ARTICLE
`
`Toxic anterior segment syndrome: Common
`causes
`
`Carolee M. Cutler Peck, MD, MPH, Jacob Brubaker, MD, Sue Clouser, RN, MSN, CRNO,
`Chris Danford, Henry E. Edelhauser, PhD, Nick Mamalis, MD
`
`PURPOSE: To identify the most common risk factors associated with toxic anterior segment
`syndrome (TASS).
`
`SETTING: Ophthalmic surgical centers in the United States, Argentina, Brazil, Italy, Mexico, Spain,
`and Romania.
`
`METHODS: A TASS questionnaire on instrument cleaning and reprocessing and extraocular and in-
`traocular products used during cataract surgery was placed on the American Society of Cataract and
`Refractive Surgery web site. A retrospective analysis of questionnaires submitted by surgical cen-
`ters reporting cases of TASS was performed between June 1, 2007, and May 31, 2009, to identify
`commonly held practices that could cause TASS. Members of the TASS Task Force made site visits
`between October 1, 2005, and May 31, 2009, and the findings were evaluated.
`
`RESULTS: Data from 77 questionnaires and 54 site visits were analyzed. The reporting centers
`performed 50 114 cataract surgeries and reported 909 cases of TASS. From January 1, 2006, to
`date, the 54 centers reported 367 cases in 143 919 procedures; 61% occurred in early 2006. Com-
`mon practices associated with TASS included inadequate flushing of phaco and irrigation/aspiration
`handpieces, use of enzymatic cleansers, detergents at the wrong concentration, ultrasonic bath,
`antibiotic agents in balanced salt solution, preserved epinephrine, inappropriate agents for skin
`prep, and powdered gloves. Reuse of single-use products and poor instrument maintenance and
`processing were other risk factors.
`
`CONCLUSIONS: The survey identified commonly held practices associated with TASS. Understand-
`ing these findings and the safe alternatives will allow surgical center personnel to change their
`practices as needed to prevent TASS.
`
`Financial Disclosure: No author has a financial or proprietary interest in any material or method
`mentioned.
`
`J Cataract Refract Surg 2010; 36:1073 1080 Q 2010 ASCRS and ESCRS
`
`Toxic anterior segment syndrome (TASS) is a sterile in-
`flammatory reaction of unknown incidence that can oc-
`cur after anterior segment surgery. It typically presents
`within 12 to 48 hours of surgery. The most common
`finding is diffuse limbus-to-limbus corneal edema
`(Figure 1) secondary to damage from a toxic insult to
`the endothelial cell layer. Widespread breakdown of
`the blood–aqueous barrier is another hallmark of this
`condition, with fibrin in the anterior chamber and hypo-
`pyon present in 75% of cases (Figure 2). Damage to the
`iris may cause the pupil to dilate or become slightly
`irregular, and glaucoma secondary to trabecular mesh-
`work damage may also occur.
`Treatment with intense topical steroidal agents will
`eventually lead to resolution of the inflammation;
`
`however, in severe cases there may be lasting sequelae,
`such as permanent corneal edema, glaucoma, and
`other effects of chronic inflammation. Various entities
`have been shown to cause TASS. These include, but
`are not limited to, endotoxin; denatured ophthalmic
`viscosurgical devices (OVDs); preservatives such as
`benzalkonium chloride, bisulfites, and metabisulfites;
`heavy-metal residue,
`fine-matter particulates, and
`substances introduced into the anterior chamber that
`are at a pH or concentration that is toxic to the sensitive
`endothelial cells. In addition, residue of materials used
`in the cleaning and sterilization of ophthalmic instru-
`ments are an increasingly important source of TASS.
`Members of industry and the American Society of
`Cataract and Refractive Surgery (ASCRS) have joined
`
`Q 2010 ASCRS and ESCRS
`
`Published by Elsevier Inc.
`
`0886 3350/$
`
`see front matter 1073
`doi:10.1016/j.jcrs.2010.01.030
`
`Novartis Exhibit 2299.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1074
`
`COMMON CAUSES OF TASS
`
`to create a TASS task force. The goal of this task force is
`to educate anterior segment surgeons on the causes,
`symptoms, and treatment of TASS and to help investi-
`gate outbreaks of TASS.
