Effect of topical ketorolac tromethamine and topical nepafenac on maintaining pupillary dilation during phacoemulsification
- Richard Atanis, MD
Prospero Ma. Tuaño, MD
Jay Vicencio, MD
Jose Ma. Martinez, MD
Lee Verzosa, MDInternational Eye Institute
St. Luke’s Medical Center
Quezon City, Philippines
PHACOEMULSIFICATION with intraocular-lens
(IOL) implantation is the current surgical treatment of
choice for cataract extraction.1-3 To prevent complications
during surgery, there should be adequate pupillary dilation
for better visualization of the posterior chamber.
Evidence has shown that intraocular manipulation can
trigger the inflammatory cascade, releasing cyclooxygenase
(COX) and prostaglandins within the eye causing
miosis. During cataract surgery, maintenance of mydriasis
is necessary to facilitate proper incision of the anterior
capsule, safe removal of the cataract, and implantation of
intraocular lens.
Mydriatics and antiprostaglandins are routinely
applied preoperatively to facilitate cataract extraction
and prevent intraoperative miosis.4 Previous studies
have demonstrated the effectiveness of various topical
nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin,
flurbriprofen, suprofen) in preventing miosis
during cataract surgery compared to placebo.5 Newer
topical NSAIDs also showed similar favorable effects.
Coste6 showed that nepafenac given 3 times a day 1
day before cataract surgery was superior to tobramycindexamethasone
eye drops in maintaining intraoperative
mydriasis measured at 4 different stages of the surgery.
Solomon5 compared the effects of topical 0.5% ketorolac
tromethamine ophthalmic solution with topical 0.03%
flurbiprofen sodium on the inhibition of surgically
induced miosis during phacoemulsification. Ketorolac
provided a more stable mydriatic effect throughout the
surgical procedure.
This study compared the effect of 2 newer topical
NSAIDs widely available in the Philippines—ketorolac
0.5% and nepafenac 0.1%. Specifically, this study determined
the horizontal and vertical pupillary diameters
in 4 different stages of phacoemulsification; compared
pupillary diameter measurements among the ketorolac,
nepafenac, and placebo groups; and determined the
total loss and percent total loss of mydriasis.
METHODOLOGY
We conducted a prospective, randomized, doublemasked
comparative study involving 47 eyes of 44 Filipino
patients diagnosed with mature cataract who underwent
cataract surgery by phacoemulsification and capsular bag
IOL implantation in a tertiary hospital from March to
August 2010.
Included were patients who:
• were 40 years of age or older,
• had been diagnosed with mature cataract according
to the Lens Opacities Classification System (LOCS III),
with classification NO and/or NC 2–3,
• were scheduled for cataract surgery by phacoemulsification
and capsular bag IOL implantation,
• had normal funduscopic exam (if retina view was
possible),
• had history of unremarkable phacoemulsification
with capsular-bag IOL implantation to the contralateral
eye, and
• had continuous, circular capsulorhexis of 5 to 6
mm diameter.
The exclusion criteria included:
• history of ocular inflammatory or infectious eye
disease,
• treatment of eye infection within 30 days prior to
inclusion in the study,
• alterations of the ocular surface (e.g., dry eye),
• history of ipsilateral ocular surgery and/or trauma,
• history of any neuro-ophthalmologic pathologies,
• knowledge or suspicion of allergy or hypersensitivity
to the preservatives, steroids, topical NSAIDs, or any
other component of the study medication,
• use of topical ophthalmic medications,
• use of topical or systemic steroids within 30 days
prior to inclusion in the study,
• use of topical or systemic NSAIDs within 14 days
prior to inclusion in the study,
• diagnosis of diabetes mellitus with/without diabetic
retinopathy and/or macular edema,
• preoperative mydriasis less than 6 mm prior to the
study,
• “Phaco time” of >1.5 minutes,
• intraoperative posterior capsular rent with or without
vitreous loss,
• use of intraoperative intracameral epinephrine,
• ocular alteration preventing adequate mydriasis
(eg. synechiae, iris atrophy),
• use of contact lens at anytime before the surgery,
• surgical events that may hasten pupillary constriction
(eg. inadvertent manipulation/aspiration of the iris,
incarceration of iris into the main wound secondary to
an accidentally shortened or mis-angled main corneal
tunnel),
• use of tamsulosin or other analogous systemic medications
that may induce increased tendency for miosis
intra-operatively (intra-operative floppy iris syndrome or
IFIS).
