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Intracameral Phenylephrine 1.5% for Prophylaxis against Intraoperative Floppy Iris Syndrome: Prospective, Randomized Fellow Eye Study
Intracameral Phenylephrine 1.5% for Prophylaxis against Intraoperative Floppy Iris Syndrome: Prospective, Randomized Fellow Eye Study Ramón Lorente, MD, PhD,1 Victoria de Rojas, MD, PhD,2 Paula Vázquez de Parga, MD,1 Claudio Moreno, MD,1 Juan Varela, PhD,3 Maria Luisa Landaluce, MD,1 Julia Méndez, MD,1 Betty Lorente, MD4 Purpose: To evaluate the efficacy of intracameral phenylephrine (IPH) administered as prophylaxis against intraoperative floppy iris syndrome (IFIS) and to analyze the ability of IPH to reverse IFIS. Design: Prospective, multicenter, randomized, comparative case series of fellow eyes. Participants: Forty-two patients receiving tamsulosin who underwent cataract surgery between January and April 2011. Methods: Phacoemulsification was performed by 2 experienced surgeons at 2 surgical sites (Complexo Hospitalario Universitario Orense and Complexo Hospitalario Universitario A Coruña). One eye of each patient was randomized to receive 0.6 ml of nonpreserved bisulfite-free IPH 1.5% (group 1) or balanced saline solution (group 2) at the start of surgery. If significant miosis or iris prolapse occurred, IPH was injected during phacoemulsification in group 2. No changes were performed in the surgeon’s standard fluidic parameters or viscoelastic preferences. Routine topical mydriatics were instilled before surgery. Intraoperative iris billowing and prolapse and pupil size were recorded and videotaped. Surgical complications; adverse events; pre- and postoperative pulse rate and blood pressure; and final best-corrected visual acuity (BCVA), intraocular pressure (IOP), and endothelial cell count (ECC) were recorded. Main Outcome Measures: Incidence of IFIS and change in pupil size after IPH administration in those eyes of group 2 requiring IPH because of significant miosis or iris prolapse. Results: Signs of IFIS were observed in 88.09% of eyes in group 2. No signs of IFS were noted in group 1 (P ⬍ 0.001). Significant miosis, iris prolapse, or both occurred in 54.76% of eyes in group 2, although the condition was successfully reverted with IPH, with a significant increase in pupil size after IPH administration (from 4.77⫾0.88 mm to 6.68⫾0.93 mm; P⫽0.000). No intraoperative complications occurred. No significant differences in ECC, BCVA, or IOP were detected between IPH-treated and nontreated eyes. Blood pressure/ pulse rate did not differ significantly from preoperative values in IPH-treated cases. Conclusions: Intracameral phenylephrine is a highly efficient measure for prophylaxis against IFIS. Moreover, the drug can reverse IFIS, restoring iris rigidity and causing the pupil to return to its preoperative size. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:2053–2058 © 2012 by the American Academy of Ophthalmology.
Intraoperative floppy iris syndrome (IFIS)1 is characterized by a triad of signs that occur during cataract surgery—iris billowing, iris prolapse, and progressive intraoperative miosis— despite standard preoperative pharmacologic measures. Pupil dilation and subsequent stability of the iris during cataract surgery are necessary for successful and safe phacoemulsification. This small-pupil syndrome has been associated with systemic administration of tamsulosin and other ␣1-adrenergic receptor antagonists, such as alfuzosin, doxazosin, and terazosin.2 However, tamsulosin leads to more common and severe IFIS than other nonselective ␣1-blockers,3 as suggested in several retrospective and prospective studies1,2,4–7 and a recent meta© 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
analysis.8 The incidence of IFIS in patients taking tamsulosin ranges from 43% to 90%,1,4,5,7,9 compared with 0% to 19% for those taking nonselective ␣1-antagonists.1,4,7 Many techniques and procedures have been proposed to mitigate potential intraoperative problems in patients with IFIS, although no definitive measures have been established.2 Management strategies can be divided into 4 main categories: pharmacologic therapy (intracameral epinephrine,10 –12 phenylephrine,13–15 and preoperative atropine11), viscomydriasis (sodium hyaluronate 2.3% [Healon5, Abbott Laboratories Inc, Abbott Park, IL]),16 devices (pupil expansion ring or iris hooks), and surgical measures to minimize anterior chamber turbulence.2,15 ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.04.028
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Ophthalmology Volume 119, Number 10, October 2012 Lundberg and Behndig17,18 reported intracameral xylocaine plus phenylephrine 1.5% to be safe in routine phacoemulsification surgery. Therefore, we hypothesized that intracameral phenylephrine (IPH) 1.5% could help prevent IFIS. After prospectively reviewing the efficacy of this approach in a large series of patients at risk of IFIS,19 we decided to evaluate the efficacy of IPH 1.5% as prophylaxis against tamsulosin-associated IFIS and to analyze its ability to reverse IFIS in a prospective randomized comparison of fellow eyes.
Patients and Methods This study was a prospective randomized comparison of fellow eyes undergoing cataract surgery performed by 2 surgeons (R.L., V.R.) at 2 sites (Complexo Hospitalario Universitario Orense and Complexo Hospitalario Universitario A Coruña). Patients receiving tamsulosin and scheduled to have routine phacoemulsification cataract surgery were included for study. Patients were excluded if there was a history of glaucoma, endothelial disease, media opacities other than cataract, ocular trauma, zonular dialysis, iridocyclitis, iris neovascularization, or prior iris surgery. Eyes with a preoperative pupil size less than 4.5 mm after topical mydriatics were not included in the study. Patients receiving treatment with any other ␣1-antagonist or other drugs associated with IFIS were excluded, because we intended to evaluate the efficacy of this prophylactic measure in those cases with the highest probability of experiencing the syndrome and in whom its manifestations were most severe.2,8 No patients discontinued the drug before surgery. The study was conducted in accordance with the tenets of the Declaration of Helsinki, and institutional review board approval was obtained at each center. All patients provided informed consent. One eye of each patient was randomized to receive 0.6 ml of nonpreserved bisulfite-free IPH 1.5% (group 1) or balanced saline solution (BSS) (group 2) at the start of surgery. Randomization was performed using computer-generated random numbers so that 1 eye was randomized to group 1, with the second eye automatically assigned to group 2. In the case of significant miosis or prolapse that could compromise the safety of surgery, IPH was injected during phacoemulsification in group 2 (group 2 IPH). Our previous retrospective study provided evidence that IPH was not only efficient for prophylaxis against IFIS but also able to reverse IFIS once it occurred.19 Thus, we considered it would have been unethical not to use it in group 2 if required. Topical mydriatics (tropicamide 1%, phenylephrine 10%) and topical diclofenac were instilled before surgery. Balanced saline solution with 0.0006 mg/ml of epinephrine was used as the irrigating solution. Microcoaxial surgery was performed under topical anesthesia through a temporal clear corneal 2.2-mm incision using torsional ultrasound (Infiniti Vison System platform, Alcon, Fort Worth, TX) and sodium hyaluronate 3%– chondroitin sulfate 4% and sodium hyaluronate 1% as ophthalmic viscosurgical devices. After paracentesis, 0.3 ml of lidocaine hydrochloride 1% was instilled into the anterior chamber, followed by injection of 0.6 ml of nonpreserved, bisulfite-free IPH 1.5% in group 1 or BSS in group 2. The ophthalmic viscosurgical devices were injected 20 seconds later. Standard phacoemulsification fluidic parameters and ophthalmic viscosurgical device preferences were maintained. The vertical phaco-chop or divide-and-conquer technique was used depending on nuclear density. Both surgeons applied the same parameters. Intraoperative iris billowing, iris prolapse, and pupil size were recorded and videotaped. Pupil size was measured with calipers at the beginning of surgery, after intracameral administration of IPH or BSS, after hydrodissection, at completion of phacoemulsification, before IPH administration (in group 2 IPH), and at the end of
