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Toxic anterior segment syndrome
J CATARACT REFRACT SURG - VOL 32, FEBRUARY 2006
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Toxic anterior segment syndrome Nick Mamalis, MD, Henry F. Edelhauser, PhD, Daniel G. Dawson, MD, Jesse Chew, MD, Russell M. LeBoyer, MD, Liliana Werner, MD, PhD
Toxic anterior segment syndrome (TASS) is a sterile postoperative inflammatory reaction caused by a noninfectious substance that enters the anterior segment, resulting in toxic damage to intraocular tissues. The process typically starts 12 to 48 hours after cataract/anterior segment surgery, is limited to the anterior segment of the eye, is always Gram stain and culture negative, and usually improves with steroid treatment. The primary differential diagnosis is infectious endophthalmitis. Review of the literature indicates that possible causes of TASS include intraocular solutions with inappropriate chemical composition, concentration, pH, or osmolality; preservatives; denatured ophthalmic viscosurgical devices; enzymatic detergents; bacterial endotoxin; oxidized metal deposits and residues; and factors related to intraocular lenses such as residues from polishing or sterilizing compounds. An outbreak of TASS is an environmental and toxic control issue that requires complete analysis of all medications and fluids used during surgery, as well as complete review of operating room and sterilization protocols. J Cataract Refract Surg 2006; 32:324–333 Q 2006 ASCRS and ESCRS
Cataract surgery with intraocular lens (IOL) implantation has evolved into a highly successful surgery. It typically results in slight transient postoperative inflammation due to minor surgical trauma. Anterior segment inflammation following cataract surgery may be due to surgical trauma, retained lens material, bacteria, sterile toxic substances, or other uncommon factors such as previous uveitis. Since 1980, there have been several reports of a severe form of anterior segment inflammation after cataract surgery that resulted in hypopyon formation and varying degrees of anterior segment damage from toxic substances.1–12 This was initially referred to as sterile postoperative
Accepted for publication December 29, 2005. From John A. Moran Eye Center, Department of Ophthalmology, University of Utah School of Medicine, Salt Lake City, Utah (Mamalis, Chew, LeBoyer, Werner), Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia (Edelhauser, Dawson), USA. Presented in part at the annual meeting of the American Academy of Ophthalmology, New Orleans, Lousiana, USA, October 2004. Supported in part by NIH grants EY-00933 and T32-EY07092 and an unrestricted departmental grant from Research to Prevent Blindness. Reprint requests to Nick Mamalis, MD, John A. Moran Eye Center, University of Utah, 50 North Medical Drive, Salt Lake City, Utah, 84132, USA. E-mail: [email protected]. Q 2006 ASCRS and ESCRS Published by Elsevier Inc.
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endophthalmitis, which is a misnomer since the inflammation primarily involves only the anterior segment of the eye (Figure 1). In 1992, Monson et al.6 accurately termed this condition toxic anterior segment syndrome (TASS). It is noteworthy that some cases of TASSdthose with localized corneal endothelial damagedhave been termed toxic endothelial cell destruction syndrome (TECDS).13–17
CLINICAL FINDINGS OF TASS
Toxic anterior segment syndrome most commonly occurs acutely following anterior segment surgery of any kind, but it can have a delayed onset. The postoperative inflammation is sterile (Gram stain and culture negative) and is due to a noninfectious substance that accidentally enters the anterior segment, eliciting toxic cellular and extracellular damage to intraocular tissues. Toxic anterior segment syndrome has a constellation of signs and symptoms similar to those of infectious bacterial endophthalmitis. Among the common complaints are blurry vision, ocular pain, and eye redness following cataract surgery. The typical hallmark of TASS is an inflammatory process that starts within 24 hours of cataract surgery, is limited to the anterior segment of the eye, is always Gram stain and culture negative, and improves with steroid treatment. The anterior segment inflammation is typically quite severe, usually resulting in hypopyon formation 0886-3350/06/$-see front matter doi:10.1016/j.jcrs.2006.01.065
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Figure 1. Diagram illustrating how cases of TASS usually affect only the anterior segment of the eye (yellow). Cases of toxic endophthalmitis may occur, which would affect both the anterior segment (yellow) and vitreous cavity (light blue), but this is rare relative to the total number of TASS cases. In contrast, bacterial endophthalmitis usually manifests in the entire ocular cavity and is often most severe in the vitreous cavity.
(Figure 2, A). Another common sign of TASS is diffuse, limbus-to-limbus corneal edema (Figure 2, B). This latter finding is apparently due to widespread endothelial cell damage. In severe cases of TASS, fibrin formation may also be noted in the anterior chamber and/or on the surface of the iris and IOL. The syndrome can result in permanent iris damage, which may cause a dilated, irregular pupil that constricts and dilates poorly (Figure 2, C), and/or trabecular meshwork damage. Although TASS patients frequently have decreased intraocular pressure (IOP) during the early postoperative course, permanent trabecular meshwork damage may eventually lead to ocular hypertension or secondary glaucoma (G.K. Kopecky, MD, J.E. Hill, MD, ‘‘TASS Symposium: What You Don’t Know Could Be Toxic,’’ presented at the annual meeting of the American Academy of Ophthalmology, New Orleans, Louisiana, USA, October 2004). It is difficult to differentiate TASS from infectious bacterial endophthalmitis. Although there are several helpful differentiating symptoms or signs of TASSdit typically occurs within 24 hours compared with 4 to 7 days for infectious bacterial endophthalmitis; it is almost always limited to the anterior segment; it improves with topical
Figure 2. Slitlamp photographs showing some characteristic clinical findings of TASS. A: Hypopyon formation. B: Diffuse limbus-to-limbus corneal edema. C: Dilated and slightly irregular pupil.
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and/or oral steroids and commonly presents with diffuse corneal edemadnone is specific enough to definitively diagnose TASS or completely rule out an infectious etiology. Vitreous involvement is usually prominent in cases of endophthalmitis. Pain is noted in 75% of endophthalmitis patients, and other signs of infection such as lid swelling and conjunctival chemosis and discharge as well as diffuse ocular injection are often present (Figure 3). Severe anterior segment inflammation with hypopyon or fibrin formation is commonly observed in TASS and endophthalmitis and initially does not help differentiate the 2 conditions. Added to this problem is that a certain percentage of patients with infectious bacterial endophthalmitis have biopsy samples (ie, vitreous or anterior chamber taps) that are Gram stain and culture negative.9,10 ETIOLOGY OF TASS
Although rare, TASS is a growing problem for intraocular surgeons, especially because it often represents an endemic outbreak of cases at a specific surgical center. Since the causes of TASS are numerous and varied (Figure 4), it can be difficult for the surgeon and faculty at a surgical center to isolate a cause directly. Any medication injected around the eye, such as subconjunctival or sub-Tenon’s injections, or placed topically in the eye at the conclusion of surgery or in the immediate postoperative period may be implicated in causing or worsening this condition. The histopathologic hallmark of TASS is toxic anterior segment damagedcellular necrosis and/or apoptosis and extracellular damage resulting in a severe acute inflammatory immune response. Since the corneal endothelium is the most sensitive anterior segment tissue to toxic agents, the cornea is usually the structure most severely affected
by TASS. It can result from simple overlooked problems such as intraocular irrigating solutions in which the chemical composition, pH, or osmolality is incompatible with tissue preservation.18–22 Additionally, toxic contaminating residues composed of denatured ophthalmic viscosurgical devices (OVDs),5 detergents,4,23,24 bacterial endotoxin,25 or other impurities may be injected into the eye, resulting in corneal endothelial cell damage. These latter causes are a particular problem with reusable intraocular instruments (eg, cannulas). Toxicity to the corneal endothelium has been directly linked to many different ocular medications and can be due to the chemical composition, the concentration, the pH, or the osmolality of the medication or vehicle or whether preservatives or additives are mixed in the medication.22,26,27 Edelhauser et al.13–15,19–22,24 have performed much of the pioneering work on the effect of intraocular irrigating solutions, instrument-related contaminants, and intraocular medications on the corneal endothelium. The common finding in all the studies is that the mechanism of corneal edema is related initially to acute breakdown of endothelial junctions and acute loss of the barrier function. Over the long-term, if the remaining viable corneal endothelial cells cannot adequately cover the damaged area(s) by migration, thinning, and spreading to cover a larger surface area, permanent edema results. Preservatives
The corneal endothelium is exquisitely sensitive to preservatives commonly used in topical ocular medications. It is important that any medication injected into the eye be preservative free. There are several reports of medications with preservatives inadvertently injected into
Irrigating solutions or ophthalmic viscosurgical devices •Incomplete chemical composition •Incorrect pH (<6.5 or >8.5) •Incorrect osmolality (<200 mOsm or >400 mOsm) •Preservatives or additives (eg, antibiotics, dilating medications) Ophthalmic instrument contaminants •Detergent residues (ultrasonic, soaps, enzymatic cleaners) •Bacterial lipopolysaccharides or other endotoxin residues •Metal ion residues (copper and iron) •Denatured OVDs Ocular medications •Incorrect drug concentration •Incorrect pH (<6.5 or >8.5) •Incorrect osmolality (<200 mOsm or >400 mOsm) •Vehicle with wrong pH or osmolality •Preservatives in medication solution Intraocular lenses •Polishing compounds •Cleaning and sterilizing compounds
Figure 3. Slitlamp photograph of a case of bacterial endophthalmitis. Prominent hypopyon formation and diffuse ocular injection can be observed. This case had significant vitreous involvement.
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Figure 4. Known causes of TASS.
