BIG T Trauma Series Ep. 21: All Things TXA

Yeah, I can imagine that could be true. I, I really don't know. I, I like the thing about randomized trials is they give you the answer In the crash two trial, there was less deaths in the tranexamic acid group, but why? It's a hypothesis, isn't it really? It's seeing you have to have two grams to get in effect, and yet two grams is where we start seeing the adverse effect. So that's why, again, I. Stay on our track of trying to pick the right patient. And then we'd done some research that showed it's really well absorbed after intramuscular injection. So you give a gram of tranexamic acid intramuscularly and you get therapeutic levels within. Three minutes of the injection. All right. Welcome back to Behind the Knife's Big T Trauma series. This is

Patrick Geoff, trauma surgeon at Duke University, and today I am joined by trauma royalty to discuss the use of TXA in trauma. First we have Dr. Jean Moore. Here's the chief of trauma at Denver General Hospital for 36 years, chief of Surgery. For 28 years and the first Bruce m Rockwell distinguished chair in trauma surgery, he is a distinguished professor of surgery at the University of Colorado, Denver, and was the editor of the Journal of Trauma from 2011 to 2021. Under Dr. Morris's Leadership, Denver General became internationally recognized and still is for innovative care of the injured patient. His trauma of research lab has been funded by the NIH for 35 consecutive years. And in fact, in July, 2018, the center was renamed Ernest e Moore Shock Trauma Center in Denver Health. Quite an honor, I must say. Our second guess is Dr. Ian Roberts. He's a professor of epidemiology at the London School of Hygiene and Tropical Medicine. He's a trained pediatrician in the UK and then in epidemiology at the University of Auckland, New Zealand, and

McGill University in Canada. He's a clinical academic who works collaboratively with health professionals worldwide to conduct really phenomenally large and important, uh, multi-centered trials that are aimed at improving outcomes in patients who have life-threatening emergencies, bleeding, trauma, et cetera. And the work he's done to put together these big, uh, consortiums is, is something that's truly special and impressive. And he's played lead roles in several large trials, including the crash trial. Relevant to our discussion today about TXA and the women trial as well. So welcome to you both, Dr. Roberts, Dr. Moore, pleasure to have you on behind the knife. So with that, let's talk TXA. So, TXA has been shown to reduce all cause mortality in trauma patients, especially when it's administered early within three hours of injury. And its safety profile has largely been affirmed in multiple, uh, studies. Most of them of decent size. Now, if you do a deep dive into the literature, though, it's enough to make. A simple trauma

surgeon's head spin. I know it. It has confused me at times throughout my career, and there are questions that persist such as, what is TX a's actual mechanism of action in these injuries? Does the mechanism of injury matter? How should I be dosing and delivering TXA should all my patients be getting it? About their vital signs. What about transport time, et cetera. So today we're gonna break through the noise and with the wisdom imparted upon us by our esteemed guests, we will finish this podcast wise to the ways of TXA. So, Dr. Roberts, Dr. Moore, let's get started. Dr. Roberts, how did you first become interested in TXA? Well, I got interested in bleeding through a, a clinical case that I had when I was a, I was working as a pediatrician in, in trauma care. So I got this 11-year-old girl who was in a high speed road crash and she had a, a lap belt on and she slid under it and rupture a lot of internal organs and she was in the Mercy

department. I was resuscitating her. And because she didn't have a head injury, she was fully conscious, but she was deathly pale, hypertensive. But she was talking to me and I said, well, look, we, we are just gonna put you to sleep and take you to the operating theater. I gave her an anesthetic and she didn't wake up. She exsanguinated on the table. I always had this thing about, oh, bleeding. It was a bit visceral for me, but what I thought is, road crash. Let's find a way to prevent road crash. So I thought prevention, that's something to do with epidemiology. And I trained in epidemiology, but then I realized it's about treatment as well. And we started looking what evidence there was and doing large scale trials. So we just finished a very large scale trial called Crash one. What? It was just called Crash then. 'cause we didn't know there was a crash, two steroids in head injury. We randomized 10,000 patients. There was no patient benefit. And I saw this. Review of tranexamic

