterior supcapsular cataract; diabetes; age-related macular diseases; corneal diseases; glaucoma; presence of anterior synechiae and history of uveitis; chemotherapy; reaction to steroids; herpes simplex keratitis; peroperative posterior capsule rupture; or peroperative iris manipulation.

Study protocol

Eligible patients were randomized into two groups at a 1:1 ratio, i.e., with a single postoperative application of physostigmine ointment 1% (magistral formulation) or without. This was an open-label study; a double-blind placebo-controlled study would not have been achievable, because the miotic effect on pupil size is still apparent at the first follow-up visit.

Ocular examination included biomicroscopy, IOP (Goldmann applanation tonometry), and best corrected visual acuity (BCVA) by Snellen chart performed before phacoemulsification (visit 1), and 1 day (visit 2) and 4 weeks (visit 3) thereafter. Pain intensity at visit 2 was rated on a 10-point numeric verbal rating scale (VRS), with 1 indicating no pain and 10 the worst pain imaginable. We also inspected the eye with respect to paracentesis and incision leakage with fluorescein at visit 2. At visit 3, gonioscopy (three or four mirror technique) was performed to assess the anterior chamber angle and the presence of abnormalities, such as PAS. All extra-postoperative visits to the outpatient clinic between visit 2 and visit 3 were documented. A laser flare count (Laser Flare Meter, Kowa Co. Ltd, Tokyo, Japan) was performed at visit 1 and visit 3 to investigate the effect of physostigmine on the aqueous flare. During this study, after inclusion of 77 patients in group 1 and 73 patients in group 2, the Kowa-FC-1000 laser flare meter was replaced by the Kowa FM600 for technical reasons.

Concurrently with this postoperative miotic treatment study, two different postoperative steroid therapies were compared. Fifty percent received a single subconjunctival injection of betamethasone acetate (5.7 mg/mL; Celestone Chronodose, Schering-Plough) at the end of surgery and 50% of the patients were instructed to administer dexamethasone eyedrops (0.1%) thrice daily for a postoperative period of 4 weeks. Randomization of participants of the two concurrent studies, with two study arms each, was designed in a two-by-two fashion (i.e., with 100 patients assigned to each of the four possible combinations). Results of the steroid study did not interfere with the outcome of the study on which we report here. The study concluded that a single subconjunctival betamethasone acetate injection is a useful alternative to prolonged postoperative administration of dexamethasone eye drops in controlling intraocular inflammation and development of macular edema after phacoemulsification.¹⁰

Surgical technique

Phacoemulsification was performed with the Alcon Infinity Vision system unit. At completion of surgery, Dexamytrex^® ointment (Tramedico BV) was administered in all patients. Peroperative complications were recorded.

Outcome measures

Primary endpoints included the change of IOP (IOP decrease ≥10 mmHg between visit 1 and visit 2), number of extra outpatient clinic visits between visit 2 and visit 3, VRS, angle status (gonioscopy), and BCVA (Snellen). The secondary endpoint included change of aqueous flare at 4 weeks postoperatively (visit 3) compared to preoperative values (visit 1).

Statistical analysis

Statistical analysis was performed using SPSS software (version 15.0, SPSS, Inc.). The Mann–Whitney U-test was used to compare the laser flare values between the two groups. The independent sample t-test was used to compare the mean IOP and BCVA. Visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) before analysis. The Pearson chi-squared test was used to compare the IOP change and numbers of patients reporting pain scores on the VRS between both groups. A P value less than 0.05 was considered to be statistically significant.

Ethics review and registration of trial

This prospective open-label, nonmasked, randomized, controlled clinical trial was conducted in accordance with the Declaration of Helsinki (October 22, 2008) and the Medical Research Involving Human Subjects Act (WMO, March 1, 2006) at The Rotterdam Eye Hospital. The study (NTR779/ISRCTN41133247) was approved by the Medical Ethical Review Committee of the Erasmus Medical Centre Rotterdam. All patients provided written informed consent before enrollment. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.

Results

Four hundred patients were included. Excluded patients (n=38) were evenly distributed between both study groups. Reasons for exclusion were not meeting postsurgical inclusion criteria, withdrawn consent, or loss to follow-up. All excluded patients were replaced. Table 1 shows the study population characteristics. By mistake, 1 patient assigned to the physostigmine group did not receive the ointment and was reassigned to the other group instead.

Table 1.

Study Population Characteristics

	General	Group with physostigmine	Group without physostigmine
n	400	199	201
Age (years)
Average	70.8	70.4	71.2
Range	41–93	41–93	48–93
Gender (%), female	60.5%	61.3%	59.7%
Eye (%), right	53.0%	53.3%	52.7%
Visit 3, day	31.4	30.8	32.9

Occasionally, measurements could not be performed or appeared unreliable (e.g., “eye-squeezing” patients hampering IOP measurement). Therefore, the numbers of correctly completed measurements are given together with the resulting mean values and standard deviations (Tables 2 –5).