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the eye during anterior segment surgery. Liu et al.16 describe several cases of TASS from inadvertent intraocular use of Eye Stream (Alcon Laboratories), an eye rinse for external use only that is preserved with benzalkonium chloride (BAK) 0.01%. All patients who were evaluated postoperatively showed generalized corneal edema with normal IOP. Only 1 of the 19 patients reported transient pain. Most eyes ended up with a final visual acuity of counting fingers secondary to persistent corneal edema. Other than corneal transplantation, no treatment was beneficial in these latter patients. Eleftheriadis et al.17 report a series of similar cases in post-cataract-surgery patients. They found significant corneal edema and endothelial damage resulting from an OVD containing BAK. If used chronically and on a frequent basis, normal concentrations of BAK in topical ocular medications (0.005% to 0.01%) have been found to damage and irritate the conjunctiva and cornea mildly; topical application of BAK 2% (200- to 400-fold higher than the normal topical concentration) has been shown to cause necrosis of the conjunctiva and cornea.17 Endothelial damage from topical ocular medications containing 0.005% to 0.01% BAK is exceedingly uncommon when these medications are used and applied correctly. The threshold for the start of physiologic and ultrastructural alterations to the corneal endothelium with BAK is 0.0001%, and the highest tolerable intraocular concentration of BAK is 0.001%.26,27 However, these latter figures are extrapolated from rabbit studies. Intraocular Anesthetics
Intracameral use of commercially available preparations of preservative-free bupivicaine hydrochloride 0.5% and preservative-free lidocaine hydrochloride 2.0% have caused significant corneal thickening and opacification postoperatively.28 Although they are preservative free, intracameral use of these commercially available anesthetic agents can potentially cause corneal endothelial cell damage.28–30 By comparison, intracameral use of preservativefree lidocaine hydrochloride 1% appears to be safe for routine cataract surgery, provided it is immediately followed by cataract surgery (ie, phacoemulsification) in which most of the lidocaine 1% is washed out of the cornea and iris.31–33 Sterilization/Detergents
Any substance used in cleaning and sterilizing ophthalmic instruments may cause TASS (Figure 5). Various enzymatic and nonenzymatic detergents are used in cleaning reusable ocular instruments between cases (eg, ultrasonic bath and cleaning detergents). The detergents may accumulate as deposits and, eventually, residues on the inner
and outer surfaces of reusable instruments; most commonly, reusable instruments that contain residual OVD material. The enzymes or other active ingredients in the detergents are deactivated only when exposed to temperatures higher than 140 C. Since most autoclaves reach 120 C to 130 C, there is a possibility of accidentally injecting the active detergents into the eye during anterior segment surgery, especially with reusable cannulas and irrigation/aspiration (I/A) tips. The only effective way to remove detergent deposits from reusable instruments immediately after cleaning is by flushing instruments with adequate amounts of sterile deionized water. For example, each port of the I/A tips should be flushed with 120 cc of sterile deionized water. Parikh et al.22,24 report in vitro data showing a doserelated increase in corneal thickness from corneal endothelial damage in rabbits and humans due to enzymatic detergents. They also report increased corneal endothelial permeability and an inflammatory response in rabbits when the enzymatic detergent is injected into the anterior chamber. Some of the earliest reported cases of TASS described as ‘‘sterile hypopyon endophthalmitis’’ were due to toxic detergent residues on reusable ocular instruments from ultrasonic cleaning solutions, heat-stable cleaning detergents, or cleaning or finishing compounds on IOLs.3,34,35 Detergent residues on ophthalmic surgical instruments have been reported to cause more localized anterior segment toxicity; this syndrome has been referred to as TECDS. Breebaart et al.13 describe severe toxic endothelial cell destruction of the cornea following extracapsular cataract surgery from detergent residues found on reusable cannulas. The patients had profound corneal edema within 24 hours of surgery that was traced to the toxic effects of an ultrasonic detergent on the corneal endothelium. In addition to detergent residues, outbreaks of TASS are thought to be related to endotoxin contamination of instruments during sterilization. Water baths, ultrasound baths, and even autoclave reservoirs may harbor gramnegative bacteria, particularly water baths and reservoirs that have not been changed regularly. Although gramnegative bacteria are destroyed during the heat-sterilization process of autoclaving, heat-stable lipopolysaccharide (LPS) endotoxins from the gram-negative bacterial cell wall remain enzymatically active and may remain attached to the instruments as deposits. When dried, the endotoxin deposits become residues that can be removed from the instrument only by rinsing and wiping with alcohol or acetone. Injection of a heat-stable LPS endotoxin into the eye during surgery has caused significant anterior segment inflammation.25 Klebsiella pneumoniae bacteria was cultured from the cleaning water bath and equipment in that outbreak. Recent outbreaks of diffuse lamellar keratitis
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Figure 5. Effects of enzymatic detergents on the corneal endothelium. A: Scanning electron microscopy (SEM) of human corneal endothelium after being perfused with BSS Plus for 3 hours in an artificial anterior chamber (ie, normal control). The SEM shows an undisrupted monolayer of corneal endothelial cells with intact intercellular junctions (original magnification 540). B: Transmission electron microscopy (TEM) of the cornea in (A) shows the healthy endothelial cells in cross-section (original magnification 4350). C: Scanning electron microscopy of corneal endothelium after being perfused with 1.56% enzymatic detergent in BSS Plus solution for 3 hours in an artificial anterior chamber (ie, toxic case). The SEM shows severe loss of the corneal endothelial cell monolayer and intercellular junctions (original magnification 540). D: Transmission electron microscopy of the cornea in (C) shows that the corneal endothelial cells were necrotic, apoptotic, or in a severe degenerative state. Notice the bare areas of exposed Descemet’s membrane (original magnification 4350).
(DLK) in patients who had laser in situ keratomileusis have been traced to LPS endotoxin contamination of microkeratome blades.36 Whitby and Hitchins37 first suggested that heat-stable bacterial endotoxin from contaminated autoclave water reservoirs can deposit on intraocular instruments even during the steam autoclave sterilization process. Another potential cause of TASS secondary to a sterilization procedure involves oxidized metal deposits and residues, which may form on reusable surgical tubing or metal hubs of cannulas when plasma gas sterilization is used.15,38 In patients with acute postoperative inflammation following cataract surgery, a toxic residue composed of trace amounts of copper and zinc ions was found on sterilized surgical instruments. The chrome covering the cannulas may have worn away or the solder joint decomposed, resulting in leaching and oxidization of the underlying
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exposed brass metal, which allowed toxic concentrations of copper and zinc deposits to accumulate. After sterilization, toxic copper and zinc residues formed and remained in the lumen of the cannula until they were flushed into the eye during surgery. Denatured Ophthalmic Viscosurgical Devices
Another potential TASS source related to reusable intraocular instruments is the introduction of retained denatured OVD residues into the anterior segment of the eye. If reusable cannulas and I/A tips are not properly flushed following surgery, residual OVD material may be broken down or altered during sterilization, which could cause toxic inflammation when flushed into the eye. Kim5 has reported the adverse effects in patients who had intraocular inflammation secondary to denatured OVD substances
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being injected into the eye. These cases probably also had detergents trapped in the retained OVD material, so it is unclear whether the OVD residue by itself caused the toxicity. Antibiotic Agents
Toxicity from antibiotic agents most commonly occurs when they are used in irrigating solutions or injected into the anterior segment at the conclusion of surgery to prevent endophthalmitis. The use of gentamicin sulfate and vancomycin in irrigating solutions or direct intracameral injection was initially devised for the prevention of endophthalmitis.39 Concern about the possibility of toxicity from intraocular gentamicin use (gentamicin has been reported to cause macular toxicity, even in a few cases given subconjunctivally40,41) as well as about possible resistance to vancomycin has been expressed. The concerns led to the investigation of other intraocular antibiotic agents for the prophylaxis of endophthalmitis, particularly the cephalosporins (eg, cefazolin, ceftazidime, cefotaxime, or cefuroxime). Two agents, cefotaxime and cefuroxime, have recently been promoted for use intracamerally at the conclusion of cataract surgery. Kramann et al.42 studied the effects of prophylactic intracameral cefotaxime on human corneal endothelium. They found no significant endothelial damage or toxicity 3 months after surgery. A dose of cefotaxime 0.25% solution instilled in the anterior chamber was not toxic. The use of intracameral cefuroxime has gained widespread acceptance for endophthalmitis prophylaxis after cataract surgery in some countries, such as Sweden. Montan et al.43 have published 2 reports showing that a 1.0 mL dose of intracameral cefuroxime apparently had no signs of local toxicity. They also report that cefuroxime had no significant effect on endothelial cell density or anterior segment inflammation measured by laser flare interferometry. The authors of the latter conclude that prophylactic intracameral cefuroxime has a major role in decreasing the rate of postoperative endophthalmitis in Sweden. However, these results are from an uncontrolled retrospective observational study and therefore must be confirmed by further prospective studies. Overall, despite some promising data, prophylactic intracameral antibiotic agents are currently not routinely recommended for endophthalmitis prophylaxis after cataract surgery in most countries, including the U.S., since the risk for toxicity and/or infectious complications is high and they have not been shown to reduce endophthalmitis rates. Water
In 2002, an outbreak of TASS after cataract surgery involved 3 surgeons at 2 affiliated facilities.11 After an initial
investigation, attention turned to the quality of the water and steam provided for sterilization by the autoclave steam generator. Samples of the feed water and autoclave steam condensates were collected and analyzed by spectroscopy, ion chromatography, pH, and conductivity studies. Results showed a carry-over of sulfate, silica, copper, zinc, and nickel in the condensates. Increased sulfate levels on the surface of cataract surgery equipment that were retired during the outbreak were documented by analysis of ultrasonic rinsates. Sulfate was the impurity found in the autoclave steam and was thought to have caused the TASS outbreak. This would explain the relatively benign course of these cases in comparison with the course in other cases, such as those attributed to copper and zinc residues.15,38 In the analysis of the 2002 TASS outbreak caused by sulfate water impurities,11 a review of maintenance records showed that the autoclave steam generator had been supplied with softened city water, which was flushed and drained weekly during its first 5 years of use. In 2000, the frequency of flushing and draining was decreased to once every 4 to 8 weeks; this might have promoted the accumulation and carry-over of impurities in feed water. No TASS cases were observed after the steam generator was replaced and a system to supply the new generator with deionized, ultrafiltered water was installed. DELAYED-ONSET POSTOPERATIVE STERILE ENDOPHTHALMITIS
While most reported TASS cases are acute, there have been several instances of delayed-onset TASS following cataract surgery. Intraocular Lens-Induced Inflammation
Jehan et al.8 report 10 cases of a delayed-onset acute IOL inflammation following cataract surgery. In all patients, a hydrophilic acrylic IOL (MemoryLens) was implanted. The onset of the inflammation occurred 1 to 21 days postoperatively. All the anterior chamber taps were Gram stain and culture negative. The patients improved with intense topical antiinflammatory medication. It was theorized that a residual polishing compound on the MemoryLens was responsible for the postoperative inflammation. One of the first terms used to describe patients with TASS was sterile hypopyon or sterile endophthalmitis. This was initially described by Meltzer1 in 1980. It is theoretically possible that the IOL was the source of inflammation and material or substance in the packaging or solution coating the lens was retained and led to a toxic inflammation. The IOL finish and design as well as chemicals used in polishing, cleaning, and sterilizing the lens have been implicated as causes of this type of inflammation.
