Comment: This issue is not going away.  It is much more prevalent on a weekly basis!  Alan N. Carlson, M.D., Duke Eye Center

Review and Update of Intraoperative Floppy Iris Syndrome

Ahmed Sallam; Hany El-Defrawy; Adam Ross; Samer J Bashir; Hamish MA Towler

Posted: 08/31/2011; Expert Rev Ophthalmol. 2011;6(4):469-476. © 2011 Expert Reviews Ltd.

Abstract and Introduction

Abstract

Intraoperative floppy iris syndrome is a well-known risk factor for complications during cataract extraction in patients who are on or who have previously used tamsulosin, the most commonly prescribed α-1 adrenergic blocker for the treatment of benign prostatic hyperplasia. It is important that both ophthalmologists and physicians appreciate the association as it occurs in a significant number of patients, and favorable visual outcome can be achieved if tamsulosin use is known before surgery and the operation is undertaken by an experienced surgeon. This article evaluates the current literature on intraoperative floppy iris syndrome and includes discussion on epidemiology, underlying mechanisms and management strategies.

Introduction

Tamsulosin is the most commonly prescribed α-1 adrenergic receptor blocker for the management of benign prostatic hyperplasia (BPH) in aging males.[1,2] The drug has a selective action on the bladder and the prostate, thus relieving lower urinary tract symptoms (LUTS) while having minimal side effects on the cardiovascular system.[2] Three types of α-1 adrenergic receptors have been described; namely α-1a, α-1b and α-1d.[3] The main α-1 receptor subtype in the prostate, bladder, neck and urethra is α-1a, while α-1b receptors predominate in peripheral blood vessels.[4,5] In vitro studies have shown that tamsulosin has a 20-fold higher affinity for the α-1a receptors than for α-1b receptors and a threefold higher affinity for α-1a receptors than for α-1d receptors.[6–8] As tamsulosin is mainly an α-1a receptor blocker, it is more uroselective than other α-1 receptor blockers used for LUTS, such as alfuzosin, terazosin and doxazosin.[4,5] A long-term, open-label, multicenter study confirmed that once-daily tamsulosin (0.4 or 0.8 mg) is effective and safe for long-term treatment of BPH and that it represents a good therapeutic alternative to surgical intervention.[5]

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) represents a spectrum of iris response during phacoemulsification surgery, ranging from iris billowing, to a tendency for the iris tissue to catch the phacoemulsification or irrigation aspiration tip or prolapse toward the main and side-ports incisions, along with progressive intraoperative pupil constriction (Figure 1). IFIS is also associated with inadequate preoperative dilatation of the pupil despite the use of standard dilating drops.[9] In contrast to other causes of small pupil, such as glaucoma and diabetes mellitus, the iris is very elastic and the pupil does not dilate with mechanical stretching, which can even make IFIS worse.[9] IFIS manifests as a continuum of severity with variability between patients and even between eyes of the same patient.[9] The severity can be classified into the following groups:[9]

 

 

Figure 1.   Iris billowing, prolapse to corneal incisions and pupil constriction in intraoperative floppy iris syndrome.
Image © Sallam, El-Defrawy, Ross, Bashir & Towler.

  • Mild form, with a well-dilated pupil preoperatively and some intraoperative iris billowing;
  • Moderate form with mid dilated pupil preoperatively and mild tendency of the iris to prolapse through ocular incisions;
  • Severe form where patients have small pupils that resist dilatation and marked intraoperative iris prolapse.

As optimum visualization is crucial for safe removal of cataract, inadequate pupil dilatation will preclude the surgeon’s view and compromise the final outcome. Small pupil size prolongs surgery time and increases the risk of posterior capsule rupture and vitreous loss. This, in turn, can increase the risk of postoperative retinal detachment and cystoid macular edema and may limit visual recovery.[10] In addition, the propensity of a floppy iris to prolapse towards the phacoemulsification tip and to the ocular incisions increases the risk of iris injury during the surgery. This may also lead to an exaggerated postoperative uveitis and pupil distortion. In one of the two first independent publications reporting the connection between IFIS and tamsulosin,[9,11] Chang and Campbell retrospectively reported posterior capsular ruptures and vitreous loss in 12% of their tamsulosin patients.[9] Compared with standard figures of posterior capsule ruptures and vitreous loss, this rate is more than ten-times higher than that of a senior grade surgeon,[12,13] and reflects the magnitude of possible IFIS-associated complications when the surgeon is faced with the unanticipated cascade of IFIS.[9]

