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Yeah, I can imagine that could be true. I really don't know. Like, the thing about randomized trials is they give you the answer. In the CRASH-2 trial, there were less deaths in the tranexamic acid group. It's a hypothesis, isn't it? is seeing you have to have two grams to get an 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 through.
We've 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... All right, welcome back to Behind the Knife's Big T Trauma Series. This is Patrick Georgiouf, 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. Gene Moore. He was 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. Moore's leadership, Denver General became internationally recognized and still is for innovative care of the injured patient. And his trauma 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 for Denver Health. Quite an honor, I must say. Our second guest is Dr. Ian Roberts. He's 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. So he's a clinical academic who works collaboratively with health professionals worldwide to conduct really phenomenally large and important multi-center trials. that are aimed at improving outcomes in patients who have life-threatening emergencies, bleeding, trauma, etc.
And the work he's done to put together these big consortiums is something that's truly special and impressive. And he's played lead roles in several large trials, including the CRAS 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 Night.
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 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 has confused me at times throughout my career. And there are questions that persist, such as what is TXA'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? What about their vital signs? What about transport time, etc.? So today, we're going to break through the noise and with the wisdom imparted upon us by our esteemed guest.
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 clinical case that I had when I was working as a pediatrician in trauma care. 11-year-old girl who was in a high-speed road crash and she had a lap belt on and she slid under it and ruptured a lot of internal organs. And she was in the emergency department. I was resuscitating her.
And because she didn't have a head injury, she was fully conscious, but she was deathly pale, hypotensive. But she was talking to me and I said, well, we're just going to put you to sleep and take you to the operating theatre. I gave her an anaesthetic 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-1. Well, it was just called CRASH then because we didn't know there was a CRASH-2. Steroids in head injury. We randomized 10,000 patients. There was no patient benefit.
And I saw this review of tranexamic acid in surgery because I was the editor of the Cochrane Injuries Group. I thought, my goodness, look at this. This stuff really reduces bleeding. Well, if it reduces bleeding in surgery, perhaps it'll reduce bleeding in trauma. And we had all of this international collaboration to do this head injury trial.
And so the same group of trauma surgeons and emergency physicians, we say, right, OK, we've got a new trial now. Can you help us with that? And then so crash one turned into crash two. And we managed to randomize 20,000 patients and got a really surprisingly positive result. Yeah, I'll say. And Dr. Moore, how about you? You are known for your research in trauma and coagulation, bleeding, etc. Do you have a similar story? How did you become interested in TXA?
Well, thank you, Patrick, for inviting Professor Roberts and I. We are long-term friends and colleagues. And it's interesting to listen to backgrounds. 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 for our mental life. Fibrinolysis was largely ignored in trauma until we all began using viscolysis.
And we were fortunate in our institution to do some of the fundamental animal work in TAG in the early 2000s. And in 2009, we reported to the American Surgical, to our surprise, and when we looked at TEG, that roughly 15% of the patients who had uncontrolled bleeding had fibromyalysis. So we wrote this paper and said fibromyalysis is critical and we need to understand the power.
So we became very enthused of the idea of TXAN. Of course, Crash 2 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 was done by our trauma fellows who were Mike Chapman and my son Hunter. They were trying to define what cutoff we should use with the LI-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 back print.
It's been amazing to watch your lab's work grow and build on itself to further define these subgroups. are clinically important. And so this underscores the idea here that TXA, again, for a simple trauma surgeon, this is a fibrinolysis inhibitor. more to it than that. And we're going to 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 clinical importance?
Well, first, we emphasize that there's no question that TXA can inhibit fibrinolysis and produce uncontrolled bleeding. But an overarching view is that TXA should be given to the right patient. at the right time, and now the right dose. That's fundamentally what we are suggesting. And Dr. Roberts, before again, we're going to talk crash here in a minute. What's your overarching principled approach at this time when it comes to the XI use and trauma?