Preoperatively, all subjects underwent a thorough
ophthalmic examination. Past medical and surgical history,
and use of concurrent medications were extensively
reviewed. Best-corrected visual acuity (BCVA) using the
ETDRS chart, slit-lamp biomicroscopy, intraocular pressure
by Goldmann applanation tonometry, and dilatedfundus
examination were done.
A general surgical consent form was obtained from all
patients. Patients who underwent phacoemulsification were eligible for inclusion. They
were randomly assigned to each of
the 3 groups based on which of the 3
sealed envelopes was chosen by a junior
resident at the time of surgery.
Patients received 1 drop of the
assigned topical NSAID or balanced
salt solution (BSS) (control group)
every 15 minutes for 4 doses (~20ml)
to the operative site one hour prior
to the scheduled operation. Five
minutes later, tropicamide 0.5% with
phenylephrine 0.5%, 1 drop every 15
minutes for 4 doses was instilled in all
treatment groups. The surgeons and
the patients were unaware of the type
of test drops given.
All subjects underwent cataract
surgery by phacoemulsification using
the Millenium machine (Microsurgical
System, Houston, TX, USA).
A one-piece, monofocal, foldable
acrylic IOL implantation inside the
capsular bag under topical anesthesia
(proparacaine) was done by 4
surgeons (one consultant and three
senior residents).
The surgeons used the same
operative technique on all patients
as follows. Two 1-mm side-ports, a
2.75-mm temporal clear corneal incision,
and a 5- to 6-mm continuous
curvilinear capsulorhexis were made.
Phacoemulsification parameters
were established prior to all surgeries
and were the same in all patients.
Balanced salt solution without epinephrine
was used for corneal irrigation.
The corneal incisions were left
unsutured at the close of surgery.
To ensure the standardization of
illumination during pupillary measurement,
all surgeons used the same
microscope (Carl Zeiss OPMI VISU
210 S88) and the illumination was
kept constant (0.5 to 0.7) in all cases.
The principal author measured the
horizontal and vertical pupillary
diameters. A sterile caliper was placed
over the cornea and measurements
were taken, in millimeters, under the
microscope at the following stages of
surgery: 1) before creating side ports,
2) after nuclear emulsification, 3)
following cortex aspiration, and 4)
after implantation of an acrylic foldable
IOL with viscoelastic removal
(Figure 1A-D). The preset standard magnification (0,75x) of the operating
microscope was ensured at each
of the 4 time points.
The primary outcome measures
were the mean horizontal and vertical
diameters of the pupil during the
four different stages of phacoemulsification.
Other data collected were age,
gender, laterality of the eye operated
on, and the corresponding category
to which they were assigned. Frequency,
percentage, mean and standard
deviation were used to describe
demographic characteristics and
values of pupillary measurements.
Comparisons of categorical variables
were analyzed using chi square or
Fisher exact tests, where applicable.
Analysis of variance (ANOVA) was
used to determine differences
between groups at each stage of
surgery, as well as changes from
baseline. All analyses were two-tailed,
with p<0.05 considered as significant.
Analyses were performed using Statistical
Package for Social Sciences
(SPSS) for Windows, version 16.0.
Figure 1. Pupillary diameters at different stages of the surgery: before creating the sideports (A), after
nuclear emulsification (B), after cortical removal (C), and after intraocular-lens implantation and viscoelastic
removal (D).