Epidemiology of IFIS & Association With Tamsulosin

The overall prevalence of IFIS in patients undergoing cataract surgery is probably around 1%.[14] However, Chang and Campbell prospectively evaluated 900 consecutive cataract procedures and reported a 2.2% IFIS prevalence.[9] Such discrepancies may be related to regional differences or variable prescribing practice of physicians,[14] as well as differences in perception of IFIS signs and recognition of the syndrome by surgeons.[15]

The association between IFIS and tamsulosin has been confirmed by several studies.[9,11,16] Incidence of IFIS among those receiving tamsulosin is reported to vary between 37.9 and 90%.[9,14–18] A further report by Pärssinen et al. also found abnormal iris behavior of at least sluggish fluttering and small pupillary diameter in 21 consecutive subjects.[19] Poor preoperative pupil dilation has been correlated with an increased likelihood of IFIS. A recent retrospective review of 59 patients (81 eyes) taking tamsulosin at the time of surgery demonstrated that preoperative dilated pupil diameter smaller than 6.5 mm is significantly associated with IFIS (p = 0.032).[15] It should be noted that while IFIS was classically described in males, the increased use of tamsulosin for various urological indications in females may result in more females developing IFIS in the future.[9]

In addition to tamsulosin, IFIS has been reported with other α-1 adrenergic receptor antagonists such as alfuzosin and doxazosin.[20,21] Reports have also linked IFIS to the use of various medications that have some α-antagonist effects, such as labetalol, mianserin and some psychiatric drugs.[22–24] Nevertheless, data from four large studies demonstrated that these drugs are not strongly associated with IFIS compared with tamsulosin and that the high affinity of tamsulosin for α-1a receptors underlies the pathogenesis of IFIS.[9,14,16,25] This also concurred with a retrospective study from Canada, which demonstrated that of those patients exclusively exposed to tamsulosin or alfuzosin, 86 and 15% developed IFIS, respectively. The adjusted odds ratio for IFIS in men exposed to tamsulosin compared with alfuzosin was 32 in this study.[20] Oshika et al. demonstrated that IFIS developed in only 19% of patients on naftopidil, a selective α-1 receptor antagonist that is mainly available in Japan with a high binding affinity to both α-1a and α-1d receptor subtypes.[25]

Other than α-1 adrenergic receptor antagonists, Schwinn and Afshari had previously suggested that IFIS could be associated with diseases that affect the tone of iris sphincter muscle, as in diabetes mellitus and hypertension.[26] However, a large prospective study by Chadha et al. showed no evidence that diabetes is an independent risk factor for IFIS.[14] A recent systematic review and meta-analysis of 17,588 eyes examining the association between IFIS and other risk factors showed that IFIS was positively associated with hypertension but not with diabetes mellitus.[27]

Underlying Mechanisms of IFIS

Current thinking for the occurrence of IFIS with tamsulosin is mainly based on pharmacological blockade of the α1 receptors present in the iris.[28–30] Evidence shows that, similar to prostate, postsynaptic α-1 adrenergic receptors predominate in iris dilator smooth muscle and that stimulation of this receptor subtype mediates muscle contraction and pupil dilatation.[29,30] By contrast, α-1a blockade results in relaxation of the dilator muscle with poor pupillary dilatation. Chang and Campbell proposed that iris billowing and prolapse in IFIS are probably due to loss of the dilator muscle tone, which normally confers iris rigidity.[9]