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surgery after implantation of the intraocular lens and removal of the viscosurgical device. Intraoperative floppy iris syndrome was scored from 0 to 3 for data analysis, with 0 corresponding to no manifestations of IFIS, 1 corresponding to the appearance of 1 sign of IFIS, and 2 and 3 corresponding to the occurrence of 2 and 3 signs of IFIS, respectively (miosis, billowing, or prolapse).20 Pulse and mean arterial pressure (MAP) were measured immediately before and after surgery to assess systemic side effects. Only data corresponding to surgery of the eye included in group 1 were considered for each patient in the case of systemic side effects. The MAP was calculated as follows: systolic blood pressure ⫻ 1/3 ⫹ diastolic blood pressure ⫻ 2/3.17 The data collected at the preoperative visit were age and sex, duration of tamsulosin intake, lens hardness (Lens Opacities Classification System III), and presence of pseudoexfoliation. All intraoperative and postoperative complications were recorded, as was any iris abnormality. Central corneal endothelial photographs were taken with a CSO noncontact specular microscope (Specular Microscope SP-02 CSO srl, Scandicci, Firenze, Italy) at 3 months to assess the endothelial cell count (ECC). Intraocular pressure (IOP) and postoperative best-corrected visual acuity (BCVA) at the final postoperative visit were also recorded. Intracameral phenylephrine 1.5% was prepared in the pharmacy department of our institution (J.V.). Briefly, 750 mg of sterile salts of phenylephrine hydrochloride was diluted with 50 ml of BSS (pH, 6.91; osmolality, 410 mOsm/kg). The 2-ml containers can be stored for up to 2 months at room temperature (González N, Pena I, González-Barcia M, Chuclá MT. Assay of stability of phenylephrine hydrochloride 1.5% in different conditions of elaboration. Poster presented at: the Spanish Society of Hospital Pharmacology, September 23, 2009). The systemic and ocular safety of IPH 1.5% were previously studied by Lundberg and Behndig.17 The use of IPH during cataract surgery is off label, and it has not been approved by the Food and Drug Administration. The incidence of IFIS in patients taking tamsulosin is 90% according to Chang et al.5 In our previous study,19 the incidence of IFIS in eyes of patients taking tamsulosin decreased to 0% when using IPH. However, these were 2 different studies, and the latter was a noncomparative, prospective study; thus, for the purpose of sample estimation in the current study, a lower efficacy of IPH was considered in the bilateral approach. Thus, by assuming that IPH was expected to reduce IFIS occurrence in at least 50%, versus an incidence of 90% in eyes without IPH, with ␣⫽0.05 and a statistical power of 90% (⫽0.10), with a bilateral approach, then a sample of 26 eyes in each group would be required. Thus, our sample of 42 eyes in each group allowed us to estimate these differences with ␣⫽0.05 and a statistical power ⬎90%. Statistical analysis was performed using SPSS software (SPSS Inc, Chicago, IL). Visual acuity was converted to the logarithm of the minimum angle of resolution for statistical analysis. Paired or unpaired t tests were used to compare mean pupil sizes. The paired t test was used to compare pupil size between different intervals during surgery in the same group. The unpaired t test was used to compare pupil size at each interval between groups. The Mann– Whitney test was used to compare ECC, BCVA, and IOP between IPH-treated and nontreated eyes. Nontreated eyes were those eyes in group 2 that did not receive IPH. The ECC, BCVA, and IOP were compared between those eyes and fellow treated eyes. Treated fellow eyes in group 2 IPH were not included in this comparison. The paired t test was used to compare preoperative and postoperative MAP and pulse rate. The Wilcoxon rank-sum test was used to compare pupil size between different time intervals in group 2 IPH eyes. The chi-square test was used to compare occurrence of IFIS between groups 1 and 2. P⬍0.05 was considered statistically significant.
Lorente et al 䡠 Prevention of IFIS with IPH 1.5% Table 1. Patient Baseline Characteristics No. of eyes Sex Male Female Mean duration of tamsulosin intake (m) Mean age (y) Presence of pseudoexfoliation Nuclear density (lens hardness) (LOCS III) Group 1 Group 2
Table 3. Mean Pupil Diameter at Different Intervals during Surgery in Groups 1 and 2
84 42 0 61.57⫾47.44 (range, 5–180) 78.09⫾5.47 3
Mean Pupil Diameter (mm)
Preoperative After hydrodissection After phacoemulsification Conclusion of surgery
2.5⫾0.87 2.43⫾0.87
Group 1
Group 2
7.48⫾1.09* 7.57⫾1.04 7.39⫾1.13 7.36⫾1.10* *P⫽0.105
7.27⫾1.05* 6.46⫾1.18* 5.91⫾1.45* 6.56⫾1.07* *P⫽0.000
P⫽0.356 P⫽0.000 P⫽0.000 P⫽0.001
*Sets of data included in the comparison. LOCS ⫽ Lens Opacity Classification System; m ⫽ months; y ⫽ years.
Results Forty-two patients (84 eyes) were enrolled in the study from January 2011 to April 2011 Two patients were excluded because of a preoperative dilated pupil size ⬍4.5 mm. Baseline characteristics are shown in Table 1. Vertical phaco-chop was performed in 19 eyes in group 1 and 17 eyes in group 2; divide-and-conquer was performed in 23 eyes in group 1 and 25 eyes in group 2. All patients completed the minimum follow-up of 3 months. The incidence of IFIS was significantly higher in group 2 (P⬍0.001). No signs of IFIS were noted in group 1 (Video 1, available at http://aaojournal.org), whereas 37 of 42 eyes (88.09%) in group 2 showed some sign of IFIS. Of these, IFIS was graded as 1 in 4 cases (9.5%), as 2 in 7 cases (16.6%), and as 3 in 26 cases (61.9%), with 83% of eyes presenting iris billowing, 76.19% of eyes presenting iris prolapse, and 69% of eyes presenting miosis (Table 2). In group 2, 23 eyes (54.76%) required IPH during surgery because of significant miosis or iris prolapse (group 2 IPH), in 1 case after hydrodissection and in the remaining cases during phacoemulsification. In all these cases, the use of IPH restored iris rigidity, thus stopping the tendency of the iris to prolapse, and caused the pupil to dilate almost back to its preoperative size (Video 2, available at http://aaojournal.org). No eyes required placement of iris hooks or any additional maneuvers. Pupil size is summarized in Tables 3 and 4 and illustrated in Figure 1. There were no significant differences in preoperative pupil size between eyes in group 1 and group 2 (P⫽0.356). There were no significant differences between preoperative and postoperative pupil size in eyes in group 1 (P⫽0.105) (Table 3). No significant changes in pupil size were observed after administraTable 2. Intraoperative Floppy Iris Syndrome Severity Score and Signs in Groups 1 and 2 Group 1
IFIS Score 0 1 2 3 Signs of IFIS Billowing Prolapse Miosis
Group 2
No. of Eyes
%
No. of Eyes
%
42/42 0 0 0
100 0 0 0
5/42 4/42 7/42 26/42
11.9 9.5 16.6 61.9
35/42 32/42 29/42
83 76.19 69
IFIS ⫽ intraoperative floppy iris syndrome.
tion of IPH or BSS at the beginning of surgery. However, in group 2 IPH, pupil size at the end of surgery was significantly larger than pupil size at administration of IPH (P⫽0.000), although it was still significantly smaller than the preoperative pupil size of the same eyes (P⫽0.000) (Table 4). Compared with before surgery, a significant decrease in pupil size was detected at each step of surgery after hydrodissection in group 2 (P⫽0.000) (Table 3). At the end of surgery, pupil size was significantly larger in group 1 than in group 2 (P⫽0.001), and that of eyes in group 2 showed a statistically significant decrease at the end of surgery compared with before surgery (P⫽0.000). Pupil size after hydrodissection and phacoemulsification was significantly larger in group 1 than in group 2 (P⫽0.000) (Table 3; Fig 1). No intraoperative complications occurred, and no adverse events were detected. Areas of mild iris atrophy were observed in 7 eyes of group 2 in which iris prolapse had occurred, whereas no sign of iris transillumination defect was detected in group 1. No statistically significant differences in BCVA (P⫽0.651), IOP (P⫽0.464), or ECC (P⫽0.805) were noted between IPH-treated and nontreated eyes (Table 5). Postoperative MAP and pulse rate did not differ significantly from preoperative values in group 1 (MAP P⫽0.492; pulse rate P⫽0.791) (Table 6).
