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Intraoperative Floppy Iris Syndrome: Facts for the Urologist
Review Article Intraoperative Floppy Iris Syndrome: Facts for the Urologist Ozgur Yaycioglu and Rana Altan-Yaycioglu Intraoperative floppy iris syndrome (IFIS) consists of a triad of flaccid and billowing iris, iris prolapse through the surgical incisions, and progressive pupil constriction. IFIS increases the risk for complications during cataract surgery. It was first described in patients on tamsulosin treatment but can also be seen in patients on other non-subtype specific ␣1-adrenergic receptor (␣1AR) antagonists. Urologists who are initiating treatment with ␣1AR antagonists should inform their patients that these drugs may increase the difficulty of cataract surgery, but once the ophthalmologists are forewarned, necessary safety measures can be taken to achieve good surgical results. UROLOGY 76: 272–276, 2010. © 2010 Elsevier Inc.
B
enign prostatic hyperplasia (BPH) is one of the most common conditions affecting men with increasing age. One half of the men ⬎50 years old and 90% of the men ⬎85 years old have BPH. According to a US community-based survey of men, approximately 25% of men aged 40-49 years and 46% of men aged 70-79 years have moderate to severe lower urinary tract symptoms.1 Medical treatment with ␣1-adrenergic receptor (␣1AR) antagonists has become the dominant form of initial treatment of men with symptomatic BPH.2-4 Cataract is the clouding of the natural crystalline lens of the eye that can result in impaired vision and total blindness in advanced stages. Similar to BPH, cataracts are also common in the elderly, and the incidence increases with age. Unlike BPH, the primary treatment of symptomatic cataracts is surgery. It has been reported that each year approximately 5.3% of elderly US residents undergo cataract procedures.5 Consequently, many patients undergoing cataract surgery also receive or have received ␣-1AR antagonists for the treatment of symptomatic BPH. ARs are G protein-coupled transmembrane receptors that mediate the catecholaminergic actions in the sympathetic nervous system. ARs bind the endogenous catecholamines epinephrine and norepinephrine. They have been broadly divided into 2 categories: ␣ARs and ARs. The ␣ARs have been further divided into ␣1ARs and ␣2ARs, with 3 subtypes of ␣1ARs. These subtypes have been identified as ␣1A, ␣1B, and ␣1D.6,7 The ␣1AR subtypes are widely distributed throughout the body, including the lower urinary tract and the eye.8,9 In the
From the Departments of Urology and Ophthalmology, Baskent University School of Medicine, Adana, Turkey Reprint requests: Ozgur Yaycioglu, M.D., F.E.B.U., Department of Urology, Baskent University School of Medicine, Adana Clinic and Research Center, Dadaloglu Mah. 39, Sokak No. 6, Yuregir, Adana 01250 Republic of Turkey. E-mail: yaycioglu@ yahoo.com Submitted: December 23, 2009, accepted (with revisions): January 17, 2010
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© 2010 Elsevier Inc. All Rights Reserved
human prostate, ␣1A is the predominant subtype and represents about 70% of the total ␣1AR population.10 The ␣1AARs mediate the contraction in the prostate, prostatic urethra, and bladder neck.8 On the other hand, in the eye, the ␣1AARs are located on the iris dilator smooth muscle.9 It has been shown that the ␣1aAR subtype mediates iris dilator muscle contraction in rats and rabbits.11,12 Therefore, ␣1AAR agonists contract the iris dilator muscle, causing mydriasis, and ␣1AAR antagonists inhibit the iris dilator muscle contraction, resulting in an inability to dilate.
INTRAOPERATIVE FLOPPY IRIS SYNDROME Adequate pupil dilation and normal iris function are important for the safety of cataract surgery. Intraoperative floppy iris syndrome (IFIS) consists of a triad of flaccid and billowing iris, iris prolapse through the surgical incisions, and progressive pupil constriction. Hence, IFIS increases the risk of complications during cataract surgery. IFIS was first described in patients who had undergone complicated cataract surgery during tamsulosin treatment of BPH.13 The original report consisted of 2 companion studies. First was a retrospective chart review of 706 eyes of 511 patients who had undergone cataract surgery. Of the 511 patients, 16 (3%; 25 eyes) were taking tamsulosin at surgery. Of the 16 patients taking tamsulosin, 10 (63%) had a diagnosis of IFIS on the operative report. The prevalence of IFIS in the 511 patients was 2.0%, and all the patients who developed IFIS were taking tamsulosin. Another 11 patients (15 eyes) were taking other ␣1AR antagonists such as prazosin, terazosin, and doxazosin. None of these 11 patients developed IFIS during cataract surgery. The second study determined the prevalence of IFIS in a prospective series of 900 consecutive surgeries on 741 patients. IFIS was diagnosed in 16 patients (2.2%). Of the 16 patients with IFIS, 15 (94%) had a history of concurrent or previous 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.01.025
tamsulosin use; 14 had been taking tamsulosin at the time of surgery and 1 had taken tamsulosin in the past but had stopped the medication for ⬎1 year before cataract surgery. None of the 725 non-IFIS patients had taken tamsulosin. Thus, all the patients (100%) taking tamsulosin developed IFIS. The investigators concluded that IFIS significantly increases the risk of cataract surgery complications and that the correlation was strong between IFIS and the use of the ␣1AAR antagonist tamsulosin. That report has been recognized as a milestone study that described IFIS and established its association with tamsulosin; however, it also received some criticism.14 The study did not include covariates such as age, concurrent drug use, or co-existing diseases such as diabetes and hypertension. Concern has been raised that ␣1AR antagonist use might have been underreported. Additionally, ␣1AR antagonists were not stopped according to protocol before surgery, and the plasma drug levels were not available. The association of IFIS with tamsulosin has been well established since the original report, but with widely varying rates. Moreover, tamsulosin has been shown to cause patients to be 2.3 times more likely to develop postoperative complications.15 