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Ophthalmic Ointments
Another potential source of delayed-onset TASS is the ingress of ophthalmic ointment used postoperatively in the anterior segment of the eye. An outbreak of delayedonset TASS was recently described by Werner et al.12 In that study, an oily material coating the anterior surface of the IOL or forming small globules within the anterior chamber was found in a group of delayed-onset TASS patients from Canada (Figure 6, A). Several patients had significant corneal edema, and 2 had penetrating keratoplasty. Evaluation of the corneas revealed severe destruction of corneal endothelial cells (Figure 6, B). Analysis of some explanted IOLs showed a significant residue of hydrocarbons on the IOL surfaces (Figure 6, C). The composition of these hydrocarbons exactly matched the vehicle within the postoperative ointment that was placed in the eye. It is hypothesized that the use of a clear corneal wound and postoperative topical ointment containing petroleum as well as tight patching allowed ingress of this material into the anterior segment of the eye, causing delayed-onset TASS. TREATMENT OF TASS
The main treatment for TASS centers on prevention because once the toxic agent enters the eye and causes damage, the clinician can do little other than suppress the secondary inflammatory immune response. Thus, once an infectious etiology has been ruled out, the mainstay of treatment for TASS is intense topical corticosteroid drops. The patient should be started on a regimen of prednisolone acetate 1% drops every 1 to 2 hours and carefully followed, especially during the first days of topical corticosteroid use, to ensure that the inflammatory condition is not worsening and is stabilizing. Careful slitlamp examination allows the surgeon to document resolution of anterior segment inflammation and corneal edema. The IOP should also be closely followed after a toxic sterile insult to the anterior segment of the eye.1,35 As maximum damage to the anterior segment has presumably already occurred, anterior chamber washout is currently not routinely recommended for treatment of TASS. While the IOP may initially be low, recovery of the production of aqueous humor by the ciliary processes can cause a precipitous rise in IOP several days after the initial insult. This IOP change occurs because the toxic agent(s) can injure the trabecular meshwork, causing acute trabeculitis and subsequent chronic long-term damage to the trabecular meshwork. As soon as the cornea clears sufficiently to allow adequate visualization of the anterior chamber angle, the patient should have a gonioscopic evaluation to look for peripheral anterior synechias, which may indicate that
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Figure 6. Toxic anterior segment syndrome secondary to intraocular penetration of ophthalmic ointment. A: Clinical picture taken during the first postoperative week shows a distinct bubble inside the anterior chamber. B: Light photomicrograph of a histologic section obtained from a corneal button shows variable areas of epithelium thinning, thickening of the stroma, with condensation of posterior lamellae, intact Descemet’s membrane, and complete absence of the corneal endothelium (hematoxylin and eosin stain; original magnification 100). C: Explanted silicone lens with an oily material coating large areas of the anterior and posterior optic surfaces.
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chronic long-term trabecular meshwork damage has occurred.1,35 Specular or confocal microscopy of the corneal endothelium is also helpful at this point to assess the degree of endothelial cell damage. CLINICAL COURSE
The clinical outcome of individual patients with TASS depends on many factors such as the type and amount of substance introduced into the eye, the duration of exposure to the substance, and when treatment occurred in the course of the injury. Patients with relatively mild cases show rapid clearing of the inflammation, with slightly less rapid clearing of the cornea (days to weeks). Patients who have moderate TASS have a more prolonged clearing (weeks to months), with possibly slight residual corneal edema and/or increased IOP. Patients who have severe TASS generally have permanent damage to the eye such as persistent, nonclearing corneal edema that requires corneal transplantation, significant trabecular meshwork damage that leads to uncontrolled IOP, chronic anterior segment inflammation that may cause transient or permanent cystoid macular edema, or significant iris damage that may lead to a permanently fixed, dilated pupil. Patients with severe trabecular meshwork damage sometimes develop glaucoma that is relatively resistant to medical treatment alone. These cases usually require surgical treatment such as trabeculectomy or placement of a tube shunt device.1,35 ANALYSIS: TOXIC ANTERIOR SEGMENT SYNDROME
As the mainstay of treatment for TASS centers on prevention, it is critically important that the entire surgical team (surgical nurses, operating room technicians, residents, physicians, and pharmacists) knows what is appropriate for use in the eye. This is especially true for anyone involved in cleaning and sterilizing ophthalmic instruments. Those involved in ordering ocular medications to be used in anterior segment surgery or preparing these medications should also be involved. A basic step is to ensure that everyone involved in cleaning and sterilizing reusable intraocular instruments is thoroughly instructed in the protocols to properly clean and sterilize the instruments (ie, preventing the possibility of toxic residues from accumulating on the reusable instruments). Furthermore, reusable instrument use should be kept to a minimum, particularly those that are high risk for contamination (eg, cannulas or damaged instruments). The reusable instruments that cannot be switched or are chosen not to be switched to disposable types, eg, I/A tips and phacoemulsification handpieces, should be thoroughly rinsed at the conclusion of each cleaning step with sterile, deionized water. It is
especially important to rinse the phacoemulsification handpiece and I/A tips through both inflow and aspiration ports. Ultrasound water baths should be replaced daily since the dirty bath water often grows gram-negative bacteria such as Klebsiella or Pseudomonas species, which could lead to a buildup of heat-stable LPS endotoxins. The use of a steam autoclave sterilizer requires that the water reservoir be changed at least weekly to prevent the buildup of gram-negative bacteria and potentially toxic LPS endotoxins. The surgical center staff should remain vigilant when ordering any agentdirrigating solutions, OVDs, or other medicationsdthat will be used in the eye during anterior segment surgery. This includes the ordering of complete intraocular irrigating solutions such as balanced salt solution (BSS) or BSS Plus, as well as intraocular medications of any kind. The surgical staff should also be up to date on the newest, most complete irrigants that would have a limited shelf life if it were not that they come as a 2-component solution, which means the 2 components must be reconstituted before intraocular use. For example, AMO Endosol Extra is the newest ‘‘complete’’ ocular irrigant to come on the market and should be bioequivalent to BSS Plus. A major issue with Endosol Extra is that the large part-1 component, 500 mL, has a pH of 3.5. If the part-2 component is not added with part 1, severe damage to the intraocular tissue will occur. Care should also be taken to check that the intraocular medications used during anterior segment surgery are preservative-free and at the proper intraocular drug concentration. This is especially important for epinephrine, which is added to irrigating solutions, or for intracameral anesthetics or antibiotics, which are injected directly into the eye. In addition, the surgical staff should be attuned to the proper concentrations of medications and the proper pH and osmolality of vehicles needed during intraocular surgery. For example, intracameral lidocaine used to help anesthetize the eye should be methylparaben-free; intracameral lidocaine, indocyanine green, trypan blue, acetylcholine chloride (Miochol), and carbachol (Miostat) should be mixed with BSS and not sterile water (L.J. Ronge, ‘‘Toxic Anterior Segment Syndrome: Why Sterile Isn’t Clean Enough,’’ Eyenet 2002, November/December, pages 17–18).44–46 An outbreak of TASS in a surgical center is an environmental and toxin control issue that requires complete analysis of all medications and fluids used during the surgery. It is the surgeon’s responsibility to let the surgical team and center know that a case occurred since they are usually the first to recognize a case. Appointing a staff member to coordinate the clinical review and establishing flow charts to track changes or factors potentially responsible for the case or outbreak is typically helpful. It is critically
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important to prove that the medications used during surgery were the intended medications ordered for use by the surgeon. A complete review of operating room protocols should be undertaken by the surgeon as well as representatives from the surgical center and all involved nursing staff and personnel. Protocols used in the sterilization and preparation of instruments from surgery should be carefully evaluated to rule out the potential sources of TASS. The American Society of Cataract and Refractive Surgery has established a center at the University of Utah to evaluate unexplained cases of postoperative inflammation or endophthalmitis. This center has developed protocols to be used in the evaluation of patients with TASS. Ophthalmic research fellows are available to provide analyses of outbreaks of TASS, with subsequent recommendations on ways to prevent future occurrences. Contact information: Nick Mamalis, MD, Director, Intermountain Ocular Research Center, John A. Moran Eye Center, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, Utah 84132, USA; phone (801) 581-6586; e-mail: [email protected]. Edelhauser has also formed a response team at Emory University Eye Center, which has the Centers for Disease Control and Prevention adjacent to its medical campus for assistance in evaluating and preventing further cases or outbreaks or for the investigation and analysis of TASS. Contact information: Henry F. Edelhauser, PhD, Emory Eye Center, Emory University, 1365B Clifton Road NE, Atlanta, Georgia 30322, USA; phone (404) 778-5853; e-mail: [email protected]. Both centers are available as a resource to physicians and surgical centers to aid in the investigation of outbreaks of TASS to help find the etiology of these cases and eliminate potential sources of postoperative inflammation. REFERENCES 1. Meltzer DW. Sterile hypopyon following intraocular lens surgery. Arch Ophthalmol 1980; 98:100–104 2. Apple DJ, Mamalis N, Steinmetz RL, et al. Phacoanaphylactic endophthalmitis associated with extracapsular cataract extraction and posterior chamber intraocular lens. Arch Ophthalmol 1984; 102:1528–1532 3. Abrahams IW. Diagnosis and surgical management of phacoanaphylactic uveitis following extracapsular cataract extraction with intraocular lens implantation. Am Intra-Ocular Implant Soc J 1985; 11: 444–447 4. Richburg FA, Reidy JJ, Apple DJ, Olson RJ. Sterile hypopyon secondary to ultrasonic cleaning solution. J Cataract Refract Surg 1986; 12: 248–251 5. Kim JH. Intraocular inflammation of denatured viscoelastic substance in cases of cataract extraction and lens implantation. J Cataract Refract Surg 1987; 13:537–542 6. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18: 184–189 7. Nelson DB, Donnenfeld ED, Perry HD. Sterile endophthalmitis after sutureless cataract surgery. Ophthalmology 1992; 99:1655–1657
