The etiology of TASS is broad and includes any substance used during or immediately after anterior segment surgery that, upon access to the anterior chamber, can cause toxic injury to sensitive structures such as the corneal endothelium, iris, and trabecular meshwork. Possible etiologic agents include intraocular solutions, intraocular anesthetics and antibiotics, residues of materials such as ophthalmic viscosurgical devices (OVDs), and remnants of materials used to clean and sterilize ophthalmic instruments.
Balanced salt solution (BSS)
This is used as an intraocular irrigating solution in virtually all cataract surgeries. Any abnormality in the composition of the BSS (eg, incorrect pH, osmolarity, or ionic composition) could cause TASS. Any medications or solutions that are added to the BSS during surgery (eg, epinephrine or antibiotics) also may be causes of TASS. As an example, contamination of BSS was found to be responsible for a 2005 outbreak of TASS in the United States. Surgeons began to notice clusters of patients with acute postoperative inflammation that was initially thought to be infectious in many patients. However, cultures from the anterior chamber and vitreous showed no growth, and these patients responded well to treatment with intense topical corticosteroids. A cooperative investigation by the Centers for Disease Control (CDC) and the University of Utah analyzed 112 cases from this outbreak. The vast majority of patients were exposed to a particular brand of BSS used during cataract surgery. Several lots of this BSS were found to have levels of endotoxin exceeding the allowable limit of 0.5 endotoxin units per milliliter (EU/mL). The withdrawal of this brand of BSS from the market stopped this particular outbreak (U.S. Food and Drug Administration FDA—Reported Recall—Cytosol Laboratories, Inc. Product Contains Dangerous Levels of Endotoxin. February 13, 2006).
Topical Ophthalmic Drops
Many solutions used in ophthalmology contain preservatives or stabilizing agents that may be toxic to the corneal endothelium if they gain access to the anterior segment of the eye. The corneal endothelium is exquisitely sensitive to preservatives used in many topical ophthalmic drops, the most common of which is benzalkonium chloride (BAK). There are many reports of patients who developed significant corneal edema or endothelial cell damage resulting from solutions containing BAK. In addition, BAK has been found to cause significant corneal edema when used as a preservative in an OVD. While low concentrations of preservatives are relatively safe when used on the surface of the eye, BAK or other preservatives, such as methylparaben used in lidocaine, should be avoided in any medication that is used in the anterior segment or that can gain access to the anterior segment of the eye during surgery.
Agents used to stabilize intraocular medications may also lead to the development of TASS. While technically not preservatives, these agents have been found to be toxic to the endothelium and other cells in the anterior segment of the eye. The most commonly used stabilizing agents are bisulphites or metabisulphites. These are often used to stabilize epinephrine that is then added to BSS during surgery to help maintain dilation of the pupil.
Intraocular anesthetics are now commonly used during cataract surgery to help decrease pain and supplement the use of topical anesthetics. Preservative-free anesthetics in low concentrations have been found to be safe and have not caused any signs of endothelial toxicity. The most commonly used intracameral anesthetic is 1% MPF (methylparaben-free) lidocaine. However, anesthetics with preservative have caused endothelial toxicity. In addition, intracameral anesthetics at a higher concentration can potentially damage endothelial tissue. For example, lidocaine at a level of 2.0% or higher has caused significant corneal thickening and opacification postoperatively. It is critical that intracameral anesthetics used during anterior segment surgery be preservative-free and of a proper concentration.
Antibiotics are a potential source of toxicity when they are used in the irrigating solution during surgery or injected intracamerally at the conclusion of cataract or anterior segment surgery.
Antibiotics have been advocated for many years to help prevent endophthalmitis. Initially, vancomycin and gentamicin mixed into irrigating solutions were touted to prevent endophthalmitis. There are concerns, however, about the possible toxicity of these agents, especially gentamicin. This drug has a relatively narrow therapeutic index and has damaged not only the anterior segment of the eye, but also the posterior segment, causing macular infarction when used in too high a concentration. The use of these antibiotics within the BSS solution for the prevention of endophthalmitis has largely fallen out of favor.
There has been intense interest in the use of intracameral antibiotics at the conclusion of surgery for the prevention of endophthalmitis. The use of the cefuroxime was evaluated initially in multiple studies in Sweden for endophthalmitis prophylaxis. When used in the proper concentration of 1 mg/0.1 cc intracamerally, cefuroxime was found to be nontoxic and effective in the prevention of endophthalmitis. The European Society of Cataract and Refractive Surgeons (ESCRS) endophthalmitis study documented a significant reduction in the rate of endophthalmitis using intracameral cefuroxime compared to a topical third-generation fluoroquinolone antibiotic. The major issue with the use of antibiotics, such as cefuroxime, is the fact that there is no single-use antibiotic approved in the United States for intracameral injections.
Surgeons considering the use of intracameral antibiotics are encouraged to ensure the proper mixing and dosing of antibiotics in order to prevent possible dilution errors that can lead to problems with TASS. It is critical that any intracameral antibiotics be properly diluted and mixed under sterile conditions to prevent possible anterior segment inflammation or contamination.