Meanwhile, IFIS has also been reported with nonsubtype-specific ␣1AR antagonists, such as terazosin, doxazosin, and alfuzosin, indicating that IFIS is a potential complication of this entire class of drugs. Comparative studies have shown that although nonsubtype-specific ␣1AR antagonists contribute to this complication, the syndrome seems to be less common and less severe compared with IFIS after tamsulosin use. When the surgeon does not anticipate or recognize IFIS, the rate of complications increases significantly. However, when experienced surgeons have been forewarned by a history of tamsulosin use and use appropriate operative strategies to manage the iris, the complication rate has been low and the success rate excellent.16 In cataract surgery series, 1.8%-3.9% of the patients were, or had been, taking tamsulosin, and 4%-7.7% of the patients were, or had been, taking other ␣-1AR antagonists.15-24 Because most of the male patients undergoing cataract surgery are in the same age group as those receiving BPH treatment, concern has been raised that these reported rates might have been underestimated. The reported incidence of IFIS has been 0.6%3.7% in the general population, 40.4%-100% in patients exposed to tamsulosin, and 0%-66.7% in patients exposed to nonsubtype-specific ␣1AR antagonists such as doxazosin, alfuzosin, and terazosin.15-24 Also, the incidence of IFIS in patients taking ␣-1AR antagonists might actually be lower than that reported if the studies failed to identify all patients taking ␣-1AR antagonists. In patients receiving naftopidil, which is a selective ␣1A and ␣1D AR antagonist, IFIS was observed in 19% of the eyes.19 Silodosin is the most recent selective ␣1AAR antagonist approved by the Food and Drug AdministraUROLOGY 76 (2), 2010
tion for the treatment of BPH symptoms. The clinical experience with silodosin is insufficient to date. However, because it is a selective ␣1AAR antagonist, one might expect it to behave similar to tamsulosin in terms of IFIS. The likely reasons for the variability in the reported incidence include the subjectivity of the clinical definition and the significant variation in the severity of IFIS, in that only some of the 3 classic clinical signs might be present. In addition, studies that used retrospective evaluation of the operative notes might not be reliable because flaccid iris, iris billowing, and pupil constriction are not always reported in these notes. Anecdotal reports have been published of other classes of drugs causing IFIS. Some of these agents have ␣-blocking actions such as antidepressant mianserin, antipsychotic zuclopenthixol, and antihypertensive labetalol.25-27 IFIS has also been reported to be caused by saw palmetto (Serenoa repens), which is known to have ␣-blocking action.28 A case report has described IFIS in 2 patients using finasteride.29 However, the significance of that report is controversial, because the mechanism of IFIS in patients taking finasteride is not clear. Male gender, hypertension, tamsulosin use, and a history of other ␣1-antagonist use have been associated with IFIS.9,22 Because ␣1-antagonists are also prescribed for urinary retention or hypertension in women, and tamsulosin has been prescribed for ureteral calculi, it is important to remember that IFIS can arise in either sex. It was reported that more than one half of the patients who showed clinical signs of IFIS had other underlying conditions that can cause endothelial dysregulation, such as diabetes, hypertension, and angiotensin-converting enzyme inhibitor therapy.30 Endothelial dysregulation might contribute to the poor mydriatic effect on the iris and thereby have a role in the occurrence of IFIS.9 However, in other studies, diabetes was not found to be significantly associated with IFIS.22,24 It is not clear why nonsubtype-specific ␣1AR antagonists and tamsulosin do not cause IFIS with a similar frequency and severity. A potential factor might be that tamsulosin has a stronger affinity for the ␣1AAR subtype. One study compared the effect of alfuzosin and tamsulosin on the contractile response of isolated pigmented rabbit prostatic and iris dilator smooth muscles.31 In that study, tamsulosin acted as a competitive antagonist in the iris in the same concentration range as the maximal plasma concentration after a 0.4-mg dose in humans. In contrast, the antagonistic effect of alfuzosin was weaker, and the concentrations with an equipotent antagonistic effect were approximately 100-300 times greater than the maximal plasma concentrations after a 10-mg dose of alfuzosin in humans. If these findings are also proved valid in humans, they suggest that the plasma concentrations of tamsulosin are able to antagonize the iris dilator muscle and that those of alfuzosin are too low to have an antagonist effect in patients who use the standard doses of these drugs for the treatment of BPH. 273
Stopping ␣1AR antagonists before cataract surgery does not necessarily prevent or decrease the severity of IFIS.16,32 IFIS can occur up to several years after the discontinuation of tamsulosin. It has been shown that in patients taking tamsulosin, the drug can remain in detectable amounts in the aqueous humor even after a pause of 28 days, and no correlation has been found between the tamsulosin concentrations in the aqueous humor and serum.33 This finding suggests that tamsulosin binds to the postsynaptic ␣1AARs of the iris for a period even after cessation of the drug. It has also been suggested that tamsulosin might lead to disuse atrophy of the muscular plate responsible for pupil dilation. Such atrophic changes might explain the flaccid nature of this tissue, such as that found during cataract surgery, and why IFIS occurs in patients who had been exposed to this medication in the past and had discontinued the drug some time before surgery. Histologic analyses of the iris in patients who developed IFIS revealed findings that suggested that the drug–melanin interaction might be responsible for dilator muscle atrophy, thereby playing an important role in the development of IFIS.34 Another study examined the iris thickness and pupillary diameter in patients taking ␣1AR antagonist treatment and untreated controls.35 Most of the patients were taking tamsulosin. The pupil diameter and