No study has established a minimum duration of intake of tamsulosin leading to IFIS. However, there are several reports suggesting that IFIS can occur within weeks of commencing tamsulosin[17,18] and one case report showed that IFIS can develop as early as 2 days after treatment.[31] Tamsulosin has a long half-life, with detectable levels in the aqueous humor of patients who stopped the medication up to 28 days previously.[19] Nevertheless, discontinuation of tamsulosin therapy preoperatively for periods longer than 28 days (and sometimes for several years) does not necessarily eliminate the occurrence of IFIS.[9] A plausible explanation that constant blockade of the iris dilator muscle by tamsulosin may result in permanent disuse atrophy of the muscle.[9] Evidence for this assumption can be drawn from a histological study of cadaver eyes that showed decreased iris dilator muscle thickness in patients receiving tamsulosin compared with a control group,[29] as well as a further study that demonstrated thinning of dilator muscle region in tamsulosin patients when examined by optical coherence tomography.[32] A recent immunohistochemical study of iris tissue from a patient with tamsulosin-related IFIS undergoing glaucoma surgery provided some evidence to suggest that IFIS may also develop owing to vascular dysfunction.[30] In addition to the dilator muscle, localization of α-1a receptors in iris arteriolar muscularis was demonstrated in this report. However, histological thickness and structure of the iris dilator muscle were normal. The authors suggested that tamsulosin-induced dysfunction at the level of iris vessels can lead to loss of the ability of the iris vessels to coil resulting in poor pupillary dilatation and iris flaccidity.[30]

Management of IFIS

Preoperative Planning

Preoperative planning and anticipation of IFIS can impart significant protective effect in preventing major complications during surgery.[14,18,19] Chang et al. carried out a large prospective multicenter trial involving 167 eyes of tamsulosin patients operated on by 15 highly experienced surgeons. The surgeons were aware of the drug history and were allowed to employ appropriate compensatory measures to tackle IFIS.[18] Results of this study demonstrated an incidence of posterior capsule rupture of 0.6% (95% CI: 0–1.8) and 95% of patients achieved a best-corrected visual acuity of 6/12 or more.[18] Comparable data were also reported by other independent investigators and similarly reflect that the surgeon’s awareness and anticipation of IFIS greatly influence the outcome of cataract surgery in this cohort of patients.[14,19,33–37] However, even for forewarned surgeons, patients who have a drug history that includes tamsulosin are still regarded as high-risk cases and can potentially be a challenge to the trainee surgeon. A retrospective review of 59 patients (81 eyes) taking tamsulosin at the time of cataract surgery and operated by trainees demonstrated an increased likelihood of complication with a posterior capsular rupture rate of 7.4% and a significantly prolonged operative time.[15]

Nursing staff involved in preoperative assessment of cataract surgery should be educated regarding the implications of α-adrenergic receptor blockers and particularly tamsulosin on cataract surgery. A full drug history should be included in the physician referral letter and must be carefully reviewed before cataract surgery. Patients (males as well as females) should also be directly questioned regarding the use of tamsulosin, particularly as tamsulosin has recently become available without prescription in some countries and thus its use may not appear on communications from physicians.[38] In addition, tamsulosin patients should be educated regarding their increased likelihood of a technically difficult operation and the potential intraoperative risks related to IFIS. It is vital that during the consent process, the patient is appropriately informed, thus allowing them to make better judgments on the ‘risk-to-benefit’ ratio of their surgery.

Primary care physicians’ awareness of the association between tamsulosin and IFIS also needs to be increased. In a survey from an ophthalmic unit in the UK published in 2008, 96.8% of 64 physicians involved in patient referring were not aware of IFIS, although more than three-quarters of those physicians were prescribing tamsulosin to their patients.[39] Although unsubstantiated, one would expect that physicians’ knowledge regarding IFIS has improved in recent years given the increased awareness of IFIS within the ophthalmic community and the issuing of educational updates by ophthalmologists to physicians.[18,40] Generally, recommendations from ophthalmologists to physicians are not to change prescribing practices with regard to tamsulosin, but to educate their patients about IFIS and encourage them to disclose tamsulosin or other prostate medications use to their cataract surgeons.[18,40]