Discussion The present study compared fellow eyes of patients requiring cataract surgery who were taking tamsulosin and were randomized to receive IPH or BSS at the beginning of surgery as a measure to prevent IFIS. We evaluated the incidence and grade of IFIS. No signs of IFIS were observed in group 1, whereas 88.09% of eyes in group 2 presented some sign of IFIS, which was scored as grade 3 in 61.9% of cases. This finding demonstrates the success of IPH in preventing IFIS; the efficacy of this solution is underscored by its ability to reverse IFIS once it occurred in 54.76% of eyes in group 2, in which significant miosis or prolapse were noted. The results of the current study support the conclusion of our previous investigation.19 We included only patients taking tamsulosin, because tamsulosin leads to more common and severe IFIS than other nonselective ␣1-blockers,1,2,4 – 8 and we wanted to evaluate the efficacy of phenylephrine in the worst possible scenario. Tamsulosin was taken by 3.2% of patients undergoing cataract surgery in our previous study;19 this percentage is consistent with the findings of previous studies in the United States,1 lower than findings reported in Japan,7 and higher than findings reported in the United Kingdom.20
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Ophthalmology Volume 119, Number 10, October 2012 Table 4. Mean Pupil Diameter in Group 2 Eyes Requiring Intracameral Phenylephrine for Significant Pupil Miosis or Iris Prolapse: Preoperatively, Pre–Intracameral Phenylephrine Administration, and Postoperatively
Mean pupil diameter (mm) Group 2 IPH Stage of surgery during which IPH was administered After hydrodissection During phacoemulsification
Preoperatively
Pre-IPH Administration
Postoperatively
7.15⫾1
4.77⫾0.88
6.68⫾0.93
P⫽0.000
2 cases 21 cases
IPH ⫽ intracameral phenylephrine.
It is difficult to conclude whether one IFIS management technique is superior to another without a randomized prospective trial, because the severity of IFIS varies widely between patients.2 The current study was designed not only as a randomized and prospective trial but also as a comparison of fellow eyes to prevent any variations in the individual tendency to develop the syndrome from inducing bias in the results. To our knowledge, this is the first investigation in which a strategy to prevent or to manage IFIS has been evaluated in a prospective, randomized, comparative pairedeye study. The incidence of IFIS— considered as the occurrence of any sign of IFIS—was 88.09% in group 2. This rate is higher than the incidence of 65% found by Cheung et al20 and similar to the rate of 90% published in the multicenter study by Chang et al.5 Differences in the incidence of IFIS between studies may be attributed to differences in the criteria used to identify or score the occurrence of IFIS. In the survey of the American Society of Cataract and Refractive Surgery,6 one-third of respondents said they routinely used multiple strategies for IFIS. Furthermore, staged protocols allowing progressive addition of new measures according to severity have been recommended.2,13 Among the many pharmacologic methods advocated to directly stimulate the iris dilator smooth muscle receptors, intracameral ␣1-adrenergic receptor agonists such as phenylephrine Pupil size (mm) 8
7 Group 1 Group 2 Group 2 IPH Group 2 w/IPH
6 5 4
rg er y
n tio io n
of
m ul si C
on c
lu s
oe
Figure 1. Mean pupil size (mm) in group 1, in group 2 as a whole, in the subgroup of eyes of group 2 that required intracameral phenylephrine (IPH) administration during surgery (group 2 IPH), and in the subgroup of eyes of group 2 that did not require IPH administration (group 2 w/IPH) at different intervals during surgery: preoperatively, after hydrodissection, after phacoemulsification, and at the conclusion of surgery.
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Table 5. Mean Postoperative Endothelial Cell Count, Intraocular Pressure, and Best-corrected Visual Acuity in Intracameral Phenylephrine–treated and Nontreated Eyes
su
fic a
ec is s Ph ac
yd ro d H
Pr eo
pe ra t
tio n
iv e
3
or epinephrine have proven useful for preventing IFIS.10 –15 These agents not only induce pupil dilatation but also restore iris rigidity by increasing dilator smooth muscle tone, thus markedly reducing the tendency toward iris prolapse and billowing. Shugar10 described successful prevention of IFIS using intracameral epinephrine, a finding that was confirmed by Schulze.12 Masket and Belani11 also combined epinephrine with preoperative atropine for management of IFIS and found that intracameral epinephrine was less effective than the combined regimen. Moreover, contrary to Shugar’s experience,10 it did not reverse established IFIS. Chen et al21 recently reported that prophylactic intracameral lidocaineepinephrine did not reduce the incidence of IFIS, although the authors hypothesized that this result could be biased by the confounding effect of preoperative dilated pupil size.21 Phenylephrine hydrochloride acts predominantly on the ␣1-receptors of the iris.22 Intracameral phenylephrine 1.5% provides adequate intraoperative dilatation in routine phacoemulsification surgery. Manvikar and Allen13 and Gurbaxani and Packard14 found that IPH 0.3125% and 0.625% prevented iris prolapse and billowing and further pupil constriction in patients with medium-to-small pupils before surgery in 22 eyes and 7 eyes, respectively. Manvikar and Allen13 found that IPH, unlike intracameral epinephrine, was effective for reversing pupil constriction. Bäckström and Behndig23 also showed IPH to be effective in redilating constricting pupils during routine phacoemulsification. Our results confirm these findings, because IPH successfully reverted miosis and iris prolapse in 23 eyes in group 2, thus restoring iris rigidity and inducing a significant increase in pupil size that allowed surgery to conclude without intraoperative complications in all cases.
2
ECC (cells/mm ) IOP (mmHg) BCVA (logMAR)
Group 1
Group 2 w/IPH
2445.71⫾291.18 13.35⫾2.4 0.029⫾0.07
2447.71⫾309.95 14.14⫾1.86 0.042⫾0.07
P⫽0.805 P⫽0.464 P⫽0.651
BCVA ⫽ best-corrected visual acuity; ECC ⫽ endothelial cell count; IOP ⫽ intraocular pressure; IPH ⫽ intracameral phenylephrine; logMAR ⫽ logarithm of the minimum angle of resolution; w/IPH: eyes in group 2 that did not require IPH administration.
Lorente et al 䡠 Prevention of IFIS with IPH 1.5% Table 6. Mean Preoperative and Postoperative Blood Pressure and Pulse Rate in Group 1
MAP (mmHg) Pulse rate (beats/min)
Preoperative
Postoperative
104.46⫾10.03 65.40⫾11.51
105.44⫾10.12 65.04⫾10.81
P⫽0.492 P⫽0.791
MAP ⫽ mean arterial pressure.
