Dr. Paul Pepe: TXA in EMS (3/4/2023

Who's going to be talking about his airway CQI using the video laryngoscope scope.

We have Casey Patrick going to come on talking about difficult intubation cases in ems.

We have Randy Schaefer talking about whole blood.

We're going to have Stephanie White talking about the use of marijuana amongst EMS providers that becoming legalized and some departments. New York City.

And.

We have another violence against paramedics report publication. So we have a lot of good things coming up.

So let's just see if.

All right, so the recording has started, so that's nice.

Just waiting on Dr. Pepe to join us again.

Awesome. Thanks, Dr. Daya. Yeah, and if there's. If there's any other papers.

Any papers that you want to hear directly from the authors, I've literally gotten responses from every single person I've email, and they all say yes. So.

If you have people out there who are interested or have a good paper.

That'S really the goal here.

In June. Already have a skip, people schedule out to June.

More airway stuff in June on the June 6th.

And my next open date is the June 13th, believe it or not.

All right.

All right, let me. Let me call Dr. Pepe. Something clearly is going wrong there. I can't log back in.

Bear with us. Sorry about this, guys.

The good news is I open up my.

Okay, here we go.

All right. Dr. Pepe should be on any moment here. We're waiting. I have him on the. I have him on the line. You got a big crowd here, Dr. Pepe. All right, all right, so give it a second. There he comes.

Okay, it's me. Now the question is, can I share? Is the big question right? Desktop window.

Right.

Is it showing up? Anything? Is it showing up? Are you seeing anything yet?

Not yet.

Entire screen. Here we go. Entire screen. Share. Okay. Please work.

Am I there? Don't try this at home, folks. We're professionals here. Right? All right, here we go. Let's see. Txa, Right? That's what I'm talking about today. What's that stand for, by the way? Okay. All right. Am I okay now to go with this? Geez, this is like pain.

Yes. Okay, so I got it. Without any further. Without any further ado. All right, so you've cut into your.

Own time a little bit, unfortunately, Paul, but that's okay.

I'm sure you can do it. You're the king of 600 seconds. But you have more than that today.

I actually asked Dr. Pepe to come.

On because I think TXA is one of these topics that has been researched. Yeah, it has been researched with these very large studies. And essentially the outcomes of these studies can be looked at one way or the other.

Depending on how the study was done. And really the dose, the timing, I.

Think it's really nuanced.

So I asked Dr. Pepe to come on and talk about if you can denuance this for us and help us understand TXA. So Dr. Pepe, thanks for coming on.

And take it away. Is that painful? Denuancing. Is that painful? I just, I've heard about it, but. All right, can you hear me okay though?

Peter, can you hear me okay? Yeah, we can hear you. Okay, good. Thank you guys. All right, let me move on through here. So I'm gonna. There's some recent, this is some recent publications we had from your team. This is actually a presentation I did literally three and a half years ago. Okay. But.

Some of you have already heard this. So I think that's going to be a little bit of deja vu all over again for many of you, but it still keeps you a little bit more refreshed about the rationale for what we're doing, particularly in most of our protocols, not only here locally, but across the nation. As we'll go ahead. One of the papers we first wrote was not using just tourniquets and stopping the bleeding with, you know, hemostasis with a tool but you know, non mechanical hemostasis that we're saying. And that was sort of the. And we started saying this is part of it. Then we wrote up an update about using TXA and tbi. And even though most of us are talking about using this with whole blood, the, the idea about the TXA is actually cool because we learned a lot from that study when they did the studies on TXA using the Resuscitation Outcomes Consortium. But what was kind of cool is about the same time I was writing this up, look what comes out in the jsom, which is the.

Tactical Combat Casualty Care Committee proposes this change. And so sure enough, for 2022 and this was written I think in 2019 in fact if I remember correctly. But they are saying there the most significant updates include traumatic brain injury as an indication change in a dose to a single and this becomes really important single 2 gram IV IO dose and also recommending that it's done by V IV, the slow IV oil push. And one of the reasons why they don't have Im here, Im in here and we'll talk about that. There's maybe one caveat for using it is that if you're in a shock state, it may not have the right, you know, let's say perfusion, that will help you out. But having said that, if you have nothing else to use, we might go there. All right, let's move on. I'm going to skip this for now because that's a paper I'm publishing in the second. Here's the background on it. The main thing you need to know, I think is that it was used originally for these elective surgeries. And what happened then is they would give a gram up front, this is back in the 1960s and then during the surgery over the next few hours they would give the dose. And it also happened in postpartum hemorrhage. So that becomes really important because that became the model for all the other studies that were done. And what I'm going to tell you not to bury the headline is that that extra dose that you do over the next few hours may be actually harmful or not appropriate. And we much better if we just. The risk benefit is much better if you give the 2 grams upfront because the risk benefit ratio starts reversing in my opinion after the first hour. And we'll go through this. And by the way, here's the main thing. It impairs fibrolysis, makes it a more coagulable state. But we really don't know completely how this works. It has powerful anti inflammatory roles. It is basically has the ability to decrease endothelial permeability. So that may have a lot to do with things and then it even may reduce brain edema. But it's a complex nature. The bottom line is what happens if you give this. All right, so the thing that really got this going for all of us is the crash 2 study that was done. I don't know what's showing up here. Is something blocking the screen right now. Something just sort of showed up on my screen.