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... soon after injury as possible. When blood vessels are cut or ruptured, they release tissue plasminogen activator. So there's a very early burst of fibrolysis. 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 fibrolysis. so it's in that kind of early fibrinolytic gap that you need tranexamic acid The exact duration of that period, I couldn't be sure about, but we specified in the CRASH-2 trial. before seeing any results, that we'd look at patients within three hours and beyond three hours. And only because three hours broadly cut the patient population into two.
And what we saw is very strong evidence of mortality benefit for those who got it in the first three hours, 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, there's different views about dose. Obviously, in a big, simple trial, you pick one dose. So we picked a gram.
stat as soon as possible after injury and then another gram over eight hours. And you'll be surprised, the rationale for that. The gram was like, well, the gram is easy to remember. And we looked at some of the cardiac surgery trials and it wouldn't be too much for someone who's quite thin. And it wouldn't be too little for someone who's very big. And so we thought, well, a gram's about right. It inhibits fibrinolysis, whether you're...
that or thin, heavy or light. And then we thought the second gram was just to stop. If someone's really bleeding severely, We just didn't want to make sure that our first gram of tranexamic acid is not on the emergency room floor. So we kept an infusion going because some of these patients have a lot of blood and you can lose it all through dilution.
So that was the rationale. Well, let's talk crash. I think the best way we could approach this is for Dr. Roberts to talk about the crash trials. And then we're going to turn it over to Dr. Moore for Stamp and Patch and the Rock TXA 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 TXA use and 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 2, played a massive role in Crash 3. So congratulations on that massive effort. These are extremely important trials that drive a lot of what we talk about. pragmatic in every way. Can you do us a favor and summarize both trials?
Just a quick background. The area that seems to make 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 treatment.
And why have they got that? Because 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 multi-center international randomized trial where we aim to randomize 20,000 bleeding trauma patients. and really broad criteria of bleeding if the patient's either got or suspected to have significant hemorrhage.
You randomize, 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, all matching placebo. And the main outcome was death. And death is a great outcome measure in 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.
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 analyses.
And we could see that this time to treatment thing made a huge difference. You know, if you got it within three hours, it reduced your risk of bleeding to death by about a third. But if you got it late, there was no benefit at all. So that was the CRASH-2 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?
So we ended up randomizing another 12,000, 13,000 patients, this time with isolated traumatic brain injury. Which is crash three. That's crash three. And the results were... Almost the same as crash 2. There was an early reduction in all-cause mortality for those who got the treatment early. 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 some infectious complication down the line. So the treatment effect was good, but it wasn't quite as good as CRASH-2. But I saw it very much as not a separate trial, but... A missing subgroup of the CRASH-2 trial, really. It was like a fill-in trial. So before we move on, let's go back and ask one question about CRASH-2. Roughly 50% of patients in each arm received.
blood. That's not a lot. And at least when this trial launched, our thought was we're going to stop bleeding through antifibrillinic mechanism of TXA. That's an interesting finding because 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, bleeding is not a particularly good outcome measure. in clinical trials of treatment for hemorrhoids.
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. It's very difficult to know how much blood a patient has lost. in a in a trauma patient and 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. So you give them this many units of this many units of this and some plate. So first, the initial blood transfusion is nothing to do with the bleeding. It's just the recipe that you get. Second, you've got this bias that...
If you only transfuse alive patients and there are more alive patients in the treated group, so you're going to get more blood transfusion in the tratexamic acid group. 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. 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. Well, 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 is... The amount of blood you get is an imprecise measure of a 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 Trenxamic acid just before someone had their major trauma, we might see less blood transfusion.
but that's actually not 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 big lump of the blood transfusion is the bleeding that's already happened. That can't 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 3 when we talk about mechanism of action, because 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 without intracranial hemorrhage, and we're giving TXA.
So what's it doing then? Because something's happening. So Dr. Moore, let's start with Stamp, if you would. What's the takeaway that you have? from the STAMP trial, because this is an interesting trial to talk about side-by-side with CRASH-2. Yes, first of all, let me start by answering the question I hear almost every day. Why is there ongoing confusion about when to give TXA in trauma? Well, I think the three trials I'm going to mention, I think explain why there is some confusion.