the iris thickness at the dilator muscle region were significantly lower in patients receiving ␣1AR antagonist treatment than in the controls. That study found a significant difference in iris morphology in the patients with a history or current use of ␣1AR antagonists compared with the controls. The alterations seemed to be related to the duration of ␣1AR antagonist treatment. These structural alterations in the iris might account for the clinical presentation of IFIS and could also be helpful in developing methods for the prediction of IFIS before cataract surgery in patients with a history or current use of ␣1AR antagonists. However, more studies are needed to prove that ␣1AR antagonists actually cause muscular atrophy, which, in turn, results in IFIS. No safe lower limit for the duration of exposure to ␣1AR antagonists to avoid IFIS has been determined. The syndrome has been reported to occur even after only 2 days of tamsulosin intake.36 Also, reports have been published of patients undergoing bilateral cataract surgery who had IFIS in only 1 eye and of those who developed IFIS in both eyes.31,32 Thus, no IFIS in 1 eye does not mean that IFIS will not manifest itself during surgery of the opposite eye. Additional research on topics such as apoptosis and the effect of these drugs on the level of the spinal cord might prove useful for a better understanding of the mechanisms underlying IFIS. It has been shown in rats that doxazosin might act at the level of the spinal cord and ganglia, thereby reducing the activity in the parasympathetic nerves to the bladder. It has also been observed that the ␣1AR antagonists tera274
zosin and doxazosin induce apoptosis in human epithelial and stromal prostate cells.37,38 Because not all patients taking ␣1AR antagonists develop IFIS, the preoperative prediction of this syndrome is very important. However, no reliable method has been determined to predict which patients with a history of ␣1AR antagonist use will develop IFIS or how severe the manifestation will be. In an effort to identify a preoperative predictor of IFIS in patients taking ␣1AR antagonist treatment, several studies have been performed, without satisfactory results.39,40 Structural alterations in iris morphology in patients taking ␣1AR antagonist medication might prove useful for the prediction of IFIS before cataract surgery.35 A survey was undertaken among the members of the American Society of Cataract and Refractive Surgery on IFIS.41 Of the respondents, 59% believed that patients with cataracts or decreased vision should see an ophthalmologist before starting treatment with tamsulosin, and 21% believed that all patients should be referred, regardless of their ocular history. According to the survey, 85% of respondents believed that fewer than one third of patients taking ␣-blockers reported it to their cataract surgeon, and 91% of the respondents believed that more education on ␣1AR antagonists causing IFIS is needed for prescribing physicians. Another survey from the United Kingdom showed that 68% of ophthalmologists had patients discontinue tamsulosin preoperatively; however, they also reported no consistent benefit from this step.42 One of the rare articles in the published urologic literature on IFIS recommended that urologists should not change the prescribing habits of ␣-blockers for treating BPH but should ask the patient whether he has known cataracts or whether cataract surgery has been planned.43 The authors also recommended that if cataract surgery has been planned, consideration should be given to inform the patient’s ophthalmologist. The ophthalmologists were recommended to consider discontinuing tamsulosin 7 days before planned intraocular surgery. Others suggested that tamsulosin should be suspended for 4 weeks before cataract surgery.44 However, because it has been shown that stopping ␣1AR antagonists before cataract surgery does not prevent IFIS, the recommendation to stop ␣1AR antagonists before surgery is no longer valid. More recently, it has been suggested that urologists and primary care practitioners should ask their patients about possible eye problems and suggest an ophthalmologic consultation before prescribing tamsulosin and, possibly, other ␣-blockers.45 Theoretically, if the patient is a candidate for cataract surgery, tamsulosin treatment should be deferred until after the surgery. However, suggesting an ophthalmologic evaluation to every patient who is a candidate for ␣1AR antagonist treatment of BPH does not seem to be practical. Ophthalmologists, in contrast, were encouraged to obtain a full medication history from patients who are candidates for cataract UROLOGY 76 (2), 2010
surgery, with particular attention given to tamsulosin, similar to the standard questioning regarding the use of anticoagulants. The United States Food and Drug Administration instituted a labeling warning about ␣1AR antagonists and cataract surgery in 2005 that includes IFIS as a “general precaution.” The American Society of Cataract and Refractive Surgery, the American Academy of Ophthalmology, and the American Urological Association issued a joint press release in 2006 highlighting the need for patients taking systemic ␣1AR antagonists to inform their ophthalmologist before cataract surgery. It is advisable for cataract surgeons to ask about current or previous use of ␣1AR antagonists when taking the patient’s medication history preoperatively. The American Society of Cataract and Refractive Surgery and the American Academy of Ophthalmology issued a joint educational update statement in July 2008 that was disseminated by the American College of Physicians and the American Academy of Family Physicians to their members.46 Prescribing physicians were asked to consider involving an ophthalmologist before initiating nonemergent ␣1AR antagonist treatment for patients with known cataracts. Physicians should also remind patients already taking systemic ␣1AR antagonists to report this medication history before undergoing eye surgery. The need for this effort was underscored by a survey among general practitioners from the United Kingdom.47 Although 79.6% of the respondents were involved in prescribing ⬎5 tamsulosin prescriptions monthly, 96.8% were not aware of the association between tamsulosin and IFIS.
