 All right, so our second speaker of the morning is going to be Nathan Ellis. And he's also one of our ophthalmic pathology research fellows. And Nathan's going to be talking a little bit about an issue that we don't like to hear about. But it's important that we know about toxic antihir segment syndrome or TAS. And specifically, the role of preservatives and stabilizing agents in some of the fluids that we use in terms of causing TAS. So Nathan. Thank you, Dr. Mamelis. Like Dr. Mamelis said, my name's Nathan Ellis. And I will be talking about toxic antihir segment syndrome associated with preservatives and stabilizing agents. I have no financial interest or with the material presented this morning as well. Here's a little bit about our lab. This is Dr. Mamelis, who you just saw, and Dr. Liliana Warner and some of the research that they work with. So toxic antihir segment syndrome or TAS, as coined by our very own Dr. Mamelis, is most commonly seen after cataract surgery. However, it can be after any type of antihir segment surgery, whether it be cornea or glaucoma or any of these. It is an acute inflammatory process seen within 12 to 48 hours postoperatively, although on occasion rarely it can be seen farther postoperatively, but most often within a two day per time period. It is, as the name suggests, limited to the antihir segment of the eye, although also on occasion, very rarely you can have some mild vitreous involvement. However, this is mild and very small. It is always gramstain negative as well as cultural negative. And you can have associate symptoms such as corneal edema that can be diffused. And as Dr. Olsen coined, limbis to limbis, as well as fibrin formation resulting in hypopoions, dilated irregular pupils, an early decrease in intraocular pressure with the possibility of a secondary glaucoma later. This is a great example of the cornea after a severe case of TAS. You can tell that the corneal edema is limbis to limbis as well because of the widespread endothelial damage. This endothelial damage is due to the market antihir segment inflammation. This inflammation can result in this hypopoion that you see at the very bottom, right there, as well as fibrin formation. And this, yeah, excuse me, this anterior segment inflammation can result in fibrin formation. This fibrin formation is then going, can adhere to the pupil, the trapezoid meshwork, and the implanted intraocular lens. When the inflammation and the fibrin will adhere to the iris, it can cause dilated irregular pupils, which you see here, as well as clogging the trapezoid meshwork and causing secondary glaucoma later. However, it's important to distinguish that TAS or toxic anterior segment syndrome is not endothelitis. Therefore, we must rule out an infectious etiology. Like I mentioned earlier, TAS is gramstain negative, as well as cultural negative, whereas endothelitis is often not. Endothelitis has a later onset of four to seven days, although now we're thinking that it maybe is late as two weeks postoperatively. Or as, like I mentioned earlier, TAS is within 24 hours to 48 hours postoperatively. Endothelitis has a prominent vitreous involvement, whereas TAS is mostly anterior segment. And endothelitis is more often associated with pain, as well as lid swelling, conjectival commosis and discharge, and diffuse ocular injection, as you can see here. Dr. Edelhauser wrote this paper in 1982. He was kind of the founder of the TAS Suggestion Committee, which is now known as the TAS-TAS Force. And he wrote this paper that described and a bunch of factors that could decrease the pump function of the corneal endothelium. And I've listed a few of them here that we relate highly with TAS, solutions that are injected into the anterior chamber that are outside of the pH range of 6.8 to 8.2 and preserved in the medication that we inject, including sodium bisosulfate, thymersal, benzalconium chloride, and others. And solutions outside of the osmolality of 200 to 400 milliosmals. So this TAS-TAS Force that I mentioned earlier, if a surgery center is unfortunate enough to have an outbreak of TAS, they can go onto the ASERS website and fill out this TAS questionnaire regarding their surgical techniques and their cleaning and sterilization techniques. And then this goes to Dr. Manless, who then can make recommendations and hopefully prevent TAS in the future at their surgery center. Over the years, this has provided quite a bit of data where we've been able to write papers and analyze and see trends in TAS. In 2010, the first paper came out, the exam was 77 questionnaires and we were able to determine some of the most common causes of TAS. This being inadequate flushing of fake-owned IA handpieces, the use of enzymatic cleaners, detergents at the wrong concentration, and preserved epinephrine. In 2012, we wrote another paper and this was kind of to determine where we had come and where we were going with TAS. We took the questionnaires from 2009 to 2012 and analyzed them to prior questionnaires. Overall, this was 130 questionnaires that evaluated over 69,000 surgeries and over 1,400 cases of TAS. We were able to determine that