The SAM trial was a four-center, level one, double-blinded study. Well, well done. And it was coordinated by the University of Pittsburgh. Pajama surgery 2020. It was done between 2015 and 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 Grand Prix hospital. Another one gave a grand pre-hospital and during eight hours, as Dr. Roberts has used in his trials.
And then they had a third one. They gave a gram pre-hospital, a gram when they arrived, and a gram over the next eight hours. So I 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 927 patients in the group, relatively minor 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 Kappenmeyer, the two lines are interposable throughout the entire time. But again, like 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. And the first was somewhat surprising to me, but basically the only group that had improved survival significantly was the three-grams. So now we add in this considerable variation of doses.
And, you know, of course, one of the problems when you 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. Anyway, the three things they found. The first was a three-gram dose. It was the only dosing that had a benefit.
But the latter two findings, I think, are incredibly consistent in the literature. I'd like to see what Ian thinks about that. First of all, the benefit was only seen if the TXA was given within the first hour. And secondly, it was only seen in the group with a systole blood pressure of less than 70. And I've seen this in multiple ones. And parenthetically, I don't think... We should use non-randomized trials to get into this discussion. There are a myriad.
And I've been doing this myself. If you don't randomize them, now we've had enough time. We should be really focusing on randomized trial to guide how we use TXS. Anyway, I think a strictly 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 a systolic of less than 90. And overall mortality was less than 10%. And then you take these 460 patients for randomized tranexamic acid divided by three different doses, hence some of the confusion. Dr. Rock, any comments on that? Yeah, I think Damur 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've 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. In fact, when you put the stamp trial result in a meta-analysis with the crash trial, It's actually slightly bigger treatment effect than the Crestron.
And it's in the same direction. So I think it's consistent, very with a survival benefit. But the main weakness is it was a rather small trial. All right, 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 were in shock at risk for coagulopathy. This trial was conducted between 2014 and 2021, and it was done in Australia, New Zealand, and Germany. Now, in this trial, fortunately, I just used one standard dosing that Dr. Roberts introduced. That is a gram bolus and a gram over 8 hours. The inclusion criteria were COAST greater than 3, which is an Australian system to identify patients at risk for trauma-induced quality.
Their primary endpoint was six months survival with functional outcome. And they used the glass counter outcome score E. Now, there are 1,310 patients in this, so about the same. a seismal number. The fundamental result was that at six months, there was no improvement in survival with a functional neurologic outcome. And that was, again, principally based on the Glasgow Outcome Scale.
But if you looked at the figure in their publication, the survival distributed by functional outcome was virtually identical between the two groups. Now, they too, though. certainly looked at subgroup, and they found that if, 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 statistically significant because there weren't enough patients in these groups. So the overall summary of...
Past trial was, but there appeared to be some early survival benefit. If you looked at six months, there was no benefit of TXA. Yeah, interesting that the Glasgow outcome scale was used. Okay, we have one more high-level review of ROC TXA to underscore this idea of confusing outcomes amongst these trials. This was JAMA 2020. Right. So in summary, then, this ROC TBI used different dosing. They fundamentally had two groups, the standard one gram and one gram of read hours versus two gram boa.
And their outcome was interestingly the same. The Glasgow outcome score greater than four at six months. And the conclusion was there is no difference between the TXA and the control group. Now, if they went back and post hoc looked at patients who had intracranial hemorrhage, there was an improvement in 28K 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, look at patients who got the dose. before and after 45 minutes. The benefit appeared to be isolated again to those less than 45, consistent, I think, with a lot of...
