Nick Mamalis, MD
Contents
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Clinical Signs and Symptoms |
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Etiology Of Toxic Anterior Segment Syndrome |
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Cleaning and Sterilization of Ophthalmic Instruments |
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Treatment of Toxic Anterior Segment Syndrome |
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Analysis of Toxic Anterior Segment Syndrome Outbreaks |
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Prevention of Toxic Anterior Segment Syndrome |
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CHAPTER HIGHLIGHTS |
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Toxic anterior segment syndrome (TASS) is an acute, sterile postoperative anterior segment inflammation following any anterior segment surgery. This entity is by definition sterile or noninfectious. This condition was initially described as sterile postoperative endophthalmitis, but in 1992, Monson et al.[1] coined the term toxic anterior segment syndrome (TASS). In addition, cases of TASS which are characterized by localized corneal endothelial damage have been termed toxic endothelial cell destruction syndrome (TECDS).[2–6] A recent review/update on TASS as well as its accompanying editorial has provided a detailed, in-depth discussion of this entity.[7,][8]
TASS occurs most commonly following cataract surgery, but may occur following anterior-segment surgeries of any kind including glaucoma or cornea transplant surgeries. While TASS is most commonly noted to occur acutely following anterior segment surgery, in rare instances it can have a delayed onset. This postoperative inflammation is sterile or noninfectious and is felt to be caused by a substance that enters the anterior segment either during or immediately after surgery, resulting in toxic damage to intraocular tissues.
Clinical signs and symptoms
The most common complaint that patients with TASS have is blurred vision. Pain is usually absent which is distinct from cases of postoperative infectious endophthalmitis. The patients may have signs of ocular inflammation and injection. The clinical hallmark of TASS is the fact that the inflammation presents with a relatively immediate onset, usually within 12–48h of surgery. This inflammation is sterile and Gram-stain and cultures are negative.
The most common clinical finding in TASS is diffuse corneal edema which has been described as “limbus-to-limbus” corneal edema (Figure 48-1). This diffuse corneal edema is due to widespread damage of the corneal endothelial cells. This finding is very different from the focal areas of corneal edema which may occur after routine cataract surgery. A second common finding associated with this entity is marked anterior segment inflammation. This is characterized by diffuse breakdown of blood–aqueous barrier with a marked increase in inflammatory cells in the anterior chamber. These cells may settle to the lower part of the anterior chamber forming a hypopyon (Figure 48-2). In addition, significant breakdown of the blood–aqueous barrier may lead to fibrin formation in the anterior chamber which may extend across the pupil from the iris onto the surface of the intraocular lens and toward the incisions. Finally, TASS may result in damage to the iris which can cause a permanently dilated or irregular pupil with thinning of the iris stroma (Figure 48-3). There may be associated trabecular meshwork damage which can lead to secondary glaucoma which may be difficult to control.
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Figure 48-1 Diffuse limbus-to-limbus corneal edema. |
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Figure 48-2 Anterior segment inflammation with hypopyon formation. |
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Figure 48-3 Atrophic iris with dilated, slightly irregular pupil. |
It is important to differentiate the sterile inflammation seen in TASS from an infectious postoperative endophthalmitis. One of the signs that are most helpful in differentiating these two entities is the fact that TASS occurs acutely in the vast majority of cases with signs appearing within the first 12–48h. In bacterial endophthalmitis, the typical signs do not often appear until 4–7 days postoperatively. The symptoms in these entities are different in that greater than 75% of patients who have an infectious endophthalmitis will have pain. The majority of cases of TASS are pain free. The anterior segment inflammatory changes in both of these entities are often very similar with significant inflammation and hypopyon formation. However, the diffuse corneal edema seen in TASS is often not noted in infectious endophthalmitis. It is important if there is any question of an infectious etiology that anterior chamber and vitreous samples be taken for staining and culture.