Table 2.

Intraocular Pressure (Mean mmHg±SD; Patients)

	n^a	IOP Visit 1	IOP Visit 2	IOP Visit 3	ΔIOP ≥10
Physostigmine	174–188	16±3.1	15±4.4	14±2.8	n=3
No physostigmine	183–188	16±3.3	16±4.7	14±3.0	n=2
P value		0.150	0.137	0.442	0.605

Number of patients with reliable IOP measurements.

IOP, intraocular pressure; SD, standard deviation.

Table 3.

Best Corrected Visual Acuity by Snellen chart in LogMAR (mean±SD)

	n^a	BCVA Snellen preoperative	BCVA Snellen day 1	BCVA Snellen 4 weeks
Physostigmine	168–199	0.43±0.32	0.21±0.23	0.04±0.18
No physostigmine	173–200	0.43±0.31	0.22±0.21	0.03±0.15
P value		0.785	0.526	0.680

Number of patients with reliable BCVA measurements.

BCVA, best corrected visual acuity; LogMar, logarithm of the minimum angle of resolution; SD, standard deviation.

Table 4.

Verbal Rating Scale of pain: Frequency of Patients per Score

	n^a	1	2	≥3
Physostigmine	196	155	16	25
No physostigmine	200	173	15	12
P value				0.021 ^b

Number of patients with reliable verbal pain score.

P value<0.05.

Table 5.

Laser Flare Measurement (Mean±SD)

	n^a	Preoperative	4 Weeks
Physostigmine	194–198	11.0±36.3	11.0±11.9
No physostigmine	196–200	14.8±50.8	10.9±12.2
P value		0.584	0.264

Number of patients with reliable laser flare measurements.

SD, standard deviation.

Inspection with fluorescein did not reveal any wound leakage at the first day after surgery. The mean preoperative and postoperative IOP and BCVA, and a decrease of more than 10 mmHg in IOP between visit 1 and visit 2, did not significantly differ between both groups (Tables 2 and 3).

Table 4 shows the numbers of patients reporting pain scores on the VRS. Most patients scored a pain level of 1. There were more patients who reported a pain score of more than 3 in the physostigmine group. This difference appears to be significant (Table 4).

A comparison between both groups of pre- and postoperative flare values (Table 5) did not show any statistical difference. Gonioscopy 4 weeks after cataract surgery did not reveal PAS in any patient of either group. In both groups, an equal number of 26 patients visited the outpatient clinic between the first day and 4 weeks after phacoemulsification.

Discussion

The progression of surgical techniques requires the re-evaluation of the risk of complications that may be associated with either surgery or the traditional postoperative treatment. With phacoemulsification, the incidence of postoperative complications has been substantially reduced. We assessed whether physostigmine (eserine), as a long-acting miotic, still can be of any use after phacoemulsification. In The Rotterdam Eye Hospital, a single dose of physostigmine ointment was given postoperatively together with a steroid/antibiotic ointment until about 2006.

In this study, lens dislocation or PAS were not observed in either group. Theoretically, the concurrent study with two different postoperative steroid therapies could have influenced the formation of PAS. However, this risk would have been similar in both groups with and without physostigmine.

Physostigmine did not have an effect on mean postoperative IOP, nor did any postoperative hypotonic case occur. It has been reported, however, that patients with a high preoperative IOP are more at risk to have postoperative IOP spikes.¹¹ Glaucoma patients were not included in this study and all our patients had a preoperative IOP <30 mmHg. Therefore, it cannot be excluded that physostigmine has the desired hypotensive effect for glaucoma patients.

Significant differences between both groups with respect to BCVA and laser flare value were not observed, neither preoperatively nor postoperatively. The assumed better initial postoperative visual acuity with physostigmine, due to the pinhole effect, was not confirmed by our results. In both groups, an equal number of 26 unscheduled visits to the outpatient clinic were recorded. The higher pain level at the first postoperative day in the physostigmine group may be due to muscle spasms.

No beneficial effect of physostigmine could be demonstrated. We conclude that the routine use of miotics such as physostigmine in patients with “normal” eyes has lost its rationale and, therefore, we do not recommend its routine use after phacoemulsification.

Footnotes

Acknowledgment

This study was supported by the Research Foundation SWOO Flieringa, Rotterdam. This funding organization had no role in the design or conduct of this research.

Author Disclosure Statement

The authors have no competing financial interests.

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