REVIEW/UPDATE

Mydriatic insert and intracameral

injections compared with mydriatic
eyedrops in cataract surgery: Controlled studies
Anders Behndig, MD, PhD, Jean-François Korobelnik, MD

Mydriatic eyedrops are the standard method for pupil dilation in cataract surgery, but their limi-
tations have prompted a search for alternative techniques. Two alternativesdan ophthalmic insert
containing phenylephrine and tropicamide and intracameral injections of various combinations
of lidocaine, cyclopentolate, and phenylephrine, with or without epinephrine in the irrigating
solutiondhave been assessed in prospective controlled studies, including randomized controlled
trials (RCTs). We reviewed the safety and efficacy of mydriatic ophthalmic inserts and intracam-
eral mydriatic injections compared with the safety and efficacy of mydriatic eyedrops using a sys-
tematic PubMed search (1963 to 2014). We identified 9 prospective studies (7 RCTs, 637 patients)
of the mydriatic ophthalmic insert and 15 prospective studies (14 RCTs, 1020 patients) of intra-
cameral mydriatic injections; 7 of the RCTs compared intracameral mydriatic injections and mydri-
atic eyedrops and 7 RCTs studied the optimum intracameral mydriatic injection protocol. The latter
showed that a lidocaine and phenylephrine–based solution, without irrigating epinephrine, was
optimum for intracameral mydriatic injections. The mydriatic ophthalmic insert and intracameral
mydriatic injections were consistently shown to be safe and as effective as mydriatic eyedrops.
Each method has distinct advantages and limitations.
Financial Disclosure: Dr. Behndig has received fees from Th
ea Pharma GmbH as a member of the
European Team for the Prophylaxis of Infection in Cataract Surgery group. Dr. Korobelnik has
received consultancy fees from Alcon Surgical, Inc.; Allergan, Inc.; Alimera, Inc.; Bayer HealthCare
AG; Carl Zeiss Meditec AG; Novartis Corp.; Roche Innovatis AG; and Th
ea Pharma GmbH.
J Cataract Refract Surg 2015; 41:1503–1519 Q 2015 ASCRS and ESCRS

Adequate and stable mydriasis is required in cataract
surgery because pupil constriction increases the risk
for intraoperative complications such as damage to
Submitted: June 26, 2014.
Final revision submitted: October 6, 2014.
Accepted: December 2, 2014.
From the Department of Clinical Sciences/Ophthalmology (Behn-
dig), Umeå University Hospital, Sweden, and Service d’ophtalmolo-
gie, Centre Hospitalier Universitaire de Bordeaux, Institut de Sant
e
Publique, d’Epid
emiologie et de D
eveloppement, and the Institut
National de la Sant
e et de la Recherche M
edicale U897-
Epidemiologie-Biostatistique (Korobelnik), Bordeaux, France.
Bruno Trumbic, MD, Cap Evidence, Paris, France, wrote a draft
version of the manuscript with financial support from Laboratoires
Th
ea, Clermont-Ferrand, France.
Corresponding author: Anders Behndig, MD, PhD, Department of
Clinical Sciences/Ophthalmology, Umeå University Hospital, SE-
901 85 Umeå, Sweden. E-mail: anders.behndig@ophthal.umu.se.
the iris or corneal endothelium, incomplete cortex
removal, posterior capsule rupture, and vitreous
loss.1–5 Pharmacologically induced mydriasis is classi-
fied as weak (pupil size !4.0 mm), moderate (4.0 to
6.0 mm), large (6.0 to 8.0 mm), or very large (O8.0 mm).6
Mydriasis Physiology
The pupil size is regulated by the iris sphincter and
dilator,7,A which are stimulated by parasympathetic
nerves and sympathetic nerves, respectively. Thus,
mydriasis can be induced pharmacologically by a sym-
pathomimetic/adrenergic agent (active mydriasis) or
an anticholinergic agent (passive mydriasis). The a1-
receptors of the iris dilator are the most important me-
diators of the sympathomimetic mydriatic effect.8–10
The iris sphincter also bears sympathomimetic b-recep-
tors that relax the sphincter and cause mydriasis when
activated by an agonist.3,11 Individual factors, such as
iris color, age, diabetes, or pseudoexfoliation syndrome,