acid in surgery. 'cause I was the editor of the Cochrane Injuries Group. I thought, my goodness, look at this. This stuff really reduces bleeding. Well, I want, if it reduces bleeding in surgery, perhaps it'll reduce bleeding in trauma. And we had all of these, this international collaboration to do this head injury trial. And so the same group of trauma surgeons and emergency physicians, we say, right, okay, we've got a new trial now. Can you help us with that? And then so Crash one turned into crash two, and we've managed to randomize 20,000 patients and got a really surprisingly positive result. Yeah, I'll say. And and Dr. Moore, how about you? You are known for your research in trauma and coagulation, bleeding, et cetera. Do you have a similar story or how did you become interested in TXA? Well thank you Patrick, for inviting Professor Roberts and I and we are long term friends and colleagues and it's interesting

to listen to backgrounds and I think it's important when you hear people speak, you recognize where they come from. Interestingly, we became interested in TXA because of our work in FAR isis, far. ISIS was largely ignored in trauma until we all began using visco acid essence. And we were fortunate in our institution to do some of the fundamental animal work in TAG in the early two thousands. And in 2009, we reported to the American Surgical, to our surprise, and when we looked at tags that roughly 15% of the patients who, uh, had uncontrolled bleeding, bleeding had lysis. So we wrote this paper and said, fibrinolysis is critical and we need to understand it better. So we became very enthused of the idea of, uh, TXN. Of course, crash two came out in 2010, and that punctuated

the point that this may have a great application to trauma in our lab. Most of this work is done by our trauma fellows, who are Mike Chapman and my son Hunter. They were trying to define what cutoff we should use with the LR 30 on tag to give TXA. So that set off our question, are there phenotypes that might direct where we use TXA? So that's fundamentally been our background. It's been amazing to watch your labs work, grow, and build on itself to farther define these subgroups that are clinically important. And so this underscores the idea here that TXA, again, for a simple trauma surgeon, this is a lysis inhibitor. There's, there's more to it than that, and we're gonna talk about that today. So as an opening salvo then, Dr. Moore, how do you teach your fellows and your residents about TXA And its, uh, clinical importance. Well

first, uh, we emphasize that there's no question that TXA can inhibit fibrinolysis and produce uncontrolled bleeding, but our overarching view is that TXA should be given to the right patient at the right time, and now the right dose that's fundamentally where we're, what we are, uh, suggesting. Dr. Roberts before, again, we're gonna talk crash here in a minute. What's your overarching principled approach at this time? Uh, when it comes to the XA use and trauma? Um, surprisingly not that dissimilar. I think the right patients at the right time and the right dose, I think the right time. We've got quite strong evidence that the right time is. As soon after injury is possible. When blood vessels are cut or ruptured, they release

tissue plasminogen activator. So there's a very early burst of fibrinolysis, but this early burst of fibrinolysis doesn't last a long time. It worsens bleeding while it's there, but eventually the body's own inhibitors wake up and turns off fibrinolysis. So it's in that kind of early fibrinolytic gap that you need tranexamic acid, the exact duration of that period, I, I, I couldn't be sure about, but we specified in the crash two trial before seeing any results that we'd look at patients within three hours and beyond. Three hours and mar and only because three hours broadly cut the patient population into two. Right. What we saw is very strong evidence of mortality benefit for those who got it in the first three hours. Mm-hmm. Uh, started treatment in the first three hours and

very little evidence of benefit for those who got it late. So I think the right patient bleeding trauma, patients who are within three hours of injury and the right dose, I think. Yeah. Uh. There's been, there's different views about dose. Obviously in a big, simple trial, you pick one dose, so we picked a gram stat, uh, as soon as possible after injury, and then another gram over eight hours. And you, you'll be surprised, the rationale for that. But a gram was like, well, the gram is easy to remember. And we, we looked at some of the cardiac surgery trials. And it wouldn't be too much for someone who's quite thin and it would, wouldn't be too little for someone who's very big. And so we thought, well, the gram's about right. It inhibits fibrinolysis, whether you are that or thin, the heavy or light and, and then we thought the