study that suggests maybe our is the cutoff. And as Dr. Roberts said, he pointed out very nicely that every 10 minutes makes a difference. So I don't think there's any 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 disturbing. And for the first time that I'm aware of, that really clarified, if the patient's 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 TX has no adverse effects, I think they're a little short-sighted. Now, the relevance of these, I don't know. But all I'm saying is there's a signal that if you give TX a late... whatever that is, and you can't get a benefit, then there may be some significant adverse effects. All right, so let's get down to the practical bits now in terms of what the folks whose world do not revolve around TXA and hemorrhagic shock research.
can take away from these trials, all of which, again, we should take our hats off to the 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. 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 going to happen. Most of the trials suggest bad things won't happen, but just as Dr. Moore pointed out, we can't say that 100% definitively. How does someone frame this in their mind when it comes to the mechanism of action? What are you doing? I like to do things to treat patients with medications, the mechanism of action understood, the outcome is understood.
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, especially from the crash trials with the massive size and pragmatic nature that. The findings are what the findings are. There's improvement in mortality when it's given early, so I'm going to give it, and that's what we do. Yeah, if you have all of the data across all of the trials, you see, the information in a clinical trial is in the primary endpoint of that.
So if you're interested in trauma survival, then the information's in the deaths. How many deaths were there in the trial? Now in the patch and stamp trials... A couple of hundred deaths across the whole trial, divided into the tranexamic acid group of Cebu. In the crash trials, there's over 4,000 deaths. So you can't compare this trial and this trial. Because one of the trials is 20 times bigger. Instead of publishing the CRASH-2 trial as one big trial, we could have said it was...
40 different national trials. So it's the totality of evidence that you've got to take into account. And the totality of evidence shows without any doubt that tranexamic acid is life-saving if you give it early. There is no evidence of any increased risk of thromboembolic event. But I agree with Dr. Moore 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, like in cardiac surgery, they often use six to 10 grams and they get more seizures. Give a dose of tranexamic acid. Give it early. That would be my... take-home message. When people ask you, okay, I work in the U.S. at a busy urban trauma center, and I get my GSW sent to me in 10 minutes by the local EMS ground transport system.
And patch and stamp, these are trials that I identify with because of the settings they were performed in. And yeah, crash may be really big. Crash 2 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? What is it about why is a bleeding trauma patient in the United States? Different physiologically from a bleeding trauma patient in, say, Colombia, in Medellin, for example.
They're not. They're not. I wanted to hear you say it. They're not. They're just the same. People, when they're cut, they bleed. The physiology of fibrinolysis is remarkably consistent. We divided the CRASH-2 trial results up by continents. And the treatment effects were directly in a line. Sure. The baseline risk of death was different. You've got a higher risk of dying from trauma in Africa than in Europe. But the effect of tranexamic acid was the same. Dr. Robert...
How do you square the improved outcomes in TBI patients without intracranial hemorrhage? Given TXA, when it all started at least, thinking about it as a way to stop bleeding. I believe that the main treatment effect of tranexamic acid is to reduce bleeding. And in TBI, it's intracranial bleeding. Intracranial bleeding is bad. in TBI, worsens outcome and increases the risk of death. And if tranexamic acid works in TBI, it's because it reduces the risk of intracranial bleeding.
Now, others have a different view. 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. Well, and you 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 extracranial hemorrhage. Is that correct? That's right, yeah. And then the results were significant when we looked at outcomes in patients with GCS 9 to 15.
Is that right? 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 a lot of intensive care and... rehabilitation, you can eventually go home.
death is inevitable in some low 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 saw a benefit Dr. Moore, when it comes to clinical utility of TXA and TBI, how do you use it? The stamp, the patch, the rock, TBI, the standard dose, so-called one gram and one gram over hours, had absolutely zero effect on outcome. The lines that Kappa-Meier are...
So it wouldn't matter whether you have 10,000 or 20,000. It looked like, at least in those street trials, that the one gram and one gram simply had no benefit. Now why, I don't know, but I'm just reporting the fact. The other remarkable thing is that... The differential in survival is incredibly quick. And in the patch trial, I don't think they published the Captain Byron. I saw the graphs. Literally, the difference in survival was kind of for within the first 10 minutes.