Manvikar and Allen13 limited administration of IPH because of safety concerns in patients with miosis or in those with small or mid-dilated pupils before surgery. Lundberg and Behndig,17 however, found no statistically significantly different rates of endothelial cell loss among patients who had received intracameral mydriatics including IPH 1.5%. The ECC in the present study is consistent with previously reported data. No adverse events were detected in any of the 65 eyes that received IPH, either at the beginning of or during surgery, and no significant differences in BCVA or IOP were detected between IPH-treated and nontreated eyes. A larger sample, however, would be required to rule out unexpected rare adverse events. In regard to systemic side effects, despite 1 report of a hypertensive episode related to intracameral ␣-agonists,24 the risk of systemic adverse reactions seems to be low, because MAP and heart rate did not differ significantly from preoperative values in our study or a previous report on the subject.17 In addition, although IPH can reverse IFIS, our results clearly show that preoperative administration of IPH is more advantageous than administration when IFIS occurs. Two findings support this statement: firstly, postoperative pupil size in group 1 was not statistically different from preoperative pupil size, whereas postoperative pupil size in group 2 overall or even in group 2 IPH was significantly smaller than preoperative pupil size. Secondly, mild areas of iris atrophy were noted only in group 2, whereas no eyes in group 1 showed any signs of iris atrophy, because no eyes in group 1 presented iris prolapse. Therefore, we think that IPH should be used as routine prophylaxis at the beginning of surgery in any patient receiving tamsulosin. Manvikar and Allen13 reported increased pupil size after intracameral injection of phenylephrine in some cases, whereas in others it remained unchanged. However, in all the patients who received IPH for miosis, pupil size returned to its preoperative value.13 Our previous study19 and the current study support these findings. Therefore, when the pupil is previously dilated with routine topical mydriatics, IPH has no significant effect on pupil size, and its administration does not change the convenience or limitations of surgical maneuvers. Consequently, eyes with a preoperative pupil size ⬍4.5 mm after topical mydriatics were excluded from the study, because no further increase in pupil size is expected after administration of IPH and mechanical pupil expansion devices are required from the beginning of surgery. The comfort level and proficiency of operating through small pupils vary greatly according to individual surgeon skill and experience, and thus, mechanical retractors could be useful even with preoperative pupils ⬎4.5 mm for less-experienced surgeons. In those cases in which the
drug was omitted and miosis occurred, IPH was able to restore the pupil to near its preoperative size, thus allowing surgery to conclude uneventfully. Intracameral drug solutions must be prepared carefully. Toxic anterior segment syndrome has been associated with several ocular medications and may be due to the chemical composition, concentration, pH, or osmolality of the solution, or whether preservatives or additives are included. Particular emphasis must be given to pH and osmolality, whose impact on the functions of corneal endothelial cells means that they have to be within ranges compatible with tissue preservation.25 González et al compared the pH and osmolality of 3 different solutions of IPH 1.5% (using distilled water, saline 0.9%, or BSS as solvent) (González N, Pena I, González-Barcia M, Chuclá MT. Assay of stability of phenylephrine hydrochloride 1.5% in different conditions of elaboration. Poster presented at: the Spanish Society of Hospital Pharmacology, September 23, 2009). Although drug stability did not differ significantly between the different solutions, the pH and osmolality values of the BSS solution were found to be the most compatible with those recommended for intracameral administration, that is, a pH of between 6.5 and 8.526 and osmolality of between 200 and 400 mOsm/kg,27 which explains our use of BSS as a solvent. Care must also be taken to ensure that the solution is preservative- and sulfite-free, because preservative agents are potentially toxic to the corneal endothelium.28 Surgery in eyes with IFIS has been associated with a higher rate of complications than routine cases, especially when the condition is not recognized or anticipated.1,2,5 Conversely, and not surprisingly, because no eyes developed IFIS in group 1 and IFIS appearing in group 2 was successfully reverted, no intraoperative complications occurred in the current series. It is therefore of paramount importance to question patients with cataract before surgery about current or previous use of ␣1-antagonists. Preoperative recognition of patients at risk for IFIS allows preventive measures to be taken. Intracameral phenylephrine presents several advantages over other agents considered for IFIS prophylaxis.2 It is simpler, less traumatic, and quicker than placing iris hooks. The solution is easy to prepare and can be stored for up to 2 months at room temperature in the operating room. Our study is limited in that we did not evaluate whether the lower concentration of phenylephrine used in previous studies would be as effective as IPH 1.5%. In conclusion, the absence of IFIS manifestations in the group of eyes receiving phenylephrine at the beginning of surgery and the ability of phenylephrine to reverse IFIS once it occurred demonstrate that IPH 1.5% is a simple, efficient measure for prophylaxis and management of IFIS.
References 1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005;31: 664 –73. 2. Chang DF, Braga-Mele R, Mamalis N, et al, ASCRS Cataract Clinical Committee. ASCRS White Paper: clinical review of
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3.
4. 5. 6.
7.
8. 9.
10. 11.
12. 13. 14. 15.
intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008;34:2153– 62. Palea S, Chang DF, Rekik M, et al. Comparative effect of alfuzosin and tamsulosin on the contractile response of isolated rabbit prostatic and iris dilator muscles: possible model for intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008;34:489 –96. Chadha V, Borooah S, Tey A, et al. Floppy-iris behaviour during cataract surgery: associations and variations. Br J Ophthalmol 2007;91:40 –2. Chang DF, Osher RH, Wang L, Koch DD. Prospective multicenter evaluation of cataract surgery in patients taking tamsulosin (Flomax). Ophthalmology 2007;114:957– 64. Chang DF, Braga-Mele R, Mamalis N, et al, ASCRS Cataract Clinical Committee. Clinical experience with intraoperative floppy-iris syndrome: results of the 2008 ASCRS member survey. J Cataract Refract Surg 2008;34:1201–9. Oshika T, Ohashi Y, Inamura M, et al. Incidence of intraoperative floppy iris syndrome in patients on either systemic or topical alpha(1)-adrenoceptor antagonist. Am J Ophthalmol 2007;143:150 –1. Chatziralli IP, Sergentanis TN. Risk factors for intraoperative floppy iris syndrome: a meta-analysis. Ophthalmology 2011; 118:730 –5. Bidaguren A, Irigoyen C, Mendicute J, et al. Floppy-iris syndrome associated with tamsulosin: a prospective casecontrol study [in Spanish]. Arch Soc Esp Oftalmol 2007;82: 349 –54. Shugar JK. Use of epinephrine for IFIS prophylaxis [letter]. J Cataract Refract Surg 2006;32:1074 –5. Masket S, Belani S. Combined preoperative topical atropine sulphate 1% and intracameral nonpreserved epinephrine hydrochloride 1:4000 [corrected] for management of intraoperative floppy-iris syndrome. J Cataract Refract Surg 2007;33: 580 –2. Schulze R Jr. Epi-Shugarcaine with plain balanced salt solution for prophylaxis of intraoperative floppy-iris syndrome [letter]. J Cataract Refract Surg 2010;36:523. Manvikar S, Allen D. Cataract surgery management in patients taking tamsulosin: staged approach. J Cataract Refract Surg 2006;32:1611– 4. Gurbaxani A, Packard R. Intracameral phenylephrine to prevent floppy iris syndrome during cataract surgery in patients on tamsulosin. Eye (Lond) 2007;21:331–2. Soler F, Lorente R. Síndrome de iris flácido intraoperatorio: IFIS. In: Lorente R, Mendicute J, eds. Cirugía del cristalino.
16. 17. 18.
19.
20. 21.
22.
23. 24. 25. 26. 27. 28.
vol 2. Madrid, Spain: Sociedad Española de Oftalmología; 2008:1016 –30. Arshinoff SA. Modified SST-USST for tamsulosin-associated intraoperative [corrected] floppy-iris syndrome. J Cataract Refract Surg 2006;32:559 – 61. Lundberg B, Behndig A. Intracameral mydriatics in phacoemulsification cataract surgery. J Cataract Refract Surg 2003; 29:2366 –71. Lundberg B, Behndig A. Separate and additive mydriatic effects of lidocaine hydrochloride, phenylephrine, and cyclopentolate after intracameral injection. J Cataract Refract Surg 2008;34:280 –3. Lorente R, de Rojas V, Vázquez de Parga P, et al. Prevention of tamsulosin-associated IFIS with intracameral phenylephrine 1.5% in 250 eyes. J Emmetropia 2011;2:59 – 63. Available at: http://www.journalofemmetropia.org/2171-4703/jemmetropia. 2011.2.59.63.html. Accessed August 28, 2011. Cheung CM, Awan MA, Sandramouli S. Prevalence and clinical findings of tamsulosin-associated intraoperative floppyiris syndrome. J Cataract Refract Surg 2006;32:1336 –9. Chen AA, Kelly JP, Bhandari A, Wu MC. Pharmacologic prophylaxis and risk factors for intraoperative floppy-iris syndrome in phacoemulsification performed by resident physicians. J Cataract Refract Surg 2010;36:898 –905. Lowe FC. Role of the newer alpha1-adrenergic-receptor antagonists in the treatment of benign prostatic hyperplasiarelated lower urinary tract symptoms. Clin Ther 2004;26: 1701–13. Bäckström G, Behndig A. Redilatation with intracameral mydriatics in phacoemulsification surgery. Acta Ophthalmol Scand 2006;84:100 – 4. Lee KJ, Figueira EC, Sharma NS, et al. Iris prolapse and the floppy-iris syndrome [letter]. J Cataract Refract Surg 2007;33: 757– 8. Mamalis N, Edelhauser HF, Dawson DG, et al. Toxic anterior segment syndrome. J Cataract Refract Surg 2006;32:324 –33. Gonnering R, Edelhauser HF, van Horn DL, Durant W. The pH tolerance of rabbit and human corneal endothelium. Invest Ophthalmol Vis Sci 1979;18:373–90. Edelhauser HF, Hanneken AM, Pederson HJ, van Horn DL. Osmotic tolerance of rabbit and human corneal endothelium. Arch Ophthalmol 1981;99:1281–7. Hull DS, Chemotti MT, Edelhauser HF, et al. Effect of epinephrine on the corneal endothelium. Am J Ophthalmol 1975; 79:245–50.