we were improving on some areas and regressing in some other areas as well. For example, there was a 26% reduction in the insights reporting that they were flushing adequately as well, or inadequately, as well as an increase in, by 27%, insights that were using DI&Is distilled water for the flushes as opposed to tap water. There was also an improvement in the use of preserved epinephrine, but however, we degressed in areas such as handling of instruments and IOLs with our gloves, as well as poor instrument maintenance. So because of these papers, we know there are many known causes of TAS and one of the most common causes of TAS is ophthalmic instrument contamination. This can be done through a variety of different mechanisms and a variety of different contaminants. One of the most common ones is detergent residues. This can be from either the soaps that we use, the enzymatic cleaners, or the ultrasonic bass, which can harprogram negative bacteria. It can also be due to bacterial lipopolysaccharides and other endotoxins found in these gram negative bacteria, which can be in tap water as well as these ultrasonic bass that I mentioned. We don't see metal ion residues so often, but earlier in recent, in further back years, we would see copper and iron in the metal pipes within the hospitals and this could cause TAS as well, as well as denatured ophthalmic viscosurgical devices or OVD. So because this is such a large problem and large cause of TAS, Dr. Mamelis and the TAS Task Force makes recommendations on how to clean your instruments and prevent TAS this way. And first off, we recommend that you flush your FACO and IA handpieces as quickly as possible after surgery. This will not allow the OVD and the cortical material to dry. Once this material dries, it is very difficult to remove and becomes a primary cause of TAS. We also recommend flushing with 120 cc's of sterile deionized water. While this may cause your arm to go into tetanine flushing the IA ports, it ensures that the handpieces will be free of this cortical material and OVD. And we recommend flushing at least the final push with sterile deionized distilled water. We don't want any ions in the handpieces once they go into autoclave because these handpieces will retain the ions that can cause TAS. And also, if we flush with tap water, tap water is known to contain small amounts of gram-negative bacteria, which, yes, are killed in the autoclave. However, the lipopolysaccharides and the endotoxins in the cell wall are not in this can cause TAS. And we recommend against the use of detergents and ultrasonic bass. Ultrasonic bass, if not cleaned properly, can harbor a gram-negative bacteria and once again cause TAS. And detergents have these enzymes in it that help clean. However, these enzymes are active and are inactivated at temperatures of 140 degrees Celsius or higher. That's all well and good until you determine, until we remember that autoclaves only reach temperature of about 130 degrees Celsius. Thus, these enzymes are still active and still able to cause TAS. And once again, we recommend flushing with sterile deionized distilled water. And I already mentioned these gram-negative bacteria found in tap water as well as in ultrasonic bass, if not cleaned properly, can cause TAS because of the lipopolysaccharides. I mentioned the metal deposits found in the piping of old hospitals, as well as reusable canyons and IE tips are often where we find that retained OVD and cortical material is retained and thus we recommend flushing very often and frequently to prevent that. Another primary known cause of TAS is ocular medication. This can be caused through multiple different reasonings. Incorrect drug concentration is one of them. Incorrect osmolality, which I mentioned earlier, if it is outside of the 200 to 400 milli osmols, it can cause damage to the corneal endothium as well as the incorrect pH. If it's outside of 6.5 to 8.5 range, it can be toxic to the corneal endothium and preservatives and medication solutions. One of the first preservatives known to cause TAS was benzalconium chloride. Benzalconium chloride has been used in our topical drops for quite some time now. However, there has been inadvertent use into the intraocular and anterior chambers. This top paper mentioned a case where it was injected into the anterior chamber and the bottom paper mentions a case where benzalconium chloride was actually used as a preservative and OVD. However, that did not last long because both these cases resulted in very raging cases of TAS and very poor vision for the patients. So now I'd like to talk about a couple of different outbreaks that we've seen recently. For outbreak number one, which was at a surgery center in Virginia, we saw this a couple of months ago, actually. There's 276 cases of fecal molestification and eye well implantation surgery performed over a two-month period. This was performed by five different surgeons and 14 cases of TAS presented during this time period. Luckily, the cases were mild and 13 recovered to 20-20 vision. That's correct to visual acuity two weeks post-operatively. The second outbreak is very similar