`Questionnaires are available on the ASCRS web
`siteA to facilitate the reporting of TASS cases. The in-
`formation entered into the questionnaires is reviewed
`by members of the TASS Task Force with the goal of
`identifying potential causes of TASS. Recommenda-
`tions on preventative measures to stop recurrences
`are then made. This study will focus on common
`practices that may lead to TASS as well as alternative
`measures that will help protect patients having
`anterior segment surgery.
`
`MATERIALS AND METHODS
`The TASS questionnaires were posted on the ASCRS web
`site in 2007. A retrospective analysis was performed on ques
`tionnaires submitted between June 1, 2007, and May 31,
`2009. The questionnaires address instrument cleaning and
`reprocessing practices and surgical protocols as well as
`substances and techniques used for cleaning phaco and
`irrigation/aspiration (I/A) handpieces. They also address
`products used extraocularly and intraocularly, such as med
`ications, and the reuse of cannulas and other disposable
`items. Responses were analyzed, and commonly held prac
`tices that lead to cases of TASS are presented here.
`In addition, members of the TASS Task Force made site
`visits at the request of centers with TASS cases. The visits
`occurred between October 1, 2005, and May 31, 2009. During
`the visits, task force members observed preoperative, intra
`operative, and instrument processing procedures to identify
`practices that could be associated with TASS. The data
`gathered from these visits are presented.
`
`RESULTS
`During the study period, 77 TASS questionnaires were
`submitted through the ASCRS web site, 9 of which
`
`Submitted: December 15, 2009.
`Final revision submitted: January 25, 2010.
`Accepted: January 26, 2010.
`
`From the John A. Moran Eye Center (Cutler Peck, Brubaker,
`Mamalis), University of Utah, Salt Lake City, Utah; UT Southwestern
`Medical Center (Clouser), Dallas, and Alcon Laboratories, Inc.
`(Danford), Fort Worth, Texas; and Emory University (Edelhauser),
`Atlanta, Georgia, USA.
`
`Supported in part by unrestricted grants from Research to Prevent
`Blindness, Inc., New York, New York, USA, to the Department of
`Ophthalmology & Visual Sciences, University of Utah.
`
`IOL and
`the ASCRS Symposium on Cataract,
`Presented at
`Refractive Surgery, San Francisco, California, USA, April 2009.
`
`Corresponding author: Nick Mamalis, MD, John A. Moran Eye
`Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake
`City, Utah 84132, USA. E-mail: nick.mamalis@hsc.utah.edu.
`
`Figure 1. Toxic anterior segment syndrome after phakic IOL surgery.
`Note the limbus to limbus corneal edema.
`
`were excluded from analysis. Of those excluded, 5
`were duplicates, 2 did not report any TASS cases,
`and 2 were reporting cases of endophthalmitis. Of
`the centers included, 62 were in the United States; 6 in-
`ternational centers responded, with 1 each from Ar-
`gentina, Brazil, Italy, Mexico, Spain, and Romania.
`Members of the TASS Task Force made 54 site visits,
`all in the United States. Overall, 909 cases of TASS
`were reported in 50 114 cataract surgeries performed
`concurrently at the reporting centers that submitted
`questionnaires. From January 1, 2006, to date, the 54
`centers visited by a TASS Task Force member reported
`367 cases of TASS in 143 919 procedures performed;
`61% of them occurred in 2006.
`Table 1 shows the cleaning procedures associated
`with TASS. Inadequate flushing of the phaco and
`I/A handpieces after surgery was the most commonly
`observed and reported behavior that can lead to TASS.
`
`Figure 2. Hypopyon is seen in the anterior chamber of this patient
`with TASS.
`
`J CATARACT REFRACT SURG VOL 36, JULY 2010
`
`Novartis Exhibit 2299.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`COMMON CAUSES OF TASS
`
`1075
`
`Of the 68 centers that filled out questionnaires, more
`than 60% used less than the recommended 120 cc per
`port (range 2 to 100 cc per port). Other factors were
`occluded I/A tips during surgery, a symptom of
`inadequate flushing.