Footnotes and Financial Disclosures Originally received: October 5, 2011. Final revision: April 27, 2012. Accepted: April 27, 2012. Available online: June 17, 2012.
4
Manuscript no. 2011-1467.
Centro de Oftalmología Barraquer, Barcelona, Spain.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
1
Department of Ophthalmology, Complejo Hospitalario Universitario Orense, Orense, Spain.
2
Department of Ophthalmology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain.
3
Department of Pharmacy, Complejo Hospitalario Universitario Orense, Orense, Spain.
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Presented at: the European Society of Cataract and Refractive Surgery Annual Meeting, September 21, 2011, Vienna, Austria. Correspondence: Ramón Lorente, MD, PhD, C/Calle del Paseo, 19-2°, 32003 Orense, Spain. E-mail: [email protected].
Intraoperative floppy iris syndrome (IFIS)1 is characterized by a triad of signs that occur during cataract surgery—iris billowing, iris prolapse, and progressive intraoperative miosis— despite standard preoperative pharmacologic measures. Pupil dilation and subsequent stability of the iris during cataract surgery are necessary for successful and safe phacoemulsification. This small-pupil syndrome has been associated with systemic administration of tamsulosin and other ␣1-adrenergic receptor antagonists, such as alfuzosin, doxazosin, and terazosin.2 However, tamsulosin leads to more common and severe IFIS than other nonselective ␣1-blockers,3 as suggested in several retrospective and prospective studies1,2,4–7 and a recent meta© 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
analysis.8 The incidence of IFIS in patients taking tamsulosin ranges from 43% to 90%,1,4,5,7,9 compared with 0% to 19% for those taking nonselective ␣1-antagonists.1,4,7 Many techniques and procedures have been proposed to mitigate potential intraoperative problems in patients with IFIS, although no definitive measures have been established.2 Management strategies can be divided into 4 main categories: pharmacologic therapy (intracameral epinephrine,10 –12 phenylephrine,13–15 and preoperative atropine11), viscomydriasis (sodium hyaluronate 2.3% [Healon5, Abbott Laboratories Inc, Abbott Park, IL]),16 devices (pupil expansion ring or iris hooks), and surgical measures to minimize anterior chamber turbulence.2,15 ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.04.028
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Ophthalmology Volume 119, Number 10, October 2012 Lundberg and Behndig17,18 reported intracameral xylocaine plus phenylephrine 1.5% to be safe in routine phacoemulsification surgery. Therefore, we hypothesized that intracameral phenylephrine (IPH) 1.5% could help prevent IFIS. After prospectively reviewing the efficacy of this approach in a large series of patients at risk of IFIS,19 we decided to evaluate the efficacy of IPH 1.5% as prophylaxis against tamsulosin-associated IFIS and to analyze its ability to reverse IFIS in a prospective randomized comparison of fellow eyes.
Patients and Methods This study was a prospective randomized comparison of fellow eyes undergoing cataract surgery performed by 2 surgeons (R.L., V.R.) at 2 sites (Complexo Hospitalario Universitario Orense and Complexo Hospitalario Universitario A Coruña). Patients receiving tamsulosin and scheduled to have routine phacoemulsification cataract surgery were included for study. Patients were excluded if there was a history of glaucoma, endothelial disease, media opacities other than cataract, ocular trauma, zonular dialysis, iridocyclitis, iris neovascularization, or prior iris surgery. Eyes with a preoperative pupil size less than 4.5 mm after topical mydriatics were not included in the study. Patients receiving treatment with any other ␣1-antagonist or other drugs associated with IFIS were excluded, because we intended to evaluate the efficacy of this prophylactic measure in those cases with the highest probability of experiencing the syndrome and in whom its manifestations were most severe.2,8 No patients discontinued the drug before surgery. The study was conducted in accordance with the tenets of the Declaration of Helsinki, and institutional review board approval was obtained at each center. All patients provided informed consent. One eye of each patient was randomized to receive 0.6 ml of nonpreserved bisulfite-free IPH 1.5% (group 1) or balanced saline solution (BSS) (group 2) at the start of surgery. Randomization was performed using computer-generated random numbers so that 1 eye was randomized to group 1, with the second eye automatically assigned to group 2. In the case of significant miosis or prolapse that could compromise the safety of surgery, IPH was injected during phacoemulsification in group 2 (group 2 IPH). Our previous retrospective study provided evidence that IPH was not only efficient for prophylaxis against IFIS but also able to reverse IFIS once it occurred.19 Thus, we considered it would have been unethical not to use it in group 2 if required. Topical mydriatics (tropicamide 1%, phenylephrine 10%) and topical diclofenac were instilled before surgery. Balanced saline solution with 0.0006 mg/ml of epinephrine was used as the irrigating solution. Microcoaxial surgery was performed under topical anesthesia through a temporal clear corneal 2.2-mm incision using torsional ultrasound (Infiniti Vison System platform, Alcon, Fort Worth, TX) and sodium hyaluronate 3%– chondroitin sulfate 4% and sodium hyaluronate 1% as ophthalmic viscosurgical devices. After paracentesis, 0.3 ml of lidocaine hydrochloride 1% was instilled into the anterior chamber, followed by injection of 0.6 ml of nonpreserved, bisulfite-free IPH 1.5% in group 1 or BSS in group 2. The ophthalmic viscosurgical devices were injected 20 seconds later. Standard phacoemulsification fluidic parameters and ophthalmic viscosurgical device preferences were maintained. The vertical phaco-chop or divide-and-conquer technique was used depending on nuclear density. Both surgeons applied the same parameters. Intraoperative iris billowing, iris prolapse, and pupil size were recorded and videotaped. Pupil size was measured with calipers at the beginning of surgery, after intracameral administration of IPH or BSS, after hydrodissection, at completion of phacoemulsification, before IPH administration (in group 2 IPH), and at the end of
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surgery after implantation of the intraocular lens and removal of the viscosurgical device. Intraoperative floppy iris syndrome was scored from 0 to 3 for data analysis, with 0 corresponding to no manifestations of IFIS, 1 corresponding to the appearance of 1 sign of IFIS, and 2 and 3 corresponding to the occurrence of 2 and 3 signs of IFIS, respectively (miosis, billowing, or prolapse).20 Pulse and mean arterial pressure (MAP) were measured immediately before and after surgery to assess systemic side effects. Only data corresponding to surgery of the eye included in group 1 were considered for each patient in the case of systemic side effects. The MAP was calculated as follows: systolic blood pressure ⫻ 1/3 ⫹ diastolic blood pressure ⫻ 2/3.17 The data collected at the preoperative visit were age and sex, duration of tamsulosin intake, lens hardness (Lens Opacities Classification System III), and presence of pseudoexfoliation. All intraoperative and postoperative complications were recorded, as was any iris abnormality. Central corneal endothelial photographs were taken with a CSO noncontact specular microscope (Specular Microscope SP-02 CSO srl, Scandicci, Firenze, Italy) at 3 months to assess the endothelial cell count (ECC). Intraocular pressure (IOP) and postoperative best-corrected visual acuity (BCVA) at the final postoperative visit were also recorded. Intracameral phenylephrine 1.5% was prepared in the pharmacy department of our institution (J.V.). Briefly, 750 mg of sterile salts of phenylephrine hydrochloride was diluted with 50 ml of BSS (pH, 6.91; osmolality, 410 mOsm/kg). The 2-ml containers can be stored for up to 2 months at room temperature (González N, Pena I, González-Barcia M, Chuclá MT. Assay of stability of phenylephrine hydrochloride 1.5% in different conditions of elaboration. Poster presented at: the Spanish Society of Hospital Pharmacology, September 23, 2009). The systemic and ocular safety of IPH 1.5% were previously studied by Lundberg and Behndig.17 The use of IPH during cataract surgery is off label, and it has not been approved by the Food and Drug Administration. The incidence of IFIS in patients taking tamsulosin is 90% according to Chang et al.5 In our previous study,19 the incidence of IFIS in eyes of patients taking tamsulosin decreased to 0% when using IPH. However, these were 2 different studies, and the latter was a noncomparative, prospective study; thus, for the purpose of sample estimation in the current study, a lower efficacy of IPH was considered in the bilateral approach. Thus, by assuming that IPH was expected to reduce IFIS occurrence in at least 50%, versus an incidence of 90% in eyes without IPH, with ␣⫽0.05 and a statistical power of 90% (⫽0.10), with a bilateral approach, then a sample of 26 eyes in each group would be required. Thus, our sample of 42 eyes in each group allowed us to estimate these differences with ␣⫽0.05 and a statistical power ⬎90%. Statistical analysis was performed using SPSS software (SPSS Inc, Chicago, IL). Visual acuity was converted to the logarithm of the minimum angle of resolution for statistical analysis. Paired or unpaired t tests were used to compare mean pupil sizes. The paired t test was used to compare pupil size between different intervals during surgery in the same group. The unpaired t test was used to compare pupil size at each interval between groups. The Mann– Whitney test was used to compare ECC, BCVA, and IOP between IPH-treated and nontreated eyes. Nontreated eyes were those eyes in group 2 that did not receive IPH. The ECC, BCVA, and IOP were compared between those eyes and fellow treated eyes. Treated fellow eyes in group 2 IPH were not included in this comparison. The paired t test was used to compare preoperative and postoperative MAP and pulse rate. The Wilcoxon rank-sum test was used to compare pupil size between different time intervals in group 2 IPH eyes. The chi-square test was used to compare occurrence of IFIS between groups 1 and 2. P⬍0.05 was considered statistically significant.
