Introduction

Intraoperative floppy iris syndrome (IFIS) was first described by Chang and Campbell1 in 2005, being defined by flaccid iris stroma leading to fluttering and billowing of the iris, tendency of iris prolapse through the surgical incisions and progressive intraoperative pupil constriction. IFIS can be characterized as complete, when all the three features are present or incomplete, when even one feature is missing.1, 2, 3, 4 It is very important for physicians and especially ophthalmologists to be aware of IFIS, as it may lead to complications, such as posterior capsular rupture, loss of vitreous, iris prolapse, iris stroma atrophy, capsulorhexis tear, and anterior chamber hemorrhage, due to restricted surgical field secondary to miosis.3, 5

Previous studies have reported an association between IFIS and intake of α-blockers, which are commonly used for the treatment of benign prostatic hyperplasia. Specifically, IFIS was independently associated with tamsulosin,1, 6, 7, 8, 9, 10 doxazosin,2, 9, 11 terazosin,12 alfuzosin,8, 10, 13 silodosin,14 or labetalol, a selective α- and β-blocker.15 Interestingly, a meta-analysis of the risk factors for IFIS demonstrated a hierarchy in the magnitude of the associations between the various α-blockers and IFIS.16 The pooled odds ratio (OR) for IFIS after tamsulosin use was nearly 40-fold higher than that of alfuzosin, which was the second α-blocker in order of effect size, in line with Chang et al,17 who also found that severe IFIS was statistically more likely with tamsulosin that with alfuzosin. Terazosin exhibited a comparable pooled OR as alfuzosin in the meta-analysis by Chatziralli and Sergentanis,16 whereas the effect of doxazosin was rather faint.

Furthermore, several reports have been published, suggesting an association between IFIS and finasteride,9, 18, 19 mianserin,20 antipsychotic agents,21 chloropromazine,22, 23 donepezil,24 quetiapine,9, 25 imipramine,26 risperidone,27 duloxetine,28 warfarin,29 aspirin,23 losartan,23 and metformin.23 Apart from potential association with the intake of various medications, IFIS has been also noted in patients with hypertension.10, 16, 30 However, most of the published studies examining risk factors for IFIS are retrospective. In addition, as the awareness about IFIS becomes larger, the syndrome is more likely to be detected and various risk factors will be confirmed. In light of the above, the purpose of our prospective study was to investigate possible risk factors for IFIS, encompassing ophthalmological conditions, sociodemographic, and clinical data, as well as medications being taken at the time of surgery.

Materials and methods

Participants in our study were 1274 consecutive Caucasian patients, who underwent cataract surgery in our department. The study was in accordance with the tenets of Helsinki Declaration and was approved by the Institutional Review Board, whereas written informed consent was obtained from the patients before enrollment into the study.

After adequate dilation with tropicamide 0.5% (tropixal and demo) and phenylephrine hydrochloride 5% (phenylephrine and cooper) drops, a routine phacoemulsification with intraocular lens implantation was performed in all patients, using Alcon Infiniti (Alcon, TX, USA). Intracameral alpha agonists were not administered. At the time of surgery, all eyes were characterized by the surgeon as IFIS or non-IFIS using the criteria of Chang and Campbell.1 In some cases, the characteristic triad was not present, but there were one or two of the characteristics and the syndrome was designated as incomplete IFIS.

The following data were recorded: presence of IFIS, sociodemographic features (age and gender), clinical data (hypertension and diabetes mellitus), ophthalmological conditions (pseudoexfoliation, glaucoma and retinal disorders), axial length of the eye, smoking, and medications being taken at the time of surgery. To consider ‘current use’ of a medication as meaningful, at least 1 month of intake should have been documented. In addition, duration of each medication intake was recorded. It is worthy to note that an independent doctor (different from the surgeon in each case) has collected the data concerning the potential risk factors for IFIS, so as to avoid observation bias.

Statistical analysis was performed using SPSS 22.0 statistical software (SPSS Inc, Chicago, IL, USA). IFIS was treated as a dichotomous variable (0=no IFIS, 1=IFIS). The association between IFIS and possible risk factors was examined by means of univariate and multivariate analysis (multivariate logistic regression). At the univariate analysis, the associations between IFIS and possible risk factors were evaluated with χ2-test, Fisher’s exact test, and Mann–Whitney–Wilcoxon test for independent samples, as appropriate. At the multivariate logistic regression, IFIS was treated as the dependent variable and the variables found significant at the univariate analysis were examined as independent variables. Statistical significance was defined as P<0.05.