CONCLUSIONS IFIS is a syndrome that increases the risk of complications during cataract surgery and occurs in patients who use or have used ␣1AR antagonists. Urologists who are initiating treatment with ␣1AR antagonists should inform their patients that these drugs might increase the difficulty of cataract surgery. It is important that patients should be cautioned to inform their ophthalmologist if they are taking ␣1AR antagonists or have done so in the past. The patients should also be aware that once informed, the ophthalmologist will be able to foresee the possible problems and take the necessary precautions to achieve a good surgical outcome. Patients with known cataracts might wish to discuss their situation, the risks, and the timing of the cataract operation with their ophthalmologist before starting nonemergent treatment with ␣1AR antagonists. References 1. Chute CG, Panser LA, Girman CJ, et al. The prevalence of prostatism: a population-based survey of urinary tract symptoms. J Urol. 1993;150:85-89. 2. Saigal CS, Movassaghi M, Pace J, et al. Economic evaluation of treatment strategies for benign prostatic hyperplasia—is medical therapy more costly in the long run? J Urol. 2007;177:1463-1467.
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3. Sung JC, Curtis LH, Schulman KA, et al. Geographic variations in the use of medical and surgical therapies for benign prostatic hyperplasia. J Urol. 2006;175:1023-1027. 4. Souverein PC, Erkens JA, de la Rosette J, et al. Drug treatment for benign prostatic hyperplasia and hospital admission for BPH-related surgery. Eur Urol. 2003;43:528-534. 5. Williams A, Sloan FA, Lee PP. Longitudinal rates of cataract surgery. Arch Ophthalmol. 2006;124:1308-1314. 6. Michel MC, Kenny B, Schwinn DA. Classification of ␣1-adrenocepror subtypes. Naunyn Schmiedebergs Arch Pharmacol. 1995;352: 1-10. 7. Hawrylyshyn KA, Michelotti GA, Coge F, et al. Update on human alpha1-adrenoceptor subtype signalling and genomic organization. Trends Pharmacol Sci. 2004;25:449-455. 8. Roehrborn CG, Schwinn DA. ␣-1 Adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol. 2004;171:1029-1035. 9. Schwinn DA, Afshari NA. ␣1-Adrenergic receptor antagonists and the iris: new mechanistic insights into floppy iris syndrome. Surv Ophthalmol. 2006;51:501-512. 10. Andersson KA. ␣-Adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with ␣-adrenoceptor antagonists. World J Urol. 2002;19:390-396. 11. Yu Y, Koss MC. ␣1A-Adrenoceptors mediate sympathetically evoked pupillary dilation in rats. J Pharmacol Exp Ther. 2002;300: 521-525. 12. Yu Y, Koss MC. Studies of ␣ adrenoceptor antagonists on sympathetic mydriasis in rabbits. J Ocul Pharmacol Ther. 2003;19:255-263. 13. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin (Flomax). J Cataract Refract Surg. 2005;31: 664-673. 14. Schwinn DA, Afshari NA. ␣-1 Adrenergic antagonists and floppy iris syndrome: tip of the iceberg? Ophthalmology. 2005;112:20592060. 15. Bell CM, Hatch WV, Fischer WV, et al. Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA. 2009;301:1991-1996. 16. Chang DF, Osher RH, Wang L, et al. A prospective multicenter evaluation of cataract surgery in patients taking tamsulosin (Flomax). Ophthalmology. 2007;114:957-964. 17. Keklikci U, Isen K, Unlu K, et al. Incidence, clinical findings and management of intraoperative floppy iris syndrome associated with tamsulosin. Acta Ophthalmol. 2009;87:306-309. 18. Neff KD, Sandoval HP, de Castro LEF, et al. Factors associated with intraoperative floppy iris syndrome. Ophthalmology. 2009;116: 658-663. 19. Oshika T, Ohashi Y, Inamura M, et al. Incidence of intraoperative floppy iris syndrome in patients on either systemic or topical ␣1-adrenoceptor antagonists. Am J Ophthalmol. 2007;143:150-151. 20. Cheung CM, Awan MA, Peh KK, et al. Comment on: incidence of intraoperative floppy iris syndrome in patients on either systemic or topical ␣1-adrenoceptor antagonists. Am J Ophthalmol. 2007;143: 1070-1071. 21. Takmaz T, Can I. Clinical features, complications, and incidence of intraoperative floppy iris syndrome in patients taking tamsulosin. Eur J Ophthalmol. 2007;17:909-913. 22. Altan-Yaycioglu R, Gedik S, Pelit A, et al. Clinical factors associated with floppy iris signs: a prospective study from two centers. Ophthalmic Surg Lasers Imaging. 2009;40:232-238. 23. Blouin MC, Blouin J, Perreault S, et al. Intraoperative floppy-iris syndrome associated with ␣1-adrenoceptors comparison of tamsulosin and alfuzosin. J Cataract Refract Surg. 2007;33:1227-1234. 24. Chadha V, Borooah S, Tey A, et al. Floppy iris behaviour during cataract surgery: associations and variations. Br J Ophthalmol. 2007; 91:40-42. 25. Ugarte M, Leong T, Rassam S, et al. Intraoperative floppy-iris syndrome, ␣1-adrenergic antagonists, and chronic intake of mianserin: is there an association? J Cataract Refract Surg. 2007;33:170171.