Lorente et al 䡠 Prevention of IFIS with IPH 1.5% Table 1. Patient Baseline Characteristics No. of eyes Sex Male Female Mean duration of tamsulosin intake (m) Mean age (y) Presence of pseudoexfoliation Nuclear density (lens hardness) (LOCS III) Group 1 Group 2
Table 3. Mean Pupil Diameter at Different Intervals during Surgery in Groups 1 and 2
84 42 0 61.57⫾47.44 (range, 5–180) 78.09⫾5.47 3
Mean Pupil Diameter (mm)
Preoperative After hydrodissection After phacoemulsification Conclusion of surgery
2.5⫾0.87 2.43⫾0.87
Group 1
Group 2
7.48⫾1.09* 7.57⫾1.04 7.39⫾1.13 7.36⫾1.10* *P⫽0.105
7.27⫾1.05* 6.46⫾1.18* 5.91⫾1.45* 6.56⫾1.07* *P⫽0.000
P⫽0.356 P⫽0.000 P⫽0.000 P⫽0.001
*Sets of data included in the comparison. LOCS ⫽ Lens Opacity Classification System; m ⫽ months; y ⫽ years.
Results Forty-two patients (84 eyes) were enrolled in the study from January 2011 to April 2011 Two patients were excluded because of a preoperative dilated pupil size ⬍4.5 mm. Baseline characteristics are shown in Table 1. Vertical phaco-chop was performed in 19 eyes in group 1 and 17 eyes in group 2; divide-and-conquer was performed in 23 eyes in group 1 and 25 eyes in group 2. All patients completed the minimum follow-up of 3 months. The incidence of IFIS was significantly higher in group 2 (P⬍0.001). No signs of IFIS were noted in group 1 (Video 1, available at http://aaojournal.org), whereas 37 of 42 eyes (88.09%) in group 2 showed some sign of IFIS. Of these, IFIS was graded as 1 in 4 cases (9.5%), as 2 in 7 cases (16.6%), and as 3 in 26 cases (61.9%), with 83% of eyes presenting iris billowing, 76.19% of eyes presenting iris prolapse, and 69% of eyes presenting miosis (Table 2). In group 2, 23 eyes (54.76%) required IPH during surgery because of significant miosis or iris prolapse (group 2 IPH), in 1 case after hydrodissection and in the remaining cases during phacoemulsification. In all these cases, the use of IPH restored iris rigidity, thus stopping the tendency of the iris to prolapse, and caused the pupil to dilate almost back to its preoperative size (Video 2, available at http://aaojournal.org). No eyes required placement of iris hooks or any additional maneuvers. Pupil size is summarized in Tables 3 and 4 and illustrated in Figure 1. There were no significant differences in preoperative pupil size between eyes in group 1 and group 2 (P⫽0.356). There were no significant differences between preoperative and postoperative pupil size in eyes in group 1 (P⫽0.105) (Table 3). No significant changes in pupil size were observed after administraTable 2. Intraoperative Floppy Iris Syndrome Severity Score and Signs in Groups 1 and 2 Group 1
IFIS Score 0 1 2 3 Signs of IFIS Billowing Prolapse Miosis
Group 2
No. of Eyes
%
No. of Eyes
%
42/42 0 0 0
100 0 0 0
5/42 4/42 7/42 26/42
11.9 9.5 16.6 61.9
35/42 32/42 29/42
83 76.19 69
IFIS ⫽ intraoperative floppy iris syndrome.
tion of IPH or BSS at the beginning of surgery. However, in group 2 IPH, pupil size at the end of surgery was significantly larger than pupil size at administration of IPH (P⫽0.000), although it was still significantly smaller than the preoperative pupil size of the same eyes (P⫽0.000) (Table 4). Compared with before surgery, a significant decrease in pupil size was detected at each step of surgery after hydrodissection in group 2 (P⫽0.000) (Table 3). At the end of surgery, pupil size was significantly larger in group 1 than in group 2 (P⫽0.001), and that of eyes in group 2 showed a statistically significant decrease at the end of surgery compared with before surgery (P⫽0.000). Pupil size after hydrodissection and phacoemulsification was significantly larger in group 1 than in group 2 (P⫽0.000) (Table 3; Fig 1). No intraoperative complications occurred, and no adverse events were detected. Areas of mild iris atrophy were observed in 7 eyes of group 2 in which iris prolapse had occurred, whereas no sign of iris transillumination defect was detected in group 1. No statistically significant differences in BCVA (P⫽0.651), IOP (P⫽0.464), or ECC (P⫽0.805) were noted between IPH-treated and nontreated eyes (Table 5). Postoperative MAP and pulse rate did not differ significantly from preoperative values in group 1 (MAP P⫽0.492; pulse rate P⫽0.791) (Table 6).
Discussion The present study compared fellow eyes of patients requiring cataract surgery who were taking tamsulosin and were randomized to receive IPH or BSS at the beginning of surgery as a measure to prevent IFIS. We evaluated the incidence and grade of IFIS. No signs of IFIS were observed in group 1, whereas 88.09% of eyes in group 2 presented some sign of IFIS, which was scored as grade 3 in 61.9% of cases. This finding demonstrates the success of IPH in preventing IFIS; the efficacy of this solution is underscored by its ability to reverse IFIS once it occurred in 54.76% of eyes in group 2, in which significant miosis or prolapse were noted. The results of the current study support the conclusion of our previous investigation.19 We included only patients taking tamsulosin, because tamsulosin leads to more common and severe IFIS than other nonselective ␣1-blockers,1,2,4 – 8 and we wanted to evaluate the efficacy of phenylephrine in the worst possible scenario. Tamsulosin was taken by 3.2% of patients undergoing cataract surgery in our previous study;19 this percentage is consistent with the findings of previous studies in the United States,1 lower than findings reported in Japan,7 and higher than findings reported in the United Kingdom.20
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Ophthalmology Volume 119, Number 10, October 2012 Table 4. Mean Pupil Diameter in Group 2 Eyes Requiring Intracameral Phenylephrine for Significant Pupil Miosis or Iris Prolapse: Preoperatively, Pre–Intracameral Phenylephrine Administration, and Postoperatively
Mean pupil diameter (mm) Group 2 IPH Stage of surgery during which IPH was administered After hydrodissection During phacoemulsification
Preoperatively
Pre-IPH Administration
Postoperatively
7.15⫾1
4.77⫾0.88
6.68⫾0.93
P⫽0.000
2 cases 21 cases
IPH ⫽ intracameral phenylephrine.