second gram was just to stop. If someone's really bleeding severely. We just didn't wanna make, we wanted to make sure that our first gram of tranexamic acid's not in the emergency room floor. So we, we kept an infusion going. 'cause some of these patients have a lot of blood and you can lose it all through dilution. So that, that, that was the rationale. Well, let's talk crash. Uh, I think the best way we could approach this is for Dr. Roberts to talk about the, uh, crash trials. And then we're gonna turn it over to Dr. Moore for stamp and patch and the rock DXA trials. I want everyone to bear with us for the moment. These are really important. You have to understand the basics of these trials to be able to have a meaningful discussion about TXA and wrap your head around it. And there are several large randomized control trials that explore DXA use in trauma, but by far and away the crash trials dominate the discussion due to their sheer size. And Dr. Roberts, you were the first author on Crash two, played a, a massive role in crash three. So

congratulations on that. Massive effort. These are extremely important trials that drive a lot of what we talk about and. Pragmatic in, in every way. Can you do us a favor and summarize both trials? So just a quick background. The area that seems to made the a lot of progress in healthcare is cardiology. And we looked at cardiology. Why is cardiology so good? Well, cardiology, they've got safe, effective treatments. And how do, why have they got that? 'cause they've done. Huge trials. Cardiology trials are big. I thought, why couldn't we do that In trauma, there's no shortage of trauma on the earth, so we planned a large, simple, multicenter, international randomized trial where we aim to randomize 20,000 bleeding trauma patients and really broad criteria of bleeding if the patients either got or suspected to have significant hemorrhage. You randomized, put them in the trial and they'd be randomly

allocated to get a gram of tranexamic acid, followed by a gram over eight hours or matching placebo. And the main outcome was death. And the death is a great outcome measuring clinical trials because one, it matters to patients, and two, it's easy to measure. Nobody gets that one wrong, whereas a lot of other variables, outcome variables, there's a lot of misclassification. So. We randomized 20,000 bleeding trauma patients, and we just got this like really surprising result. There was a highly statistically significant reduction in death due to bleeding and all cause mortality with tranexamic acid. And because it was a big trial, we had very powerful subgroup analysis. We could see that this time to treatment thing made a huge difference. You know, if you got, if you got it within three hours, it, it reduced your risk of bleeding death by about a third. But if you got it late, there was no benefit at all. So,

so that was the crash two trial, and then it went into guidelines in the uk. But when they were making guidelines, they said, well, what about isolated traumatic brain injury? Um, so we ended up randomizing another. 12, 13,000 patients this time with isolated traumatic brain injury, which is crash three. Yeah, that's crash three. And the results were almost the same as crash two. There was an early reduction in all cause mortality for those who got the treatment early, and there was much less death on day one with tranexamic acid. But the overall treatment effect at 28 days was less because. They didn't die of bleeding, but often they would die from ventilator associated pneumonia or, or some infectious complication down the line. So the treatment effect was good, but it wasn't quite as good as crash two.

But I, I saw it very much as not a separate trial, but. A missing subgroup of the crash two trial. Really, it was like a fill in trial. So before we move on, let's go back and ask one question about crash. Two. Roughly 50% of patients in each arm received. Blood. That's not a lot and, and at least when this trial launched, our thought was we're gonna stop bleeding through anti fibrillin mechanism of TXA. That's an interesting finding 'cause your results span beyond or would be greater than just perhaps these bleeding patients. So how do you square that when people ask you, Dr. Roberts? Well, I bleeding's not a particularly good outcome measure. Clinical trials of treatment for hemorrhage, and there's a number of reasons. First, unlike in surgery where you can titrate blood transfusion with the volume of blood that's known to be lost, you don't, it's very difficult to know how much patient, how much blood a patient is lost,

has lost in a, in a trauma patient. And o obviously you can see the physiology, the pulse, and the blood pressure and that sort of thing, but you don't know. How much blood is in the abdomen, for example. And so what people do, they tend to give a recipe. They say when the patient comes in, you do this, or you give them this many units of this many units of this and some platelets. So first, the initial blood transfusion is nothing to do with the bleeding. It's, it's just the recipe that you get. Second, you've got this bias that. If you, what? You already transfuse alive patients and there are more alive patients in the treated group, so you're gonna get more blood transfusion in the uh, tranexamic acid group. And with trauma, the blood transfusion isn't for the