`Table 2 shows the observations made during site
`visits at centers with diagnosed cases of TASS. The
`top observations were inadequate flushing of phaco
`and I/A handpieces and cannulated equipment, use
`of enzymatic cleaners and detergents, use of reusable
`cannulas, and inadequate or no manual cleaning of
`instruments. Cleaned instruments were often left on
`towels that were not lint-free, and many centers did
`not
`train personnel regarding TASS and proper
`cleaning practices.
`Medications given intracamerally or added to a bal-
`anced salt solution irrigant were another potential
`source of TASS. Table 3 shows the products associated
`
`Table 1. Cleaning procedures associated with TASS.
`
`Reported Practice
`
`Amount of flush used for handpieces
`120 cc or more
`!120 cc (range 2 100 cc)
`Unknown
`Not specified
`Occluded I/A tips
`Yes
`No
`Final rinse water
`Deionized/distilled
`Sterile/pyrogen free
`Tap
`Unknown
`Not specified
`Use of enzymatic cleaners
`Yes
`No
`Unknown
`Use of US Bath
`Yes
`No
`Frequency of cleaning US bath
`After each use
`More than once daily
`Unknown
`No cleaning protocol
`Ophthalmic instruments separated for
`cleaning
`Yes
`No
`Don’t know
`
`I/A Z irrigation/aspiration; US Z ultrasonic
`
`Centers Reporting
`Practice, n (%)
`(N Z 68)
`
`18 (26)
`42 (62)
`3 (4)
`5 (7)
`
`27 (40)
`41 (60)
`
`30 (44)
`22 (32)
`12 (18)
`2 (3)
`2 (3)
`
`36 (53)
`28 (41)
`4 (6)
`
`43 (63)
`25 (37)
`
`8 (19)
`31 (72)
`3 (7)
`1 (2)
`
`55 (81)
`9 (13)
`4 (6)
`
`Table 2. Observations during site visits at centers with diag
`nosed cases of TASS.
`
`Observation Category
`
`Inadequate flushing of phaco and
`I/A handpieces and cannulated
`equipment
`Use of enzymatic cleaners and
`detergents
`Use of reusable cannulas
`Inadequate or no manual cleaning
`of instruments
`Use of preserved epinephrine
`Reuse of single use
`devices, blades, tips,
`sleeves, etc.
`Use of tap water with no sterile
`water final rinse
`Inadequate personnel or trays to
`allow proper preparation of
`instruments
`No immediate cleaning allowing
`OVD and surgical solutions to
`dry on devices
`Use of preserved medicines in the
`eye
`Reuse of tubing for flushing, latex
`bulb for irrigation, no training,
`no term sterilization,
`instruments stored on towels
`Touching of IOL or patient contact
`areas of instruments with
`gloved hands
`Off label use of lidocaine gel
`Poor instrument maintenance,
`residual autoclave residue and
`instrument mild, rust,
`particulates, lint, etc.
`Use of powdered gloves
`Additives added to balanced salt
`solution against DFU
`Improper use of prep solutions,
`detergents, and cleaners
`Failure to follow manufacturer’s
`DFU, including
`no air flush, use of unapproved
`enzymatics
`Use of postoperative ointment in
`clear cornea cases
`Povidone iodine placed in eye at
`end of procedure
`Incorrect concentration of
`detergent and enzymatic
`cleaners used
`Lack of routine cleaning of US
`
`Frequency of Observation,
`n (%) (N Z 54)
`
`48 (89)
`
`43 (80)
`
`37 (69)
`35 (65)
`
`28 (52)
`28 (52)
`
`27 (50)
`
`23 (43)
`
`20 (37)
`
`18 (33)
`
`20 (37)
`
`18 (33)
`
`17 (31)
`15 (28)
`
`15 (28)
`15 (28)
`
`14 (26)
`
`11 (20)
`
`11 (20)
`
`9 (17)
`
`4 (7)
`
`2 (4)
`
`DFU Z directions for use; I/A Z irrigation/ aspiration; IOL Z intraocu-
`lar lens; OVD Z ophthalmic viscosurgical device; US Z ultrasound
`
`J CATARACT REFRACT SURG VOL 36, JULY 2010
`
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`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1076
`
`COMMON CAUSES OF TASS
`
`Table 3. Products associated with TASS and their use.