It is difficult to conclude whether one IFIS management technique is superior to another without a randomized prospective trial, because the severity of IFIS varies widely between patients.2 The current study was designed not only as a randomized and prospective trial but also as a comparison of fellow eyes to prevent any variations in the individual tendency to develop the syndrome from inducing bias in the results. To our knowledge, this is the first investigation in which a strategy to prevent or to manage IFIS has been evaluated in a prospective, randomized, comparative pairedeye study. The incidence of IFIS— considered as the occurrence of any sign of IFIS—was 88.09% in group 2. This rate is higher than the incidence of 65% found by Cheung et al20 and similar to the rate of 90% published in the multicenter study by Chang et al.5 Differences in the incidence of IFIS between studies may be attributed to differences in the criteria used to identify or score the occurrence of IFIS. In the survey of the American Society of Cataract and Refractive Surgery,6 one-third of respondents said they routinely used multiple strategies for IFIS. Furthermore, staged protocols allowing progressive addition of new measures according to severity have been recommended.2,13 Among the many pharmacologic methods advocated to directly stimulate the iris dilator smooth muscle receptors, intracameral ␣1-adrenergic receptor agonists such as phenylephrine Pupil size (mm) 8
7 Group 1 Group 2 Group 2 IPH Group 2 w/IPH
6 5 4
rg er y
n tio io n
of
m ul si C
on c
lu s
oe
Figure 1. Mean pupil size (mm) in group 1, in group 2 as a whole, in the subgroup of eyes of group 2 that required intracameral phenylephrine (IPH) administration during surgery (group 2 IPH), and in the subgroup of eyes of group 2 that did not require IPH administration (group 2 w/IPH) at different intervals during surgery: preoperatively, after hydrodissection, after phacoemulsification, and at the conclusion of surgery.
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Table 5. Mean Postoperative Endothelial Cell Count, Intraocular Pressure, and Best-corrected Visual Acuity in Intracameral Phenylephrine–treated and Nontreated Eyes
su
fic a
ec is s Ph ac
yd ro d H
Pr eo
pe ra t
tio n
iv e
3
or epinephrine have proven useful for preventing IFIS.10 –15 These agents not only induce pupil dilatation but also restore iris rigidity by increasing dilator smooth muscle tone, thus markedly reducing the tendency toward iris prolapse and billowing. Shugar10 described successful prevention of IFIS using intracameral epinephrine, a finding that was confirmed by Schulze.12 Masket and Belani11 also combined epinephrine with preoperative atropine for management of IFIS and found that intracameral epinephrine was less effective than the combined regimen. Moreover, contrary to Shugar’s experience,10 it did not reverse established IFIS. Chen et al21 recently reported that prophylactic intracameral lidocaineepinephrine did not reduce the incidence of IFIS, although the authors hypothesized that this result could be biased by the confounding effect of preoperative dilated pupil size.21 Phenylephrine hydrochloride acts predominantly on the ␣1-receptors of the iris.22 Intracameral phenylephrine 1.5% provides adequate intraoperative dilatation in routine phacoemulsification surgery. Manvikar and Allen13 and Gurbaxani and Packard14 found that IPH 0.3125% and 0.625% prevented iris prolapse and billowing and further pupil constriction in patients with medium-to-small pupils before surgery in 22 eyes and 7 eyes, respectively. Manvikar and Allen13 found that IPH, unlike intracameral epinephrine, was effective for reversing pupil constriction. Bäckström and Behndig23 also showed IPH to be effective in redilating constricting pupils during routine phacoemulsification. Our results confirm these findings, because IPH successfully reverted miosis and iris prolapse in 23 eyes in group 2, thus restoring iris rigidity and inducing a significant increase in pupil size that allowed surgery to conclude without intraoperative complications in all cases.
2
ECC (cells/mm ) IOP (mmHg) BCVA (logMAR)
Group 1
Group 2 w/IPH
2445.71⫾291.18 13.35⫾2.4 0.029⫾0.07
2447.71⫾309.95 14.14⫾1.86 0.042⫾0.07
P⫽0.805 P⫽0.464 P⫽0.651
BCVA ⫽ best-corrected visual acuity; ECC ⫽ endothelial cell count; IOP ⫽ intraocular pressure; IPH ⫽ intracameral phenylephrine; logMAR ⫽ logarithm of the minimum angle of resolution; w/IPH: eyes in group 2 that did not require IPH administration.
Lorente et al 䡠 Prevention of IFIS with IPH 1.5% Table 6. Mean Preoperative and Postoperative Blood Pressure and Pulse Rate in Group 1
MAP (mmHg) Pulse rate (beats/min)
Preoperative
Postoperative
104.46⫾10.03 65.40⫾11.51
105.44⫾10.12 65.04⫾10.81
P⫽0.492 P⫽0.791
MAP ⫽ mean arterial pressure.
Manvikar and Allen13 limited administration of IPH because of safety concerns in patients with miosis or in those with small or mid-dilated pupils before surgery. Lundberg and Behndig,17 however, found no statistically significantly different rates of endothelial cell loss among patients who had received intracameral mydriatics including IPH 1.5%. The ECC in the present study is consistent with previously reported data. No adverse events were detected in any of the 65 eyes that received IPH, either at the beginning of or during surgery, and no significant differences in BCVA or IOP were detected between IPH-treated and nontreated eyes. A larger sample, however, would be required to rule out unexpected rare adverse events. In regard to systemic side effects, despite 1 report of a hypertensive episode related to intracameral ␣-agonists,24 the risk of systemic adverse reactions seems to be low, because MAP and heart rate did not differ significantly from preoperative values in our study or a previous report on the subject.17 In addition, although IPH can reverse IFIS, our results clearly show that preoperative administration of IPH is more advantageous than administration when IFIS occurs. Two findings support this statement: firstly, postoperative pupil size in group 1 was not statistically different from preoperative pupil size, whereas postoperative pupil size in group 2 overall or even in group 2 IPH was significantly smaller than preoperative pupil size. Secondly, mild areas of iris atrophy were noted only in group 2, whereas no eyes in group 1 showed any signs of iris atrophy, because no eyes in group 1 presented iris prolapse. Therefore, we think that IPH should be used as routine prophylaxis at the beginning of surgery in any patient receiving tamsulosin. Manvikar and Allen13 reported increased pupil size after intracameral injection of phenylephrine in some cases, whereas in others it remained unchanged. However, in all the patients who received IPH for miosis, pupil size returned to its preoperative value.13 Our previous study19 and the current study support these findings. Therefore, when the pupil is previously dilated with routine topical mydriatics, IPH has no significant effect on pupil size, and its administration does not change the convenience or limitations of surgical maneuvers. Consequently, eyes with a preoperative pupil size ⬍4.5 mm after topical mydriatics were excluded from the study, because no further increase in pupil size is expected after administration of IPH and mechanical pupil expansion devices are required from the beginning of surgery. The comfort level and proficiency of operating through small pupils vary greatly according to individual surgeon skill and experience, and thus, mechanical retractors could be useful even with preoperative pupils ⬎4.5 mm for less-experienced surgeons. In those cases in which the
drug was omitted and miosis occurred, IPH was able to restore the pupil to near its preoperative size, thus allowing surgery to conclude uneventfully. Intracameral drug solutions must be prepared carefully. Toxic anterior segment syndrome has been associated with several ocular medications and may be due to the chemical composition, concentration, pH, or osmolality of the solution, or whether preservatives or additives are included. Particular emphasis must be given to pH and osmolality, whose impact on the functions of corneal endothelial cells means that they have to be within ranges compatible with tissue preservation.25 González et al compared the pH and osmolality of 3 different solutions of IPH 1.5% (using distilled water, saline 0.9%, or BSS as solvent) (González N, Pena I, González-Barcia M, Chuclá MT. Assay of stability of phenylephrine hydrochloride 1.5% in different conditions of elaboration. Poster presented at: the Spanish Society of Hospital Pharmacology, September 23, 2009). Although drug stability did not differ significantly between the different solutions, the pH and osmolality values of the BSS solution were found to be the most compatible with those recommended for intracameral administration, that is, a pH of between 6.5 and 8.526 and osmolality of between 200 and 400 mOsm/kg,27 which explains our use of BSS as a solvent. Care must also be taken to ensure that the solution is preservative- and sulfite-free, because preservative agents are potentially toxic to the corneal endothelium.28 Surgery in eyes with IFIS has been associated with a higher rate of complications than routine cases, especially when the condition is not recognized or anticipated.1,2,5 Conversely, and not surprisingly, because no eyes developed IFIS in group 1 and IFIS appearing in group 2 was successfully reverted, no intraoperative complications occurred in the current series. It is therefore of paramount importance to question patients with cataract before surgery about current or previous use of ␣1-antagonists. Preoperative recognition of patients at risk for IFIS allows preventive measures to be taken. Intracameral phenylephrine presents several advantages over other agents considered for IFIS prophylaxis.2 It is simpler, less traumatic, and quicker than placing iris hooks. The solution is easy to prepare and can be stored for up to 2 months at room temperature in the operating room. Our study is limited in that we did not evaluate whether the lower concentration of phenylephrine used in previous studies would be as effective as IPH 1.5%. In conclusion, the absence of IFIS manifestations in the group of eyes receiving phenylephrine at the beginning of surgery and the ability of phenylephrine to reverse IFIS once it occurred demonstrate that IPH 1.5% is a simple, efficient measure for prophylaxis and management of IFIS.
