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  • ASCRS, FDA: An update on TASS

    Cataract/Anterior Segment
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    Toxic anterior segment syndrome (TASS) is an acute, sterile inflammatory reaction following anterior segment surgery that occurs secondary to a toxic insult during surgery or the perioperative period. There are multiple potential causes of TASS, including problems with instrument cleaning and sterilization, as well as any fluids or medications that are used during cataract surgery or the immediate postoperative period. In recent years, the American Society of Cataract and Refractive Surgery (ASCRS) TASS Task Force has been tracking TASS outbreaks and working to pinpoint the causes of TASS.

    Patients usually present with TASS within 12 to 48 hours after surgery. The most common clinical findings are a diffuse "limbus-to-limbus" corneal edema with increased anterior chamber inflammation and fibrin formation, as well as possible iris and trabecular meshwork damage.

    TASS Task Force

    While there have been multiple incidences of TASS reported over the last 25 years, in early 2006, a large TASS outbreak occurred throughout North America that led to the formation of the ASCRS TASS Task Force. This group included ophthalmologists, vision scientists, epidemiologists, surgical nurses, and representatives from industry, the U.S. FDA and the Centers for Disease Control and Prevention (CDC).

    Following the investigation of this outbreak, the task force published a review of potential causes of TASS and recommendations for cleaning and sterilizing intraocular ophthalmic instruments.1-3 The group subsequently developed two questionnaires for evaluating TASS outbreaks that it has used to analyze potential causes of TASS when an incident or outbreak has occurred: one regarding the cleaning and sterilization of ophthalmic instruments, and a second regarding medications and fluids used during cataract surgery.

    Proactive TASS program

    Following resolution of the 2006 TASS outbreak, the ASCRS TASS Task Force continued to collaborate with the University of Utah's Intermountain Ocular Research Center (IORC) and the FDA to develop questionnaires for a proactive TASS reporting program and to create a formal TASS registry. While a surveillance program and new questionnaires ultimately were produced through nearly three years of collaborative work between these parties, unfortunately, the FDA insisted on retaining sole and unlimited rights to the registry questionnaires and refused to share ownership and credit with ASCRS for the development of these programs. This FDA intransigence led to dissolution of the partnership.

    The FDA announced in 2012 its own proactive toxic anterior segment surveillance program in an article4 and accompanying editorial5 in the journal Ophthalmology, describing the organization's establishment of a proactive initiative for testing potential causes of TASS and the development of tools to collect data, standardize devices and improve communication among those involved in analyzing TASS cases. However, these articles failed to mention the involvement of the ASCRS TASS Task Force or the IORC in the development of these protocols.

    FDA research

    The FDA also published in Ophthalmology a series of six investigational studies examining potential causes of TASS. Among them, researchers analyzed the effects of bacterial endotoxin contamination of ophthalmic viscosurgical devices (OVDs), examined reactivity to endotoxin in a rabbit model, and evaluated intraocular reactivity to organic contaminants and enzymatic detergents.6-11

    One of the most important conclusions resulting from these studies is the FDA's statement that the most common cause of TASS is endotoxin contamination of solutions or OVDs and that problems with instrument cleaning and sterilization, and specifically the use of enzymatic detergents, should not cause TASS. There were some significant problems with this research, including use of the rabbit model. There are marked differences in the inflammatory reaction of rabbits compared with humans, as well as in the response to various toxic insults, that make it difficult to extrapolate findings from the rabbit model directly to humans. Specifically, rabbits have a very rapid and robust response to any toxins introduced. In addition, they recover rapidly from toxic insults.

    The report evaluating the effects of enzymatic detergents as a potential cause of TASS concluded that residual enzymatic detergents were unlikely to cause TASS.10 However, there are some significant issues related to how this study was conducted. The authors evaluated the effect of enzymatic detergents on the cornea by assessing corneal haze at the slit lamp postoperatively. Endothelial cell counts, corneal thickness or morphology were not evaluated using specular microscopy. Furthermore, there was no analysis or evaluation of the corneal endothelium or possible effects of the enzymatic detergents on endothelial cell membrane junctions or endothelial cell morphology. In fact, this study actually showed significant corneal haze in the early hours following injection of the enzymatic detergents in the rabbit model. The authors noted a rapid clearing of the corneal haze, which may be indicative of the rapid rabbit response to such an insult. In addition, the rabbits experienced a marked spike in anterior chamber cells and flare approximately six hours after surgery, which was associated with a significant fibrin reaction to higher doses of enzymatic detergents and decreased after approximately 48 hours. This may be indicative of the differences in inflammatory responses of rabbits to intraocular toxins compared with humans.