Now, what that is, I don't know. But to me, that suggests that there may be... benefit beyond bleeding. And we talked about the inflammation. There are in fetal studies that suggest that it protects endothelium. There's other studies, and we've published some with Chris Bader that show that. TXA reduces copper activation. And there's others that show other inflammatory markers are reduced with TXA. I am stunned at how quickly TXA works in these cell populations where it has a benefit.
But there must be something beyond coagulation that's important in the physiologic benefit of TXA. Again, in the right place. Yeah, I can imagine that could be true. I really don't know. Like the thing about randomized trials is they give you the answer. In the CRASH-2 trial, there were less deaths in the tranexamic acid group.
But why? It's a hypothesis, isn't it, really? Yeah. And that's why we use it, right? You said it's a massive trial that gave us that answer. And working backwards, though, is when you start getting... 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 trauma provider who's listening to this. How do we give it? Who do we give it to?
Well, the, again, perplexing thing is, at least in the trials I've mentioned, that it's seen you have to have two grams to get an effect, and yet two grams is where we start seeing the adverse effects. So that's why, again, I... Stay on our track of trying to pick the right pace. So at our hospital, the... The astrotransfusion protocol is any patient arriving with a systolic pressure 70 or less. Within an hour of injury and virtually all of our in our system gets two grams of.
TXA. Will EMS deliver it within your system? No. At this point, the two grams is given by us in the ED on arrival. Again, we've 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 protocol where we give two grams for a pressure less than 70, but give an IM so we can give it right away in the field.
Let's come back to the IM thing in a moment here. Dr. Roberts, so what's going on at the major trauma centers in London in terms of their use of TA? 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. And they hated that. Like 10 minutes just seemed like such a long time pushing on the end of this bridge. 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 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 intramuscular. 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 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.
And I've seen the studies recently on the pharmacokinetics of intramuscular TXA, and I saw this single trial for the shocked patient. 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 of their additional studies that you're planning on doing in larger cohorts of shock patients? Well, the pharmacokinetic data, we've done healthy volunteers, we've done bleeding trauma patients, and we've done obstetric patients. They all show the same thing. The time to therapeutic level is within five minutes in everybody. We're doing a reasonably big trial called CRASH-4, which is pre-hospital intramuscular tranexamic acid in older adults with mild TBR.
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 there's nothing mild about TBI in older adults. They can do very badly. They can get intracranial bleeds. They can die. They can need neurosurgery. And the intracranial bleeding is probably worse than their dementia. So we're comparing tranexamic acid and placebo.
Yeah, I really look forward to that one because that was going to be my next question. How do we treat an isolated head-injured patient? Do we give TXA these guidelines and protocols that we talked about are predominantly for hypotensive? presumed to be bleeding trauma patients yeah only time will tell we've randomized two and a half hours and then we 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 nearly immediately after arrival in patients who show signs of bleeding based on mechanism perhaps and certainly blood pressure. Well, I think if I looked at the big picture of that, I'd feel uncomfortable giving the two grams to anyone in profound shock. And perhaps with a caveat that...
the less capable we are as a receiving hospital, perhaps more compelling to get that TXA in. So that's, I think... When we struggle with in Colorado, where we have a lot of rural providers, they're going, well, what should we do out here? And I would say to them, I'd be comfortable if a patient came in on shock or given two grand. 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 leads you down to the root and the intramuscular root. I think you're going to get. you're going to get more patients treated quicker with that. So in a perfect world, our trauma 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. Is that correct statement? I could live with that.
Yeah, I would agree. Okay. So I think we came a long way. 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 Drs. Warren Roberts.
in the future that are going to inform this discussion even farther. So thank you again for joining us on Behind the Knife. This episode of Big T Trauma was sponsored by Teleflex, a global provider of medical devices. Learn more at teleflex.com. Be sure to check out our website at www.behindthenife.org. Download our free app available for Apple iOS and Android. Simply search for Behind the Knife in the App Store or Google Play to download the app. In the app, you can listen to our episode.
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