References 1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005;31: 664 –73. 2. Chang DF, Braga-Mele R, Mamalis N, et al, ASCRS Cataract Clinical Committee. ASCRS White Paper: clinical review of
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3.
4. 5. 6.
7.
8. 9.
10. 11.
12. 13. 14. 15.
intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008;34:2153– 62. Palea S, Chang DF, Rekik M, et al. Comparative effect of alfuzosin and tamsulosin on the contractile response of isolated rabbit prostatic and iris dilator muscles: possible model for intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008;34:489 –96. Chadha V, Borooah S, Tey A, et al. Floppy-iris behaviour during cataract surgery: associations and variations. Br J Ophthalmol 2007;91:40 –2. Chang DF, Osher RH, Wang L, Koch DD. Prospective multicenter evaluation of cataract surgery in patients taking tamsulosin (Flomax). Ophthalmology 2007;114:957– 64. Chang DF, Braga-Mele R, Mamalis N, et al, ASCRS Cataract Clinical Committee. Clinical experience with intraoperative floppy-iris syndrome: results of the 2008 ASCRS member survey. J Cataract Refract Surg 2008;34:1201–9. Oshika T, Ohashi Y, Inamura M, et al. Incidence of intraoperative floppy iris syndrome in patients on either systemic or topical alpha(1)-adrenoceptor antagonist. Am J Ophthalmol 2007;143:150 –1. Chatziralli IP, Sergentanis TN. Risk factors for intraoperative floppy iris syndrome: a meta-analysis. Ophthalmology 2011; 118:730 –5. Bidaguren A, Irigoyen C, Mendicute J, et al. Floppy-iris syndrome associated with tamsulosin: a prospective casecontrol study [in Spanish]. Arch Soc Esp Oftalmol 2007;82: 349 –54. Shugar JK. Use of epinephrine for IFIS prophylaxis [letter]. J Cataract Refract Surg 2006;32:1074 –5. Masket S, Belani S. Combined preoperative topical atropine sulphate 1% and intracameral nonpreserved epinephrine hydrochloride 1:4000 [corrected] for management of intraoperative floppy-iris syndrome. J Cataract Refract Surg 2007;33: 580 –2. Schulze R Jr. Epi-Shugarcaine with plain balanced salt solution for prophylaxis of intraoperative floppy-iris syndrome [letter]. J Cataract Refract Surg 2010;36:523. Manvikar S, Allen D. Cataract surgery management in patients taking tamsulosin: staged approach. J Cataract Refract Surg 2006;32:1611– 4. Gurbaxani A, Packard R. Intracameral phenylephrine to prevent floppy iris syndrome during cataract surgery in patients on tamsulosin. Eye (Lond) 2007;21:331–2. Soler F, Lorente R. Síndrome de iris flácido intraoperatorio: IFIS. In: Lorente R, Mendicute J, eds. Cirugía del cristalino.
16. 17. 18.
19.
20. 21.
22.
23. 24. 25. 26. 27. 28.
vol 2. Madrid, Spain: Sociedad Española de Oftalmología; 2008:1016 –30. Arshinoff SA. Modified SST-USST for tamsulosin-associated intraoperative [corrected] floppy-iris syndrome. J Cataract Refract Surg 2006;32:559 – 61. Lundberg B, Behndig A. Intracameral mydriatics in phacoemulsification cataract surgery. J Cataract Refract Surg 2003; 29:2366 –71. Lundberg B, Behndig A. Separate and additive mydriatic effects of lidocaine hydrochloride, phenylephrine, and cyclopentolate after intracameral injection. J Cataract Refract Surg 2008;34:280 –3. Lorente R, de Rojas V, Vázquez de Parga P, et al. Prevention of tamsulosin-associated IFIS with intracameral phenylephrine 1.5% in 250 eyes. J Emmetropia 2011;2:59 – 63. Available at: http://www.journalofemmetropia.org/2171-4703/jemmetropia. 2011.2.59.63.html. Accessed August 28, 2011. Cheung CM, Awan MA, Sandramouli S. Prevalence and clinical findings of tamsulosin-associated intraoperative floppyiris syndrome. J Cataract Refract Surg 2006;32:1336 –9. Chen AA, Kelly JP, Bhandari A, Wu MC. Pharmacologic prophylaxis and risk factors for intraoperative floppy-iris syndrome in phacoemulsification performed by resident physicians. J Cataract Refract Surg 2010;36:898 –905. Lowe FC. Role of the newer alpha1-adrenergic-receptor antagonists in the treatment of benign prostatic hyperplasiarelated lower urinary tract symptoms. Clin Ther 2004;26: 1701–13. Bäckström G, Behndig A. Redilatation with intracameral mydriatics in phacoemulsification surgery. Acta Ophthalmol Scand 2006;84:100 – 4. Lee KJ, Figueira EC, Sharma NS, et al. Iris prolapse and the floppy-iris syndrome [letter]. J Cataract Refract Surg 2007;33: 757– 8. Mamalis N, Edelhauser HF, Dawson DG, et al. Toxic anterior segment syndrome. J Cataract Refract Surg 2006;32:324 –33. Gonnering R, Edelhauser HF, van Horn DL, Durant W. The pH tolerance of rabbit and human corneal endothelium. Invest Ophthalmol Vis Sci 1979;18:373–90. Edelhauser HF, Hanneken AM, Pederson HJ, van Horn DL. Osmotic tolerance of rabbit and human corneal endothelium. Arch Ophthalmol 1981;99:1281–7. Hull DS, Chemotti MT, Edelhauser HF, et al. Effect of epinephrine on the corneal endothelium. Am J Ophthalmol 1975; 79:245–50.
Footnotes and Financial Disclosures Originally received: October 5, 2011. Final revision: April 27, 2012. Accepted: April 27, 2012. Available online: June 17, 2012.
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Manuscript no. 2011-1467.
Centro de Oftalmología Barraquer, Barcelona, Spain.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
1
Department of Ophthalmology, Complejo Hospitalario Universitario Orense, Orense, Spain.
2
Department of Ophthalmology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain.
3
Department of Pharmacy, Complejo Hospitalario Universitario Orense, Orense, Spain.
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Presented at: the European Society of Cataract and Refractive Surgery Annual Meeting, September 21, 2011, Vienna, Austria. Correspondence: Ramón Lorente, MD, PhD, C/Calle del Paseo, 19-2°, 32003 Orense, Spain. E-mail: [email protected].