Q 2015 ASCRS and ESCRS http://dx.doi.org/10.1016/j.jcrs.2014.12.050 1503

Published by Elsevier Inc. 0886-3350
1504 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
influence the grade and speed of mydriasis and the sta-
bility in response to mydriatic agents.12–17
Standard Mydriatic Protocols
The “ideal” mydriatic protocol should induce fast,
intense, and stable mydriasis of limited duration
(2 to 3 hours), while minimizing adverse effects.14,18
Topical mydriatic eyedrops are currently the standard
method for routine pupil dilation. However, their lim-
itations have prompted the search for alternative
methods. Many approaches have been tested during
the past 30 years, including topical viscous phenyleph-
rine or intraoperative epinephrine (called adrenalin in
some countries),19–22 preoperative diclofenac23 or atro-
pine 1.0%,24 and cellulose sponges soaked in mydriatic
agents.3,25
Review Purpose and Method
Two of the alternativesdan insoluble ophthalmic
insert, which is available, and intracameral injections
dhave been evaluated for mydriasis by several pro-
spective controlled studies, including randomized
controlled trials (RCTs). Intracameral injections for
mydriasis are currently made locally, but 1 industrial
preparation is undergoing formal clinical assessment.
Our purpose was to review the evidence of the
clinical efficacy and safety of the ophthalmic insert
and intracameral injections for mydriasis, focusing
on RCT results, and to highlight their advantages
and limitations compared with those of mydriatic
eyedrops.
In February 2013, PubMed was searched back to
1963 for published reviews or RCTs (publication
type) with Mesh headings “mydriatics,” “tropica-
mide,” “phenylephrine,” and “cyclopentolate.” After
irrelevant and duplicate citations were excluded, the
remaining 172 references were manually reviewed to
select eligible articles (ie, prospective controlled
studies) on mydriatic ophthalmic insert–based and in-
tracameral mydriatic injection–based mydriasis in
cataract surgery. The search was updated in
September 2014.
PHENYLEPHRINE AND TROPICAMIDE
OR CYCLOPENTOLATE COMBINATION EYEDROPS
Standard mydriatic eyedrop regimens in cataract sur-
gery usually combine sympathomimetic and anticho-
linergic agents because of their additive effects.26–29
This review focuses on combinations of phenylephrine
2.5% to 10.0% with tropicamide 0.5% to 1.0% or cyclo-
pentolate as these are the most thoroughly studied
protocols.29–35
J CATARACT REFRACT SURG - VOL 41, JULY 2015
Phenylephrine
Phenylephrine is a synthetic sympathomimetic agent
with a strong and selective affinity for a1-receptors.
Topical application of phenylephrine to the eye causes
dilation of the pupil and arteriolar vasoconstriction.
The mydriatic effect almost mirrors the peak concentra-
tion in the aqueous humor (60 to 90 minutes)9,36,37; it is
rapid but short lasting (up to 5 to 7 hours).38
Tropicamide, Cyclopentolate
Tropicamide is an atropine-derived anticholinergic
nonselective antagonist of muscarinic receptors.39
The onset of mydriasis with tropicamide is slower
than with phenylephrine, but the effect lasts longer.
All anticholinergic agents also cause cycloplegia.
Cyclopentolate has a long mydriatic effect, up to
24 hours,40 and low bioavailability at the iris recep-
tors3,41 due to limited penetration through the cornea.
Its maximum mydriatic effect occurs at 30 minutes
with significant systemic absorption.42
Combinations
The combination of phenylephrine and tropicamide
has a stronger mydriatic effect than either agent
alone.43 When combined with tropicamide 1.0%,
increasing concentrations of phenylephrine signifi-
cantly enlarge pupil size but also accelerate the heart
rate.44 Reduced concentrations of tropicamide and
phenylephrine in combination (0.25% and 1.25%,
respectively) can achieve sustained pupil dilation.33
Advantages and Limitations
Mydriatic eyedrops are universally available, rela-
tively fast acting, and inexpensive; the relative doses
of each active agent can be varied. Systemic adverse ef-
fects are rare except in certain at-risk populations in
which serious problems may arise.14 The main disad-
vantages of mydriatic eyedrops are related to delayed
effect and low bioavailability.45
The delayed onset of dilation is due to the slow pene-
tration of active ingredients through the cornea37,42,46,47;
ie, the time to effective dilation is longer than the cata-
ract surgery procedure itself.3,48 The limited bioavail-
ability is related to low transcorneal penetration (2%
to 10%) and high systemic absorption (up to 60% to
80%) of active agents through the conjunctiva and nasal
mucosa.5,42,49–53 Repeated instillations result in signifi-
cant amounts of administered drugs, carrying an
increased risk for systemic adverse effects such as head-
ache, increased blood pressure and heart rate, stroke, or
myocardial infarction.28,54–61 These adverse effects have
been reported in high-risk patients with a history of car-
diovascular disease and in susceptible individuals
 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
without such history,39,55,56,62–64 especially neonates
and infants.58,59,65
The effect of mydriatic eyedrops tends to wear off
during cataract surgery48 in conjunction with an intra-
operative reflex miosis66,67 caused by the release of
prostaglandins21 or operative factors (eg, light from
the microscope).68 This increases the risk for surgery-
related complications1,67 and is more frequent in
certain patients (eg, diabetics).69 Repeated instillations
are time consuming, substantially affect nurses’ work-
load, and may lead to imprecise dosing; protocols
have to be adapted to patients’ characteristics, such
as iris pigmentation.32 These drawbacks affect the rou-
tines in high-volume cataract surgery, which should
be as straightforward, safe, simple, repeatable, and
effective as possible.40
MYDRIATIC OPHTHALMIC INSERT
The mydriatic ophthalmic insert (Mydriasert) contains
the active ingredients phenylephrine (5.38 mg) and tropi-
camide (0.25 mg) in a central core surrounded by a dia-
lyzing membrane70 that allows controlled release of the
drugs. The device is aseptically applied to the inferior
conjunctival fornix, where it is soaked in the lachrymal
film, approximately 1 hour before the procedure (2 hours
maximum). The active drugs are released progressively
over a prolonged period at nearly constant tear concen-
tration, resulting in effective and stable intraocular con-
centrations. The device is preservative free and must be
removed at the beginning of surgery. The total dose
included in the insert is equivalent to 1 drop of tropica-
mide 0.5% and 1 drop of phenylephrine 10.0%.5
Comparative Studies of the Mydriatic Ophthalmic
Insert and Mydriatic Eyedrops
The mydriatic ophthalmic insert has been compared
with conventional mydriatic eyedrops in 9 prospective
studiesd7 RCTs5,6,18,70–73 and 2 cohort studies.14,74
The total number of subjects in the 9 studies was 637,
including 18 healthy volunteers and 619 patients; the
latter were 40 to 90 years of age and often had comorbid-
ities (insulin-dependent or noninsulin-dependent dia-
betes mellitus, hypertension). The reasons for
admission were cataract surgery or other surgery
(retinal detachment, diabetic retinopathy), fluorescein
angiography, or various diagnostic procedures. The
control mydriatic eyedrop was mainly the tropicamide
0.5% to 1.0%–phenylephrine 10.0% combination (1 drop
each every 5 to 15 minutes); 1 study also included a third
intracameral mydriatic injection control arm (lidocaine
1.0%–phenylephrine 2.5%).5 All studies assessed the re-
sults according to pupil diameter (or stability and
persistence) and local safety. Other outcome measures
varied across studies and included surgery duration,
J CATARACT REFRACT SURG - VOL 41, JULY 2015
1505
time to near-vision recovery, nurses’ workload, amount
of administered agents, bacterial colonization, blood
pressure and heart rate, phenylephrine serum concen-
trations, and predictive factors of response.
Findings The main results of the 9 studies are presented
in Figure 1. Despite some noteworthy differences, the
overall findings were consistent across studies.
Mydriatic Effect The mydriatic ophthalmic insert
induced an effective mydriasis (mean pupil diameter
7.0 to 9.0 mm) in all studies5,18,70; the dilation was gener-
ally comparable to that induced by mydriatic eyedrops.
Two studies found that the maximum diameter was
significantly larger in the mydriatic ophthalmic insert
groups than in the mydriatic eyedrops groups.14,74 No
study found the reverse except at early stages of the dila-
tion process. The effect was consistent across subpopu-
lations. The strongest effect in both treatment groups
was observed in young healthy volunteers.70 Young
age was an independent predictive factor for maximum
pupil diameter with the mydriatic ophthalmic insert.14
No dilation failures were observed if the insert was
adequately handled. Achieved mydriasis was stable
during the entire cataract surgery procedure in both
groups.5,18,70–73 The onset was faster with mydriatic
eyedrops than with the mydriatic ophthalmic insert,
particularly in diabetic subgroups,73 occurring after
approximately 30 to 40 minutes and 40 to 50 minutes,
respectively.14,18 Dilation was more stable with the
mydriatic ophthalmic insert; at 90 minutes, the pupil
diameter was larger in the insert group than in the
eyedrops group.73,74
Other Outcomes The mean number of nurse interven-
tions to reach effective dilation was consistently lower
in mydriatic ophthalmic insert groups than in mydriatic
eyedrops groups.6,18 The mean operative time was short
and comparable in both groups.5 Premature loss of the
mydriatic ophthalmic insert device occurred in only a
few patients.6,14 The mean total dose of tropicamide–
phenylephrine actually delivered was 5- to 10-fold lower
in mydriatic ophthalmic insert groups than in mydriatic
eyedrops groups.6,14,18,70 Time to near-vision recovery
was significantly shorter in the mydriatic ophthalmic
insert group in 1 study,18 and time to pupillary reflex re-
covery was about 3 hours in both groups.70 One study
found a nonsignificant difference in time to corrected dis-
tance visual acuity at 60 and 90 minutes.71
Safety No complications or serious adverse effects
were observed. The local tolerance of the mydriatic
ophthalmic insert was consistently reported as excel-
lent or very good, with no significant difference be-
tween treatment groups. Intolerance symptoms, if
1506 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY

Figure 1. Comparative studies of

mydriatic ophthalmic insert and
mydriatic eyedrops (* Z first author;
AE Z adverse effect; BP Z blood pres-
sure; CNVA Z corrected near visual
acuity; DBP Z diastolic blood pres-
sure; HR Z heart rate; ICM Z intra-
cameral mydriatics; MED Z
mydriatic eyedrops; MOI Z mydriatic
ophthalmic insert; NS Z not signifi-
cant; Phenyl Z phenylephrine; SBP
Z systolic blood pressure; SPK Z su-
perficial punctate keratitis; Tropic Z
tropicamide).

any, were mild to moderate and self-resolving. Super- the mydriatic ophthalmic insert group.14 There were
ficial punctuate keratitis was absent,18 equally no concerns for or significant between-group differ-
frequent in both groups,70 or found in some patients ences in blood pressure and heart rate.18,70–73 Only 1
in the mydriatic eyedrops group and no patient in study found an increased incidence of high systolic

J CATARACT REFRACT SURG - VOL 41, JULY 2015

 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY 1507

Figure 1. Continued

blood pressure in the mydriatic eyedrops group
compared with the mydriatic ophthalmic insert
group.5 Phenylephrine serum concentrations re-
mained below the detection threshold.70 No signifi-
cant bacterial contamination of the conjunctiva or
cultured mydriatic ophthalmic insert device was
found.70
Nine prospective controlled studies
Interpretation
including 7 RCTs5,6,14,18,70–74 provide a fair evidence
base showing that the mydriatic ophthalmic insert de-
vice has reproducible efficacy, safety, and feasibility
characteristics, making it a credible alternative to mydri-
atic eyedrops, with distinct advantages and limitations.
The mydriatic ophthalmic insert induces a large, sta-
ble, and persistent mydriasis across various subpopu-
lations. The maximum dilation is comparable to or
superior to that of mydriatic eyedrops. The onset of
dilation tends to be slower with the insert than with
mydriatic eyedrops, especially in diabetic subgroups.