to the first. This was performed at a surgery center in Alaska and there are five cataract surgeries performed by one surgeon on a single day. These five cases, sure enough, the next day resulted in five cases of TAS and were treated with a standard post-operative treatment. And luckily, once again, all these patients were covered at 20-20 best corrective visual acuity two weeks post-operatively. We were able to look at the task questionnaire that they both sent in. We were able to examine the similarities and differences between the two sites and realized that they had both used a medication that they had just recently ordered, which was the epinephrine that they injected into the anterior chamber. This epinephrine was made by parpharmaceuticals who, unfortunately for them, decided to change the formulation. So they, and earlier this year, they changed the formulation adding tartaric acid, which is a known preservative. They did come out with this release earlier that year, but through the FDA, which said that this epinephrine that has tartaric acid is no longer approved for ophthalmic use. However, these surgical centers were not notified. The NDC number, which is the National Drug Code, which anytime a formulation is approved has to go through the National Drug Code, was not changed. And thus, the surgery centers were left unaware and able to order the same epinephrine that they always had and, unfortunately, able to use it and cause cases of TASS. This is the molecular formula of the tartaric acid. We don't know a whole lot about this formulation, but we are pretty sure that it did cause the TASS. And thus, it's a very dire consequence for these patients just because of the formulation that everyone was unaware. Outbreak number three happened a couple of years ago. This was performed at a surgery center in Iowa. There are 12 cataract surgeries performed by one surgeon on a single day, and these 12 cases resulted in TASS, the next day postoperatively. We were able to also analyze the questionnaire and realize that the pharmacist trying to do his job and save money and how about had substituted moxazine for Vigamox. They're both the formulations of moxifloxazine. However, moxazine has preservatives, whereas Vigamox does not. These preservatives are xanthan gum, sorbitol, and tyloxapal, which, unfortunately, tyloxapal is a mucolytic as well as a detergent. Also worth a note that Vigamox has recently come off patent, unfortunately, and because of that, there's gonna be lots of generics coming out, so we may have to be aware that there may be preservatives, and there's generics as well, and hopefully we don't see that in the future. Fortunately, though, Dr. Malus was able to put out a press release warning about moxazine and preservatives of tyloxapal and moxazine, and how it is toxic to the corneal endothelium, and thus we have not seen any TASS cases due to moxazine since then. Our fourth and final outbreak was due to an intracameral injection of Vigamycin. This also was three or four years ago. The compounding pharmacy performed the incorrect elution of Vigamycin. The Vigamycin dilution was a hundredfold, a hundred times two concentrated, and because of this, the pH, which is Vigamycin is fairly acidic, was a four, which is outside of our pH range of healthy corneal endothelium. Also, the dilution was performed with sterile water instead of a balanced salt solution. Therefore, it was outside of the osmolality range as well. Unfortunately, these patients resulted in severe corneal edema, secondary glaucoma, and count finger visibility. So once the offending agent has been injected into the anterior chamber, what do we do? We want to suppress the secondary inflammatory response as quickly as possible using topical corticosteroids. Normally we recommend 1% prednisone acetate every one to two hours, and a couple surgeons are finding topical NSAIDs helpful as well. And we also recommend careful follow-up for the first few days to make sure that the inflammation is going down. However, secondary prevention is not quite as good as primary prevention or primary treatment, and we hope that we can inform the ophthalmology population that with education, the entire surgical team, of the entire surgical team of surgical nurses, operating room technicians, residents, physicians, and pharmacists that we'll be able to prevent tasks. A lot of these cases are preventable, and because of that, we think that in the long run with education, we can improve and hopefully prevent tasks in the future. That is my talk. Thank you for listening. Are there any questions? Well, just to make a comment, this is a real cautionary tale because we as surgeons need to know what's going into the patient's eye, and we often don't. We assume that what is being placed is what we wanted to be, but we don't know, and what was really scary about this epinephrine is that the company changed the formulation in January, didn't change the number, didn't tell anybody. This release they put out, although it's back-dated, didn't really get out to ophthalmologist until July when we started getting reports of people having this