Yeah, it looks like you just have to X off of it. There you go.

Okay. So any event, what happened was the crash two study was done in 274 hospitals, 40 countries, 20,000 patients. And it was criticized because there wasn't as much control and the randomization know for different things. Sometimes they didn't get the medication for hours and it was done in so many different places. So it was came under a lot of criticism that one of the good news things is that that when you really break down and this is going to be. If there's anything you remember is what I'm about to show you. It's like every Other studies, sometimes I talk to you about is that when you average outcomes, okay? And that's what it is. This was a little better outcome versus a worst outcome. Here it was because of the numbers involved. It was way out there in terms of the P value. But when you break it down, what this is, this is an average of people who got early and people who got it late. And there are some people who got it late and I'm going to argue had worse outcomes as a result. Okay, so let me go forward with this. So if you put this thing on within an hour, it was incredibly better. This means you had like a 70%, 70% numbers, your chance of dying was 70% of what it normally would be under those conditions. That's an improvement on their, you know, your mortality rates. But over then, if you look at the one to three hours, it was still a little bit better. But if you looked at three hours out, that was actually your chances of dying were, you know, here's the odds ratio, 1, 1, 1 and a half essentially, in terms of worse outcomes. And I think that's the key. This slide is maybe the key to the whole thing. And there's enough numbers to help us with this, right? So regardless, it was cost effective. We all have learned that now, and that's where we got that. Here's the but part. The but part is a lot of people working the TXA on until after they got to the hospital or they wanted to do tag or they want to do some other, you know, kind of thing to look at coagulopathy. So there's what we may call a survival bias there, that you're alive to get to that point. And so that is one aspect of it. But the other thing is that if you give it late and you are getting things under control, you're getting other therapies and get the TXA late beyond everything else. It actually may now the coagulation may be more harmful in terms of causing more clotting. So as you saw article after article, and one of the reasons why the trauma surgeons were really opposing this for a while has been the TXA is associated with increased risk. It's like, duh, that makes sense. But again, a lot of times it's because this was being delayed or given late under those circumstances. These are relatively new articles, by the way, and so keep that in mind. So I go back to this thing. By the time you get it in the hospital, sometimes you're really way out here versus here. And I'm going to show you something Important about this when we get to the head injury thing. Okay. Peter, is this going okay so far, or whoever else is on you guys following this?

Yeah.

Great. Okay, good. All right, so which way do we go? Right. All right. So the cool part was they actually did this study with. There's a new rock study that helped us. But first it was on the heels of the Crash 3, which was something to look at, the head injury study. Now, this had the same kind of things. 175 hospitals, 29 countries, a lot of the same criticisms and so on. But just as you see, I'm gonna skip through this one quickly. But as we see, I'm gonna come back to it and show you same results when you got it on board. I'm gonna skip through this real quickly, is that it was safe. There was no increase in complications. They didn't see any benefit in severe head injuries, which is kind of interesting, which I'll show you why in a second. But the earlier the better. The outcomes were definitely improved if it was given real early. Again, this study, like the original crash study, was one gram up front and one gram over eight hours. So it was still following the same pattern. Now compare this. Ready for this? Compare this to the NIH study. So Marty Schreiber, a good friend of mine, helped lead a study that was done through the Resuscitation Outcomes Consortium, funded by the nih. And what they found in that study, and thank God, he prospectively said, let's look at the people who actually have a bleed in the head and see what happens under those circumstances, because that's the target group we're going after. It turns out when you look at the group that they entered here, and these were people who had, let's say, Glasgow coma scales of 3 to 12, that is less than 13, 3 to 12. What they found was in their study was that they were giving 2 grams versus the 1.1. I mean, this is really cool that they did this, where they compared the 2 grams up front versus the 1.1 versus a placebo. And so the three arms weaken their study in the terms of strip study power and so on. But it also strengthened it from a lot of points of view because they gave us some answers here, as you'll see. So they're looking at moderate to severe TBI versus crash. And what they found was that they were giving us an early infusion. In fact, from the time of the injury, they were giving this median time. What's median time? Half the cases. Half the cases got it within 40 minutes of the injury. And so that becomes important. Now it turns out that nearly 60% had an intracranial bleed. That means that 40% of the people didn't have an intracranial bleed. Whatever the number was, I think it's like 44%. Turns out that there was no extra complication. So we had 44% without any problems. So that's a built in safety cohort. They didn't have a bleed in the head documented later on CAT scan. So there are people who got treated even though they didn't need it, in a sense. But turns out that it looks like there's a built in safety control here because as you'll see, there were no extra complications in that group. All right, so Overall results were 65% versus 62% at six months in terms of outcomes. But here's the deal. This, and this is what's interesting is that when you look at these numbers here, the differences were actually problem because they mix both the 2 grams and the 1 plus 1 gram arms together compared to. So the survival rates or whatever it was at the time were 65% versus 62%. But this is mixing in the one plus one becomes important. As you'll see this, the problem with their study in a sense is that there are smaller numbers that you're breaking up into.