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8. Jehan FS, Mamalis N, Spencer TS, et al. Postoperative sterile endophthalmitis (TASS) associated with the MemoryLens. J Cataract Refract Surg 2000; 26:1773–1777 9. West ES, Behrens A, McDonnell PJ, et al. The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology 2005; 112:1388– 1394 10. Wallin T, Parker J, Jin Y, et al. Cohort study of 27 cases of endophthalmitis at a single institution. J Cataract Refract Surg 2005; 31:735–741 11. Hellinger WC, Hasan SA, Bacalis LP, et al. Outbreak of toxic anterior segment syndrome following cataract surgery associated with impurities of autoclave steam moisture. Infect Control Hosp Epidemiol 2006, in press 12. Werner L, Sher JH, Taylor JR, et al. Toxic anterior segment syndrome and possible association with ointment in the anterior chamber following cataract surgery. J Cataract Refract Surg 2006; 32:227–235 13. Breebaart AC, Nuyts RMMA, Pels E, et al. Toxic endothelial cell destruction of the cornea after routine extracapsular cataract surgery. Arch Ophthalmol 1990; 108:1121–1125 14. Grimmett MR, Williams KK, Broocker G, Edelhauser HF. Corneal edema after miochol. Am J Ophthalmol 1993; 116:236–238 15. Duffy RE, Brown SE, Caldwell KL, et al. An epidemic of corneal destruction caused by plasma gas sterilization; the Toxic Endothelial Cell Destruction Syndrome Investigative Team. Arch Ophthalmol 2000; 118:1167–1176 16. Liu H, Routley I, Teichmann KD. Toxic endothelial cell destruction from intraocular benzalkonium chloride. J Cataract Refract Surg 2001; 27:1746–1750 17. Eleftheriadis H, Cheong M, Sandeman S, et al. Corneal toxicity secondary to inadvertent use of benzalkonium chloride preserved viscoelastic material in cataract surgery. Br J Ophthalmol 2002; 86:299–305 18. Swan KC. Reactivity of the ocular tissues to wetting agents. Am J Ophthalmol 1944; 27:1118–1122 19. Edelhauser HF, Van Horn DL, Schultz RO, Hyndiuk RA. Comparative toxicity of intraocular irrigating solutions on corneal endothelium. Am J Ophthalmol 1976; 81:473–481 20. Gonnering R, Edelhauser HF, Van Horn DL, Durant W. The pH tolerance of rabbit and human corneal endothelium. Invest Ophthalmol Vis Sci 1979; 18:373–390 21. Edelhauser HF, Hanneken AM, Pederson HJ, Van Horn DL. Osmotic tolerance of rabbit and human corneal endothelium. Arch Ophthalmol 1981; 99:1281–1287 22. Parikh CH, Edelhauser HF. Ocular surgical pharmacology: corneal endothelial safety and toxicity. Curr Opin Ophthalmol 2003; 14:178–185 23. Carter LM, Duncan G, Rennie GK. Effects of detergents on the ionic balance and permeability of isolated bovine cornea. Exp Eye Res 1973; 17:409–416 24. Parikh C, Sippy BD, Martin DF, Edelhauser HF. Effects of enzymatic sterilization detergents on the corneal endothelium. Arch Ophthalmol 2002; 120:165–172 25. Kreisler KR, Martin SS, Young CW, et al. Postoperative inflammation following cataract extraction caused by bacterial contamination of the cleaning bath detergent. J Cataract Refract Surg 1992; 18:106–110 26. Britton B, Hervey R, Kasten K, et al. Intraocular irritation evaluation of benzalkonium chloride in rabbits. Ophthalmic Surg 1976; 7(3): 46–55 27. Green K, Hull DS, Vaughn ED, et al. Rabbit endothelial response to ophthalmic preservatives. Arch Ophthalmol 1977; 95:2218–2221 28. Kadonosono K, Ito N, Yazama F, et al. Effect of intracameral anesthesia on the corneal endothelium. J Cataract Refract Surg 1998; 24:1377– 1381 29. Anderson NJ, Nath R, Anderson CJ, Edelhauser HF. Comparison of preservative-free bupivacaine vs lidocaine for intracameral anesthe-
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30.
31. 32.
33.
34.
35.
36.
37.
sia: a randomized clinical trial and in vitro analysis. Am J Ophthalmol 1999; 127:393–402 Guzey M, Satici A, Dogan Z, Karadede S. The effects of bupivacaine and lidocaine on the corneal endothelium when applied into the anterior chamber at the concentrations supplied commercially. Ophthalmologica 2002; 216:113–117 Kim T, Holley GP, Lee JH, et al. The effects of intraocular lidocaine on the corneal endothelium. Ophthalmology 1998; 105:125–130 Anderson NJ, Woods WD, Kim T, et al. Intracameral anesthesia; in vitro iris and corneal uptake and washout of 1% lidocaine hydrochloride. Arch Ophthalmol 1999; 117:225–232 Heuermann T, Hartman C, Anders N. Long-term endothelial cell loss after phacoemulsification; peribulbar anesthesia versus intracameral lidocaine 1%; prospective, randomized clinical trial. J Cataract Refract Surg 2002; 28:639–643 Nuyts RMMA, Edelhauser HF, Pels E, Breebaart AC. Toxic effects of detergents on the corneal endothelium. Arch Ophthalmol 1990; 108:1158–1162 Worst JGF. A retrospective view on the sterilization of intraocular lenses and incidents of sterile hypopyon. Am Intraocular Implant Soc J 1980; 6:10–12 Holland SP, Mathias RG, Morck DW, et al. Diffuse lamellar keratitis related to endotoxins released from sterilizer reservoir biofilms. Ophthalmology 2000; 107:1227–1233; discussion by EJ Holland, 1233–1234 Whitby JL, Hitchins VM. Endotoxin levels in steam and reservoirs of table-top steam sterilizers. J Cataract Refract Surg 2002; 18:51–57
38. Smith CA, Khoury JM, Shields SM, et al. Unexpected corneal endothelial cell decompensation after intraocular surgery with instruments sterilized by plasma gas. Ophthalmology 2000; 107:1561–1566; discussion by SM MacRae, 1567 39. Gills JP. Filters and antibiotics in irrigating solution for cataract surgery [letter]. J Cataract Refract Surg 1991; 17:385 40. Judson PH. Aminoglycoside macular toxicity after subconjunctival injection. Arch Ophthalmol 1989; 107:1282–1283 41. Campochiaro PA, Conway BP. Aminoglycoside toxicitydA survey of retinal specialists; implications for ocular use. Arch Ophthalmol 1991; 109:946–950 42. Kramann C, Pitz S, Schwenn O, et al. Effects of intraocular cefotaxime on human corneal endothelium. J Cataract Surg 2001; 27:250–255 43. Montan PG, Wejde G, Setterquist H, et al. Prophylactic intracameral cefuroxime: Evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg 2002; 28:977–981 44. Mamalis N. Inflammation. In: Charlton JF, Weinstein GW, eds, Ophthalmic Surgery Complications; Prevention and Management. Philadelphia, JB Lippincott, 1995; 313–332 45. Horiguchi M, Miyaka K, Ohta I, Ito Y. Staining of the lens capsule for circular continuous capsulorhexis in eyes with white cataract. Arch Ophthalmol 1998; 116:535–537 46. Holley GP, Alam A, Kiri A, Edelhauser HF. Effect of indocyanine green intraocular stain on human and rabbit corneal endothelial structure and viability; an in vitro study. J Cataract Refract Surg 2002; 28:1027–1033
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Toxic anterior segment syndrome Nick Mamalis, MD, Henry F. Edelhauser, PhD, Daniel G. Dawson, MD, Jesse Chew, MD, Russell M. LeBoyer, MD, Liliana Werner, MD, PhD
Toxic anterior segment syndrome (TASS) is a sterile postoperative inflammatory reaction caused by a noninfectious substance that enters the anterior segment, resulting in toxic damage to intraocular tissues. The process typically starts 12 to 48 hours after cataract/anterior segment surgery, is limited to the anterior segment of the eye, is always Gram stain and culture negative, and usually improves with steroid treatment. The primary differential diagnosis is infectious endophthalmitis. Review of the literature indicates that possible causes of TASS include intraocular solutions with inappropriate chemical composition, concentration, pH, or osmolality; preservatives; denatured ophthalmic viscosurgical devices; enzymatic detergents; bacterial endotoxin; oxidized metal deposits and residues; and factors related to intraocular lenses such as residues from polishing or sterilizing compounds. An outbreak of TASS is an environmental and toxic control issue that requires complete analysis of all medications and fluids used during surgery, as well as complete review of operating room and sterilization protocols. J Cataract Refract Surg 2006; 32:324–333 Q 2006 ASCRS and ESCRS
Cataract surgery with intraocular lens (IOL) implantation has evolved into a highly successful surgery. It typically results in slight transient postoperative inflammation due to minor surgical trauma. Anterior segment inflammation following cataract surgery may be due to surgical trauma, retained lens material, bacteria, sterile toxic substances, or other uncommon factors such as previous uveitis. Since 1980, there have been several reports of a severe form of anterior segment inflammation after cataract surgery that resulted in hypopyon formation and varying degrees of anterior segment damage from toxic substances.1–12 This was initially referred to as sterile postoperative
Accepted for publication December 29, 2005. From John A. Moran Eye Center, Department of Ophthalmology, University of Utah School of Medicine, Salt Lake City, Utah (Mamalis, Chew, LeBoyer, Werner), Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia (Edelhauser, Dawson), USA. Presented in part at the annual meeting of the American Academy of Ophthalmology, New Orleans, Lousiana, USA, October 2004. Supported in part by NIH grants EY-00933 and T32-EY07092 and an unrestricted departmental grant from Research to Prevent Blindness. Reprint requests to Nick Mamalis, MD, John A. Moran Eye Center, University of Utah, 50 North Medical Drive, Salt Lake City, Utah, 84132, USA. E-mail: [email protected]. Q 2006 ASCRS and ESCRS Published by Elsevier Inc.