unexplained inflammation, and they changed the formulation, and they wrote on there, not for ophthalmic use. And, but again, didn't tell anybody, and so as people went through their stock of epinephrine where you use it for several months, nothing was happening, and then they switched to the new one, and then we get an outbreak of tasks right away. And so, of course, we're sending out alerts and working with companies now, and one of the things that the task force is working on now is we're approaching the companies saying eyes are not blood vessels, and eyes react differently to preservatives and to stabilizing agents, and so you need to make a preservative-free, stabilizer-free epinephrine, but the second thing when we tell them is there are three million cataracts done in the United States every year, and virtually all of them use epinephrine during the bottle or intracamely, so it's a huge potential market, so I'm still puzzled as to why companies haven't seen this and jumped on it, and so at the moment, you know, you're having to go through obscure sources to get this epinephrine instead of the main companies, and the other main company that used to make this was bought by a second company who then said, well, if we don't put stabilizing agents in here, their shelf life isn't long enough, so we're gonna change it, and again, with no thought to the fact that inside the eye, which is their main market, an adding of a stabilizing agent or a preservative is potentially gonna cost toxicity, and so we need as a society to educate not only ourselves and nurses and people who are already in medications, but also the companies themselves. I felt really bad for the surgeon who had the outbreak of Banco Mycin, a pharmacist in their center said, hey, we're gonna save money, look, Moxasin, this has Moxifloxacin, and it will use that, didn't tell anybody, and so of course, they substituted it, and the patients all have raging inflammation because there was preservative agents in there, and so anything you put into an eye has to be preservative-free, stabilizer-free, so it's very important that you realize what's going into the eye, and the problem is we often don't know, we assume, and we're handed a syringe, but we need to kind of step back and say, okay, what are we using now? Yeah, so there's actually going to be a lot of questions. Oh, I was gonna ask what the history is in our center, the past, or the VA, do we have, I like vaguely remember one case that we thought was the case, that the VA- There's been a rare sporadic case, but fortunately we've been lucky, we have not had a major outbreak here, and so we spent a lot of time working with the nurses here, and it's interesting, the other thing we're fighting now is the use of enzymes, and so CMS and some of the regulatory agencies have decided that because people in California had infections from colonoscopies that don't have properly enzyme, therefore all instruments and all surgery should be treated with enzymes, and so again, we've been fighting that fight with the FDA and with CMS, and with regulatory agencies to say no, we have enzymes on ocular instruments or toxic, they're not colonoscopy, they're in the eye and they're toxic, and so here at this hospital, the U was gonna make us use enzymes, and so we had to fight them to the nail and prevent, present data and do everything to get them to say no, we don't have to do that, but again, it's something that a random surgical center will have and someone will come in and inspect them and then cite them and say you have to do this or we'll shut you down, so we've been fighting this all the way through and so we're to the point now where we're having to change manufacturers' recommendations from each manufacturer so that they don't require enzymes for other instruments, and so it's just the law of unintended consequences, and so the problem is we all have to be vigilant and so far it's only here we've got a good group, they're aware of what's going on and everybody's aware of that, I've been spending time talking to the pharmacy and they have a stable source of preservative free, stabilizer free, epinephrine, the bigamox is coming off patent and so now they're generic moxifloxacens available and so again, they're being very careful to get the preservative free moxifloxacens and even in the generic so that we can still use that safely for those who use that intracameral. I'm surprised that these are toxic to endothelial cells in blood vessels. Well, but because they're diluted in six liters of blood, I mean the effect is it's not that big, where you're talking in the anterior chamber, we're talking .3 milliliters there and so it's very concentrated as opposed to throughout the entire license. And they are, and you have the protocol for some antibiotic infusions, for instance, or the needle in it is from this particularly toxic IV administration being flush first, flush after, flush during, or you can't put it in a peripheral IV, you have to put it in a central IV. This is an issue for, but I think that it's a much easier battle than in the eye, because you can't flush. Great, thank you. Thank you.