TXA in Trauma: Dr. Paul Pepe (1/23/2023)

Hey. So good morning, good afternoon, good evening, whatever time it is that you're watching this. And thank you very much for paying attention to this. I'm Dr. Paul Pepe, primarily doing this on behalf of Broward Sheriff's Office, where I serve with Chief Clark and Dr. Roach as their medical director for education, research and also special operations. So get to have good time with great crews of folks out there from time to time. I also like to have this be available to anyone else who would like to use it, whatever purposes, you know, in their own education and hope that it'll be helpful to you as well as we as you see this session today.

So what I plan to do here is just do a review for the rationale for the txa, since many of you are now using it in your protocols. I want to kind of give you the background for why we're doing it this way and maybe provide some caveats about how we deliver the, you know, the treatment. So let's see if I can get this going here. So this is our latest thinking on txa, transaxemic acid. And there are new studies that had just recently came out that predict more routine EMS use and improved dosing and timing in trauma patients, particularly those with with severe head injury. So the main thing I'd like to get across today is that in recent publications, including those from Florida EMS leaders, there is, and not to bury the headline, there is a move now to go directly to 2 grams IV upfront IV or IO up front. Early on we'll talk a little bit about how to deliver it. But the main thing is that we think this is the best way to do it and not to deliver it late is the key issue. So an article that I published along with some other leaders in the field a couple of years ago was called Non Mechanical Hemostasis in Trauma Care. And of course that goes along with beyond tourniquets and beyond.

Actual clamping of arteries or whatever it may be. Are there non mechanical ways? And of course, the things that are evolving are blood products and NTXA as we talk about. And that's what this was about. We did an update on that the next month in terms of using TXA and tbi. And I'm going to cover the rationale for that as well. I mean, in both situations, if you're bleeding internally where we can't control it, or you're bleeding internally inside the skull, that's the rationale for doing this. In fact, in the fall of 2020, so not too long ago, the Tactile Combat Casualty Care Committee of the of the US Armed Forces came up with the concept of using transaxamic acid in or TXA in tactical combat casualty care. And the key thing about it, I want you to note is that they said the most significant updates that they had had for the guidelines are including significant traumatic brain injury as an indication for TXA and also changing the dosing to a single 2 gram IV IO administration and recommending TXA administration via slow IV IO push. Our protocol generally has called for, you know, for example, if you're over 12 years old, 2 grams and 100 mils that is to be infused in a 10 drop set with 3 drops per second to give 100 mils, et cetera. In theory though, you know, if we are really in that situation, situation where it's needed, you could give it as a. But a slow IV or IO push. IM is probably not ready for prime time because some of our concerns have been that if you're in a low shock state and it may not be absorbed as well as quickly. So that's we're going with it. So we're in agreement with what the they published in JSON in terms of the tccc. All right, so background just quickly is that here's what it looks like chemically, right. But the rationale has been that about since the 1960s, this has been used to sort of hypercoagulate somebody to promote hemostasis, meaning, you know, non mechanical hemostasis, but getting control of bleeding, using it mostly for severe nosebleeds or infused, you know, parentally meaning IV or IO for menoragia, postpartum hemorrhage and many other elective surgeries. And when they were doing that, they decided to give a gram up front, then they would sort of drip in a gram. Over time that becomes important because in the arena of trauma we think that may actually not be a good thing to do. And it's led us to where we are today. And by the way, the way this sort of works, you could read through all this, but it maintains a more coagulable state the way it works there. And it also may have a powerful anti inflammatory role. So it may not be just that TXA causes more clotting, but has the ability to decrease permeability of, you know, the blood vessels. And what happens is it sort of really helps with what blood products are meant to do, namely to help you, you know, protect the lining of the blood vessels, et cetera, and keep them from leaking. So and it has the ability to reduce brain edema as a result. All right.

So.

Where this kind of started, in many ways, it was an article that was published in the British medical journal the Lancet about a little over 10 years ago, and they said, well, if we can use it for bleeding for other surgeries, can we use it out here? So they use the same pattern, the one gram up front and then the one gram over the next eight hours or so, just mimicking what was done in surgeries. This kind of came under some fire by some people because they use 274 hospitals in 40 countries, 20,000 patients and so on. But there is only a small difference in percentages of the case where you're really getting that much and yet there could be complications and so on. But there was an interesting signal for me in this, this paper, and that is that if you gave it really early on, it really made a difference now. So overall, they said, here's better outcome over here, worse outcome over here. And this is like no difference here. And if you're out here, that means one and a half, 1.2, 1.3 chances of dying. And down here it's like, went down to 80. You know, this is like 85% chance dying. In other words, lesser than, you know, that even odds. But what was fascinating is this is actually an average of if it was given out here and if it was given here. Let me be more specific. So, for example, if you gave it in less than an hour, the chances of dying went way down, almost, almost cutting close to cutting in half, et cetera. And so that really evens out. In fact, if you gave it within the first hour, overall, it was, you know, generally better. Okay. But the main thing was that if you gave it within the.