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1508 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
Local and systemic safety is excellent. The mydriatic
ophthalmic insert is preservative free, a possibly
meaningful characteristic since measurable concentra-
tions of benzalkonium chloride can be found in the
conjunctiva and the cornea up to 7 days after a single
instillation75 and experimental studies have consis-
tently and reliably shown the toxic effects of benzalko-
nium chloride.76
The stable effect and reduced nurse workload with
the mydriatic insert could translate into an economic
advantage in the context of routine cataract surgery.B
However, the mydriatic ophthalmic insert is associ-
ated with higher unit costs and need for initial staff
training.
INTRACAMERAL MYDRIATICS
Intracameral injection of mydriatics was developed in
Sweden8,40,48,67,77–80 and other countries3,81–83 over the
past decade as an alternative to conventional mydri-
atic eyedrops. The strategy emerged in the context of
an increasing use of intracameral drugs such as antibi-
otic prophylaxis84 and epinephrine.19,85 Initial studies
showed that intracameral mydriatic injections induced
nearly immediate pupil dilation, which was main-
tained or increased during the procedure, and fast re-
covery of normal pupil function.48,80 These promising
results prompted further research.
Fifteen eligible studies were found: 14 RCTs and
1 observational study; 1020 patients. Eight studies
(7 RCTs, 1 case-control study; 646 patients) compared
the efficacy and safety of intracameral mydriatic injec-
tions with those of control mydriatics5,45,48,68,79,83,86,87;
7 RCTs (374 patients) defined the optimum intracam-
eral mydriatic injection protocol.3,8,40,67,77,78,88 All
trials used preservative-free formulations of intracam-
eral mydriatic injections.
Technique and Components: Protocol-Defining
Studies
The intracameral technique is based on injecting a
mydriatic agent(s) into the anterior chamber at the
beginning of surgery, after the initial side-port incision.
A recent RCT88 showed that mydriatic durability is
slightly better after posterior chamber injection than af-
ter anterior chamber injection. Two mydriatic solutions
were proposed in 2003. One used a combination of lido-
caine hydrochloride 1.0% with epinephrine in the irri-
gating solution80; the other used a mixture of lidocaine
1.0%, cyclopentolate 0.1%, and phenylephrine 1.5%,
associated with irrigating epinephrine also.48 The latter
Swedish protocol was subsequently amended and is
currently limited to 150 mL of a solution containing lido-
caine 10 mg/mL (1.0%) and phenylephrine 15 mg/mL
J CATARACT REFRACT SURG - VOL 41, JULY 2015
(1.5%).7 The results in these protocol-defining studies
are summarized and discussed below.
Lidocaine Intracameral injections of preservative-free
lidocaine have been used routinely since the late 1990s
for anesthesia,89–93 mydriasis, or both.79,80,83 Lidocaine
stabilizes the neuronal membrane by blocking the so-
dium channels, resulting in local anesthesia. Mydriasis
is due to the anesthetic effect of lidocaine on nerves in
iris stroma.40,83 The inhibition of both the iris sphincter
and the dilator results in pupil dilation because the
sphincter has a stronger tone than the dilator.80 Lido-
caine has no cycloplegic effect.77
Two RCTs assessed the mydriatic effect of isolated in-
tracameral lidocaine 1.0% injection and showed that it
increased the mean pupil diameter 4.5 to 4.9 mm from
baseline.40,83 This effect is persistent and stable, but the
onset is slower than with other intracameral solu-
tions.48,77 A nationwide survey of intracameral lidocaine
use for local anesthesia in the United Kingdom did not
report any serious adverse effects.94 There are no safety
concerns about the corneal endothelium.90,95–97 Intra-
cameral injections of lidocaine at doses used for mydri-
asis do not result in detectable blood levels.45,98 A
metaanalysis of 8 RCTs99 showed no significant differ-
ence in intraoperative adverse effects or corneal toxicity
between intracameral lidocaine and eyedrops.
Cyclopentolate In Sweden, cyclopentolate was
removed from the initial intracameral mydriatic
injection solution when an RCT showed that it did
not enhance the mydriatic effect of the combination of
intracameral phenylephrine and lidocaine. On postop-
erative day 1, the pupil size was significantly larger in
patients with cyclopentolate than in those without
it.40 Another RCT found that preoperative topical
cyclopentolate 1.0% drops can be omitted when phen-
ylephrine 10.0% drops and epinephrine in the irrigating
solution are combined with intracameral lidocaine.77
Epinephrine Epinephrine, a synthetic sympathomi-
metic agent, is included in irrigating solutions to
enhance mydriatic efficacy, stability, and dura-
tion.3,48,77,78,100,101 However, the addition of epineph-
rine infusion to the triple Swedish intracameral
mydriatic injection solution did not yield larger pupils,
indicating that the triple solution obviates the need for
additional epinephrine.67 This finding is not fully un-
derstood and could result from a competition between
phenylephrine and epinephrine binding to the a- and
b-adrenergic receptors of the iris.67,87 As a conse-
quence, epinephrine was removed from the protocol.
Phenylephrine While lower concentrations (0.015% to
0.500%) of isolated intracameral phenylephrine induce
a significant pupil diameter increase from baseline
(4.0 to 4.9 mm), only higher concentrations (1.5% or
REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY 1509

Figure 2. Comparative studies of the ef-

ficacy and safety of intracameral myd-
riatics. The RCT by Morgado et al.5
also included an ICM arm; results are
presented in Figure 1. (* Z first author;
† Z interquartile range; CDVA Z cor-
rected distance visual acuity; HR Z
heart rate; IC Z intracameral; ICM Z
intracameral mydriatics; IOL Z intra-
ocular lens; MED Z mydriatic
eyedrops; NS Z not significant; OCT
Z optical coherence tomography;
OVD Z ophthalmic viscosurgical de-
vice; PCO Z posterior capsule opacifi-
cation; VAS Z visual analog scale;
YAG Z neodymium:YAG).