`
`Product Used
`
`Antibiotic added to BSS
`Vancomycin
`Gentamicin
`None
`Unknown
`Intracameral antibiotic agents
`Vancomycin
`Cefuroxime
`Moxifloxacin
`Cefazolin sodium
`None
`Preserved epinephrine in BSS
`Yes
`No
`Preserved intracameral anesthetic
`agent
`Yes
`No
`
`BSS Z balanced salt solution
`
`Centers Reporting
`Use, n (%)
`
`16 (24)
`1 (1)
`50 (74)
`1 (1)
`
`7 (10)
`3 (5)
`3 (5)
`1 (1)
`54 (79)
`
`18 (36)
`32 (64)
`
`3 (6)
`44 (94)
`
`with TASS. Antibiotic agents were the most common
`additives to balanced salt solution; some centers
`added epinephrine with preservatives or stabilizers.
`Slightly more than 20% of centers used intracameral
`antibiotic agents; 17 centers (31%) used preserved
`topical lidocaine gel preoperatively.
`Poor instrument maintenance was also pervasive.
`Autoclaves were found to have autoclave residue,
`instrument milk, rust, particulates, or lint at more
`than a quarter of the sites. Other sites failed to follow
`manufacturer’s directions for use when cleaning
`instruments; this included omitting an air flush of
`cannulated equipment, although this had been recom-
`mended, or using enzymatics during processing when
`this was not approved.
`In centers in which non-ophthalmologic surgeries
`were performed, ophthalmic instruments were pro-
`cessed along with instruments from other types of
`surgeries at 9 (13%) centers responding by question-
`naire; 4 (6%) respondents did not know whether
`instruments were separated at the time of processing.
`
`DISCUSSION
`The data in this analysis were self-reported in the case
`of the questionnaires or the result of self-referrals for
`site inspection in relation to TASS cases. The data
`from the site visits were taken from written reports
`submitted at the end of the visit. Although there is mo-
`tivation on the part of surgical centers to obtain
`
`assistance when cases of TASS occur, in an effort to
`prevent future cases, not all cases of TASS may be rec-
`ognized or centers may choose not to report cases if
`only a small percentage of their cataract surgeries re-
`sult in TASS and a problem is not perceived. Because
`we do not have a tally of all TASS cases that occur in
`the United States, and because those reporting cases
`all reported various timeframes in which the reported
`cases occurred for each center, we cannot calculate the
`incidence of TASS from our data.
`The most frequently identified practice associated
`with TASS is inadequate cleaning of phaco and I/A
`handpieces after use. To be most effective, the manu-
`facturer’s directions for use should be strictly followed
`and handpieces should be wiped with a lint-free cloth,
`immediately immersed in sterile water until they are
`flushed, or both.1–3 This was not done at 89% of centers
`visited. This practice is imperative to prevent residual
`OVD and debris from drying within the handpiece
`and tips before they are flushed. This is especially
`important because dried OVD denatures after sterili-
`zation at high temperatures and if this or other
`particles or debris are irrigated into the anterior cham-
`ber, TASS may result.4 While instruments are still
`moist, they must be flushed with 120 mL of fluid per
`port, or more if
`indicated in the manufacturer’s
`directions for use. This can be performed with tap
`water as deionized water. However, the final flush
`must then consist of sterile distilled or sterile deionized
`water. If cleaned instruments are stored on towels, the
`towels should be lint free.3,5,6
`In addition to addressing the problem of inadequate
`flushing, it is important to address some of the reasons
`it occurs. Even if an adequate cleaning protocol is in
`place, if surgical centers are understaffed or there are
`too few surgical trays to allow proper cleaning of
`instruments between cases (as observed at 43% of cen-
`ters visited), time constraints will lead to insufficient
`flushing and patients will be placed at risk for TASS.
`The reuse of tubing for flushing and latex bulbs for
`irrigation is also a potential issue. These items are
`difficult to clean and hard to sterilize, which can lead
`to improper processing between cases.