bleeding that happens after you give tranexamic acid. It's for the bleeding that occurred before you gave tranexamic acid. So it's the outcome. It it, so the bleeding that you're treating happened before the treatment for a variety of reasons. It's not a particularly good outcome measure in clinical trials. I think it's a thing that doctors do to patients. It's not a patient endpoint. Do you have any thoughts on that? Well, I, I agree that it's imprecise. I'm not here to debate crash trials. I just think some people said, as I think you're asking, wait a second. If TXA is given to reduce blood transfusion, then why do these patients have the same amount of blood transfusion? And again, I'm not here to criticize, I'm just reiterating. I think the question you're asking, and I think what Ian's saying. Amount of blood you get

is an imprecise measure of physiology, and it depends on who gives it at what time and what indication to perhaps explain why that would not make sense in terms of the hypothesis. So Patrick, in surgery there's very strong evidence that if you give a dose of tranexamic acid before you cut, the patient bleeds less and requires less blood transfusion. Now I think if we could give tranexamic acid just before someone had their major trauma, we might see less blood transfusion. But that's actually not hap what happens in a trauma trial? In a trauma trial, the patients are injured and then two hours later they're often an hour, half an hour, anything up to several hours later, they arrive in a trauma center or a trauma hospital, and they're transfused. But the treatment. Has come after the bleeding, so you can't prevent it. So a, a big lump of the blood

transfusion is for bleeding. That's already happened. That's can be affected by the trial treatment. Understood. Let's move on to talk about the stamp patch and rock TXA trials as important bleeding trials and we can come back to crash three when we talk about mechanism of action. 'cause again, this is where. Things get a little confusing for the folks who aren't deep in the world of TXA. You know, we have patients with head injuries, uh, without intracranial hemorrhage, and we're giving TXA. So what are we, what's it doing then? Because something's happening. Uh, so Dr. Moore, let's start with, uh, stamp, if you would. What's the takeaway that you have, uh, from the stamp trial? Because this is an interesting, um, trial to talk about side by side with Crash two. Yes. First of all, let start by answering the question I hear almost every day. Why is there ongoing confusion about one to give TXA and trauma? Well, I, I think the three trials I'm gonna mention, I think, explain why

there is some confusion. Yeah. The SAM trial was a four center level, one double blinded study. Well, well done. And it was coordinated by the University of Pittsburgh JAMA Surgery 2020. Uh, and is, it was done between 2015 2019, but I think this is where the water gets a little cloudy. First of all, of course, I wasn't involved in the study. They gave three different doses, right? They gave a gram prehospital. Another one gave a gram prehospital. And during eight hours, as Dr. Roberts says, uh, used in his trials and then they had a third one, they gave a gram, prehospital a gram when they robbed and the gram over the next eight hours. So they have three different, considerably different dosing of the TXA. They basically included patients who they believed were in shock, and then the primary endpoint was 30 day mortality.

They had 9 27 patients in the group, relatively mire compared to 20,000 in crash two, right? So the results were that there was absolutely no overall effect on mortality, 28 day mortality. In fact, if you look at the, uh, Kaplan Meier, the two lines are, are inter posable, uh, throughout the entire time course. But again, like it, a lot of these trials done. When they went back and did a post hoc analysis, they found there are three groups that benefited from TXN. Mm-hmm. Uh, and uh, the first was somewhat surprising to me, but basically the only group that had improved survival significantly was the three gram. So now we add in this considerable variation in dosing and yeah, of course, one of the problems when you. Have

different treatment groups, then you need more patients to have any kind of power to interpret it. That's the only problem. But they actually, they struggled because they had to terminate the study early because they couldn't get recruitment. And it's just, it's frustrating because we really need the large numbers to be able to analyze it. Anyway, the three things they found. The first was a three gram dose, uh, was the only dosing that had a benefit, but the latter two earnings I think are incredibly consistent of literature, and I'd like to, to see what Ian thinks about that. First of all, the, the benefit, it was only seen if the TXA was given within the first hour, and secondly, it was only seen in the group with a cystoid blood pressure, less than 70. I've seen this in multiple ones and parenthetically, I, I don't think we should use non-randomized trials to get into this discussion. They're a