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1510 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
3.0%) display a dose-response relationship and yield
significantly larger pupil sizes than lower concentra-
tions.8 The onset of dilation is significantly faster with
higher doses, and pupil sizes continue to increase over
the observation period. Thus, it has been recommended
that intracameral phenylephrine should not be used at
concentrations of less than 15.0 mg/mL (1.5%).8
An additive mydriatic effect of intracameral phenyl-
ephrine and intracameral lidocaine was found when
randomly assigned sequential injections showed that
intracameral phenylephrine significantly increased
the pupils previously dilated with intracameral lido-
caine.40 Indirect external comparisons also suggest
that the mydriatic effect of the combined solution is
stronger than that of either agent alone.8
One RCT3 compared the initial Swedish triple
solution with bisulfite-free epinephrine (the so-called
epi-Shugarcaine solution), which combines epineph-
rine 0.025% and lidocaine 0.75% in a fortified balanced
salt solution (BSS Plus). It found significantly larger
pupil sizes in the bisulfite-free epinephrine group at
all intraoperative timepoints. Safety and tolerability
were excellent in both groups. The authors commented
that bisulfite-free epinephrine was originally devel-
oped100 because in the United States, phenylephrine
requires compounding; bisulfite-free epinephrine has
the disadvantage of being stable at room temperature
for only about 4 hours, while phenylephrine degrades
at a slower rate.3 The reasons for the apparent superior-
ity of epinephrine over phenylephrine are not fully
understood.8 It may be explained by epinephrine’s
dual effect on both a1- and b1-receptors.3
The use of intracameral epinephrine is currently
limited by the unavailability of a bisulfite-free product
in some countries.
Comparative Studies of Intracameral Combined
Solutions and Mydriatic Eyedrops
Intracameral mydriatic injections were compared
with control mydriatics in 8 studies, including 7
RCTs and 1 prospective case-control study. Four of
the RCTs had a blinded design5,48,86,87 and 3 an
open-label design.68,79,83 A triple solution of cyclopen-
tolate, lidocaine, and phenylephrine was used in 4
studies,45,48,86,87 a double solution of lidocaine and
phenylephrine solution in 2 studies,5,79 and single
agents in 2 studies (lidocaine83 or epinephrine,68 1 study
each). Dilation in control arms was based on mydriatic
eyedrops, usually the combination of cyclopentolate
0.85% to 1.0% and phenylephrine 5.0% to
10.0%45,48,79,83,87 or tropicamide 0.5% to 1.0% and phen-
ylephrine 2.5% to 10.0%.5,68 Intracameral injections of
lidocaine 1.0% were associated with mydriatic
eyedrops in 5 studies45,48,79,86,87; epinephrine
J CATARACT REFRACT SURG - VOL 41, JULY 2015
0.6 mg/mL in irrigating balanced salt solution was
used in both the experimental and control arms in 3
studies48,86,87; 1 RCT compared the effects of intracam-
eral mydriatic injections and those of mydriatic
eyedrops and the mydriatic ophthalmic insert across 3
parallel groups.5
Pupil diameter was most often evaluated on digital
video recordings. Surgical performance was assessed
by the overall surgical time and subjective ratings on
a 3-level performance scale, discriminating between
uncomplicated, slightly complicated, and complicated
procedures. Ocular safety was extensively assessed,
including measurement of corneal endothelial charac-
teristics (swelling) and anterior chamber cells and
flare, retinal effects (thickness and macular edema on
optical coherence tomography [OCT]), visual acuity,
posterior capsule opacification (PCO), intraocular
pressure (IOP), and complications. One RCT reported
long-term safety findings87 in an earlier RCT.48
Findings The main results in 7 of the 8 studies are pre-
sented in Figure 2. The other study is included in Figure 1.
Mydriatic Effect The initial 2003 Swedish RCT48
showed that the triple intracameral solution caused a
nearly instantaneous onset of effective mydriasis, the
pupil diameter reaching 95% of its final value within
20 seconds. Pupil size was significantly smaller in
the intracameral mydriatic injection group than in
the mydriatic eyedrops group throughout the proce-
dure, but with no intraoperative contraction; the pupil
sizes increased from the start to the end of surgery in
the intracameral mydriatic injection group.48 Subse-
quent studies found comparable sizes of mydriatic
response and kinetic profiles.67,81 The pupil size was
significantly larger 1 day after surgery in the intracam-
eral mydriatic injection group than in the mydriatic
eyedrops group but without significant differences in
the corrected distance visual acuity (CDVA),48
suggesting that this extended dilation does not alter
the visual restoration.45 This effect was later attributed
to the use of intracameral cyclopentolate.40,86
One RCT5 that was discussed above compared a
dual intracameral mydriatic injection solution (lido-
caine 1.0%–phenylephrine 2.5%) with the mydriatic
ophthalmic insert. It found that the pupil size was
significantly larger with the mydriatic ophthalmic
insert at the beginning and end of surgery (Figure 1).
The subjectively assessed iris stability was signifi-
cantly better in the mydriatic ophthalmic insert group.
Feasibility, Surgical Performance, and Other Outcomes The
simplification of preoperative routines is 1 objective of
intracameral mydriatic injection protocols. Total surgi-
cal time and measures of surgical performance were
 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
assessed in several RCTs.40,48,67,77–79,86 These measures
were consistently found to be comparable in the intra-
cameral mydriatic injection and mydriatic eyedrops
groups (Figure 2).
A dedicated case-control study45 assessed the feasi-
bility of intracameral mydriatic injections in the context
of routine high-volume cataract surgery. The study
compared 198 prospective patients dilated with intra-
cameral mydriatic injections with 198 historical controls
dilated with mydriatic eyedrops and found that cataract
surgery durations were comparable in the 2 groups.
Overall surgical performance was equally good in