`It is imperative that surgical centers ensure that
`there are adequate numbers of personnel and surgical
`trays to allow all steps of cleaning and sterilization to
`be completed between uses of ophthalmic instru-
`ments. It is also crucial that personnel are trained
`sufficiently in the causes of TASS and the proper steps
`of cleaning and sterilization.2,3,7–9
`Eighty percent of surgical centers visited and 53% of
`those responding via questionnaire were using enzy-
`matic detergents in the processing of their ophthalmic
`instruments. The benefit of using enzymatic deter-
`gents to clean ophthalmologic instruments has not
`
`J CATARACT REFRACT SURG VOL 36, JULY 2010
`
`Novartis Exhibit 2299.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`COMMON CAUSES OF TASS
`
`1077
`
`been established and may actually be prohibited in the
`manufacturer’s directions for use for specific products.
`Furthermore, the use of detergents mixed at the wrong
`concentration has been linked to TASS outbreaks.10
`Seven percent of centers visited were using the wrong
`concentration of detergents, putting their patients at
`risk for TASS as a result of residual detergents and in-
`complete rinsing.
`Enzymatic detergents often have the exotoxin sub-
`tilisin or a-amylase enzymes as their active ingredi-
`ents. These are only deactivated at
`temperatures
`higher than 140C, and most autoclaves do not reach
`temperatures higher than 120C to 130C. Thus, it is
`likely that residue from enzymatic detergents will
`build up on reused instruments.11 Human and rabbit
`studies evaluating the effect of enzymatic detergents
`on the anterior chamber showed dose-related corneal
`swelling; ultrastructural damage to the endothelial
`layer, leading to increased corneal permeability; and
`an increased inflammatory response in the iris.12
`The purpose behind the use of enzymatic detergents
`is to rid ophthalmic instruments of debris. If instru-
`ments are kept moist immediately after use before
`flushing and if proper flushing with an adequate
`volume is performed, there should be no adherent
`debris and thus no need for enzymatic detergents. If
`detergents are used,
`it
`is imperative that strict
`attention is paid to the dilution and expiration date.
`Furthermore, instruments processed with detergents
`must be rinsed with copious amounts of fluid accord-
`ing to the manufacturer’s directions for use. Recom-
`mended volumes should be considered a minimum
`volume, and the final rinse should be performed
`with sterile distilled or sterile deionized water.1
`Sixty-three percent of reporting facilities used an
`ultrasonic bath as part of the processing of their
`ophthalmologic instruments. This has been associated
`with the accumulation of heat-stable endotoxins
`produced by bacteria in the bath water.13 Endotoxin
`remaining on instruments after cleaning and steriliza-
`tion can induce the inflammatory reaction of TASS.
`As with enzymatic detergents, the purpose of the
`ultrasonic bath is to dislodge dried debris from instru-
`ments, particularly OVDs. Again, if instruments are
`kept moist after use and then properly flushed with
`an adequate volume of water, there should be no
`adherent debris and thus no need for an ultrasonic
`bath.
`If an ultrasonic bath is used, the manufacturer’s
`directions for use for instruments should be verified
`because some instruments should not be processed
`in this manner. In addition, the ultrasonic bath should
`be designated for medical use only and the manufac-
`turer’s directions for maintenance should be strictly
`followed. Furthermore, all gross material should be
`
`completely removed from instruments before they
`are immersed in bath water. Then, after each use,
`and if in accordance with the manufacturer’s direc-
`tions for use, the bath water should be emptied and
`the tub cleaned with an Environmental Protection
`Agency–registered facility-approved disinfectant.
`This should be followed with a rinse using volumes
`of sterile or tap water adequate to remove the cleaning
`agent completely. Then, 70% to 90% ethyl or isopropyl
`alcohol should be used to clean the tub if this is in
`accordance with the manufacturer’s directions for
`use and not associated with a risk of fire. Endotoxin
`can be removed from the walls of the bath by wiping
`the walls with ethyl or isopropyl alcohol.1,14 The tub
`should then be dried completely with a lint-free cloth
`and refilled immediately before use.