mirroring of, and I've been building this myself, if you don't randomize them now, we had enough time. We should be really focusing on randomized trial to guide how we use TXA anyway. I think it's frankly, consistent. One is just less than one hour and blood pressure less than 70. Yeah, and one of the commentary on the stamp trial is that mean ISS was 12 relatively low, and 22% were hypotensive as defined by systolics of less than 90, and overall mortality was less than 10%. And then you take these 460 patients, randomized tranexamic acid divided by three different doses, hence some of the confusion. Dr. Rocks, any comments on that? Yeah, I think Damour said. It's great that they've done a randomized trial, but when they added together all of the tranexamic acid groups together and compared it with placebo, the reduction in the risk of death was the relative risk was 0.8. So that means there's

20% less death in those who got tranexamic acid compared to placebo, but it wasn't a statistically significant result because of the small, I would say possibly because of the small sample size I. In fact, when you put the stamp trial result in a meta-analysis with the crash trials, it's actually slightly bigger treatment effect than the crash trials and it's in the same direction. So I think it's consistent, varied with a survival benefit, but the main weaknesses, it was a rather small trial. Alright, Dr. Moore, let's move on to the patch trial. So pre-hospital tranexamic acid for severe trauma. This is published in the New England Journal of Medicine in 2023. Yes, the patch had a similar design in that they wanted to study patients who, uh, were in shock at risk or coagulopathy. This trial was conducted between 2014 and 2021, and it was done in Australia, New Zealand,

and Germany. Mm-hmm. Now, this trial, fortunately, I just used one, uh, standard, standard dosing that Dr. Roberts introduced. That is a gram bolus and a gram over eight hours. The inclusion criteria were coast greater than three, which is an Australian system to identify patients at risk for trauma induced pathy. Their primary endpoint was six months survival with functional outcome, and they used the glass count outcome score E. Now there are 1,310 patients in this, so. A sizeable number. The fundamental result was that at six months there was no improvement in survival with a functional neurologic outcome. And that that was again, uh, principally based on the ow outcome scale. But if you looked at the figure in their publication, the survival

and distributed by uh, functional outcome was virtually identical between the two groups. Now they too though, certainly looked at subgroup and they found that they again looked at the patients in profound shock and given early that there appeared to be survival. But this was not very, well, it wasn't statist a sign 'cause there were enough patients in these groups. So the overall summary of the. Past trial was, but there appeared to be some early survival benefit. If you looked at six months, there was no benefit of TXA hmm. Yeah. Interesting that the Glasgow on outcome scale was used. Okay. We have one high level review of rock TXA to underscore this idea of confusing outcomes amongst these trials. This was JAMA 2020. Right. So in in summary then this, uh, rock TBI

used different dosing. They fundamentally had two groups with standard one gram and one gram r, eight hours versus two gram bolus. And their outcome, uh, was interestingly the same glass cow outcome score greater than four at six months. And the conclusion was there's no, uh, difference between the TXA and the control groups. Now if they went back and post-op looked at patients who had intracranial hemorrhage, there was a improvement in 28 K survival of that particular subgroup. So that importantly raised the question of is two grams the magic bullet? Again, similar to the stamp trial, it suggested maybe for whatever reason, that a dose needs to be higher. The Rock TBI group then went on to, in a subsequent publication and looked at patients who got the dose

before and after 48, 5 minutes, the benefit appeared to be isolated again to those less than 45. The, the consistent, I think with a lot of study that suggests maybe hour is the cutoff. And as Dr. Robert said, he pointed out very nicely that every 10 minutes makes a difference. So I don't think there's question. That if you can pick out the right patient, they should get it as soon as they're recognized. But in this study, a little disturbingly and for the first time that I'm aware of that really clarified patient, if you, if the patients got two grams greater than 45 minutes, where they didn't find a difference in survival, they did have increased seizures, increased deep venous thrombosis, increased kidney injury, and increased cerebral vasospasm. So. For those who say TXS has no, uh, adverse effects, I think they're a little shortsighted. Now, the relevance of these, I don't know, but all I'm saying