both groups. Other authors have suggested that the
simplification of preoperative routines associated with
intracameral mydriatic injections would reduce the de-
mand on nursing time and staff and produce a small but
recurrent cost saving.81 Patients are spared the discom-
fort of intensive topical mydriatics preoperatively,
which they may consider a significant benefit.
Safety The 2003 Swedish RCT48 showed excellent
overall ocular safety of intracameral mydriatic injec-
tions, with no significant differences from mydriatic
eyedrops in CDVA, IOP, inflammation, corneal endo-
thelial cell loss or postoperative corneal swelling, and
complications up to a 1-month follow-up (Figure 2).
Several subsequent RCTs provided additional safety
data that are summarized below.40,45,67,68,78,79,87
Corneal Endothelium Since intracameral epinephrine
may be associated with toxic effects on the corneal endo-
thelium,87,102–105 corneal effects were repeatedly as-
sessed in intracameral mydriatic injection
studies.40,45,48,67,78,79,87 Corneal swelling/thickness and
endothelial morphology (hexagonal shape factor, cell
elongation, coefficient of variation in cell size) were
the main outcome criteria. The initial Swedish RCT
showed a significant reversible morphologic modifica-
tion of corneal endothelial cells (irregular and elongated
shape) compared with preoperative assessment in the
intracameral mydriatic injection and mydriatic
eyedrops groups, with no significant between-group
difference. There was no between-group difference in
postoperative endothelial cell loss, inflammatory reac-
tion, or corneal swelling.48 Another study45 found no
significant difference in corneal swelling and postoper-
ative inflammation between intracameral mydriatic in-
jections and mydriatic eyedrops in the context of routine
high-volume cataract surgery.
A continuous endothelial cell loss, exceeding the rate
of natural reduction, has been observed after cataract
surgery.87,106 Available studies had limited follow-up
periods and reported variable loss rates.107–113 The 6-
year follow-up of the 2003 RCT87 found that the
J CATARACT REFRACT SURG - VOL 41, JULY 2015
1511
endothelial cell loss was comparable in the intracam-
eral mydriatic injection and mydriatic eyedrops treat-
ment groups, which is consistent with the results in
other studies with longer follow-up.97,106,107,114
Retina The retinal effects of intracameral mydriatic in-
jections and mydriatic eyedrops were compared in 2
RCTs using OCT.68,79 Retinal evaluation was justified
by the association of topical epinephrine with cystoid
macular edema (CME) in aphakic eyes.115–118 Although
usually presenting as a reversible change, epinephrine-
associated maculopathy may evolve to CME, which is a
significant cause of decreased vision after cataract sur-
gery.68,119,120 Optical coherence tomography is sensitive
enough to detect subclinical changes in macular thick-
ness during the postoperative period,79,119,121 and tem-
porary increased macular thickness was observed
with OCT after uneventful cataract surgery.119,122
The first RCT compared a dual intracameral solu-
tion (phenylephrine 1.5%–lidocaine 1.0%) and mydri-
atic eyedrops (cyclopentolate 1.0%–phenylephrine
10.0%) associated with intracameral lidocaine.79 It
found a significant increase from preoperative values
in mean retinal thickness and macular volume in
both treatment groups at 1 week, with no significant
between-group difference.79 The second RCT
compared retinal changes in patients dilated with the
usual mydriatic eyedrops and with or without intra-
cameral epinephrine. The follow-up extended to
6 months.68 The study found significantly increased
macular thickness from baseline at 1, 3, and 6 months
in both groups, with no significant between-group dif-
ference at any time. The authors indicated that the in-
crease in macular thickness was probably not due to
the mydriatics but to other factors, such as the cataract
surgery or the postoperative use of preserved
eyedrops.68
Posterior Capsule Opacification Since intracameral
mydriatic injections induce slightly smaller pupil sizes
than mydriatic eyedrops, they carry the risk for less
meticulous cortex removal and possibly increased rates
of PCO. This issue was addressed in a 6-year follow-up
study, which found comparable PCO scores (fraction
and severity) in the intracameral mydriatic injections
and mydriatic eyedrops treatment groups.87 The result
was deemed consistent with those in other studies using
comparable methods and follow-up.87,123,124
Visual Acuity A significantly larger pupil diameter was
found on the first postoperative day with intracameral
mydriatic injections than with intracameral placebo
and mydriatic eyedrops in all studies that assessed
this outcome. However, the CDVA was not signifi-
cantly different between groups.45,48,78,86 One
1512 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
observational study found that the CDVA and increase
in CDVA from preoperative values were significantly
better on day 1 in the intracameral mydriatic injections
group than in the mydriatic eyedrops group in routine
cataract surgery.45 The CDVA did not differ between
the groups at the 6-year follow-up assessment.87
Administered Doses and Cardiovascular Effects The com-
parison of drug doses administered with the initial
Swedish triple solution or with conventional mydriatic
eyedrops showed that the mean amount was 6.2-fold
and 4.3-fold larger in the mydriatic eyedrops group
for cyclopentolate and phenylephrine, respectively
(assuming a drop size of 37 mL).48 This means that the
intracameral route delivers only 23% of the phenyleph-
rine dose administrated by a standard mydriatic
eyedrops protocol and may reduce the risk for cardio-
vascular adverse effects in high-risk patients.45
Compared with standard mydriatic eyedrops, the
intracameral route uses 10-fold lower concentrations
of the same drugs and delivers minute doses directly
to the target organ.81 The systemic absorption of intra-
cameral mydriatics is limited by the aqueous humor
turnover.45,52 Intracameral lidocaine at doses used for
mydriasis does not yield detectable blood levels.45,98
The intracameral injection of epinephrine causes little