Stopping tamsulosin before surgery does not appear to prevent IFIS.[17–19] In the prospective tamsulosin trial, Chang et al. demonstrated that preoperative discontinuation of tamsulosin did not result in any difference in IFIS severity when compared with eyes of patients who continued to take tamsulosin.[18] However, patients who stopped the medication had a slightly larger pupil size at the outset of the surgery (mean pupil diameter was 6.9 mm in stopped cases vs 6 mm in nonstopped cases) but this was not statistically significant. Moreover, stopping tamsulosin can aggravate LUTS and put the patient at risk of developing acute urine retention and therefore should be avoided.[18]

Modification of Surgical Technique

Successful management of IFIS includes modification of routine surgical techniques. Attention to wound design with appropriately sized tunnels and entry anterior to the iris root may decrease the risk of iris prolapse during surgery. Use of gentle hydrodissection, low-flow fluidic parameters, bimanual irrigation-aspiration and microincisional phacoemulsification techniques increase anterior chamber stability and may also help reduce the magnitude of iris fluttering and prolapse to the phacoemulsification tip or to the wounds.[9,18]

Pharmacological Measures

Preoperative use of atropine eye drops can help avoid progressive miosis seen with IFIS[33,34] and was first suggested by Masket.[41] Atropine blocks the cholinergically mediated action of the iris constrictor muscle, resulting in improved pupillary dilatation. When used to prevent IFIS, atropine drops need to be started at least 2 days before surgery.[34] In the prospective tamsulosin trial by Chang et al., preoperative atropine was infrequently used by surgeons in the management of IFIS, and although eyes that received topical atropine drops had the largest mean pupil diameter preoperatively (7.2 ± 0.9 mm), 58% of these eyes required an additional intraoperative measure to manage IFIS.[18] In addition, systemic absorption of atropine can increase LUTS in patients with BPH and thus it is important to inform the patient’s primary care physician about the plan of management and not to discontinue tamsulosin.[34]

Other pharmacological methods for IFIS management include the use intracameral α1 receptor agonist drugs[34–37] as a means to counteract the effect of tamsulosin on the iris receptors (Figure 2). This modality was not investigated by the prospective tamsulosin trial as the trial was initiated before the introduction of this class of drugs into the management of IFIS. In 2006, Sugar was the first to describe the use of intracameral epinephrine for the prophylaxis of IFIS.[35] His regimen includes intracameral injection of diluted preservative-free epinephrine at a 1:4000 concentration at the beginning of surgery before the installation of the ophthalmic viscosurgical device (OVD). He reported uniform success to prevent IFIS in 71 operated tamsulosin patients.[35] Using the same concentration of intracameral epinephrine in combination with preoperative atropine drops, Masket and Belani also reported a high success rate in the prevention of IFIS in a study of 20 eyes.[34]

 

 

Figure 2.   Intracameral phenylephrine. (A) Iris billowing and pupil constriction in intraoperative floppy iris syndrome. (B & C) Absence of iris billowing and pupil dilatation after injection of intracameral phenylephrine.
Image © Sallam, El-Defrawy, Ross, Bashir & Towler.

Manvikar and Allen used diluted intracameral phenylephrine (1:360) prepared from single-use minims in 22 eyes of tamsulosin patients that had small pupils preoperatively or displayed IFIS features intraoperatively.[36] Additional pupillary dilatation was observed in only 73% of eyes. However, in all eyes that had intracameral phenylephrine owing to significant iris prolapse into the incisions or progressive miosis, it resulted in restoration of iris tone, decreased tendency to flutter and prolapse and caused the pupil to dilate back to its preoperative size. Similar results were also reported by Gurbaxani and Packard in another study of seven tamsulosin subjects using an intracameral phenylephrine concentration of 1:200.[37] Potential ocular toxicity remains a concern with the use of intracameral drugs, although recent safety studies showed that phenylephrine and diluted epinephrine had no discernible deleterious effect on either the corneal endothelium or the macula.[42–45] It is worth mentioning that intracameral use of α-1 receptor agonists may be associated with systemic side effects, and blood-pressure spikes have been reported.[46]