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endophthalmitis, which is a misnomer since the inflammation primarily involves only the anterior segment of the eye (Figure 1). In 1992, Monson et al.6 accurately termed this condition toxic anterior segment syndrome (TASS). It is noteworthy that some cases of TASSdthose with localized corneal endothelial damagedhave been termed toxic endothelial cell destruction syndrome (TECDS).13–17
CLINICAL FINDINGS OF TASS
Toxic anterior segment syndrome most commonly occurs acutely following anterior segment surgery of any kind, but it can have a delayed onset. The postoperative inflammation is sterile (Gram stain and culture negative) and is due to a noninfectious substance that accidentally enters the anterior segment, eliciting toxic cellular and extracellular damage to intraocular tissues. Toxic anterior segment syndrome has a constellation of signs and symptoms similar to those of infectious bacterial endophthalmitis. Among the common complaints are blurry vision, ocular pain, and eye redness following cataract surgery. The typical hallmark of TASS is an inflammatory process that starts within 24 hours of cataract surgery, is limited to the anterior segment of the eye, is always Gram stain and culture negative, and improves with steroid treatment. The anterior segment inflammation is typically quite severe, usually resulting in hypopyon formation 0886-3350/06/$-see front matter doi:10.1016/j.jcrs.2006.01.065
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Figure 1. Diagram illustrating how cases of TASS usually affect only the anterior segment of the eye (yellow). Cases of toxic endophthalmitis may occur, which would affect both the anterior segment (yellow) and vitreous cavity (light blue), but this is rare relative to the total number of TASS cases. In contrast, bacterial endophthalmitis usually manifests in the entire ocular cavity and is often most severe in the vitreous cavity.
(Figure 2, A). Another common sign of TASS is diffuse, limbus-to-limbus corneal edema (Figure 2, B). This latter finding is apparently due to widespread endothelial cell damage. In severe cases of TASS, fibrin formation may also be noted in the anterior chamber and/or on the surface of the iris and IOL. The syndrome can result in permanent iris damage, which may cause a dilated, irregular pupil that constricts and dilates poorly (Figure 2, C), and/or trabecular meshwork damage. Although TASS patients frequently have decreased intraocular pressure (IOP) during the early postoperative course, permanent trabecular meshwork damage may eventually lead to ocular hypertension or secondary glaucoma (G.K. Kopecky, MD, J.E. Hill, MD, ‘‘TASS Symposium: What You Don’t Know Could Be Toxic,’’ presented at the annual meeting of the American Academy of Ophthalmology, New Orleans, Louisiana, USA, October 2004). It is difficult to differentiate TASS from infectious bacterial endophthalmitis. Although there are several helpful differentiating symptoms or signs of TASSdit typically occurs within 24 hours compared with 4 to 7 days for infectious bacterial endophthalmitis; it is almost always limited to the anterior segment; it improves with topical
Figure 2. Slitlamp photographs showing some characteristic clinical findings of TASS. A: Hypopyon formation. B: Diffuse limbus-to-limbus corneal edema. C: Dilated and slightly irregular pupil.
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and/or oral steroids and commonly presents with diffuse corneal edemadnone is specific enough to definitively diagnose TASS or completely rule out an infectious etiology. Vitreous involvement is usually prominent in cases of endophthalmitis. Pain is noted in 75% of endophthalmitis patients, and other signs of infection such as lid swelling and conjunctival chemosis and discharge as well as diffuse ocular injection are often present (Figure 3). Severe anterior segment inflammation with hypopyon or fibrin formation is commonly observed in TASS and endophthalmitis and initially does not help differentiate the 2 conditions. Added to this problem is that a certain percentage of patients with infectious bacterial endophthalmitis have biopsy samples (ie, vitreous or anterior chamber taps) that are Gram stain and culture negative.9,10 ETIOLOGY OF TASS
Although rare, TASS is a growing problem for intraocular surgeons, especially because it often represents an endemic outbreak of cases at a specific surgical center. Since the causes of TASS are numerous and varied (Figure 4), it can be difficult for the surgeon and faculty at a surgical center to isolate a cause directly. Any medication injected around the eye, such as subconjunctival or sub-Tenon’s injections, or placed topically in the eye at the conclusion of surgery or in the immediate postoperative period may be implicated in causing or worsening this condition. The histopathologic hallmark of TASS is toxic anterior segment damagedcellular necrosis and/or apoptosis and extracellular damage resulting in a severe acute inflammatory immune response. Since the corneal endothelium is the most sensitive anterior segment tissue to toxic agents, the cornea is usually the structure most severely affected
by TASS. It can result from simple overlooked problems such as intraocular irrigating solutions in which the chemical composition, pH, or osmolality is incompatible with tissue preservation.18–22 Additionally, toxic contaminating residues composed of denatured ophthalmic viscosurgical devices (OVDs),5 detergents,4,23,24 bacterial endotoxin,25 or other impurities may be injected into the eye, resulting in corneal endothelial cell damage. These latter causes are a particular problem with reusable intraocular instruments (eg, cannulas). Toxicity to the corneal endothelium has been directly linked to many different ocular medications and can be due to the chemical composition, the concentration, the pH, or the osmolality of the medication or vehicle or whether preservatives or additives are mixed in the medication.22,26,27 Edelhauser et al.13–15,19–22,24 have performed much of the pioneering work on the effect of intraocular irrigating solutions, instrument-related contaminants, and intraocular medications on the corneal endothelium. The common finding in all the studies is that the mechanism of corneal edema is related initially to acute breakdown of endothelial junctions and acute loss of the barrier function. Over the long-term, if the remaining viable corneal endothelial cells cannot adequately cover the damaged area(s) by migration, thinning, and spreading to cover a larger surface area, permanent edema results. Preservatives
The corneal endothelium is exquisitely sensitive to preservatives commonly used in topical ocular medications. It is important that any medication injected into the eye be preservative free. There are several reports of medications with preservatives inadvertently injected into
Irrigating solutions or ophthalmic viscosurgical devices •Incomplete chemical composition •Incorrect pH (<6.5 or >8.5) •Incorrect osmolality (<200 mOsm or >400 mOsm) •Preservatives or additives (eg, antibiotics, dilating medications) Ophthalmic instrument contaminants •Detergent residues (ultrasonic, soaps, enzymatic cleaners) •Bacterial lipopolysaccharides or other endotoxin residues •Metal ion residues (copper and iron) •Denatured OVDs Ocular medications •Incorrect drug concentration •Incorrect pH (<6.5 or >8.5) •Incorrect osmolality (<200 mOsm or >400 mOsm) •Vehicle with wrong pH or osmolality •Preservatives in medication solution Intraocular lenses •Polishing compounds •Cleaning and sterilizing compounds
Figure 3. Slitlamp photograph of a case of bacterial endophthalmitis. Prominent hypopyon formation and diffuse ocular injection can be observed. This case had significant vitreous involvement.
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Figure 4. Known causes of TASS.