or no adverse cardiovascular effects.19 Changes in car-
diovascular variables associated with intracameral
mydriatic injections (blood pressure, heart rate, oxygen
saturation) are minimal and do not differ from those ex-
pected with conventional mydriatic eyedrops.5,45,48,81
One study found that the incidence of intraoperative
high systolic blood pressure was 30.0% in the mydriatic
eyedrops group, 10.0% in the mydriatic ophthalmic
insert group, and 6.6% in the intracameral mydriatic in-
jections group.5 No cardiovascular event associated
with intracameral mydriatic injection was reported in
any study included in this review.
Other Adverse Events and Complications The RCTs
included in this review found no intracameral mydriatic
injection–associated complications.3,8,40,48,67,68,77,78,83,86
One prospective case-control study done in a routine
practice setting added interesting data to safety assess-
ment.45 It reported that the rarely observed adverse ef-
fects (need for the use of capsular tension ring or iris
hooks in capsulorhexis, dropped lens fragment, phaco-
donesis, exceptionally hard nucleus, incomplete cortex
aspiration, iris prolapse, posterior capsule rupture,
tense or nervous patient) occurred most often in both
the intracameral mydriatic injections and the mydriatic
eyedrops groups. Complications observed in only the
mydriatic eyedrop group were atonic iris and use of
an ophthalmic dye (Vision Blue); small pupils occurred
in only the intracameral mydriatic injections group.
J CATARACT REFRACT SURG - VOL 41, JULY 2015
One RCT was a noticeable exception because it
reported that 36% of patients in the intracameral
mydriatic injections group versus none in the
mydriatic eyedrops and mydriatic ophthalmic insert
groups had iris-related complications; this finding
was associated with the observation of a significantly
inferior mydriasis stability in the intracameral mydri-
atic injections group compared with the other 2
groups.5 No other RCT directly compared intracam-
eral mydriatic injections and the mydriatic ophthalmic
insert. Therefore, no formal conclusion about the rela-
tive advantages and limits of these methods can be
drawn. Intracameral mydriatic injections have the po-
tential to reduce the nursing time, whereas the mydri-
atic ophthalmic insert can have the benefit of wider
indications outside anterior segment surgery.
Acetylcholine-Induced Contraction Pupil contraction
with acetylcholine may play a crucial role if complica-
tions such as posterior capsule rupture or zonulysis
occur during cataract surgery. The ability to quickly
reverse the mydriatic effect of intracameral mydriatic
injections is thus an important safety issue that was
tested in a recent RCT comparing intracameral
injections and mydriatic eyedrops.86 The study found
no significant between-group difference in pupil
size and contractions 30 and 120 seconds after
acetylcholine intracameral injection, indicating that
acetylcholine-induced contraction was preserved after
primary dilation with intracameral mydriatic injections.
Role in Rescue Dilation
It has been emphasized that small pupils and reflex
miosis during cataract surgery carry an increased risk
for complications.1,66,67,78 A retrospective review of
1163 charts125 found that pupil diameters smaller than
6.5 mm were significantly associated with an increased
incidence of intraoperative floppy-iris syndrome (IFIS).
Conversely, adequate and stable dilation reduced the
risk for iris prolapse and engagement.3
Preventing Intraoperative Miosis with Epinephrine The
maintenance of adequate mydriasis during the entire
cataract surgery procedure is of paramount impor-
tance, and various techniques have been proposed,78
including mechanical devices (eg, iris retractors),126
preoperative nonsteroidal antiinflammatory
drugs,23,127,128 viscous phenylephrine,20 and intra-
operative epinephrine.19,22,85,129
Several studies have shown that epinephrine is
required to oppose intraoperative miosis and maintain
stable mydriasis when pupils are initially dilated with
mydriatic eyedrops.19,66,67,78,129 Other studies have
emphasized that epinephrine should be tried before
mechanical methods68 because the latter may cause
 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
iris trauma and sphincter rupture, are time
consuming, and require additional incisions.130
Intracameral Mydriatic Injections for Rescue Mydriasis The
effect of epinephrine suggested the possibility of redi-
lating pupils that contract during surgery with an intra-
operative intracameral mydriatic injection. To assess
this possibility, 1 RCT78 compared intraoperative
redilation with intracameral mydriatic injections and
redilation with intracameral placebo with or without
epinephrine in the irrigating solution across 4 randomly
assigned groups. Primary dilation was with the usual
mydriatic eyedrops. The study found that intracameral
mydriatic injections redilated contracted pupils better
than the intracameral placebo 30 seconds and
2 minutes after the injection, but only in the group
without epinephrine infusion. The authors concluded
that intracameral mydriatic injections could be used for
salvage mydriasis after primary dilation with mydriatic
eyedrops.78 Insufficient adrenergic stimulation was
interpreted as a major factor in intraoperative pupil
contraction. The intracameral injection of commercially
available eyedrops containing tropicamide 0.5% and
phenylephrine 0.5% was effective for dilating pupils of
patients with previously established poor response to
the topical instillation of the same solution.131
Intraoperative Floppy-Iris Syndrome Intraoperative
floppy-iris syndrome was recently reviewed132; only a
few aspects are summarized here. The syndrome is
characterized by poor initial mydriasis, sudden pupil
contraction during surgery, and a tendency toward
iris prolapse through the incisions.133 Although the inci-
dence in the general population is low, it may reach high
rates (50% to 60%) in patients who are or were treated
with tamsulosin or other a-receptor antagonists such
as alfuzosin or doxazosin used in the treatment of
benign prostate hypertrophy.133–139 Intraoperative
floppy-iris syndrome is believed to result from the