is there's a signal that if you give TXA late whatever that is, and you can't get a benefit, then there may be some significant adverse effects. That's all It's completed. So let's get down to the practical bits now in terms of what the folks whose world do not revolve around TXA and and hemorrhagic shock research can take away from these trials. All of which again, we should take our hats off to the, uh, folks running these massive endeavors that add to the body literature and allow us to even have these discussions. So thank you to all the authors and people that put the time in. So you have these. Groups of patients who are sick, and to me it's the bleeding patient who's in hemorrhagic shock, and then there's head injured patients with or without bleeding in their head, and you have either some degree of signals or definitive data that says, give TXA, give it early,

and good things are gonna happen. Most of the trials suggest bad things won't happen, but just as Dr. Moore pointed out, we can't say that a hundred percent definitively. So how does someone frame this in their mind when it comes to the mechanism of action? What are you doing? How I, I like to do things to treat patients with medications. The, the mechanism of action. Understood the is understood or give blood or do surgery when you know what you're getting into. And here I still feel a little cloudy about. What it all means, and especially from the crash trials with the passive size and pragmatic nature, that the findings are, what the findings are. There's improvement in mortality when it, when it's given early, so I'm gonna give it, and that's what we do. Yeah. If you probably feeling a little unset all of the data across all of the trials you see the information in a clinical trial is in the end primary endpoint events. So if you're interested in. Trauma survival. Then the in the information's in the deaths, how

many deaths were there in the trial now in the patch and stamp trials? Couple of hundred deaths across the whole trial divided into the tranexamic acid group of super. In the crash trials, there's over 4,000 deaths, so you can't co compare this trial and this trial because. One of the trial is 20 times bigger. Instead of publishing the crash two trial as, uh, one big trial, we could have said it was 40 different national trials. So it's the totality of evidence that you've gotta take into account and the totality of evidence shows without any doubt that choix stomach acid is life saving. You forgive it early, there is no evidence of any increased risk of thromboembolic events. I agree with, um, Dr. Muir that in high dose, and I

think there's other evidence to support this in high dose tranexamic acid causes seizures. It doesn't cause seizures in the doses that we normally use in trauma, but in high dose, um, like in cardiac surgery, they often use six to 10 grams and they get more seizures. So I think don't escalate the dose. Give, give a, give a dose of texa acid, give it early. That would be my take home message. And what do you tell what, when people ask you. Okay. I work in the US at a busy urban trauma center and I get my GSW sent to me in 10 minutes by the local EMS round transport system and patch and stamp these. These are trials that I identify with because it's setting as they were performed in. And yeah, crash may be really big. Crash two is really big, but that doesn't apply to my patient population. What's the response to that? It's okay. What is it about your patient

population that makes them different? Tell what is it about, why is a bleeding trauma patient in the United States different physiologically from a bleeding trauma patient in Hmm. Say Columbia in Medelen, for example. They're not, that's, that's they're not, I wanted to hear you say it. They're not, they, they're just the same people. When they're cut, they bleed. The physiologic physiology of fibrinolysis is remarkably consistent. We divided the crash two trial results up by continent, and the, the treatment effects were directly in the line. Sure. I see that the, the baseline risk of death was different. You've got a high risk of dying from trauma in Africa. Than in Europe, but the effect of tranexamic acid was the same. And Dr. Uh, Roberts, how do you square the improved outcomes in TBI patients without intracranial hemorrhage

given TXA and when it all started, at least? Yeah. Thinking about it as a, a way to stop bleeding. Well. I believe that the main treatment effect of tranic stomach acid is to reduce bleeding. And in the, in, in TBI, it's intracranial bleeding. Intracranial bleeding is bad. In TBI, it worsens outcome and, um, increases the risk of death. Um, and if tranexamic acid works in TBI, it's because it reduces the risk of intracranial bleeding. Now others have a different view. Um, they believe there are anti-inflammatory effects and I think there is some evidence for that. But I think I put my money on bleeding being the main effect, but there is an anti-inflammatory effect. I think that'd be great. But I think it works through bleeding, but, well, and it remind me in crash three, correct. These were patients enrolled with a head injury GCS less than