Mechanical Measures

Mechanical measures to dilate the pupil and restrain iris movement have been tried with varying success in IFIS.[47–52] Viscomydriasis using Healon5® (sodium hyaluronate 2.3%) is one of these measures.[47] The highly concentrated long-chained molecules of this higher viscosity OVD are able to move the iris effectively, dilate the pupil more than any other OVD and mechanically decrease iris billowing and prolapse. However, the main shortcoming of this method is that Healon5 in the anterior chamber tends to be consumed during surgery, but this may be minimized by using slow-motion fluidics for phacoemulsification and irrigation aspiration.[53] Caution is also needed when using Healon5, as overfilling the anterior chamber can result in difficult manipulation of the anterior capsule[47] and can also predispose to corneal wound burn.[54,55] Creating a fluid space around the phacoemulsification tip before starting phacoemulsification should circumvent these problems. This can be performed by partially filling the anterior chamber with the OVD and injecting balanced salt solution underneath, as described by Arshinoff in the ultimate soft-shell technique.[47]

Iris retractors (hooks) are commonly used for tackling IFIS.[17,18,48–51] They can dilate the pupil and resist the tendency of the iris to billow and prolapse. Compared with Healon5, Iris retractors have the advantage of maintaining a constant pupil size during the surgery. While most surgeons usually employ four hooks to stretch the iris in a square or diamond configuration,[56,57] different techniques for placing the hooks have been described, including the use of a single hook posterior to the main incision,[49] two iris hooks to straddle the main incision[50] and inserting five hooks in a pentagon shape.[34] Placing four hooks in a diamond configuration offers several advantages in IFIS and has been recommended by the American Society of Cataract and Refractive Surgery (ASCRS) committee for managing IFIS.[51] The subincisional iris is pulled posterior to the phacoemulsification wound through a separate incision, making prolapse far less probable (Figure 3). In addition, this technique maximizes pupillary dilatation infront of the phacoemulsification tip and provides more space for cataract removal.[57]

 

 

Figure 3.   Iris retractors placed in a diamond configuration. Image © Sallam, El-Defrawy, Ross, Bashir & Towler.

Pupil expander rings have been used successfully for managing IFIS.[52] Similar to hooks, pupil expander rings restrain the iris movement and decrease the severity of billowing and prolapse to the incisions. In general they are less traumatic than iris hooks, do not overstretch the iris and can be inserted without the need of additional incisions. Several designs are available, including the Morcher Pupil Ring® (Figure 4), the Milvella Perfect Pupil® and the Eagle Vision Graether Ring®. The Malyugin Ring® is the newest form of pupil expansion devices and, compared with the other pupil expansion rings, it has the advantage of being thin and light and hence easier to insert and remove in eyes with shallow anterior chambers using a special injector. Two sizes of this ring are now available; 6.25 and 7 mm. The 6.25 mm is the commonly used size and is easier to insert in eyes with shallow anterior chambers (Figure 5). The 7-mm device has recently been introduced and could be helpful in cases of IFIS with very flaccid iris to increase exposure and keep the iris further way from the surgeon’s working plane. In a study of 30 eyes with IFIS, Chang reported excellent results with the Malyugin device in terms of maintaining a constant pupillary expansion of 6 mm and decreasing iris billowing. No major intraoperative adverse events were reported by the author, but iris prolapse still occurred in some cases.[52]

 

 

Figure 4.   Morcher pupil ring®.
Reprinted courtesy of Youssef T, Cornwall Community Hospital, ON, Canada.

 

 

Figure 5.   6.25-mm Malyugin® pupil expansion device.
Image © Sallam, El-Defrawy, Ross, Bashir & Towler.

The best strategy for managing IFIS is still not known.[17,18,48] A surgeon’s choice is mainly based on personal experience and case difficulty. Different modalities can also be complementary when combined and having experience with more than one method is an advantage, particularly as clinical circumstances may change during surgery.[18,48] Data from the 2008 ASCRS survey that was completed by 957 members showed intracameral α1 agonists and iris hooks to be the most preferred methods in managing IFIS (38 and 23%, respectively), although a third of respondents in this survey also reported that they routinely use more than one strategy for managing IFIS.[51] The practice pattern of ophthalmologist in the UK has been reported to be in favor of using iris hooks and Healon5 in managing floppy irides.[17] In a nationwide survey of consultants’ experiences published in 2007, 61% of the participants reported using hooks and 27% used Healon5. Intracameral phenylephrine was uncommonly used in this survey, with only 2% of surgeons employing this technique; however, 12% of the respondents reported that they would consider using this modality in future.[17]