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Etiology of toxic anterior segment syndrome
Any substance that is used during or immediately after cataract surgery which can access the anterior segment of the eye can cause TASS. The corneal endothelium is especially sensitive to any form of toxic insult as are many of the structures in the anterior segment of the eye in general. The etiology of TASS is relatively broad and may include problems involving irrigating solutions such as balanced saline solution (BSS) and any additives included.[9–13] In addition, any other ophthalmic solutions used during surgery, especially those which contain preservatives or stabilizing agents may cause toxicity to corneal endothelium and precipitate TASS.[13–15] Medications such as antibiotics and anesthetics which are injected into the eye may also be associated with TASS. Additionally, residues of ophthalmic viscosurgical devices (OVDs) may cause significant postoperative inflammation.[16] Lastly, it is important to remember that any enzymes or detergents that are used in the cleaning of instruments used in anterior-segment surgery may leave behind a residue which could cause TASS.[17–19]
Intraocular irrigating solutions
Intraocular irrigating solutions such as BSS have the potential for causing problems with TASS if there are problems with the composition of the BSS such as incorrect ionic composition, osmolarity, or pH.[9–13]
It is also important to remember that any medication or solutions that are added to the BSS may be associated with potential problems with inflammation. Examples of these include agents to dilate the pupil, such as epinephrine, and antibiotics which are placed into the irrigating solution.
Furthermore, it is important to ensure that there is no contamination in the BSS secondary to materials such as endotoxin. There was an outbreak of TASS in the fall of 2005 which was found to be secondary to endotoxin contamination of BSS. Multiple patients throughout the United States were found to have signs and symptoms of TASS, but cultures of the anterior chamber and vitreous showed no signs of infectious endophthalmitis. These patients tended to occur in clusters and responded well to intense topical corticosteroid treatments. This outbreak was evaluated by investigators from the Intermountain Ocular Research Center at the University of Utah, as well as investigators from the United States Centers for Disease Control (CDC). A thorough investigation of 112 cases from this outbreak by the CDC found that the vast majority of patients were exposed to one particular brand of BSS that was used during cataract surgery. Samples were taken from many different lots of BSS and tested for endotoxin. Several lots of BSS were found to have levels ofendotoxin exceeding the allowable limit of 0.5EU/mL. It was found that this BSS was manufactured by Cytosol Laboratories and distributed by AMO as Endosol. This BSS was withdrawn from the market which resulted in termination of the outbreak (U.S. Food and Drug Administration FDA – Reported Recall – Cytosol Laboratories, Inc. Product Contains Dangerous Levels of Endotoxin. February 13, 2006).
Preservatives
Ophthalmic solutions which contain preservatives or stabilizing agents may be toxic to the corneal endothelium and result in TASS.[13–15] The corneal endothelium is exquisitely sensitive to preservatives which are used in many topical ophthalmic drops or solutions. One of the most commonly used preservatives is benzalkonium chloride (BAK). There have been multiple reports of patients with significant corneal edema or endothelial cell damage resulting from solutions which are preserved with BAK.[5] In addition, BAK has been found to cause significant corneal edema when used as a preservative with an OVD.[6] Low levels of BAK are safe to use on the surface of the eye, but should be avoided in medications which gain access to the eye during anterior segment surgery.
In addition to preservatives, agents which are used to stabilize intraocular medications have been found to be associated with TASS. The most commonly used stabilizing agents are bisulphites or metabisulphites, which are often used as a stabilizing agent for epinephrine (to maintain the epinephrine in the reduced state) which is added to the BSS to help maintain pupil dilation during cataract surgery. While these stabilizing agents are not considered to be traditional preservatives, they can be toxic to the corneal endothelium, as well as other cells within the anterior segment of the eye and can lead to TASS.[20] It is imperative that any medications placed into the eye during surgery are not only preservative free but free of stabilizing agents.[21]
Intraocular anesthetics
Intracameral anesthetics are often used in routine cataract surgery to help supplement topical anesthetics. Preservative-free anesthetics which are in a relatively low concentration have not been found to be toxic to the endothelium. However, doses of lidocaine which is preservative free (methylparaben free-MPF) at a level of 2% or higher have been known to cause significant corneal thickening and opacification postoperatively.[22] Although these agents are preservative free, intracameral use of anesthetics can potentially cause corneal endothelial cell damage at a high enough dose.[22–24] Therefore, it is very important that any anesthetics used in anterior-segment surgery are not only of the proper dose but are free of preservatives.
Intraocular antibiotics
Antibiotic agents are an additional source of toxicity when either they are used in irrigating solutions or are injected into the anterior segment of the eye at the conclusion of surgery. These agents are often used to help prevent endophthalmitis. Surgeons had initially advocated the use of either gentamicin sulfate or vancomycin in the irrigating solution (BSS) to help prevent endophthalmitis.[25] However, concerns were raised about the possibility of toxicity, especially with intraocular gentamicin, which has a relatively narrow range of therapeutic versus toxic doses and has been found to cause macular toxicity.[26,][27] These agents have been mostly discontinued for use in the BSS for prevention of infection.
