Intraocular miotics and postoperative inflammation

Intraocular miotics and postoperative inflammation Calvin W. Roberts, M.D.

ABSTRACT Sixty patients scheduled for planned extracapsular cataract extraction with intraocular lens (IOL) implantation were randomly assigned to receive acetylcholine chloride, carbachol, or balanced salt solution (BSS) immediately after IOl placement and at the end of the surgical case. As part of the postoperative evaluation, patients were examined at the first and eighth postoperative day with a Kowa FC-1000 laser flare and cell meter to assess objectively the amount of postoperative inflammation. At day one and day eight, the amount of cell and flare in the carbachol group was significantly greater than in the acetylcholine group or in the BSS control group. The acetylcholine group had significantly less flare than the BSS group at day one; yet there was no difference between the two groups at day eight, nor was there a significant difference in the amount of cells between day one and day eight. It is presumed that the prolonged miosis seen in the carbachol group delays the re-establishment of the blood-aqueous barrier after surgery, causing the inflammatory response. Key Words: acetylcholine, carbachol, cataract surgery, inflammation, intraocular lens, miotics

Intraocular miotics are routinely used in cataract surgery. Miosis after implantation of a posterior chamber intraocular lens (IOL) has been shown to aid centration of the IOL, ensure that the pupil is round and does not adhere to capsule fragments or the lens haptics, and prevent incarceration ofthe iris in the operative wound. Several recent studies have demonstrated that intraocular miotics help control intraocular pressure (lOP) in the early postoperative period. I - 7 The ideal intraocular miotic would achieve these benefits without adversely affecting intraocular tissues or the postoperative healing process. We evaluated the impact of intraocular miotics on postoperative inflammation. Assessing intraocular inflammation has previously been limited by the inherent subjectivity and observer-ta-observer variability of slitlamp measurement. The recent development of the Kowa FC-I 000 laser flare and cell meter makes clinical assessment of intraocular inflammation more precise. This diagnostic instrument objectively measures the amount of anterior chamber intraocular inflammation with separate determinations of cell and flare. We used

it to compare the extent of postoperative inflammation in patients receiving acetylcholine and those receiving carbachol during routine planned extracapsular cataract extraction (ECCE).

SUBJECfS AND METHODS This prospective, double-masked study comprised 60 patients scheduled for cataract extraction and posterior chamber implantation. The patients were randomly assigned preoperatively to one of three treatment groups. Group I received acetylcholine chloride I %; Group 2, carbachol 0.01 %; and Group 3, a placebo of balanced salt solution (BSS®). All patients received 0.5 cc of the miotic or BSS immediately after implantation of the posterior chamber lens and a second 0.5 cc injection at the close of the operation after the viscoelastic had been removed. Only patients with normal lOP and no clinically significant disease in either eye, apart from cataracts, were eligible. Patients were excluded if they had previous

Presented at the Symposium on Cataract. IOL and Refractive Surgery. Boston. April 1991. Supported by grants /rom the Deborah and Leon Black Foundation. The Michael and Gina Ricciardi Foundation. The Sylvia and Leonard Marx, Jr. Foundation. and The Paul and Bobbi Bent Foundation. The author has no proprietary interest in any of the instrumentation. techniques, or medications discussed in this manuscript. Reprint requests to Calvin W Roberts. M.D .. Cornell University Medical Col/ege, 520 East 70th Street. New York, New York 10021. J CATARACf REFRACf SURG-VOL 19. NOVEMBER 1993