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the eye during anterior segment surgery. Liu et al.16 describe several cases of TASS from inadvertent intraocular use of Eye Stream (Alcon Laboratories), an eye rinse for external use only that is preserved with benzalkonium chloride (BAK) 0.01%. All patients who were evaluated postoperatively showed generalized corneal edema with normal IOP. Only 1 of the 19 patients reported transient pain. Most eyes ended up with a final visual acuity of counting fingers secondary to persistent corneal edema. Other than corneal transplantation, no treatment was beneficial in these latter patients. Eleftheriadis et al.17 report a series of similar cases in post-cataract-surgery patients. They found significant corneal edema and endothelial damage resulting from an OVD containing BAK. If used chronically and on a frequent basis, normal concentrations of BAK in topical ocular medications (0.005% to 0.01%) have been found to damage and irritate the conjunctiva and cornea mildly; topical application of BAK 2% (200- to 400-fold higher than the normal topical concentration) has been shown to cause necrosis of the conjunctiva and cornea.17 Endothelial damage from topical ocular medications containing 0.005% to 0.01% BAK is exceedingly uncommon when these medications are used and applied correctly. The threshold for the start of physiologic and ultrastructural alterations to the corneal endothelium with BAK is 0.0001%, and the highest tolerable intraocular concentration of BAK is 0.001%.26,27 However, these latter figures are extrapolated from rabbit studies. Intraocular Anesthetics
Intracameral use of commercially available preparations of preservative-free bupivicaine hydrochloride 0.5% and preservative-free lidocaine hydrochloride 2.0% have caused significant corneal thickening and opacification postoperatively.28 Although they are preservative free, intracameral use of these commercially available anesthetic agents can potentially cause corneal endothelial cell damage.28–30 By comparison, intracameral use of preservativefree lidocaine hydrochloride 1% appears to be safe for routine cataract surgery, provided it is immediately followed by cataract surgery (ie, phacoemulsification) in which most of the lidocaine 1% is washed out of the cornea and iris.31–33 Sterilization/Detergents
Any substance used in cleaning and sterilizing ophthalmic instruments may cause TASS (Figure 5). Various enzymatic and nonenzymatic detergents are used in cleaning reusable ocular instruments between cases (eg, ultrasonic bath and cleaning detergents). The detergents may accumulate as deposits and, eventually, residues on the inner
and outer surfaces of reusable instruments; most commonly, reusable instruments that contain residual OVD material. The enzymes or other active ingredients in the detergents are deactivated only when exposed to temperatures higher than 140 C. Since most autoclaves reach 120 C to 130 C, there is a possibility of accidentally injecting the active detergents into the eye during anterior segment surgery, especially with reusable cannulas and irrigation/aspiration (I/A) tips. The only effective way to remove detergent deposits from reusable instruments immediately after cleaning is by flushing instruments with adequate amounts of sterile deionized water. For example, each port of the I/A tips should be flushed with 120 cc of sterile deionized water. Parikh et al.22,24 report in vitro data showing a doserelated increase in corneal thickness from corneal endothelial damage in rabbits and humans due to enzymatic detergents. They also report increased corneal endothelial permeability and an inflammatory response in rabbits when the enzymatic detergent is injected into the anterior chamber. Some of the earliest reported cases of TASS described as ‘‘sterile hypopyon endophthalmitis’’ were due to toxic detergent residues on reusable ocular instruments from ultrasonic cleaning solutions, heat-stable cleaning detergents, or cleaning or finishing compounds on IOLs.3,34,35 Detergent residues on ophthalmic surgical instruments have been reported to cause more localized anterior segment toxicity; this syndrome has been referred to as TECDS. Breebaart et al.13 describe severe toxic endothelial cell destruction of the cornea following extracapsular cataract surgery from detergent residues found on reusable cannulas. The patients had profound corneal edema within 24 hours of surgery that was traced to the toxic effects of an ultrasonic detergent on the corneal endothelium. In addition to detergent residues, outbreaks of TASS are thought to be related to endotoxin contamination of instruments during sterilization. Water baths, ultrasound baths, and even autoclave reservoirs may harbor gramnegative bacteria, particularly water baths and reservoirs that have not been changed regularly. Although gramnegative bacteria are destroyed during the heat-sterilization process of autoclaving, heat-stable lipopolysaccharide (LPS) endotoxins from the gram-negative bacterial cell wall remain enzymatically active and may remain attached to the instruments as deposits. When dried, the endotoxin deposits become residues that can be removed from the instrument only by rinsing and wiping with alcohol or acetone. Injection of a heat-stable LPS endotoxin into the eye during surgery has caused significant anterior segment inflammation.25 Klebsiella pneumoniae bacteria was cultured from the cleaning water bath and equipment in that outbreak. Recent outbreaks of diffuse lamellar keratitis
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Figure 5. Effects of enzymatic detergents on the corneal endothelium. A: Scanning electron microscopy (SEM) of human corneal endothelium after being perfused with BSS Plus for 3 hours in an artificial anterior chamber (ie, normal control). The SEM shows an undisrupted monolayer of corneal endothelial cells with intact intercellular junctions (original magnification 540). B: Transmission electron microscopy (TEM) of the cornea in (A) shows the healthy endothelial cells in cross-section (original magnification 4350). C: Scanning electron microscopy of corneal endothelium after being perfused with 1.56% enzymatic detergent in BSS Plus solution for 3 hours in an artificial anterior chamber (ie, toxic case). The SEM shows severe loss of the corneal endothelial cell monolayer and intercellular junctions (original magnification 540). D: Transmission electron microscopy of the cornea in (C) shows that the corneal endothelial cells were necrotic, apoptotic, or in a severe degenerative state. Notice the bare areas of exposed Descemet’s membrane (original magnification 4350).
(DLK) in patients who had laser in situ keratomileusis have been traced to LPS endotoxin contamination of microkeratome blades.36 Whitby and Hitchins37 first suggested that heat-stable bacterial endotoxin from contaminated autoclave water reservoirs can deposit on intraocular instruments even during the steam autoclave sterilization process. Another potential cause of TASS secondary to a sterilization procedure involves oxidized metal deposits and residues, which may form on reusable surgical tubing or metal hubs of cannulas when plasma gas sterilization is used.15,38 In patients with acute postoperative inflammation following cataract surgery, a toxic residue composed of trace amounts of copper and zinc ions was found on sterilized surgical instruments. The chrome covering the cannulas may have worn away or the solder joint decomposed, resulting in leaching and oxidization of the underlying
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exposed brass metal, which allowed toxic concentrations of copper and zinc deposits to accumulate. After sterilization, toxic copper and zinc residues formed and remained in the lumen of the cannula until they were flushed into the eye during surgery. Denatured Ophthalmic Viscosurgical Devices
Another potential TASS source related to reusable intraocular instruments is the introduction of retained denatured OVD residues into the anterior segment of the eye. If reusable cannulas and I/A tips are not properly flushed following surgery, residual OVD material may be broken down or altered during sterilization, which could cause toxic inflammation when flushed into the eye. Kim5 has reported the adverse effects in patients who had intraocular inflammation secondary to denatured OVD substances
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being injected into the eye. These cases probably also had detergents trapped in the retained OVD material, so it is unclear whether the OVD residue by itself caused the toxicity. Antibiotic Agents
Toxicity from antibiotic agents most commonly occurs when they are used in irrigating solutions or injected into the anterior segment at the conclusion of surgery to prevent endophthalmitis. The use of gentamicin sulfate and vancomycin in irrigating solutions or direct intracameral injection was initially devised for the prevention of endophthalmitis.39 Concern about the possibility of toxicity from intraocular gentamicin use (gentamicin has been reported to cause macular toxicity, even in a few cases given subconjunctivally40,41) as well as about possible resistance to vancomycin has been expressed. The concerns led to the investigation of other intraocular antibiotic agents for the prophylaxis of endophthalmitis, particularly the cephalosporins (eg, cefazolin, ceftazidime, cefotaxime, or cefuroxime). Two agents, cefotaxime and cefuroxime, have recently been promoted for use intracamerally at the conclusion of cataract surgery. Kramann et al.42 studied the effects of prophylactic intracameral cefotaxime on human corneal endothelium. They found no significant endothelial damage or toxicity 3 months after surgery. A dose of cefotaxime 0.25% solution instilled in the anterior chamber was not toxic. The use of intracameral cefuroxime has gained widespread acceptance for endophthalmitis prophylaxis after cataract surgery in some countries, such as Sweden. Montan et al.43 have published 2 reports showing that a 1.0 mL dose of intracameral cefuroxime apparently had no signs of local toxicity. They also report that cefuroxime had no significant effect on endothelial cell density or anterior segment inflammation measured by laser flare interferometry. The authors of the latter conclude that prophylactic intracameral cefuroxime has a major role in decreasing the rate of postoperative endophthalmitis in Sweden. However, these results are from an uncontrolled retrospective observational study and therefore must be confirmed by further prospective studies. Overall, despite some promising data, prophylactic intracameral antibiotic agents are currently not routinely recommended for endophthalmitis prophylaxis after cataract surgery in most countries, including the U.S., since the risk for toxicity and/or infectious complications is high and they have not been shown to reduce endophthalmitis rates. Water
In 2002, an outbreak of TASS after cataract surgery involved 3 surgeons at 2 affiliated facilities.11 After an initial
investigation, attention turned to the quality of the water and steam provided for sterilization by the autoclave steam generator. Samples of the feed water and autoclave steam condensates were collected and analyzed by spectroscopy, ion chromatography, pH, and conductivity studies. Results showed a carry-over of sulfate, silica, copper, zinc, and nickel in the condensates. Increased sulfate levels on the surface of cataract surgery equipment that were retired during the outbreak were documented by analysis of ultrasonic rinsates. Sulfate was the impurity found in the autoclave steam and was thought to have caused the TASS outbreak. This would explain the relatively benign course of these cases in comparison with the course in other cases, such as those attributed to copper and zinc residues.15,38 In the analysis of the 2002 TASS outbreak caused by sulfate water impurities,11 a review of maintenance records showed that the autoclave steam generator had been supplied with softened city water, which was flushed and drained weekly during its first 5 years of use. In 2000, the frequency of flushing and draining was decreased to once every 4 to 8 weeks; this might have promoted the accumulation and carry-over of impurities in feed water. No TASS cases were observed after the steam generator was replaced and a system to supply the new generator with deionized, ultrafiltered water was installed. DELAYED-ONSET POSTOPERATIVE STERILE ENDOPHTHALMITIS
While most reported TASS cases are acute, there have been several instances of delayed-onset TASS following cataract surgery. Intraocular Lens-Induced Inflammation
Jehan et al.8 report 10 cases of a delayed-onset acute IOL inflammation following cataract surgery. In all patients, a hydrophilic acrylic IOL (MemoryLens) was implanted. The onset of the inflammation occurred 1 to 21 days postoperatively. All the anterior chamber taps were Gram stain and culture negative. The patients improved with intense topical antiinflammatory medication. It was theorized that a residual polishing compound on the MemoryLens was responsible for the postoperative inflammation. One of the first terms used to describe patients with TASS was sterile hypopyon or sterile endophthalmitis. This was initially described by Meltzer1 in 1980. It is theoretically possible that the IOL was the source of inflammation and material or substance in the packaging or solution coating the lens was retained and led to a toxic inflammation. The IOL finish and design as well as chemicals used in polishing, cleaning, and sterilizing the lens have been implicated as causes of this type of inflammation.