    Another study found a dose response to corneal swelling when enzymatic detergents were perfused onto the rabbit corneal endothelium.12 Careful evaluation of the endothelial cell layer with electron microscopy revealed disruption of the endothelial monolayer, as well as damage to endothelial cells and their junctions directly. Perfusion of enzymatic detergents markedly increased corneal permeability and also increased corneal thickness. Following careful analysis of the FDA paper, we believe that the results of this study actually confirm the potential for enzymatic detergents to cause TASS.

    ASCRS analysis

    An extensive analysis of 130 questionnaires collected over six years and a review of 71 site visits evaluating TASS cases over the past seven years by the ASCRS TASS Task Force has shown problems with instrument cleaning and sterilization to be by far the most common cause of TASS.14,15 The centers that reported data found 1,454 cases of TASS following approximately 69,000 surgeries.

    The most recent study compared data reported during the past three years with data from the three years before that. This analysis found that the incidence of monthly TASS cases reported to the task force gradually declined over time.

    There were several positive trends noted in the most recent reports. These included a reduction in inadequate hand piece flushing volume and an increase in the use of distilled/deionized water for the final rinse of the instruments. In addition, there was a reduction in the use of enzymatic detergents and ultrasound baths. Unfortunately, there were some negative trends noted, including an increase in poor instrument maintenance and an increase in ultrasound bath use without adequate routine cleaning of the bath.

    Whenever a TASS outbreak did occur, improved surgical instrument cleaning and adherence to strict cleaning protocols lead to the elimination of further cases of TASS. The common findings in these analyses were that instrument cleaning and sterilization are the most common factors associated with TASS. The primary conclusion of this large study was that the incidence of TASS might have been reduced by improved instrument cleaning and sterilization, as well as improvement in other perioperative practices.

    Conclusions

    The findings from the ASCRS TASS Task Force studies confirm that a proactive TASS program is important for both the analysis and prevention of TASS outbreaks. The task force and the IORC continue to provide analyses and recommendations to surgical facilities and surgeons reporting cases of TASS. This initiative is funded by ASCRS and performed independently of the FDA. It is unfortunate that the FDA has announced its own reporting program without acknowledgement of the significant involvement and contributions of the ASCRS task force and the IORC throughout the years.

    References

    1. Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic anterior segment syndrome. J Cataract Refract Surg. 2006;32(2):324-333.
    2. Mamalis N. Anatomy of a TASS outbreak. J Cataract Refract Surg. 2007;33(3):357-358.
    3. Hellinger WC, Bacalis LP, Edelhauser HF, Mamalis N, Milstein B, Masket S; ASCRS Ad Hoc Task Force on Cleaning and Sterilization of Intraocular Instruments. Recommended practices for cleaning and sterilizing intraocular surgical instruments. J Cataract Refract Surg. 2007;33(6):1095-1100.
    4. Eydelman MB, Tarver ME, Calogero D, Buchen SY, Alexander KY. The Food and Drug Administration's proactive toxic anterior segment syndrome program. Ophthalmology. 2012;119(7):1297-1302.
    5. Gottsch GD, Schein OD. Taking TASS to task (Editorial). Ophthalmology. 2012;119(7):1295-1296.
    6. Buchen SY, Calogero D, Hilmantel G, Eydelman MB. Rabbit ocular reactivity to bacterial endotoxin contained in aqueous solution and ophthalmic viscosurgical devices. Ophthalmology. 2012;119(7):e4-e10.
    7. Buchen SY, Calogero D, Hilmantel G, Eydelman MB. Detecting endotoxin contamination of ophthalmic viscosurgical devices: intracameral versus intravitreal assays in rabbits. Ophthalmology. 2012;119(7):e11-e18.
    8. Nussenblatt RB, Calogero D, Buchen SY, Leder HA, Goodkin M, Eydelman MB. Rabbit intraocular reactivity to endotoxin measured by slit-lamp biomicroscopy and laser flare photometry. Ophthalmology. 2012;119(7):e19-e23.
    9. Buchen SY, Calogero D, Tarver ME, Hilmantel G, Tang X, Eydelman MB. Evaluation of intraocular reactivity to organic contaminates of ophthalmic devices in a rabbit model. Ophthalmology. 2012;119(7):e24-e29.
    10. Leder HA, Goodkin M, Buchen SY, et al. An investigation of enzymatic detergents as a potential cause of toxic anterior segment syndrome. Ophthalmology. 2012;119(7):e30-e35.
    11. Calogero D, Buchen SY, Tarver ME, Hilmantel G, Lucas AD, Eydelman MB. Evaluation of intraocular reactivity to metallic and ethylene oxide contaminants of medical devices in a rabbit model. Ophthalmology. 2012;119(7):e36-e42.
    12. Parikh C, Sippy BD, Martin DF, Edelhauser HF. Effects of enzymatic sterilization detergents on corneal endothelium. Arch Ophthalmol. 2002;120(2):165-172.
    13. Edelhauser HF. The balance between corneal transparency and edema: the Proctor Lecture. Invest Ophthalmol Vis Sci. 2006;47(5):1755-1767.