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26. Pringle E, Packard R. Antipsychotic agent as a n etiologic agent of IFIS. J Cataract Refract Surg. 2005;31:2240-2241. 27. Calotti F, Steen D. Labetalol causing intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2007;33:170. 28. Yeu E, Grostern R. Saw palmetto and intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2007;33:927-928. 29. Issa SA, Dagres E. Intraoperative floppy-iris syndrome and finasteride intake. J Cataract Refract Surg. 2007;33:2142-2143. 30. Srinivasan S, Radomski S, Chung J, et al. Intraoperative floppy-iris syndrome during cataract surgery in men using alpha-blockers for benign prostatic hypertrophy. J Cataract Refract Surg. 2007;33: 1826-1827. 31. 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 smooth muscles: possible model for intraoperative floppyiris syndrome. J Cataract Refract Surg. 2008;34:489-496. 32. Takmaz T, Can I. Intraoperative floppy-iris syndrome: do we know everything about it? J Cataract Refract Surg. 2007;33:1110-1112. 33. Parssinen O, Leppanen E, Keski-Rahkonen P, et al. Influence of tamsulosin on the iris and its implications for cataract surgery. Invest Ophthalmol Vis Sci. 2006;47:3766-3771. 34. Goseki T, Shimizu K, Ishikawa H, et al. Possible mechanism of intraoperative floppy iris syndrome: a clinicopathological study. Br J Ophthalmol. 2008;92:1156-1158. 35. Prata TS, Palmiero PM, Angelilli A, et al. Iris morphologic changes related to ␣1 adrenergic receptor antagonists implication for intraoperative floppy iris syndrome. Ophthalmology. 2009;116:877-881. 36. Shah N, Tendulkar M, Brown R. Should we anticipate intraoperative floppy iris syndrome (IFIS) even with very short history of tamsulosin? Eye. 2009;23:740. 37. Thiyagarajan M. ␣-Adrenoceptor antagonists in the treatment of benign prostate hyperplasia. Pharmacologist. 2002;65:119-128.
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38. Andersson KE. ␣-Adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with ␣-adrenoceptor antagonists. World J Urol. 2002;19:390-396. 39. Altan-Yaycioglu R, Yaycioglu O, Gul U, et al. The effects of two systemic ␣1-adrenergic blockers on pupil diameter: a prospective randomized single-blind study. Naunyn Schmiedebergs Arch Pharmacol. 2007;375:199-203. 40. Altan-Yaycioglu R, Yaycioglu O, Tufan H, et al. The effects of systemic alpha-1 adrenergic antagonists on pupil diameter in rats. Curr Eye Res. 2007;32:217-221. 41. Chang DF, Baraga-Mele R, Mamalis N, et al. Clinical experience with intraoperative floppy-iris syndrome: results of the 2008 ASCRS member survey. J Cataract Refract Surg. 2008;34:1201-1209. 42. Nguyen DQ, Sebastian RT, Kyle GS. Experience of the intraoperative floppy iris syndrome in the United Kingdom. Surgery. 2007; 21:443-444. 43. Lawrentschuk N, Bylsma GW. Intraoperative “floppy iris” syndrome and its relationship to tamsulosin: a urologist’s guide. BJU Int. 2006;97:2-4. 44. Nguyen DQ, Sebastian RT, Philip J. Intraoperative floppy iris syndrome associated with tamsulosin. BJU Int. 2006;97:197. 45. Leibovici D, Bar-Kana Y, Zadok D, et al. Association between tamsulosin and intraoperative “floppy-iris” syndrome. IMAJ. 2009; 11:45-49. 46. Chang DF, Braga-Mele R, Mamalis N, et al., for the ASCRS Cataract Clinical Committee. ASCRS White Paper: clinical review of intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2008;34:2153-2162. 47. Sallam A, Gunasekera V, Kashani S, et al. Awareness of IFIS among primary care physicians. J Cataract Refract Surg. 2008;34: 882.