long-term inhibition of the iris dilator by a-antagonists,
which leads to dilator atrophy132,140,141 and explains
why IFIS may occur years after tamsulosin use. Signifi-
cant risk for IFIS was recently associated with the preop-
erative use of both selective and nonselective oral a-
antagonists,142 but IFIS occurs more frequently with
tamsulosin than with other a-antagonists. It has also
been reported that moderate to severe IFIS can occur
in a significant proportion (12.4%) of low-risk patients
(ie, those with no history of oral a-antagonists use) if
epinephrine is omitted from the irrigation bottle.138 Out-
comes vary from increased surgery duration or need for
an early second procedure137 to complications such as
iris atrophy, posterior capsule rupture, and zonular dis-
insertion.132 The risk for surgical complications is signif-
icantly increased in all groups with IFIS.142
J CATARACT REFRACT SURG - VOL 41, JULY 2015
1513
The best strategy would be to prevent IFIS by avoid-
ing the use of tamsulosin and a-antagonists in patients
who need cataract surgery.132 Pharmacologic inter-
ventions include preoperative atropine and intraoper-
ative sympathomimetics.143 Preoperative atropine
1.0% eyedrops, combined or not combined with intra-
cameral epinephrine, have shown promising results in
small series,144,145 but this strategy is debated by other
authors since IFIS is primarily due to the inhibition of
adrenergic receptors.132
Intracameral Mydriatics for Intraoperative Floppy-Iris
Management It has been emphasized that the intra-
cameral injection of a-receptor agonists is probably
the most effective strategy opposing IFIS,132 next to
the use of mechanical devices (eg, Malyugin ring).146
Intracameral phenylephrine 2.5% was used in 2 pro-
spective uncontrolled studies,147,148 and a retrospective
study149 assessed the effects of combined intracameral
epinephrine and lidocaine. Overall findings showed
reversion or stabilization of the pupil constriction and
substantially improved iris rigidity, most often result-
ing in the prevention of iris prolapse and IFIS complica-
tions.147,148 The bisulfite-free epinephrine intracameral
solution was formulated for IFIS prophylaxis in pa-
tients with a history of tamsulosin use,3 and no cases
of IFIS were found in 71 successive cataract surgery per-
formed in these high-risk patients.101
In contrast to these favorable results, a retrospective
review of 1163 charts, including pharmacologic
prophylaxis of IFIS during cataract surgery in patients
taking tamsulosin, found that the overall IFIS inci-
dence was lower than previously reported (29.6%)
but reached 38.5% in patients who received prophylac-
tic intracameral lidocaine–epinephrine.125 Other au-
thors commented that this surprising finding may
have been due to bias.132
Important data were recently added by a prospec-
tive fellow-eye controlled multicenter RCT of IFIS pre-
vention with intracameral phenylephrine 1.5% in
patients taking tamsulosin.150 Signs of IFIS were
observed in 0% of eyes treated with prophylactic intra-
cameral phenylephrine and in 88% of eyes that did not
receive this prophylaxis, a highly significant difference
(P ! .001) Problematic signs (significant miosis, iris
prolapse, or both) occurred in 54% of eyes with no pro-
phylaxis but were successfully reverted with intra-
cameral phenylephrine. No complications were
observed. The authors concluded that intracameral
phenylephrine is a highly effective prophylactic treat-
ment of IFIS in at-risk patients.150 Another RCT151
compared a sub-Tenon injection of lidocaine 2.0%
and an intracameral injection of lidocaine 1.0% for
IFIS prevention during cataract surgery in patients
taking oral a-antagonists for more than 12 months.
1514 REVIEW/UPDATE: MYDRIATIC INSERT AND INTRACAMERAL INJECTIONS IN CATARACT SURGERY
The study found that the sub-Tenon lidocaine injection
was significantly better than the intracameral route in
the overall IFIS incidence (8.8% versus 48.6%), occur-
rence of severe IFIS (0% versus 8.1%), iris prolapse
(5.8% versus 27.0%), and IFIS incidence in
tamsulosin-treated subgroups (16.6% versus 76.9%).
Topical mydriatics were used in all cases, and intra-
cameral phenylephrine or epinephrine was not given.
CONCLUSION
Routines in high-volume cataract surgery should be as
straightforward, safe, simple, repeatable, and effective
as possible. From this perspective, the disadvantages
of mydriatic eyedrops are slow penetration of active
ingredients through the cornea and delayed effect,
low bioavailability, and need for repeated instillations,
which carry increased risk for systemic adverse effects
and are time consuming. The weakening of the mydri-
atic effect, in addition to reflex miosis during surgery,
increases the risk for surgery-related complications.
The mydriatic ophthalmic insert device induced an
effective mydriasis in all studied cataract surgery sub-
populations; the pupil diameter was comparable to or
larger than the diameter with mydriatic eyedrops. The
onset is slower than with mydriatic eyedrops but the
induced dilation lasts longer. There are no local safety
concerns, particularly regarding intolerance or bacte-
rial contamination. Total administered doses of tropi-
camide and phenylephrine are reduced 5- to 10-fold.
Reduction in nurse workload to reach effective dila-
tion may translate into an economic advantage.
Mydriatics can also be safely injected into the
anterior or posterior chamber in phacoemulsification
surgery and allow the procedure to be performed
without topical mydriatics. The intracameral mydri-
atic injection produces smaller pupils initially, but
the pupils continue to increase during the procedure;
the intracameral mydriatic injection has been repeat-
edly shown to be effective in counteracting intraoper-
ative pupil constriction and IFIS. Furthermore,
intracameral mydriatic injections are likely to carry a
smaller risk for systemic adverse effects.
The present review suggests that the mydriatic
ophthalmic insert and intracameral mydriatic
injections have favorable risk:benefit ratios and are
credible alternatives to mydriatic eyedrops, with
distinctive advantages and limitations.
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