You know, one point, you know, the 1.1 plus the 2 grams. But examining those with the CT confirmed intracranial hemorrhage. Again, this is the overall results of all patients entered. But if you look at those with the CT confirmed intracranial hemorrhage, the target group, from our point of view, 16% mortality with 2 grams up front. Okay, and then that was versus 27% with the 1 plus 1 gram infusion versus 26% with a placebo. So essentially no differences between the 1 plus 1 and the 26%. Whereas you had a, I think it was 28 day mortality of 16%, the 2 grams up front. So there is an, there was an increased risk of seizures. And what that meant was out of say 300 patients in the subgroup, you might have 13 versus say 8. So really not a major difference is people with placebos, in other words, get seizures, they'll have them. This is a little bit more. But there were no permanent complications, There was no other increased complications. They had good outcomes and so it was deemed to be safe. So what were the takeaways? For me, it goes back to that crash one study, right, in which.

Given it within the first hour is much better. Right. And Then if you go out here, it's too late. So the protocols even today that we have out there say give the TXA within the first three hours because of this. But this is out there at three hours. I mean, what I'm, I'm trying to argue for is that you gotta get it on board, you know, within the first hour actually, as far. And we could do it in the pre hospital setting. That's what's kind of cool about that, right? If you go back to Cash Crash three, like I said, they had its own issues, but if you look at those people who had ratio races, your chance of dying is, you know, one to one, it's like, that's normal, right? But now you have less of a chance of dying way down in this realm if it's done within the first seed, here's 60 minutes. So if it's done in that first little while, your chances are going down is a lot less. It's the same old thing that we saw in the original crash study. And this is the Crash three for the head injury one. So again, if you go to the Rocks, the Rock TXA thing where we, they looked at the 1 gram versus 1 gram plus 1 versus the 2 gram versus placebo, the 2 gram bolus definitely improved outcome versus the other. See those of them out there? That's your survival curves. So here's mortality, right? And it's very low up here, if you get it early on. And these are the groups up here, that's placebo. But what's interesting is that you can see all along that the bolus group, the 2 grams up front, do much better. And you're having very low mortality down here. This is seven days. So you got to really, you know, jump it down here. But the point is, the whole thing is that earlier the intervention, the better results. That's my mantra. It's always been my mantra. Okay. The Stamp trial later came on and started looking at people with general shock states from hemorrhage. By the way, Francis Guyet and I shared this right about the same time. And what he pointed out to me, he had better outcomes even if they got only one gram up front, but they got another gram within the first hour. They did really well. They had much better outcomes, particularly if you were hypotensive. So in other words, the sicker patients, it's kind of duh, benefited from that. So if you look at these numbers, here's a repeat dose. If they got the repeat dose, it favored txa. If they got, let's See, this is the time from injury. If it was less than an hour, guess what? Favorite txa by far. And then if you were hypotensive, then you even did much better. Here's the. If you can't see it, it's the systolic blood pressure, less than 70.

Can I stop you on that slide for one second?

Sure. Yeah.

That. That second. That second graph there shows time from injury, less than an hour. It says favors placebo.

Where does that say favors placebo? Over here. Try B. Oh, I see. You're right. Okay. Yeah, you're. But then I'm. Oh, you're absolutely right there. So I'm not sure what that was about.

The top one. It's flipped. That's weird, isn't it? Mortality.

There's something wrong with this, by the way. That's actually because what he told me was. It was. You were better off there. That's why he was. So let me see what it says here. Standard dose. Let me come back to it. But thank you for picking up on that, Peter, because.