Say, out, out beyond three hours, then the chances of actually dying got worse. So how do you explain that? Well, what I'm going to basically put out to you is that in our opinion, and this is a joint opinion of many of us working in this area, is that the risk benefit ratio flips. In other words, the benefit completely outweighs the risk of the coagulation that you get when you give it really early on, and it will save lives. However, if you wait a little bit and then you're actually living longer, maybe it's not going to really enhance your chances of living, and then it's just going to give you more complications from, you know, from getting the coagulation effects, you know, like blood clots and so on, that'll happen later on. So you're going to See, the main theme here is that let's just give everything up front and let's do it as soon as possible and you'll see where I'm going and I'll provide more evidence for that as we go along. So turns out chancexamic acid TXA was very cost effective. Effective that crash two people, as this thing was called, that study, you know, we're very excited about it. It all sounded, you know, pretty good from that point of view. But here's the but over the last 10 years, as people were looking at their coagulations, this looks like someone we better treat. It was a little bit later in the game and often in the hospitals. And so trauma surgeons were starting to say it's associated with an increased risk of post traumatic venous thrombolism. And so it had a really downside. And I just want to put that, that goes on to my theme, that when you did give it later you were seeing more complications. So what happens now is the risk benefit ratio kind of flips and now there's more risk than benefit from it at that point in time. So it goes back to this slide when I really broke this thing down to the timing of txa and that's, I think this is a great thing. It doesn't mean that TXA is good or bad. It depends on how you use it and when you use it. So again, if you give it within an hour, I think it's going to be really good. And hopefully the earlier the better by the way. But if you wait too much longer, you're losing that effect and you may have more worse outcomes as a result. Okay, so which way do we go? Well, the next thing we wanted to look at is how about in the area of head injury? And so that becomes interesting because it turns out that if you have people with pretty severe head injuries, for example, in one study that was recently done, if you had a Glasgow less than 13, in other words, let's say they treated people between a Glasgow of 3 and 12. What they found was that over half the people had a so called space occupying lesion in the brain, in the skull and that was like an epidural or a subdural or other kind of bleed that was in there. So one of the things that becomes important about is that if it continues to bleed, and of course especially epidurals are known, that people will actually talk and then die because they are okay at first. But as the arterial blood continues to accumulate, that's that causes the problem. So the earlier we can get to them and treat them. It would be fantastic. So there Crash three study was done as a result. So they again, our team out of the UK with all these other countries here at this time, they had 175 hospitals in 29 countries. And they looked at it and what they found was they kind of only found help in this case for people with moderate head injuries or mild head injuries and not with severe head injuries. And you'll see later there are cases or studies that which those severe head injuries help. But I think the takeaway from this, it had the same kind of criticisms or same kind of limitations or perspectives, caveats that you have to put into this. But I came away with the same thing, you know, when and what they did was they give 1 gram bolus plus the 1 gram over 8 hours, which I'm going to be arguing against doing that versus the placebo. They looked at mild to moderate hemorrhage and they gave it within three hours, which again, I have some issues with. Okay. And again, it was about a lot of patients, 6,000 versus 6,000. And they did have improved outcomes. Although the actual percentages, like if it was like 18% versus 20%, I don't know the exact numbers, it was better, but it was just not a major benefit in those studies. But of course it had all these other issues, as I was telling you about, that the groups may have gotten it late, they were not all, well, standardized, et cetera. But the good news out of this are two takeaways for me, safe and no increase in complications. But there was, they said there was no benefit in severe head injury cases, but overall they just still said in terms of mortality, the earlier the better. And I'll show you a graphic from that study that I'll sort of tell you what I mean for that. Now, there was another study in looking at TBI came out of the United States. It was sponsored by the National Institutes of Health. And in that study, they prospectively said, hey, are they doing better overall at six months if we gave this stuff? But cleverly, they also said, let's make sure we look at the subpopulation who actually in the end got a bleed. Okay. And as I mentioned before, half of the people you know that have, let's say head injury between a Glasgow 3 and 12 are going to have, you know, you know, have active bleeds in the head based on CAT scan findings later. But the other interesting thing, that means that whatever, 40, 45% don't have that bleed. So if we give them the drug Is that going to be harmful? So this is kind of cool. This study is great because not only did it give you a sort of an in built in safety group to see if you didn't have it, would it harm you. And also they were specifically looking at the target audience, namely the people that had a bleed in the head, you know, in retrospect. But there's one other thing they did here beyond that was that they actually compared the two grams up front to the one gram plus one over eight hours and then compared to placebo, meaning, you know, just saline or whatever it was that they were given at the time. So again, back to these. Now we're looking at again at serious cases and again their criteria were Those less than 13, Glasgow Coma score 3 to 12. So this was also known as the ROC TXA study, that's the Resuscitation Outcomes Consortium study that was led by Dr. Marty Schreiber, who's just the fantastic genius in this arena and very cleverly, as I said, designed this in a way that answered a lot of questions for us. So it was published in jama. And when they looked at the trans examic acid versus placebo, there's a little bit of an improvement in the neurological outcomes with people who are moderate to severe head injury at six months, but they didn't show real statistical significance. But as I said, they cleverly decided to look at patients that had actual bleeds to see if there was a difference made for that group. Right. So this is published in September 8, 2020, journal the American Medical Association. Again, they gave 2 grams versus another arm with 1 gram plus 1 gram over 8 hours plus versus the placebo. And they were looking at moderate to severe TBI versus the crash three, that was looking pretty much just mild to moderate tbi. And the other thing that was, I think, impressive is they really went prehospital with this. And there was early infusion after the time of the incident. You would actually have a 40 minute median time to delivery. What's median time? Median time means half the people got it within that period of time, which is impressive. So, so basically.