`This process of cleaning must be followed after each
`use to prevent endotoxin buildup. However, only 19%
`of centers responding to the questionnaire cleaned the
`ultrasonic bath after each use as recommended and 4%
`of centers visited had no protocol for routine cleaning
`of the ultrasonic bath.
`Of centers reporting via questionnaire, 25% added
`antibiotic agents to the balanced salt solution irrigant
`and 21% used intracameral antibiotic agents. The use
`of antibiotic agents may be associated with toxicity
`when they are included in anterior chamber irrigant
`and when injected intracamerally at
`the end of
`a case.7 If antibiotic agents are improperly mixed, the
`concentration may be too high or the pH incorrect,
`both of which can prove toxic to the anterior chamber
`tissues.
`The use of vancomycin and gentamicin sulfate in
`anterior segment surgery has been described for
`prophylaxis against endophthalmitis.15 However, the
`use of these products is associated with concerns
`over vancomycin-resistant organisms as well as
`aminoglycoside-related macular toxicity, respectively.
`Furthermore,
`the concentration used in irrigating
`solution and the time of contact with a possible
`contaminant is inadequate for their bacteriostatic or
`bacteriocidal properties to function.
`Studies to evaluate intraocular cefotaxime for endo-
`thelial toxicity have been performed. A prospective
`randomized masked study of 66 patients by
`Kramann16 found no toxicity with 0.4 mL of 0.25%
`cefotaxime in the anterior chamber. Other studies
`evaluating the use of cefuroxime17,18 found no toxicity
`and a role for the agent in endophthalmitis prevention.
`These findings were strengthened with the results in
`a prospective randomized partially masked study in
`which 1.0 mg cefuroxime in 0.1 mL normal saline
`injected into the anterior chamber after surgery de-
`creased the risk for endophthalmitis (0.05% incidence
`rate when counting all
`endophthalmitis
`cases)
`
`J CATARACT REFRACT SURG VOL 36, JULY 2010
`
`Novartis Exhibit 2299.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1078
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`COMMON CAUSES OF TASS
`
`compared with a placebo or perioperative treatment
`with a third-generation fluoroquinolone drop.19 How-
`ever, an endophthalmitis incidence of 0.056% was
`found with the perioperative use of a fourth-
`generation fluoroquinolone drop.20
`At this time, because there are effective alternatives
`and because there is a risk for TASS from toxicity due
`to the wrong concentration or pH of an improperly
`mixed antibiotic agent, use of intracameral antibiotic
`agents must be viewed with caution.7
`Of surgical centers visited, 52% were using preserved
`epinephrine in balanced salt solution and 37% were
`using other preserved medications intracamerally. In
`addition, at least 36% of questionnaire respondents
`were adding preserved epinephrine to balanced salt so-
`lution. Although bisulfites are not technically a preser-
`vative but rather an antioxidant, they can also cause
`ocular toxicity. Benzalkonium chloride (BAC), a com-
`monly used preservative, is highly toxic to ocular tis-
`sues,21 and rabbit studies22 show a dose-response
`pattern of conjunctivitis,
`flare,
`iritis, and corneal
`changes. In the rabbit study, a safety factor of 10 was
`used to set the safest intraocular concentration at
`0.001%, a level at which the preservative efficacy is
`questionable.
`An outbreak of TASS was associated with the use of
`Eye Stream rinse solution (Alcon Laboratories) pre-
`served with 0.01% BAC, in which a concentration of
`0.013% was inadvertently irrigated into the anterior
`chamber.23 Toxic anterior segment syndrome has
`also been reported after use of OVD preserved with
`BAC,24 and the use of lidocaine gel preserved with
`BAC was recently implicated in a TASS outbreak
`(unpublished data). We recommend that no products
`with preservatives or additives (stabilizers), such as
`bisulfites and metabisulfites, be used in the anterior
`chamber.7,11
`Twenty percent of sites visited were using intraocular
`ointment after clear corneal cases. This practice was
`associated with a TASS outbreak in 8 cases. Of the
`patients affected, 4 required penetrating keratoplasty
`and glaucoma with no light perception developed in
`1 patient. Examination of each of these patients showed
`that petroleum-based ophthalmic ointments had
`gained access to the anterior chamber through a clear
`corneal wound that was patched postoperatively.25
`Site visits showed that 69% of centers were using
`reusable cannulas. Cleaning cannulas is difficult to
`perform and validate, and there are no manufacturer’s
`directions for use. Furthermore, if the cannulas are
`processed with enzymatic detergents, residue will
`likely build up and then be irrigated into the anterior
`chamber. Therefore, when possible, disposable cannu-
`las should be used.7,11 In addition, it is important that
`single-use devices, such as cannulas, blades, tips, and
`
`sleeves, not be reused. Fifty-two percent of centers vis-
`ited were reusing these items. The reprocessing of
`these items is regulated and enforced by the U.S.