RESULTS
A total of 47 eyes of 44 patients,
13 males and 34 females, were
included in the study. The mean age
was 66.04 ± 8.87 years. There was no
significant difference in age, gender,
and laterality of eye operated on
among the three groups (Table 1).
Significant differences among the
three groups were seen after IOL
implantation, with the nepafenac
group having the largest mean
diameters in both horizontal (p =
0.012) and vertical (p = 0.012) pupil
measurements (Tables 2 and 3).
Comparison of total loss of mydriasis,
which is the difference between
pupil diameter before surgery and
after IOL implantation, revealed
significant differences in both
horizontal (p = 0.005) and vertical
(p = 0.009) pupil measurements
with the nepafenac group having
the least change from baseline. The least loss in mydriasis in horizontal
pupil diameter was observed in
the nepafenac group with 17.69%
loss which was significantly lower
(p = 0.002) compared to 29.89%
and 30.02% losses of the control
and ketorolac groups respectively
(Table 2).
Similarly, the vertical pupil measurements
showed significant differences
in percent of total loss with
the nepafenac group having 17.32%
compared with the 27.89% and
28.80% total losses of the mydriasis
of the ketorolac and control groups
respectively (Table 3).
Table 1. Demographic characteristics of the study population.
Table 2. Mean horizontal diameter of the pupil at different stages of cataract surgery.
Table 3. Mean vertical diameter of the pupil at different stages of cataract surgery.
DISCUSSION
Mechanical ocular trauma from
phacoemulsification can cause various
ocular changes, such as conjunctival
hyperemia, inflammation, pain,
cystoid macular edema, breakdown
of the blood–aqueous barrier, rise
in intraocular pressure, and most
especially surgically-induced miosis
creating access for cataract removal
difficult.7-8 Prostaglandins play an
important role in these changes.
NSAIDs inhibit COX enzymes that
promote prostaglandin production;
hence, providing both analgesic and
antiinflammatory activities.6 Ophthalmic
NSAIDs are used to decrease
the various changes brought about
by intraocular surgeries.
Due to the topical nature of this
drug class, systemic absorption is
minimal. Nepafenac 0.1%, after
topical dosing, is subsequently converted
by ocular tissue hydrolases to
amfenac, which is thought to inhibit
the action of the cyclooxygenase
prostaglandin H synthase.9
Nepafenac 0.1% met its primary
objective in this present study by
showing advantage over the control
group in terms of maintaining mydriasis
during phacoemulsification.
In addition, nepafenac 0.1% has
also shown to be more effective than
placebo at maintaining mydriasis at
every stage of the surgery.
Most interesting, however, is the comparison between
nepafenac 0.1% and ketorolac 0.5%. Previous studies
have established the effectiveness of ketorolac 0.5% for
the treatment of both pain and inflammation following
cataract surgery.10 Consequently, ketorolac 0.5% was used
as a standard against which the efficacy of nepafenac 0.1%
was measured. In this study, nepafenac 0.1% reached
statistical superiority compared to ketorolac 0.5% in all
four stages of phacoemulsification.
Nepafenac has been shown to penetrate the cornea rapidly
and provides a complete and longer-lasting inhibition
of prostaglandin synthesis and vascular permeability.11-12
Perhaps, this advantage in absorption and bioavailability
was the reason behind its superiority in maintenance of
mydriasis seen in this study.
Prescribing a consistent technique as well as dictating
microscope illumination minimized the confounding effects
of surgeon variability. Surgeons were, likewise, able
to perform the procedure with relative ease since the
phacoemulsification time was within acceptable limits.
Although a single surgeon series would have been ideal,
we feel that the quality of the surgeries in this series came
very close in terms of consistency. A larger sample size
would have allowed us to analyze the results with a higher
confidence level.
Future studies can evaluate the diameter of the pupil
when other types of acrylic intraocular lenses are used
(e.g. accommodating IOLs, multifocal IOLs).
In conclusion, topical nepafenac 0.1% has been shown
to be a more effective inhibitor of miosis during phacoemulsification
with IOL implantation compared with
topical ketorolac or BSS.