Half of the people got it within 40 minutes. And that's going to be, you'll see how that's going to weigh on things very importantly here in the study. All right, so nearly 60% of the people had an intracranial bleed, as I sort of alluded to before. So we're able to look at that population as well as the population as a whole. And so again, about 44% didn't have a bleed. So we were giving them TXA. Yeah, they didn't have a bleed, but it turned out, you'll see in a second, there was a built in safety cohort and sure enough, it turned out to be safe for them. All right, so the overall results, as I said before, was that there was a mild, you know, improvement. But with the small numbers studied in this group, it didn't show statistical significance. But there is that trend there. But when you examine those with CT confirmed intracranial hemorrhage, the target group, what we found was there were 16% mortality with 2 grams up front. With these, you know, severely injured patients. 60, keep that in mind. 16% died. That means 84% survived. But okay, let's look at the 1 gram plus 1 gram. Okay. And if you look at it, what's interesting is that they had a 27% mortality, which was eventually the same as the placebo group. So it kind of goes along with my working assessment of all these studies is that if you give it up front, you're in good shape, but if you give it later, you're going to be more apt to live long enough, I guess, to get complications. And so it would be better just to give everything up front. And this study kind of corroborated, at least in the realm of tbi, but most of us now believe that that's probably the appropriate way to do this anyways as you go through this. So that's an important piece of data there. And there was some risk of seizures, but if I remember correctly, it was like 13 cases out of 300 versus 8 cases of seizures out of 300. Where they're comparing them to. And so I don't. It turned out that no one had any complications afterwards. And it turns out that seizures are what you see in a certain percentage of the cases. Not a lot, but you see them. So we have to be prepared to take care of them any. And if it didn't change the outcome long, long, you know, in the long haul, then we, we deem that this was turning out to be safe, you know, as we followed up in all these patients so long. So what were the takeaways? Well, the takeaways for me is this, is that the signal was there from the beginning, is that if you treat them less than an hour, it's much better. Okay. As we showed here before, and you treat them too late, you know, then it's a worse outcome. Our protocol says up to three hours because you see this here, but again, this is averaging things out. And I'm a proponent for trying to get everything on board within an hour, if not a shorter time. And that's why we're going pre hospital with it in our area. If you go to the crash 3 study about that, you know, the head injury patients, again, they didn't show much difference. What we're looking at here is the relative risk of dying, okay? It's called risk ratio. And if you look at this with the severe Glasgow COPA score in their study, remember they're only giving one gram up front and one gram over a period of time. They didn't see much difference. But when we look at time to treatment with the other patients who had the good outcomes, again, the chances of risk ratio goes down almost near half. That's 0.58, not 0.50, but close. And here's your 50, 50 chance of dying, right? But here you've gone down to about 50% of what you, what you had overall for the group. And again, this whole thing says the earlier the better. Here's that first hour or so. So I think you were seeing a trend not only with them, but then you get to this TBI study where they actually looked at getting it on board. Remember the Median time was 40 minutes. And you get this is all measured in days. But you could see, I mean the whole point of this is that in those, that if you get it on board early on, the bolus only group, the 2 grams up front was doing much better and it continued to do much better all along. If you look at this. So again, same signal, the earlier the intervention, the better the results. And just do the bolus upfront with the two grams. Okay? More recently there was a study that came out of JAMA surgery about the same time. And again, what that did was there was better outcomes with a higher dose and treatment within the hour, especially with hypotension. So if you go through all these data here, when they, they gave 1 gram of PRMPA, then they gave a 1 gram dose I