731

ocular surgery, glaucoma, ocular or systemic inflamma- Table 2. Statistical analysis of flare at day one and week one. tory disease, a chronic need for ocular medication, or Mean ± SEM (photons/ms) insulin dependent diabetes. Patients were also excluded if they had been taking any medication in the past two Medication Group n Day 1 Week 1 months, either topically or systemically, that had anti- Control 20 47.5 ± 4.0 26.8 ± 2.6 inflammatory properties including aspirin, acetaminoAcetylcholine 20 38.0 ± 2.9 24.4 ± 3.2 phen, and nonsteroidal anti-inflammatory drugs. Carbachol 20 82.7 ± 6.2 40.7 ± 4.6 All surgery was performed by me; I was unaware of which drug was given to the patient. A computer-gen- P-values erated list randomly assigned each patient to one of the .001 Control vs. carbachol .003 three study groups. The study coordinator sealed the Acetylcholine vs. .001 .002 study drug in a paper bag labeled with the patient's carbachol name; the bag was given to the operating room nurse. Acetylcholine vs. .002 .1l9 The nurse opened the bag and prepared the syringe out control of my sight. All patients had the same preoperative, operative, and postoperative routine. Pupils were dilated with three sets of 2.5 % phenylephrine and 2 % cyclopentolate 15 minutes apart. No patient received preoperative topical flur- or subconjunctival steroids at the time of surgery and biprofen or other nonsteroidal anti-inflammatory drops. were given a suspension of prednisolone acetate 1% four Intravenous sedation was achieved with midazolam times a day beginning after their examination on the first (1 mg to 3 mg) and alfentanil (250 Ilg to 500 Ilg). A postoperative day. modified Van Lindt (5 cc) and retrobulbar block (2 cc) Postoperative inflammation on the first and eighth was given with a combination mixture of 2% lidocaine postoperative day was measured with the Kowa FCwith epinephrine and 0.75% bupivacaine. A Honan bal- 1000 laser cell and flare meter. A technician who was loon at a pressure of 30 mm Hg was applied to the eye masked to which miotic each patient had received made for 20 minutes. all measurements. We followed the guidelines in the A standard manual ECCE was performed on all pa- Kowa FC-I000 instruction manual and recorded the tients. No intracameral epinephrine was used. Sodium value for each examination as the mean of at least five hyaluronate was injected before the capsulectomy was measurements with background values differing by less made and the IOL implanted. A 6 mm, no-hole Sinskey- than 10%. type IOL with 10% angled polypropylene (Prolene®) haptics was implanted in all patients and was followed by the first injection of miotic or BSS. The surgical wound was closed with interrupted 10-0 nylon sutures. RESULTS The sodium hyaluronate was then aggressively irrigated out of the anterior chamber and a second injection of The results for cell and flare are presented in Tamiotic or BSS administered. Gentamicin sulfate drops bles 1 and 2. The Student's two-tailed t-test was used to were instilled beneath the sterile patch. No subconjunc- statistically analyze the data. tival injections were given. Patients received no topical There were significant differences in the amount of flare and cell among the three groups at day one and day eight. The amount of flare in the carbachol group was significantly greater at day one than the acetylcholine (P < .001) or the BSS control (P < .001). At day group Table 1. Statistical analysis of cells at day one and week one. one, the amount of cell in the carbachol group was significantly greater than in the acetylcholine group Mean ± SEM (cells/0.075 mm 3 ) (P < .008) or the BSS control (P < .004). At day eight, Day 1 Week 1 Medication Group n the amount of flare in the carbachol group was signifiControl 20 9.31 ± 2.0 31.4 ± 3.0 cantly greater than in the acetylcholine group (P < .(02) 4.90 ± 1.2 Acetylcholine 20 27.5 ± 3.0 or the BSS control (P < .003). At day eight, the amount of cell in the carbachol group was significantly greater Carbachol 20 11.56 ± 2.3 40.6 ± 3.1 than in the acetylcholine treated group (P < .002) or the P·values BSS control (P < .011). There was no significant differControl vs. carbachol .Oll .008 ence between the acetylcholine and control groups in the Acetylcholine vs. .004 .002 amount of cells at day one or day eight. The acetylchocarbachol line group had significantly less flare than the control Acetylcholine vs. .363 .053 group at day one; no difference was detected between control these groups at day eight. 732

J CATARACT REFRACT SURG-VOL 19, NOVEMBER 1993

DISCUSSION Acetylcholine is the naturally occurring neurohumoral transmitter for autonomic ganglia and skeletal muscle (nicotinic action) and for postganglionic parasympathetic nerve fibers (muscarinic action). In the eye, postganglionic parasympathetic fibers from the ciliary ganglion innervate the sphincter pupillae, causing miosis, and the ciliary muscle, resulting in changes in accommodation and in the facility of outflow. Exogenous acetylcholine administered intracamerally can duplicate some of the effects of parasympathetic stimulation. Amsler and Verrey8 first established the miotic effect of intracameral acetylcholine in 1949. Barraquer9 may have been the first to use acetylcholine routinely in anterior segment surgery. Since then, the value of acetylcholine-induced miosis for cataract surgery and IOL implantation has been established. 10-16 Acetylcholine is rapidly broken down by the action of acetylcholinesterase and thus is commonly classified as a short-acting miotic. Carbachol (carbaminoylcholine) is a potent synthetic choline ester that differs from acetylcholine by a carbaminoyl (NH 2CO) group in place of an acetyl (CH 3CO) group attached to the choline base. Kreitmair l7 first described its general pharmacologic properties in 1932. As acetylcholine, carbachol is primarily a direct-acting agent,18 with muscarinic and nicotinic effects. It may also cause the release of endogenous acetylcholine from cholinergic nerve fiber terminals l9 or partially inhibit cholinesterase. It inhibits secretion by the ciliary body. Because carbachol is resistant to hydrolysis by cholinesterase, it is active for much longer than acetylcholine. On a weight-for-weight basis, it is 100 times more potent than acetylcholine. 2o Thus commercial preparations are a 0.0 I % solution compared with 1.0% for acetylcholine. In the noninflamed eye, the blood-aqueous barrier in the ciliary body maintains the aqueous free from plasma proteins and cellular components. Inflammation as a result of the routine trauma of cataract surgery results in a breakdown of the normal blood-aqueous barrier. By slitlamp examination, aqueous proteins can be seen as flare, while white blood cells in the aqueous are observed as suspended cells. Prior to the development ofthe Kowa FC-! 000, all observations of cell and flare were subjective. Our results demonstrate that intraocular carbachol potentiates the normal postoperative inflammatory reaction in the anterior chamber compared with acetylcholine and the BSS placebo. We believe the sustained intense miosis associated with carbachol is responsible for this prolonged inflammation. Although carbachol's effect on the pupil is no longer present on the eighth postoperative day, increased levels of inflammation caused by the delay in re-establishment of the bloodaqueous barrier can still be measured. The miotic effect of acetylcholine only lasts about six hours, which may explain why inflammation in the acetylcholine group