12 without intracranial hemorrhage on CT scan and without any major extra cranial hemorrhage. Is that correct? That's right, yeah. And then the results were significant when we looked at outcomes in patients with GCS nine to 15. Is that right? Yeah, it, it was, it seemed to be there was a bigger treatment effect in the less severely head injured patients. Now, what I think was happening is that in some of the centers where we did the trial, if you got a severe head injury with a low GCS, death is inevitable regardless of treatment in the uk. You can have a GCS of three and a fixed dilated pupil, and with lot of intensive care and rehabilitation, you can eventually go home, but it death is inevitable in some lower and middle income countries because they just can't keep

those patients alive. So I think what happened is in the low GCS group. All the patients died regardless of whatever they got. They were unsurvivable injuries. So it was a kind of methodological weakness of the trial that we included too many patients with unsurvivable injuries to see a treatment effect. But in the less severely injured patients, the moderate and the mild, we, we saw a benefit. Dr. Moore, when it comes to clinical utility of TXA and TBI, how do you use it? All these trials I mentioned, the stamp, the patch, the rock, TBI, the standard dose, so-called one gram and one gram over a hour had absolutely zero effect on outcome. The align that kame are totally reproducible, so it wouldn't matter whether you have 10,000 or 20,000. It looked like at least those three trials.

The one gram and one gram simply had no benefit. Now why? I don't know, but I'm just reporting the facts. The other remarkable thing is that the differential in survival is incredibly quick. Yeah, and in the past trial, I don't think they published the cap buyer. I saw the graphs. Literally the difference in survival was accounted for within the first 10 minutes. Now what that is, I, I don't know, but to me that suggests that there may be a benefit beyond bleeding. And we talked about the inflammation. There are in vitro studies that suggests that it protects endothelium. There's other studies, and we've published some with Chris Barr, that show that TXA reduces comp activation. And there's others that show other inflammatory markers are reduced with TXA. So I, I'm stunned at how quickly

TXA works in these subpopulations where it has a benefit, but there must be something beyond coagulation that's important, uh, in the, uh, physiologic benefit of TXA, again, in the right patient. I can imagine that could be true. I, I really don't know. I, I like the thing about randomized trials is they give you the answer in the crash two trial, there was less deaths in the tranexamic acid group. But why? It's a hypothesis, isn't it really? Yeah, sure. And that's why we use it, right? Yeah. And you said it's a massive trial that gave us that answer. Uh, and working backwards though is when you start getting. Confused. Let's talk about bleeding patients. When it comes to the actual clinical application, 2025 in your trauma center, you're a trauma surgeon or a trauma provider who's listening to this. How do we give it? Who do we give it to? What's the dose? Well, the uh, again, perplexing thing

is at least in the trials tion, that it's seeing you have to have two grams again, in effect. And yet two grams is where we start seeing the adverse effect. So that's why, again, I. Stay on our track of trying to pick the right patient. So in our hospital, the VA transfusion protocol is any patient arriving with a cysto pressure, seven or less within an hour of injury, and virtually all our, and, and our system gets two grams of TXA. Will EMS deliver it within your system or no? Well, I was gonna, yeah, the, at this point, the two grams is given by us in the ED on arrival. Okay. Again, our, we got a little different system. We're all inner city and our median transport time is 18 minutes, so we really get these patients quickly. But I would agree with Ian that we should give it earlier. And so we are now entertaining a, uh, protocol where we give two grams

for pressure, less than 70. But given I am, so we can give it right away in the field. Let's come back to the Im thing in a moment here. Mm. Uh, Dr. Roberts, so what's going on at the major trauma centers in London in terms of, of their use of TXA? So, just like Dr. Moore, we've tried to reduce time to treatment by taking the tranexamic acid to the patient and so. Up until about last year, paramedics used to give a gram of tranexamic acid at the scene of the crash or the scene of the injury, they used to give a gram by intravenous injection. They didn't really like doing that though because paramedics have to follow the recommendations on the summary of product characteristics, which is to give it slowly over 10 minutes, right? They hated that like 10 minutes just seemed like such a long time pushing on the end of his syringe. Of