think in the emergency department early on, but it was all pretty much within the hour. Again, this says as if you look at these, this means they, it favors, it favors transaxement. If they got that additional dose which gave them kind of 2 grams within an hour. And that was statistically significant. So that was kind of interesting. And again you see this same risk ratio here's one to one. But then you get down here and your chances in this sub population here, you know, goes much down lower towards, you know, 70% chance of dying, what you would normally have, that risk ratio goes down. They also found, interestingly enough, is that you look at time from injury, if you got it done within an hour, again, same thing, you start seeing that these are statistically significant numbers there. And also if your blood, the sicker you were, the blood pressure less than 70, that was again, stronger. Stronger associations with better outcomes. So everything I've seen keeps pointing to the fact that give everything upfront as a bolus, give it, if you can, within the first half an hour, but the earlier the better. Hopefully within the first hour altogether and then, and then after that, you know, the, the risk for complications begins to go and eventually outweighs the complications that you could get from this. And that's one of the reasons why many of the surgeons who were trying to evaluate we should, we should treat with txa, you know, later on in the hospital, were seeing these complications and didn't favor it. And I'm just really favoring that. Just like the combat guys do, that we should give it early on. If it was my family member, that's what I would do when it was, if it's the appropriate situation, such as a person we want to give blood to. Okay, so the summary, and of course for heterogeneity as well. So here's the summary for TXA, for TBI, better outcomes, but only if given early. As a 2 gram bolus, it's safe. If it's given earlier, it's likely good for all trauma cases, including internal beating and TBI for all the same reasons I mentioned. So it just goes back when I said, let's not bury the headline. The most significant updates for the TCCC guidelines are including significant trauma traumatic brain injury as an indication for it, changing the dosing protocol to a single gram IV IO administration and recommending that TXA administration is done by a, you know, via a slow IV IO push, or as we're doing, is to give it, you know, in the drip over several minutes. We'll come in about the way we're doing. It'll be in within five minutes. One little technical thing that's come up for me is that we say that you should give it and you can give it at the same time as a blood infusion. You're doing it for the same indications, for example, but hopefully in different lines. There is some theoretical issue about putting it into the line with the temperature changes or whatever. But if, let's say you could only get one line in, what you could do is infuse the blood first, which I think is going to be the most important thing to do. And then that's only going to take a couple of minutes. And then use that same line, flush it, and, you know, hep lock or whatever it may be that you have in, and go ahead and infuse it then at that time. And the delay of three or four minutes is not as big an issue of delaying it more than, say, half an hour or 45 minutes. I'm trying to think if there's any other practical matters, but that this may not reflect exactly what you have in your protocol. You've got the protocol, but I'm giving you the background, my best advice. And, you know, and again, if it was my family, this is what I'd want done. And so remember, if you're going to be giving to someone who needs blood, that would be appropriate candidates. And also if you're going to be using it for a severe head injury. We're again going along what they found in the NIH study, which is a Glasgow Coma Scale, somewhere between 3 and 12. But we're just going to say, you know, under. Under. Under 13 is. Would be the appropriate way to do it. I don't know if there's anything else to come in, but I'm available for questions, answers, and I hope this is what. This would be helpful and it just gives you an interesting insight to how we got to where we are today. And in conclusion, I hope we're going to get back people we never got back before. And the road to the 22nd century will make life better for future generations. So with that, thank you very much. I'm Paul Pepe and I approve this message. Okay, thanks.

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