UROLOGY 76 (2), 2010
B
enign prostatic hyperplasia (BPH) is one of the most common conditions affecting men with increasing age. One half of the men ⬎50 years old and 90% of the men ⬎85 years old have BPH. According to a US community-based survey of men, approximately 25% of men aged 40-49 years and 46% of men aged 70-79 years have moderate to severe lower urinary tract symptoms.1 Medical treatment with ␣1-adrenergic receptor (␣1AR) antagonists has become the dominant form of initial treatment of men with symptomatic BPH.2-4 Cataract is the clouding of the natural crystalline lens of the eye that can result in impaired vision and total blindness in advanced stages. Similar to BPH, cataracts are also common in the elderly, and the incidence increases with age. Unlike BPH, the primary treatment of symptomatic cataracts is surgery. It has been reported that each year approximately 5.3% of elderly US residents undergo cataract procedures.5 Consequently, many patients undergoing cataract surgery also receive or have received ␣-1AR antagonists for the treatment of symptomatic BPH. ARs are G protein-coupled transmembrane receptors that mediate the catecholaminergic actions in the sympathetic nervous system. ARs bind the endogenous catecholamines epinephrine and norepinephrine. They have been broadly divided into 2 categories: ␣ARs and ARs. The ␣ARs have been further divided into ␣1ARs and ␣2ARs, with 3 subtypes of ␣1ARs. These subtypes have been identified as ␣1A, ␣1B, and ␣1D.6,7 The ␣1AR subtypes are widely distributed throughout the body, including the lower urinary tract and the eye.8,9 In the
From the Departments of Urology and Ophthalmology, Baskent University School of Medicine, Adana, Turkey Reprint requests: Ozgur Yaycioglu, M.D., F.E.B.U., Department of Urology, Baskent University School of Medicine, Adana Clinic and Research Center, Dadaloglu Mah. 39, Sokak No. 6, Yuregir, Adana 01250 Republic of Turkey. E-mail: yaycioglu@ yahoo.com Submitted: December 23, 2009, accepted (with revisions): January 17, 2010
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© 2010 Elsevier Inc. All Rights Reserved
human prostate, ␣1A is the predominant subtype and represents about 70% of the total ␣1AR population.10 The ␣1AARs mediate the contraction in the prostate, prostatic urethra, and bladder neck.8 On the other hand, in the eye, the ␣1AARs are located on the iris dilator smooth muscle.9 It has been shown that the ␣1aAR subtype mediates iris dilator muscle contraction in rats and rabbits.11,12 Therefore, ␣1AAR agonists contract the iris dilator muscle, causing mydriasis, and ␣1AAR antagonists inhibit the iris dilator muscle contraction, resulting in an inability to dilate.
INTRAOPERATIVE FLOPPY IRIS SYNDROME Adequate pupil dilation and normal iris function are important for the safety of cataract surgery. Intraoperative floppy iris syndrome (IFIS) consists of a triad of flaccid and billowing iris, iris prolapse through the surgical incisions, and progressive pupil constriction. Hence, IFIS increases the risk of complications during cataract surgery. IFIS was first described in patients who had undergone complicated cataract surgery during tamsulosin treatment of BPH.13 The original report consisted of 2 companion studies. First was a retrospective chart review of 706 eyes of 511 patients who had undergone cataract surgery. Of the 511 patients, 16 (3%; 25 eyes) were taking tamsulosin at surgery. Of the 16 patients taking tamsulosin, 10 (63%) had a diagnosis of IFIS on the operative report. The prevalence of IFIS in the 511 patients was 2.0%, and all the patients who developed IFIS were taking tamsulosin. Another 11 patients (15 eyes) were taking other ␣1AR antagonists such as prazosin, terazosin, and doxazosin. None of these 11 patients developed IFIS during cataract surgery. The second study determined the prevalence of IFIS in a prospective series of 900 consecutive surgeries on 741 patients. IFIS was diagnosed in 16 patients (2.2%). Of the 16 patients with IFIS, 15 (94%) had a history of concurrent or previous 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.01.025
tamsulosin use; 14 had been taking tamsulosin at the time of surgery and 1 had taken tamsulosin in the past but had stopped the medication for ⬎1 year before cataract surgery. None of the 725 non-IFIS patients had taken tamsulosin. Thus, all the patients (100%) taking tamsulosin developed IFIS. The investigators concluded that IFIS significantly increases the risk of cataract surgery complications and that the correlation was strong between IFIS and the use of the ␣1AAR antagonist tamsulosin. That report has been recognized as a milestone study that described IFIS and established its association with tamsulosin; however, it also received some criticism.14 The study did not include covariates such as age, concurrent drug use, or co-existing diseases such as diabetes and hypertension. Concern has been raised that ␣1AR antagonist use might have been underreported. Additionally, ␣1AR antagonists were not stopped according to protocol before surgery, and the plasma drug levels were not available. The association of IFIS with tamsulosin has been well established since the original report, but with widely varying rates. Moreover, tamsulosin has been shown to cause patients to be 2.3 times more likely to develop postoperative complications.15 Meanwhile, IFIS has also been reported with nonsubtype-specific ␣1AR antagonists, such as terazosin, doxazosin, and alfuzosin, indicating that IFIS is a potential complication of this entire class of drugs. Comparative studies have shown that although nonsubtype-specific ␣1AR antagonists contribute to this complication, the syndrome seems to be less common and less severe compared with IFIS after tamsulosin use. When the surgeon does not anticipate or recognize IFIS, the rate of complications increases significantly. However, when experienced surgeons have been forewarned by a history of tamsulosin use and use appropriate operative strategies to manage the iris, the complication rate has been low and the success rate excellent.16 In cataract surgery series, 1.8%-3.9% of the patients were, or had been, taking tamsulosin, and 4%-7.7% of the patients were, or had been, taking other ␣-1AR antagonists.15-24 Because most of the male patients undergoing cataract surgery are in the same age group as those receiving BPH treatment, concern has been raised that these reported rates might have been underestimated. The reported incidence of IFIS has been 0.6%3.7% in the general population, 40.4%-100% in patients exposed to tamsulosin, and 0%-66.7% in patients exposed to nonsubtype-specific ␣1AR antagonists such as doxazosin, alfuzosin, and terazosin.15-24 Also, the incidence of IFIS in patients taking ␣-1AR antagonists might actually be lower than that reported if the studies failed to identify all patients taking ␣-1AR antagonists. In patients receiving naftopidil, which is a selective ␣1A and ␣1D AR antagonist, IFIS was observed in 19% of the eyes.19 Silodosin is the most recent selective ␣1AAR antagonist approved by the Food and Drug AdministraUROLOGY 76 (2), 2010