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Ophthalmic Ointments
Another potential source of delayed-onset TASS is the ingress of ophthalmic ointment used postoperatively in the anterior segment of the eye. An outbreak of delayedonset TASS was recently described by Werner et al.12 In that study, an oily material coating the anterior surface of the IOL or forming small globules within the anterior chamber was found in a group of delayed-onset TASS patients from Canada (Figure 6, A). Several patients had significant corneal edema, and 2 had penetrating keratoplasty. Evaluation of the corneas revealed severe destruction of corneal endothelial cells (Figure 6, B). Analysis of some explanted IOLs showed a significant residue of hydrocarbons on the IOL surfaces (Figure 6, C). The composition of these hydrocarbons exactly matched the vehicle within the postoperative ointment that was placed in the eye. It is hypothesized that the use of a clear corneal wound and postoperative topical ointment containing petroleum as well as tight patching allowed ingress of this material into the anterior segment of the eye, causing delayed-onset TASS. TREATMENT OF TASS
The main treatment for TASS centers on prevention because once the toxic agent enters the eye and causes damage, the clinician can do little other than suppress the secondary inflammatory immune response. Thus, once an infectious etiology has been ruled out, the mainstay of treatment for TASS is intense topical corticosteroid drops. The patient should be started on a regimen of prednisolone acetate 1% drops every 1 to 2 hours and carefully followed, especially during the first days of topical corticosteroid use, to ensure that the inflammatory condition is not worsening and is stabilizing. Careful slitlamp examination allows the surgeon to document resolution of anterior segment inflammation and corneal edema. The IOP should also be closely followed after a toxic sterile insult to the anterior segment of the eye.1,35 As maximum damage to the anterior segment has presumably already occurred, anterior chamber washout is currently not routinely recommended for treatment of TASS. While the IOP may initially be low, recovery of the production of aqueous humor by the ciliary processes can cause a precipitous rise in IOP several days after the initial insult. This IOP change occurs because the toxic agent(s) can injure the trabecular meshwork, causing acute trabeculitis and subsequent chronic long-term damage to the trabecular meshwork. As soon as the cornea clears sufficiently to allow adequate visualization of the anterior chamber angle, the patient should have a gonioscopic evaluation to look for peripheral anterior synechias, which may indicate that
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Figure 6. Toxic anterior segment syndrome secondary to intraocular penetration of ophthalmic ointment. A: Clinical picture taken during the first postoperative week shows a distinct bubble inside the anterior chamber. B: Light photomicrograph of a histologic section obtained from a corneal button shows variable areas of epithelium thinning, thickening of the stroma, with condensation of posterior lamellae, intact Descemet’s membrane, and complete absence of the corneal endothelium (hematoxylin and eosin stain; original magnification 100). C: Explanted silicone lens with an oily material coating large areas of the anterior and posterior optic surfaces.
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chronic long-term trabecular meshwork damage has occurred.1,35 Specular or confocal microscopy of the corneal endothelium is also helpful at this point to assess the degree of endothelial cell damage. CLINICAL COURSE
The clinical outcome of individual patients with TASS depends on many factors such as the type and amount of substance introduced into the eye, the duration of exposure to the substance, and when treatment occurred in the course of the injury. Patients with relatively mild cases show rapid clearing of the inflammation, with slightly less rapid clearing of the cornea (days to weeks). Patients who have moderate TASS have a more prolonged clearing (weeks to months), with possibly slight residual corneal edema and/or increased IOP. Patients who have severe TASS generally have permanent damage to the eye such as persistent, nonclearing corneal edema that requires corneal transplantation, significant trabecular meshwork damage that leads to uncontrolled IOP, chronic anterior segment inflammation that may cause transient or permanent cystoid macular edema, or significant iris damage that may lead to a permanently fixed, dilated pupil. Patients with severe trabecular meshwork damage sometimes develop glaucoma that is relatively resistant to medical treatment alone. These cases usually require surgical treatment such as trabeculectomy or placement of a tube shunt device.1,35 ANALYSIS: TOXIC ANTERIOR SEGMENT SYNDROME
As the mainstay of treatment for TASS centers on prevention, it is critically important that the entire surgical team (surgical nurses, operating room technicians, residents, physicians, and pharmacists) knows what is appropriate for use in the eye. This is especially true for anyone involved in cleaning and sterilizing ophthalmic instruments. Those involved in ordering ocular medications to be used in anterior segment surgery or preparing these medications should also be involved. A basic step is to ensure that everyone involved in cleaning and sterilizing reusable intraocular instruments is thoroughly instructed in the protocols to properly clean and sterilize the instruments (ie, preventing the possibility of toxic residues from accumulating on the reusable instruments). Furthermore, reusable instrument use should be kept to a minimum, particularly those that are high risk for contamination (eg, cannulas or damaged instruments). The reusable instruments that cannot be switched or are chosen not to be switched to disposable types, eg, I/A tips and phacoemulsification handpieces, should be thoroughly rinsed at the conclusion of each cleaning step with sterile, deionized water. It is
especially important to rinse the phacoemulsification handpiece and I/A tips through both inflow and aspiration ports. Ultrasound water baths should be replaced daily since the dirty bath water often grows gram-negative bacteria such as Klebsiella or Pseudomonas species, which could lead to a buildup of heat-stable LPS endotoxins. The use of a steam autoclave sterilizer requires that the water reservoir be changed at least weekly to prevent the buildup of gram-negative bacteria and potentially toxic LPS endotoxins. The surgical center staff should remain vigilant when ordering any agentdirrigating solutions, OVDs, or other medicationsdthat will be used in the eye during anterior segment surgery. This includes the ordering of complete intraocular irrigating solutions such as balanced salt solution (BSS) or BSS Plus, as well as intraocular medications of any kind. The surgical staff should also be up to date on the newest, most complete irrigants that would have a limited shelf life if it were not that they come as a 2-component solution, which means the 2 components must be reconstituted before intraocular use. For example, AMO Endosol Extra is the newest ‘‘complete’’ ocular irrigant to come on the market and should be bioequivalent to BSS Plus. A major issue with Endosol Extra is that the large part-1 component, 500 mL, has a pH of 3.5. If the part-2 component is not added with part 1, severe damage to the intraocular tissue will occur. Care should also be taken to check that the intraocular medications used during anterior segment surgery are preservative-free and at the proper intraocular drug concentration. This is especially important for epinephrine, which is added to irrigating solutions, or for intracameral anesthetics or antibiotics, which are injected directly into the eye. In addition, the surgical staff should be attuned to the proper concentrations of medications and the proper pH and osmolality of vehicles needed during intraocular surgery. For example, intracameral lidocaine used to help anesthetize the eye should be methylparaben-free; intracameral lidocaine, indocyanine green, trypan blue, acetylcholine chloride (Miochol), and carbachol (Miostat) should be mixed with BSS and not sterile water (L.J. Ronge, ‘‘Toxic Anterior Segment Syndrome: Why Sterile Isn’t Clean Enough,’’ Eyenet 2002, November/December, pages 17–18).44–46 An outbreak of TASS in a surgical center is an environmental and toxin control issue that requires complete analysis of all medications and fluids used during the surgery. It is the surgeon’s responsibility to let the surgical team and center know that a case occurred since they are usually the first to recognize a case. Appointing a staff member to coordinate the clinical review and establishing flow charts to track changes or factors potentially responsible for the case or outbreak is typically helpful. It is critically