There has been recent work done mainly in Europe on the use of intracameral antibiotics which are injected at the conclusion of the surgery to help prevent endophthalmitis. Initial studies in Sweden regarding the use of intracameral cefuroxime for endophthalmitis prophylaxis showed no signs of toxicity with a 1mg/0.1cc dose of intracameral cefuroxime.[28] The European endophthalmitis study which has recently been published showed a significant reduction of endophthalmitis following the intracameral injection of cefuroxime at the conclusion of the case.[29] The issue of the use of intracameral antibiotics to prevent endophthalmitis is an important topic that will need to be addressed by surgeons in the United States in the near future. The American Society of Cataract and Refractive Surgery (ASCRS) has established a subcommittee to evaluate the various treatments of endophthalmitis, including intracameral antibiotics. Careful measures need to be taken to ensure that the proper mixing and dosing of the antibiotic is done in the pharmacy in order to prevent the possibility of TASS outbreaks due to improperly dosed or mixed intracameral antibiotics.
In addition to topical drops which may gain access to the eye during cataract surgery, there have been recent reports regarding a relatively delayed-onset TASS secondary to topical ophthalmic ointments gaining access to the anterior chamber of the eye following surgery and causing inflammation.[30] A series of patients were found to have delayed-onset TASS-like symptoms with film or oil-like substance in the anterior chamber, coating the endothelium or on the intraocular lens (IOL). Analysis of this material using chromatography – mass spectral analysis revealed that this material contained a mixed chain hydrocarbon which was also found in the analysis of the steroid-antibiotic ointment that was placed on the patient's eyes following the conclusion of the surgery. Such cases raised the possibility that ointment placed on the surface of the patient's eye at the conclusion of the case followed by tight patching in the setting of a clear cornea wound may lead to ointment gaining access into the anterior chamber of the eye and causing inflammation.
Ophthalmic viscosurgical devices
An additional potential source of TASS are commonly used OVDs (previously referred to as viscoelastics). A large amount of remnant OVD in the anterior chamber of the eye can cause an increase in intraocular pressure (IOP) as well as increased inflammation postoperatively.
An additional problem is the possibility of denatured residual OVD left in either reusable cannulas, tips or handpieces which have not been properly flushed following surgery. This residual OVD may be broken down during sterilization and can cause toxic inflammation following flushing of this material into the eye in subsequent cases.[16] In addition, this OVD may actually retain other materials such as detergents or enzymes which are used during cleaning and processing of instruments that could conceivably lead to inflammation in the anterior segment of the eye or TASS. It is critically important that any reusable cannulas or instruments be thoroughly flushed at the conclusion of a case in order to not allow the OVD to dry on the instruments which can occur when cannulas are exposed to the air, making cleaning very difficult. It is recommended that all cannulas, handpieces orphacoemulsification tips that are exposed to OVD be thoroughly flushed using sterile, deionized, or distilled water to ensure that there is no residue left on the instruments between cases.
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Cleaning and sterilization of ophthalmic instruments
The cleaning and sterilization of instruments for use in anterior segment surgery has become an important factor in many recent cases of TASS. Beginning in February of 2006, the number of TASS cases reported to the Intermountain Ocular Research Center of the University of Utah, as well as to the TASS center at Emory University and to industry representatives began to increase markedly. Multiple clusters of cases of TASS were found in surgical centers throughout the United States and Canada. The Ad Hoc TASS Task Force was established with funding from the ASCRS to help investigate this outbreak. Two questionnaires regarding instrument reprocessing as well as the use of products in anterior segment surgery were developed and a database was established to investigate the causes of the TASS outbreak
Approximately 130 different centers reporting TASS were evaluated. The Ad Hoc TASS Task Force issued its final report on September 22, 2006 regarding the analysis of this TASS outbreak (Toxic Anterior Segment Syndrome (TASS) Outbreak: Task Force Final Report - www.ascrs.org and www.aao.org).
There was no conclusive epidemiologic evidence to suggest any one product was responsible for the increase in the TASS cases reported. Also, analysis of the information did not reveal a single cause or point source related to this particular TASS outbreak. However, there were multiple potential etiologic factors which were found to be related to the cases of TASS. The issue of cleaning and sterilization of instruments for cataract surgery was found to be the most important factor involved in many of the cases of TASS. Specifically, the taskforce found that the short time available between cases to properly clean and reprocess instruments was an area of concern. The use of reusable cannulated instruments of any kind was found to be a potential source of TASS because they normally have small internal diameters and openings as small as 0.3mm. This includes ultrasound and irrigation–aspiration (I–A) handpieces for use during surgery. It is critically important that all reusable handpieces and cannulas are flushed thoroughly at the conclusion of each case. Inadequate flushing may allow a buildup of residual cortex and OVD which could lead to toxic anterior segment inflammation.