tion for the treatment of BPH symptoms. The clinical experience with silodosin is insufficient to date. However, because it is a selective ␣1AAR antagonist, one might expect it to behave similar to tamsulosin in terms of IFIS. The likely reasons for the variability in the reported incidence include the subjectivity of the clinical definition and the significant variation in the severity of IFIS, in that only some of the 3 classic clinical signs might be present. In addition, studies that used retrospective evaluation of the operative notes might not be reliable because flaccid iris, iris billowing, and pupil constriction are not always reported in these notes. Anecdotal reports have been published of other classes of drugs causing IFIS. Some of these agents have ␣-blocking actions such as antidepressant mianserin, antipsychotic zuclopenthixol, and antihypertensive labetalol.25-27 IFIS has also been reported to be caused by saw palmetto (Serenoa repens), which is known to have ␣-blocking action.28 A case report has described IFIS in 2 patients using finasteride.29 However, the significance of that report is controversial, because the mechanism of IFIS in patients taking finasteride is not clear. Male gender, hypertension, tamsulosin use, and a history of other ␣1-antagonist use have been associated with IFIS.9,22 Because ␣1-antagonists are also prescribed for urinary retention or hypertension in women, and tamsulosin has been prescribed for ureteral calculi, it is important to remember that IFIS can arise in either sex. It was reported that more than one half of the patients who showed clinical signs of IFIS had other underlying conditions that can cause endothelial dysregulation, such as diabetes, hypertension, and angiotensin-converting enzyme inhibitor therapy.30 Endothelial dysregulation might contribute to the poor mydriatic effect on the iris and thereby have a role in the occurrence of IFIS.9 However, in other studies, diabetes was not found to be significantly associated with IFIS.22,24 It is not clear why nonsubtype-specific ␣1AR antagonists and tamsulosin do not cause IFIS with a similar frequency and severity. A potential factor might be that tamsulosin has a stronger affinity for the ␣1AAR subtype. One study compared the effect of alfuzosin and tamsulosin on the contractile response of isolated pigmented rabbit prostatic and iris dilator smooth muscles.31 In that study, tamsulosin acted as a competitive antagonist in the iris in the same concentration range as the maximal plasma concentration after a 0.4-mg dose in humans. In contrast, the antagonistic effect of alfuzosin was weaker, and the concentrations with an equipotent antagonistic effect were approximately 100-300 times greater than the maximal plasma concentrations after a 10-mg dose of alfuzosin in humans. If these findings are also proved valid in humans, they suggest that the plasma concentrations of tamsulosin are able to antagonize the iris dilator muscle and that those of alfuzosin are too low to have an antagonist effect in patients who use the standard doses of these drugs for the treatment of BPH. 273
Stopping ␣1AR antagonists before cataract surgery does not necessarily prevent or decrease the severity of IFIS.16,32 IFIS can occur up to several years after the discontinuation of tamsulosin. It has been shown that in patients taking tamsulosin, the drug can remain in detectable amounts in the aqueous humor even after a pause of 28 days, and no correlation has been found between the tamsulosin concentrations in the aqueous humor and serum.33 This finding suggests that tamsulosin binds to the postsynaptic ␣1AARs of the iris for a period even after cessation of the drug. It has also been suggested that tamsulosin might lead to disuse atrophy of the muscular plate responsible for pupil dilation. Such atrophic changes might explain the flaccid nature of this tissue, such as that found during cataract surgery, and why IFIS occurs in patients who had been exposed to this medication in the past and had discontinued the drug some time before surgery. Histologic analyses of the iris in patients who developed IFIS revealed findings that suggested that the drug–melanin interaction might be responsible for dilator muscle atrophy, thereby playing an important role in the development of IFIS.34 Another study examined the iris thickness and pupillary diameter in patients taking ␣1AR antagonist treatment and untreated controls.35 Most of the patients were taking tamsulosin. The pupil diameter and the iris thickness at the dilator muscle region were significantly lower in patients receiving ␣1AR antagonist treatment than in the controls. That study found a significant difference in iris morphology in the patients with a history or current use of ␣1AR antagonists compared with the controls. The alterations seemed to be related to the duration of ␣1AR antagonist treatment. These structural alterations in the iris might account for the clinical presentation of IFIS and could also be helpful in developing methods for the prediction of IFIS before cataract surgery in patients with a history or current use of ␣1AR antagonists. However, more studies are needed to prove that ␣1AR antagonists actually cause muscular atrophy, which, in turn, results in IFIS. No safe lower limit for the duration of exposure to ␣1AR antagonists to avoid IFIS has been determined. The syndrome has been reported to occur even after only 2 days of tamsulosin intake.36 Also, reports have been published of patients undergoing bilateral cataract surgery who had IFIS in only 1 eye and of those who developed IFIS in both eyes.31,32 Thus, no IFIS in 1 eye does not mean that IFIS will not manifest itself during surgery of the opposite eye. Additional research on topics such as apoptosis and the effect of these drugs on the level of the spinal cord might prove useful for a better understanding of the mechanisms underlying IFIS. It has been shown in rats that doxazosin might act at the level of the spinal cord and ganglia, thereby reducing the activity in the parasympathetic nerves to the bladder. It has also been observed that the ␣1AR antagonists tera274