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important to prove that the medications used during surgery were the intended medications ordered for use by the surgeon. A complete review of operating room protocols should be undertaken by the surgeon as well as representatives from the surgical center and all involved nursing staff and personnel. Protocols used in the sterilization and preparation of instruments from surgery should be carefully evaluated to rule out the potential sources of TASS. The American Society of Cataract and Refractive Surgery has established a center at the University of Utah to evaluate unexplained cases of postoperative inflammation or endophthalmitis. This center has developed protocols to be used in the evaluation of patients with TASS. Ophthalmic research fellows are available to provide analyses of outbreaks of TASS, with subsequent recommendations on ways to prevent future occurrences. Contact information: Nick Mamalis, MD, Director, Intermountain Ocular Research Center, John A. Moran Eye Center, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, Utah 84132, USA; phone (801) 581-6586; e-mail: [email protected]. Edelhauser has also formed a response team at Emory University Eye Center, which has the Centers for Disease Control and Prevention adjacent to its medical campus for assistance in evaluating and preventing further cases or outbreaks or for the investigation and analysis of TASS. Contact information: Henry F. Edelhauser, PhD, Emory Eye Center, Emory University, 1365B Clifton Road NE, Atlanta, Georgia 30322, USA; phone (404) 778-5853; e-mail: [email protected]. Both centers are available as a resource to physicians and surgical centers to aid in the investigation of outbreaks of TASS to help find the etiology of these cases and eliminate potential sources of postoperative inflammation. REFERENCES 1. Meltzer DW. Sterile hypopyon following intraocular lens surgery. Arch Ophthalmol 1980; 98:100–104 2. Apple DJ, Mamalis N, Steinmetz RL, et al. Phacoanaphylactic endophthalmitis associated with extracapsular cataract extraction and posterior chamber intraocular lens. Arch Ophthalmol 1984; 102:1528–1532 3. Abrahams IW. Diagnosis and surgical management of phacoanaphylactic uveitis following extracapsular cataract extraction with intraocular lens implantation. Am Intra-Ocular Implant Soc J 1985; 11: 444–447 4. Richburg FA, Reidy JJ, Apple DJ, Olson RJ. Sterile hypopyon secondary to ultrasonic cleaning solution. J Cataract Refract Surg 1986; 12: 248–251 5. Kim JH. Intraocular inflammation of denatured viscoelastic substance in cases of cataract extraction and lens implantation. J Cataract Refract Surg 1987; 13:537–542 6. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18: 184–189 7. Nelson DB, Donnenfeld ED, Perry HD. Sterile endophthalmitis after sutureless cataract surgery. Ophthalmology 1992; 99:1655–1657
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8. Jehan FS, Mamalis N, Spencer TS, et al. Postoperative sterile endophthalmitis (TASS) associated with the MemoryLens. J Cataract Refract Surg 2000; 26:1773–1777 9. West ES, Behrens A, McDonnell PJ, et al. The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology 2005; 112:1388– 1394 10. Wallin T, Parker J, Jin Y, et al. Cohort study of 27 cases of endophthalmitis at a single institution. J Cataract Refract Surg 2005; 31:735–741 11. Hellinger WC, Hasan SA, Bacalis LP, et al. Outbreak of toxic anterior segment syndrome following cataract surgery associated with impurities of autoclave steam moisture. Infect Control Hosp Epidemiol 2006, in press 12. Werner L, Sher JH, Taylor JR, et al. Toxic anterior segment syndrome and possible association with ointment in the anterior chamber following cataract surgery. J Cataract Refract Surg 2006; 32:227–235 13. Breebaart AC, Nuyts RMMA, Pels E, et al. Toxic endothelial cell destruction of the cornea after routine extracapsular cataract surgery. Arch Ophthalmol 1990; 108:1121–1125 14. Grimmett MR, Williams KK, Broocker G, Edelhauser HF. Corneal edema after miochol. Am J Ophthalmol 1993; 116:236–238 15. Duffy RE, Brown SE, Caldwell KL, et al. An epidemic of corneal destruction caused by plasma gas sterilization; the Toxic Endothelial Cell Destruction Syndrome Investigative Team. Arch Ophthalmol 2000; 118:1167–1176 16. Liu H, Routley I, Teichmann KD. Toxic endothelial cell destruction from intraocular benzalkonium chloride. J Cataract Refract Surg 2001; 27:1746–1750 17. Eleftheriadis H, Cheong M, Sandeman S, et al. Corneal toxicity secondary to inadvertent use of benzalkonium chloride preserved viscoelastic material in cataract surgery. Br J Ophthalmol 2002; 86:299–305 18. Swan KC. Reactivity of the ocular tissues to wetting agents. Am J Ophthalmol 1944; 27:1118–1122 19. Edelhauser HF, Van Horn DL, Schultz RO, Hyndiuk RA. Comparative toxicity of intraocular irrigating solutions on corneal endothelium. Am J Ophthalmol 1976; 81:473–481 20. Gonnering R, Edelhauser HF, Van Horn DL, Durant W. The pH tolerance of rabbit and human corneal endothelium. Invest Ophthalmol Vis Sci 1979; 18:373–390 21. Edelhauser HF, Hanneken AM, Pederson HJ, Van Horn DL. Osmotic tolerance of rabbit and human corneal endothelium. Arch Ophthalmol 1981; 99:1281–1287 22. Parikh CH, Edelhauser HF. Ocular surgical pharmacology: corneal endothelial safety and toxicity. Curr Opin Ophthalmol 2003; 14:178–185 23. Carter LM, Duncan G, Rennie GK. Effects of detergents on the ionic balance and permeability of isolated bovine cornea. Exp Eye Res 1973; 17:409–416 24. Parikh C, Sippy BD, Martin DF, Edelhauser HF. Effects of enzymatic sterilization detergents on the corneal endothelium. Arch Ophthalmol 2002; 120:165–172 25. Kreisler KR, Martin SS, Young CW, et al. Postoperative inflammation following cataract extraction caused by bacterial contamination of the cleaning bath detergent. J Cataract Refract Surg 1992; 18:106–110 26. Britton B, Hervey R, Kasten K, et al. Intraocular irritation evaluation of benzalkonium chloride in rabbits. Ophthalmic Surg 1976; 7(3): 46–55 27. Green K, Hull DS, Vaughn ED, et al. Rabbit endothelial response to ophthalmic preservatives. Arch Ophthalmol 1977; 95:2218–2221 28. Kadonosono K, Ito N, Yazama F, et al. Effect of intracameral anesthesia on the corneal endothelium. J Cataract Refract Surg 1998; 24:1377– 1381 29. Anderson NJ, Nath R, Anderson CJ, Edelhauser HF. Comparison of preservative-free bupivacaine vs lidocaine for intracameral anesthe-
J CATARACT REFRACT SURG - VOL 32, FEBRUARY 2006
REVIEW/UPDATE: TASS
30.
31. 32.
33.
34.
35.
36.
37.
sia: a randomized clinical trial and in vitro analysis. Am J Ophthalmol 1999; 127:393–402 Guzey M, Satici A, Dogan Z, Karadede S. The effects of bupivacaine and lidocaine on the corneal endothelium when applied into the anterior chamber at the concentrations supplied commercially. Ophthalmologica 2002; 216:113–117 Kim T, Holley GP, Lee JH, et al. The effects of intraocular lidocaine on the corneal endothelium. Ophthalmology 1998; 105:125–130 Anderson NJ, Woods WD, Kim T, et al. Intracameral anesthesia; in vitro iris and corneal uptake and washout of 1% lidocaine hydrochloride. Arch Ophthalmol 1999; 117:225–232 Heuermann T, Hartman C, Anders N. Long-term endothelial cell loss after phacoemulsification; peribulbar anesthesia versus intracameral lidocaine 1%; prospective, randomized clinical trial. J Cataract Refract Surg 2002; 28:639–643 Nuyts RMMA, Edelhauser HF, Pels E, Breebaart AC. Toxic effects of detergents on the corneal endothelium. Arch Ophthalmol 1990; 108:1158–1162 Worst JGF. A retrospective view on the sterilization of intraocular lenses and incidents of sterile hypopyon. Am Intraocular Implant Soc J 1980; 6:10–12 Holland SP, Mathias RG, Morck DW, et al. Diffuse lamellar keratitis related to endotoxins released from sterilizer reservoir biofilms. Ophthalmology 2000; 107:1227–1233; discussion by EJ Holland, 1233–1234 Whitby JL, Hitchins VM. Endotoxin levels in steam and reservoirs of table-top steam sterilizers. J Cataract Refract Surg 2002; 18:51–57
38. Smith CA, Khoury JM, Shields SM, et al. Unexpected corneal endothelial cell decompensation after intraocular surgery with instruments sterilized by plasma gas. Ophthalmology 2000; 107:1561–1566; discussion by SM MacRae, 1567 39. Gills JP. Filters and antibiotics in irrigating solution for cataract surgery [letter]. J Cataract Refract Surg 1991; 17:385 40. Judson PH. Aminoglycoside macular toxicity after subconjunctival injection. Arch Ophthalmol 1989; 107:1282–1283 41. Campochiaro PA, Conway BP. Aminoglycoside toxicitydA survey of retinal specialists; implications for ocular use. Arch Ophthalmol 1991; 109:946–950 42. Kramann C, Pitz S, Schwenn O, et al. Effects of intraocular cefotaxime on human corneal endothelium. J Cataract Surg 2001; 27:250–255 43. Montan PG, Wejde G, Setterquist H, et al. Prophylactic intracameral cefuroxime: Evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg 2002; 28:977–981 44. Mamalis N. Inflammation. In: Charlton JF, Weinstein GW, eds, Ophthalmic Surgery Complications; Prevention and Management. Philadelphia, JB Lippincott, 1995; 313–332 45. Horiguchi M, Miyaka K, Ohta I, Ito Y. Staining of the lens capsule for circular continuous capsulorhexis in eyes with white cataract. Arch Ophthalmol 1998; 116:535–537 46. Holley GP, Alam A, Kiri A, Edelhauser HF. Effect of indocyanine green intraocular stain on human and rabbit corneal endothelial structure and viability; an in vitro study. J Cataract Refract Surg 2002; 28:1027–1033
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