Another important area when evaluating the cleaning and sterilization of instruments that was also evaluated by the task force was the use of enzymes or detergents in the cleaning of the instruments. Enzymes or detergents that are used in the cleaning of instruments for anterior-segment surgery may leave a residue which could cause TASS.[18,][19]
If any of this residual enzyme or detergent is not properly rinsed from the instruments, it has the potential to cause TASS. Detergents have been found to accumulate on the inner surfaces of reusable instruments, especially when there is dried or residual OVD. It should be noted that the enzymes and detergents are not completely inactivated when exposed to high temperatures used in the autoclaving of instruments. There is a possibility that the residue of detergents and enzymes left in cannulas or phaco or I–A handpieces may cause potential inflammation. There have been reports of an increase in corneal thickness secondary to endothelial damage in both rabbits and humans due to enzymatic detergents.[13,][19]
Initial evaluations of the toxicity of detergents to the corneal endothelium were referred to as the toxic endothelial cell destruction (TECD) syndrome. Reports of severe TECD following cataract surgery have been found to occur from detergent residues on reusable cannulas.[2]
Furthermore, the use of ultrasound baths to clean ophthalmic instruments between cases is a potential source of TASS. The ultrasound baths may become contaminated by Gram-negative bacteria which can produce a heat-stable endotoxin that can survive autoclaving and cause TASS. Even though the bacteria are incapacitated by heat from the autoclave, the endotoxin remains viable. Deposits of the heat-stable lipopolysaccharide endotoxins can remain attached to the instruments or cannulas and can cause significant inflammation in the anterior segment of the eye if they are injected into the eye.[31] Endotoxin is difficult to remove from ophthalmic instruments and may require an alcohol rinse. Consideration should be given to eliminating the use of ultrasound baths in the cleaning of ophthalmic instruments. Ultrasound baths are often necessary to remove bulk contamination on instruments which is important in areas such as general surgery, but is not a factor in most anterior segment ophthalmic surgeries.
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Treatment of toxic anterior segment syndrome
Once again, it is important to ensure that an infectious etiology has been adequately ruled out of cases of suspected TASS. Once the toxic agent enters the eye and causes inflammation and damage which leads to TASS, the mainstay of treatment is the suppression of the secondary inflammatory response. The primary treatment for patients with TASS is the use of intense topical corticosteroids to help calm the inflammation and limit the damage not only from the initial toxic insult but also from the secondary immune response. Patient's should be started on topical prednisolone acetate 1% drops every 1–2h and be carefully followed in the first several days following the onset of TASS. In addition, the IOP should be closely monitored in patients with TASS. Although the pressure may initially be low, recovery of aqueous production by the ciliary body may cause a rapid increase in IOP as the inflammatory reaction decreases. The initial toxic insult causing TASS not only may injure the cornea and iris, but also can cause significant damage to the trabecular meshwork. Lastly, the inflammation can lead to formation of peripheral anterior synechia, which may also contribute to a rise in IOP.
Patients should be followed closely to ensure that the inflammation is not worsening and that the pressure remains stable. Careful slit-lamp examinations of the anterior segment of the eye should be performed regularly to document the resolution of the anterior segment inflammation and corneal edema if it is present.
Clinical course
The clinical outcome of a patient with TASS is directly related to the degree of toxic insult to the anterior segment of the eye occurring during or immediately following the surgical procedure. Patients who have a relatively mild case of TASS tend to undergo rapid clearing of the corneal edema over the course of several days to weeks. In addition, the inflammation will clear relatively rapidly with minimal associated sequelae and no permanent damage (Figure 48-4). Patients who have suffered a more moderate insult causing TASS may have a more prolonged course lasting weeks to months with eventual clearing of the cornea and possibility of small residual corneal edema. These patients may also have increased IOP. Patients who have a more severe initial insult often suffer permanent damage to the anterior segment of the eye. This can include diffuse corneal edema which is non-clearing and may require cornea transplantation for treatment (Figure 48-5). In addition, the patient's may suffer other inflammatory sequelae, such as chronic cystoid macular edema. The significant damage to the trabecular meshwork, as well as possible peripheral synechia, may lead to a very difficult to control glaucoma, which is often resistant to treatment. Damage to the iris may also lead to a fixed, dilated pupil with significant iris thinning.