Results

IFIS was observed in 63/1274 eyes (4.9%, 95% CI: 3.9–6.7%). Among 63 cases, 41 presented complete IFIS and 22 incomplete. Table 1 shows the demographic and clinical data of our study sample. Male sex, short axial length, hypertension, α-blocker use (tamsulosin, alfuzosin, and terazosin), benzodiazepine use, finasteride use, quetiapine use, and rivastigmine use were associated with IFIS. On the other hand, no significant associations were observed regarding age, diabetes mellitus, pseudoexfoliation, glaucoma, retinal disorders, and warfarin or aspirin use. In addition, duration of intake of any significantly associated medication was not found to be associated with IFIS (P>0.05 for all medications).

Table 1 Demographic and clinical data of our study sample
Full size table

Table 2 presents the results of the multivariate analysis. Hypertension and the use of tamsulosin, alfuzosin, terazosin, benzodiazepines, finasteride, and quetiapine were all independently associated with IFIS, as reflected upon the mutually adjusted ORs. Male sex, short axial length, and rivastigmine lost their significance at the multivariate approach.

Table 2 Variables retained in the multivariate logistic regression analysis with their respective odds ratios
Full size table

Discussion

The principal message of this prospective study was that apart from the well-established association between IFIS and α-blockers, other medications, that is, benzodiazepines, finasteride, and quetiapine, as well as hypertension, were significantly associated with IFIS. Our results confirm the findings of previous studies and isolated case reports.6, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 23, 25, 30, 31

It is worthy to mention that tamsulosin was found to be the most significant factor independently associated with IFIS. Noticeably, the OR for tamsulosin was significantly higher than that regarding alfuzosin or terazosin. This could be possibly explained based on a rabbit experimental model, postulating the existence of a hypothetical additional receptor besides the a1-receptor with relevance to iris dilator muscle, which may exhibit higher affinity for tamsulosin.32

Another interesting finding of our study was the positive association between benzodiazepine use and IFIS, which confirmed the results of our previous retrospective study in a different population.9 The mechanism by which benzodiazepines were associated with IFIS remains elusive, although we hypothesized that a biochemical link may exist. In fact, it has been shown that benzodiazepine receptors are present in various regions of the eye, including the ciliary body and specifically the iris, as well as in the retina and optic nerve.33

Concerning finasteride, the evidence in the literature is relatively low, as there is only a retrospective study and two case reports dealing with the association between finasteride and IFIS.9, 18, 19 It should be noted that in all these cases, the patients had never received tamsulosin or other α-blocker, suggesting that the effect of finasteride seems independent. The underlying mechanism remains unknown; therefore, experimental studies are needed to confirm this finding.

Regarding quetiapine, our results are in line with the existing scarce data from previous case reports and retrospective studies.9, 25 Interestingly, the observation on quetiapine, which is an antipsychotic agent, can be analogous to that of chloropromazine, attributing the effects of both medications to a1-adrenergic antagonism.22, 34 Moreover, hypertension was another positively associated factor with IFIS, a finding that has been also emerged at previous studies31 and our previous meta-analysis on the field.16

Of note, duration of any of the medications was not found to be associated with IFIS. In fact, the onset of IFIS following α-blockers use and its discontinuation before cataract surgery remains controversial. It has been shown that IFIS cannot be prevented by cessation of the α-blocker and that it has been described even shortly after α-blocker intake, suggesting that potential irreversible structural changes occur on the iris muscle after α-blockers use.35 However, there is lack of large studies to confirm or not this finding.

In conclusion, this study confirms the association of α-blockers with IFIS and additionally points to benzodiazepine, finasteride, and quetiapine use, as well as to hypertension as potential risk factors for IFIS. Caution is also advised for patients receiving rivastigmine or those with short axial length concerning their elevated risk for IFIS. It is important for ophthalmologists to know whether a patient has increased risk for IFIS, so as to prevent potential complications and inform appropriately the patient preoperatively.