was statistically the same as that in the BSS control group. The BSS group had more flare at one day than the acetylcholine group, perhaps because the surgeon must manipulate the iris more to close the wound in the absence of pupillary miosis pulling the peripheral iris out of the incision. The clinical significance of the prolonged inflammation observed in this study has to be determined. The use of a long-acting miotic can result in more pigment deposition on the IOL surface. Of greater clinical significance would be any observable effect on wound healing, cystoid macular edema, or recovery of visual acuity.

REFERENCES 1. Hollands RH, Drance SM, Schulzer M. The effect of acetylcholine on early postoperative intraocular pressure. Am J Ophthalmol 1987; 103:749-753 2. Hollands RH, Drance SM, Schulzer M. The effect of intracameral carbachol on intraocular pressure after cataract extraction. Am J Ophthalmol 1987; 104:225-228 3. Ruiz RS, Wilson CA, Musgrove KH, Prager TC. Management of increased intraocular pressure after cataract extraction. Am J Ophthalmol 1987; 103:487-491 4. Linn OK, Zimmerman TJ, Nardin GF, et al. Effect of intracameral carbachol on intraocular pressure after cataract extraction. Am J Ophthalmol 1989, 107:133-136 5. Ruiz RS, Rhem MN, Prager TC. Effects of carbachol and acetylcholine on intraocular pressure after cataract extraction. Am J Ophthalmol 1989; 107:7-10 6. McKinzieJW, BoggsMBJr. Comparison of postoperative intraocular pressures after use of Miochol and Miostat. J Cataract Refract Surg 1989; 15:185-190 7. Roberts CWo Control of cataract extraction: postoperative intraocular pressure with intracameral miotics. In: Cangelosi GC, ed, Advances in Cataract Surgery. New Orleans Academy ofOphthalmology, Thorofare, New Jersey, Slack Inc, 1991; 71-86 8. Amsler M, Verrey F. Mydriase et myose directes et instantanees par les mediateurs chimiques. Ann Ocul 1949; 182:936-937 9. Barraquer JI. Acetylcholine as a miotic agent for use in surgery. Am J Ophthalmol 1964; 57:406-408 10. Harley RD, Mishler JE. Acetylcholine in cataract surgery. Am J OphthalmoI1964; 57:817-819 11. Harley RD, Mishler JE. Acetylcholine in cataract surgery. Br J Ophthalmol 1966; 50:429-433 12. Ray RR. Use of acetylcholine in peripheral iridectomy. Am J Ophthalmol 1965; 60:728-730 13. Rizzuti AB. Acetylcholine in surgery of the lens, iris and cornea. Am J Ophthalmol1967; 63:484-487 '14. Beasley H. Miotics in cataract surgery. Arch Ophthalmol 1972; 88:49-51 15. Douglas GR. A comparison of acetylcholine and carbachol following cataract extraction. Can J Ophthalmol 1973; 8:75-77 16. Schirmer RA. Intraocular instillation of acetylcholine in anterior segment operations. Eye Ear Nose Throat J 1966; 28:63-66 17. Kreitmair H. Eine neue klasse cholinester. Arch Exp Pathol Pharmakol 1932; 164:346-351

J CATARACT REFRACT SURG-VOL 19. NOVEMBER 1993

733

18. Yamauchi, DeSantis L, Patil PN. Relative potency of cholinomimetic drugs on the bovine iris sphincter strips. Invest Ophthalmol 1973; 12:80-82 19. McKinstry ON, Koelle GB. Effects of drugs on acetylcholine release from the cat superior cervical ganglion by

734

carbachol and by preganglionic stimulation. J Pharmacol Exp Ther 1967; 157:328-336 20. McDonald TO, Beasley C, Borgmann A, Roberts O. Intraocular administration of carbamylcholine chloride. Ann Ophthalmol 1969; 1:232-239

J CATARACf REFRACf SURG-VOL 19, NOVEMBER 1993