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Figure 48-4 Resolving toxic anterior segment syndrome with clearing cornea, rapidly clearing anterior segment inflammation with small residual keratic precipitates. |
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Figure 48-5 Severe toxic anterior segment syndrome with permanent damage showing marked corneal edema and residual chronic anterior segment inflammation. Copyright 2006, with permission from Elsevier. |
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Analysis of toxic anterior segment syndrome outbreaks
The issue of cleaning and sterilization of instruments has been found to be increasingly related to outbreaks of TASS. Therefore, it is important to analyze how instruments are not only sterilized but also, just as importantly, cleaned prior to actual sterilization. The first step in the proper cleaning of instruments involves flushing or cleaning off any reusable instruments or cannulas at the conclusion of the previous case prior to final sterilization. It is important that any reusable cannulas, handpieces, or tips from phacoemulsification or I–A handpieces be thoroughly flushed at the conclusion of each case. It is important that any residual cortex or OVDs be removed prior to allowing them to dry on the instruments. Many manufacturers recommend that at least 120cc of sterile, deionized, or distilled water be used to thoroughly flush through all handpieces. It is also important that all instruments which have received any other treatments prior to sterilization undergo a thorough final rinse, once again with sterile deionized water prior to autoclaving or final sterilization.
Processes used for the cleaning of instruments prior to sterilization should also be carefully evaluated. The use of enzymes or detergents for the cleaning of instruments should be re-evaluated, as the use of these materials have the potential to cause TASS. It is unclear whether it is necessary to use either enzymes or detergents following routine ophthalmic surgery, as ophthalmic instruments do not normally have a large bioburden or large amounts of tissue attached to them following surgery. If possible, consideration should be given to the elimination of the use of enzymes or detergents for the cleaning of ophthalmic instruments. Similarly, the use of ultrasound water baths may not be necessary because once again, ophthalmic instruments do not tend to have large bioburdens on them. If ultrasound water baths are used, they should be drained and thoroughly cleaned on a regular basis to prevent the buildup of Gram-negative bacteria and possible endotoxin contamination.
Care should be taken to completely review all of the medications that are used in the cataract surgery and its aftermath. It is important that confirmation be obtained that the anesthetics used intracamerally are preservative free and of the proper dose. In addition, any additives to the BSS, such as epinephrine, should not only be preservative free but should also be bisulphite free. If any intracameral antibiotics or antibiotics in the BSS are used, the proper dosing and dilution of these medications should also be confirmed. Both are off label uses in cataract surgery.
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Prevention of toxic anterior segment syndrome
Since TASS has the possibility of causing significant ocular morbidity, major effort should be focused on the prevention of TASS. It is imperative that surgical centers and hospitals have protocols in place regarding the cleaning and sterilization of instruments and that the entire surgical staff involved in this process is aware of the protocols. It is crucial that the entire surgical team including nurses, operating room technicians, physicians, and pharmacists are aware of what is appropriate for use in ophthalmic surgery and that they be educated about protocols that are in place. The TASS task force investigations of outbreaks of TASS at various surgical centers found that often there were not adequately established protocols in place for the cleaning, processing, and sterilization of instruments. The level and intensity of cleaning of instruments often depended on who was doing the cleaning of the instruments on a particular day and it was often obvious that there were not well-established guidelines in place for the surgical staff.
To help increase the awareness of TASS and to help guide in the prevention of this complication, the Ad Hoc TASS Task Force has taken several steps to create educational materials for surgeons and surgical staff. A video symposium discussing the findings of TASS, etiological factors, and possible ways to prevent TASS comprised of members of the Task Force, as well as representatives from ophthalmic nurse's organizations is available at www.TASSFacts.com.
In addition, the members of the Ad Hoc TASS Task Force were involved in a symposium held at Emory University in the fall of 2006 with representatives from the major ophthalmic nurses associations, as well as other personnel with expertise in the cleaning and sterilization of ophthalmic instruments. Input was also obtained from other organizations such as the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) regarding the development of proper guidelines for the cleaning, sterilization, and processing of ophthalmic instruments. These guidelines are now available to surgeons and their staff on the ASCRS website (www.ASCRS.org), as well as the ASORN website and were disseminated with the March 2007 issue of the Journal of Cataract and Refractive Surgery. These guidelines should help the surgeons and their staff in the critical process of cleaning and sterilization of instruments with the goal of preventing further TASS outbreaks.
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References
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