In addition, antibiotics or ointments placed on the eye at the conclusion of surgery must not be allowed to gain access to the anterior segment. Wounds that are poorly constructed and are not water-tight may allow ingress of topical solutions or ointments into the anterior segment. In several cases, patients with a delayed-onset, TASS-like syndrome were found to have a filmy or oily-like substance either in the anterior chamber or on the intraocular lens itself. Analysis showed that the material was consistent with a topical corticosteroid–antibiotic placed on the patient’s eye after surgery. The presence of an incompetent wound followed by tight pressure patching may also lead to ingress of ointment into the anterior chamber, with resulting inflammation.
Ophthalmic Viscosurgical Devices
OVDs, previously referred to as viscoelastics, are a potential source of TASS if significant amounts are left in the anterior segment at the conclusion of the surgery. This is especially a problem in the case of complicated cataract surgeries with posterior capsular rupture and vitreous loss where OVD may be left in the remnant capsular bag or behind the iris. In addition, residual OVD left in the lumen of reusable cannulas or handpieces may also cause postoperative inflammation. If these instruments are not properly flushed following cataract surgery, the residual OVD may be subsequently broken down during the process of sterilization. This can cause TASS when the material is flushed into the anterior segment of the eye during subsequent cataract cases. It has also been theorized that residual OVD may help retain materials such as detergents or enzymes used during the cleaning and processing of instruments, which could once again lead to possible problems with TASS if these are injected intracamerally during surgery.
Cleaning and Sterilization of Ophthalmic Instruments
The cleaning and sterilization of instruments used in anterior segment surgery emerged as a critical factor in recent cases of TASS. A large outbreak of TASS throughout North America, not associated with the use of Cytosol, which peaked in April 2006, was heralded by an increase in the number of cases reported to the Intermountain Ocular Research Center at the University of Utah, as well as to Emory University and industry representatives. An ad hoc TASS task force was established with funding from the American Society of Cataract and Refractive Surgery (ASCRS) to help investigate this outbreak, which eventually dissipated by mid-summer of 2006.
The task force evaluated more than 130 different centers reporting cases of TASS. While the task force found no conclusive epidemiologic evidence to suggest that any single product was responsible for the increase of TASS, careful analysis revealed multiple potential etiologic factors related to TASS. The most important factor in this outbreak was the issue of cleaning and sterilization of instruments for ophthalmic surgery. Many centers reported a very short time available between cases to properly clean and process instruments. This is an area of concern for several reasons, including the proper flushing of handpieces and cannulas at the conclusion of the case. The use of reusable, small-bore instruments such as cannulas was found to be a potential source of TASS due to the small internal diameters and openings of these instruments. In addition, ultrasound and irrigation/aspiration handpieces used during phacoemulsification may allow a buildup of residual OVD and cortex that could lead to inflammation when these instruments are used in subsequent cases. It is of utmost importance to thoroughly flush reusable cannulas and handpieces at the end of each case in order to not allow any materials within these cannulas and instruments to dry and build up.
Enzymes and Detergents
The TASS task force also found that enzymes and/or detergents used in the cleaning of ophthalmic instruments were an important factor in the etiology of TASS. Enzymes and detergents are toxic to the corneal endothelium in both humans and animal models and can cause corneal edema. Residues of these cleaning materials are potentially toxic as well when they accumulate on the inside surfaces of reusable cannulas or handpieces, especially in the setting of residual OVD or cortex. Enzymes and detergents are not completely inactivated when the instruments are treated with the high temperatures used in autoclaving.
The task force found that the use of ultrasound baths in the cleaning of ophthalmic instruments is another potential source of TASS. There have been multiple reports of ultrasound baths that were contaminated by Gram-negative bacteria producing heat-stable endotoxins that caused TASS. While the bacteria themselves are killed by the heat used in autoclaving, the endotoxins on the cell surface can remain active. A residue of the endotoxins can then become attached to instruments or cannulas being cleaned in the ultrasound bath and cause toxicity if it is injected into the eye. Endotoxins are extremely difficult to remove from ophthalmic instruments once they gain access. Surgeons and surgical centers are encouraged to reconsider the use of ultrasound baths for the cleaning of ophthalmic instruments. While these baths are useful in removing the bulk contamination of instruments that occurs commonly in general surgery, this is usually not a factor in anterior segment surgery. Thorough flushing of ophthalmic handpieces and cannulated instruments at the conclusion of each case should eliminate any residual material, such as cortex or OVD. As there is little bioburden retained in reusable ophthalmic instruments, ultrasonic cleaning may not be necessary. If it is used, there should be strictly followed protocols in place to prevent contamination or endotoxins in the ultrasound water bath.
A final source of TASS was related to problems with the water in the devices used for cleaning and sterilizing instruments. Residual heavy metal condensates as well as sulphate condensates and impurities have been found in the water supply to the steam sterilizers of autoclave systems. These may eventually build up to the point where a residue could gain access to the ophthalmic instruments being sterilized. An outbreak of TASS has been reported associated with impurities and heavy metals in autoclave steam moisture, secondary to inappropriate maintenance of the steam sterilizer.