`Food and Drug Administration.B
`Poor autoclave maintenance, including autoclave
`residue, instrument milk, rust, particulates, and lint
`within the autoclave, was documented at 28% of cen-
`ters visited. Any such contaminants would be suspect
`for causing TASS. One documented example of poor
`maintenance leading to heavy-metal contamination
`of instruments showed carryover of sulfate, silica,
`copper, zinc, and nickel from feedwater into steam
`condensates associated with TASS outbreaks.26 This
`was found to be the result of changing from flushing
`and draining the steam generator once a week to
`once every 4 to 8 weeks when maintenance was
`outsourced.
`Surgical centers should make sure that preventive
`maintenance, cleaning, and inspection of autoclaves
`are performed as directed by the manufacturer’s direc-
`tions for use and also be documented. In addition, it
`should be verified that the sterilizer is functioning
`properly on a daily basis where possible, or at least
`weekly. Steam sterilization should be performed in
`accordance with published guidelines, and instru-
`ments should be sterilized according to directions for
`use provided by their manufacturer as well as the
`sterilizer’s manufacturer. A terminal sterilization
`should be performed at the end of each surgical
`day.3,5 Glutaraldehyde should not be used in the
`sterilization process because it is highly toxic to the
`tissues of the anterior chamber and will cause TASS
`if inadequately rinsed.27 Plasma gas sterilization has
`also been shown to lead to degradation of brass to
`copper and zinc on cannulated surgical instruments
`and should not be used because this has led to heavy
`metal–induced TASS.28
`The use of powdered gloves can also be a source of
`TASS because the powder can be toxic to the anterior
`chamber structures. Of sites visited, 28 were using
`powdered gloves during anterior chamber cases.
`Powder-free gloves can also pose a risk for develop-
`ing TASS. These gloves are made with a releasing com-
`pound that allows the glove to be easily removed from
`the mold after production. The releasing compound
`stays on the surface of the gloves and can cause ante-
`rior chamber toxicity if it comes in contact with IOLs
`or any instrument entering the anterior chamber.C
`This can occur if the IOL or other instruments entering
`the anterior chamber are touched during cataract
`surgery, a practice observed at 18 surgical centers
`visited (33%).
`Of questionnaire respondents, at least 13% indicated
`that ophthalmic instruments were processed for clean-
`ing alongside dirty surgical
`trays
`from other,
`
`J CATARACT REFRACT SURG VOL 36, JULY 2010
`
`Novartis Exhibit 2299.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`COMMON CAUSES OF TASS
`
`1079
`
`nonophthalmic surgeries. However, ASCRS experts
`recommend that all ophthalmic instruments be kept
`separate from other types of surgical
`instruments
`during all steps of processing to avoid contamination
`with bioburden or cleaning chemicals.1
`In conclusion, analysis of data reported in question-
`naires as well as in site visits from centers reporting
`TASS were analyzed carefully. The most common fac-
`tors associated with TASS were inadequate cleaning
`and flushing of ophthalmic instruments and handpie-
`ces. This included the use of detergents and ultra-
`sound water baths. In addition, the use of intraocular
`medications with preservatives or additives was
`associated with TASS in a significant number of cases.
`The proper cleaning and sterilization of ophthalmic in-
`struments, as well as proper attention regarding the
`use of any intraocular medications during surgery,
`can help prevent the occurrence TASS. These findings
`continue to validate the need to follow the recom-
`mendations detailed in the recommended practices
`document created by the TASS Task Force.1
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