zosin and doxazosin induce apoptosis in human epithelial and stromal prostate cells.37,38 Because not all patients taking ␣1AR antagonists develop IFIS, the preoperative prediction of this syndrome is very important. However, no reliable method has been determined to predict which patients with a history of ␣1AR antagonist use will develop IFIS or how severe the manifestation will be. In an effort to identify a preoperative predictor of IFIS in patients taking ␣1AR antagonist treatment, several studies have been performed, without satisfactory results.39,40 Structural alterations in iris morphology in patients taking ␣1AR antagonist medication might prove useful for the prediction of IFIS before cataract surgery.35 A survey was undertaken among the members of the American Society of Cataract and Refractive Surgery on IFIS.41 Of the respondents, 59% believed that patients with cataracts or decreased vision should see an ophthalmologist before starting treatment with tamsulosin, and 21% believed that all patients should be referred, regardless of their ocular history. According to the survey, 85% of respondents believed that fewer than one third of patients taking ␣-blockers reported it to their cataract surgeon, and 91% of the respondents believed that more education on ␣1AR antagonists causing IFIS is needed for prescribing physicians. Another survey from the United Kingdom showed that 68% of ophthalmologists had patients discontinue tamsulosin preoperatively; however, they also reported no consistent benefit from this step.42 One of the rare articles in the published urologic literature on IFIS recommended that urologists should not change the prescribing habits of ␣-blockers for treating BPH but should ask the patient whether he has known cataracts or whether cataract surgery has been planned.43 The authors also recommended that if cataract surgery has been planned, consideration should be given to inform the patient’s ophthalmologist. The ophthalmologists were recommended to consider discontinuing tamsulosin 7 days before planned intraocular surgery. Others suggested that tamsulosin should be suspended for 4 weeks before cataract surgery.44 However, because it has been shown that stopping ␣1AR antagonists before cataract surgery does not prevent IFIS, the recommendation to stop ␣1AR antagonists before surgery is no longer valid. More recently, it has been suggested that urologists and primary care practitioners should ask their patients about possible eye problems and suggest an ophthalmologic consultation before prescribing tamsulosin and, possibly, other ␣-blockers.45 Theoretically, if the patient is a candidate for cataract surgery, tamsulosin treatment should be deferred until after the surgery. However, suggesting an ophthalmologic evaluation to every patient who is a candidate for ␣1AR antagonist treatment of BPH does not seem to be practical. Ophthalmologists, in contrast, were encouraged to obtain a full medication history from patients who are candidates for cataract UROLOGY 76 (2), 2010
surgery, with particular attention given to tamsulosin, similar to the standard questioning regarding the use of anticoagulants. The United States Food and Drug Administration instituted a labeling warning about ␣1AR antagonists and cataract surgery in 2005 that includes IFIS as a “general precaution.” The American Society of Cataract and Refractive Surgery, the American Academy of Ophthalmology, and the American Urological Association issued a joint press release in 2006 highlighting the need for patients taking systemic ␣1AR antagonists to inform their ophthalmologist before cataract surgery. It is advisable for cataract surgeons to ask about current or previous use of ␣1AR antagonists when taking the patient’s medication history preoperatively. The American Society of Cataract and Refractive Surgery and the American Academy of Ophthalmology issued a joint educational update statement in July 2008 that was disseminated by the American College of Physicians and the American Academy of Family Physicians to their members.46 Prescribing physicians were asked to consider involving an ophthalmologist before initiating nonemergent ␣1AR antagonist treatment for patients with known cataracts. Physicians should also remind patients already taking systemic ␣1AR antagonists to report this medication history before undergoing eye surgery. The need for this effort was underscored by a survey among general practitioners from the United Kingdom.47 Although 79.6% of the respondents were involved in prescribing ⬎5 tamsulosin prescriptions monthly, 96.8% were not aware of the association between tamsulosin and IFIS.
CONCLUSIONS IFIS is a syndrome that increases the risk of complications during cataract surgery and occurs in patients who use or have used ␣1AR antagonists. Urologists who are initiating treatment with ␣1AR antagonists should inform their patients that these drugs might increase the difficulty of cataract surgery. It is important that patients should be cautioned to inform their ophthalmologist if they are taking ␣1AR antagonists or have done so in the past. The patients should also be aware that once informed, the ophthalmologist will be able to foresee the possible problems and take the necessary precautions to achieve a good surgical outcome. Patients with known cataracts might wish to discuss their situation, the risks, and the timing of the cataract operation with their ophthalmologist before starting nonemergent treatment with ␣1AR antagonists. References 1. Chute CG, Panser LA, Girman CJ, et al. The prevalence of prostatism: a population-based survey of urinary tract symptoms. J Urol. 1993;150:85-89. 2. Saigal CS, Movassaghi M, Pace J, et al. Economic evaluation of treatment strategies for benign prostatic hyperplasia—is medical therapy more costly in the long run? J Urol. 2007;177:1463-1467.
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