course, the doctors in the hospital give it as a whoosh and one big push, but the paramedics were giving it as a slow intra intravenous injection and they didn't like it. And then we'd done some research that showed it's really well absorbed after intramuscular injection. So you give a gram of tranexamic acid intramuscularly, and you get therapeutic levels within three minutes of the injection. And it's even in shocked patients. So now they're moving from a gram intravenously pre-hospital to a gram intramuscularly pre-hospital. That's 500 milligrams, five mils into two body parts, two, two muscles, and then they forget about it and they can give it really quickly. You can give it literally within a few seconds and then they'll get another gram when they arrive at the trauma center. That's what we use in the Royal London Hospital where

where I've got my clinical appointment. I've seen the, uh, the studies recently on the pharmacokinetics of intramuscular TXA and I saw this single trial for the shocked patients. Are we satisfied? Are you satisfied with the data so far to say that we have enough pharmacokinetic data to say that it works Intramuscularly. To roll out. Are there additional studies that you're planning on doing in, uh, larger cohorts of shock patients? Well, the, the pharmacokinetic data, we've done healthy volunteers, we've done bleeding trauma patients, and we've done obstetric patients, and they all share the same, the same thing. The time to therapeutic level is within five minutes in everybody. We're doing a reasonably big trial called Crash four, which is it pre-hospital intramuscular tranexamic acid in. Older adults with mild TBI. So this will be an interesting one for your, how does it work in head injury? Because our hypothesis is that these older adults have mild

TBI, but actually they did. There's nothing mild about TBI. In older adults, they can do very badly. They can get intracranial bleeds, they can die, they can get need neurosurgery, and the intracranial bleeding probably worse than their dementia. So we're comparing tranexamic acid and placebo. I really look forward to that one because that was gonna be my next question. How do we treat, uh, a isolated head injured patient? Do we give TX a these, the guidelines and protocols that we talked about are predominantly for hypotensive, presumed to be bleeding trauma patients. Now, how many time will tell we, we've randomized two and a half thousand that we've got another two and a half thousand to go? Okay, so based on the data available should. The average clinically busy trauma provider feel confident and safe about giving TXA, either pre-hospital or, or nearly immediately after arrival in patients who show signs of bleeding

based on mechanism perhaps, and, and certainly blood pressure. Dr. Moore. Well, I, I think if I looked at the big picture that I'd feel uncomfortable giving the two grams to anyone in profound shock, and perhaps with a caveat that the less capable you are as a receiving hospital, perhaps more compelling to get that TXA in. So that's, I think what we struggle with in Colorado where we have a lot of rural providers that are going, well, what should we do out here? And I would say to 'em, I would be comfortable if a patient came in on shock or given two grams, Dr. Roberts. Okay. I'm uncertain about the dose, whether one gram or two gram is better, but I certainly think that the most important thing in a bleeding trial patient is to give them a gram of tranexamic acid or gram or two grams as soon as possible after injury. I

don't think two grams will do them any harm and. It's almost for me, it's not, the dose isn't, if it's one gram versus two grams, the dose isn't a big question. I just want them to get it. Getting it and getting it early for me is the important thing. And early it bleeds you down to the root and the intramuscular route. I think you're gonna get, you're gonna get more patients treated quicker with that. Uh, so in a perfect world, our trauma on patient who may be bleeding. Should get intramuscular TXA one or two grams, ideally at the scene or en route before arriving to the trauma center. That may be 10 minutes away and maybe an hour away. That is a correct statement. I could live with that. Yeah, I would agree. Okay, so I think we, we came a long way and we have some consensus, and again, for people who are listening, the idea

is that you can. Wrap your head around it a little bit better and feel more comfortable with its use, however it's set up within your system and your guidelines. And we look forward to all the phenomenal research coming from Doctors Warren Roberts in the future that are gonna inform this discussion even farther. So thank you again, uh, for joining us up behind the Knife.