Expert Commentary

Intraoperative floppy iris syndrome occurs in a significant number of patients with tamsulosin-associated cataract extractions. It is important that possible sequelae are anticipated and surgery is carefully planned, so that visual outcome is not adversely affected.[14,18,19] Based on available data,[9,18] we recommend that patients who are taking or have taken tamsulosin should only be operated on by senior cataract surgeons who have the capacity to handle complex cases and can employ compensatory measures to manage IFIS.

In our practice, we do not discontinue tamsulosin before surgery but we educate our patients about IFIS and its implications so that their consent is properly informed. For patients with a preoperative dilated pupil diameter of 6 mm or more, we do not employ any prophylactic measures; however, we prepare intracameral phenylephrine (1:360) and use it at the earliest signs of IFIS, if it is encountered. When used in such a context, phenylephrine is effective in decreasing iris flutter and prolapse as well as restoring preoperative pupil dilatation.[36] For cases with small pupil at the outset, we routinely use four iris hooks in a diamond configuration before performing the capsulorhexis, and more recently we have been using a 6.25 mm Malyugin ring with good success.

In our hands, neither the use of Healon5 nor preoperative atropine drops has been reliable for the management of IFIS. Despite the use of low–moderate fluidics, we find it difficult to maintain Healon5 in a sufficient volume in the anterior chamber to control the iris throughout surgery, and its effect is therefore short lived, even with repeat injections. Similar to the findings of the prospective tamsulosin trial,[18] we also find atropine drops insufficient for preventing IFIS and thus we seldom utilize it as a preventative measure.

Five-year View

Since its description by Chang and Campbell in 2005,[9] there have been in excess of 100 reports published regarding IFIS. While our knowledge and awareness of the etiology and management of IFIS have significantly improved,[18,19,33–37] there are still certain aspects of this condition that need to be explored further and could impact future treatment strategies of IFIS within the next 5 years.

The exact pathophysiology of IFIS and the effect of tamsulosin on iris mechanics are not completely understood. We know that the occurrence of IFIS with this class of drugs is mainly based on pharmacological blockade of the α1-adrenergic receptors present in the iris.[28–30] However, there is insufficient evidence to explain why this blockade is permanent and whether this is due to disuse atrophy of the dilator muscle,[29,32] vascular dysfunction[30] and/or iris denervation. It is reasonable to suggest that future focus should be directed at the localization of the α-1 adrenergic receptors in the iris as well as the histology of the human iris in tamsulosin patients.

There are no published trials to inform the most appropriate method for managing IFIS. Randomized prospective trials are needed to compare the safety and efficacy of the different management modalities of IFIS, particularly as our experience with the use of intracameral α-1 agonists, a strategy of growing popularity in our armamentarium for managing IFIS, is mainly based on a few uncontrolled small series and case reports.[34–37]

Sidebar

Key Issues

  • Intraoperative floppy iris syndrome (IFIS) occurs owing to drug-induced blockade of the α-1a receptors present in the iris dilator muscle in a large proportion of patients who take or have previously used tamsulosin.
  • Unless anticipated before surgery, IFIS may compromise and prolong cataract surgery.
  • Primary care physicians should be familiar with the association of IFIS and α-1 blockers, particularly tamsulosin.
  • Stopping tamsulosin before cataract surgery does not prevent IFIS and may increase benign prostatic hyperplasia symptoms.
  • Different preoperative methods for managing IFIS exist and could be complementary.
  • Intracameral phenylephrine is a reliable method for restoring iris rigidity and maintaining pupillary dilatation and is most suitable
  • Iris hooks and pupillary rings are recommended modalities for tackling IFIS if the pupil is small at the outset.
  • Favorable outcome is achieved if tamsulosin use is known before surgery and the operation is undertaken by an experienced cataract surgeon.

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