But I'm. I mean, what he told me is that's not what they saw there. Okay. And so that's what's kind of weird. Okay. On this thing here. We'll figure it out, but let's go on. Yeah, something's wrong there. But if they were severely injured. Again, if they were. Oh, here, it says it's favorable placebo. So I think this is flipped. Something's wrong here. It.

It couldn't.

That doesn't make sense. Okay. Because that's what they're. They were saying they did better. So I'll get that squared away. Apologize for putting this up if it's wrong.

Okay.

Or if it was trans.

That's okay.

Thanks.

Thanks for looking into it.

I will. Okay. But anyways, the point was, I'm going to tell you. He. He was telling me his results were. You know what I just told you. So that's. That's a good pickup here. That's weird. Wonder if they had their chart flip. Because you see this here? Favors transmitted. Favors placebo. I think they had it flipped. That's. There's something wrong with that. Okay, well, we can even look over here in terms of. This is mortality. And it's 7.6 versus 4.6 with transexemic acid. So this is just flipped. Good pickup. Okay. Blood pressure less than 70. If you're a placebo, you had a 35% mortality chance versus 18%. So what I'm telling you is correct. It's Just the chart's wrong. Okay, thank you, Peter. I'll get that straightened out. Okay, so better outcomes, but only if given. Sorry about this. I'm almost finished though. So there's the summary is that the TXA for TBI is better outcomes, but only if given early on as the two grand bullets. In my opinion that you should not just give it within the first three hours, even though our protocol say that I, I want it on board within the first hour, if not the first half hour, simply it was my family member. If it was after that, I'm not sure I'd go because it's starting to reverse the ratio at that point in time with the risk benefit. So from all points of view, whether it's a head injury patient who's going to have a seizure or if it's a bleeding patient, whatever it may be, it's safe if it's given early and likely good for all trauma patients, including internal bleeding and TBI patients. And probably with the exception of possibly GI bleeds, which I'll explain in a second, that is, you know, it probably is very useful there. And I think about if we're going to give blood, let's give this as well. Okay. And of course that someone wants to talk to me now when I try to get home last night. So any event, what I was going to say was a couple things that came up. If we're going to give with the blood is the GI bleeds because we don't know when that started. Especially we're giving it to some with varices and all that. There's some things that maybe we ought to be careful. We talked about the IM and then. But finally, let's say if you're giving blood and you only have one line, I would just because of the temperature issues and some other things theoretical. I mean, you can wait another minute or two. So I would say get the blood in first, that's important. And then wait, give a good flush and then you can give the TXA afterwards up there. But I'd get it on board before we even get to the hospital in the cases that that are indicated. Okay. So I think.

What'S interesting, I looked up this trial while you're talking.

Yes.

And it indeed does say that when comparing TXA effects stratified by time to treatment and qualifying shock severity in a Post hoc comparison, 30 day mortality was lower when TXA was administered within 1 hour of injury 4.6 versus 7.6 with a P of less than 0.002.

Yeah, you're saying the same thing. Yeah, right, right. The graphic was wrong. That's all. Let me, I gotta get finished here. So anyways, because I want to take questions too. But anyways, just going back what Jason said. The T, triple C, they're out there doing it and they're right. Okay. As far as I'm concerned. So in conclusion, we're going to get back people we never got back before on the road to 26. If we take it to the streets and as the Doobies would say, let's take it to the streets. Okay. And that would be it. We'll make life better for future generations. And I'm going to skip that. I'm Paul Pepe. I approved this message. Thanks. Questions for me?

Okay. Awesome. All right, so I know that, I know that the txa and the reason I, I stopped to. Just to clarify, because I, I know that there's a, the camp, there's two camps out there. You know, the people who are reading the studies verbatim and saying, yeah, these studies. And then you, of course, who with your eye are looking at these nuances of TXA given at a different dose within one hour, even ideally within 40 minutes. And obviously there are a lot of people who are on the fence, including mainly the surgeons. That's why really I wanted you to come on today to talk about this.

But because their experience appropriately was it's a worse outcome if you give it by the time you get there to them or. Okay, so that's a large part of it and that makes sense. So it was really kind of cool because you had people like Randy Schaefer and others that have seen this or John Holcomb and they are saying, absolutely what you're saying is the right direction. So there is not just me saying that.

So there's a lot of. Really, this is, this is probably one of the most attended webinars we've had and which means it's a very important topic. So I'm hoping we get some folks out here who can raise their hand, unmute their microphones and ask Dr. Pepe some, some questions here. Anyone currently not using and considering using it, or anyone who is using it and that has any. That is, that is collecting their own data that can report back to us here as well.

Hey, Peter, can you unshare me or how do I unshare? Is there a way to do that?

Look at share tray again. There should be an X in the middle of it.

Click that. Oh, maybe it's here. Okay. Ah, here we go. Unshare I think this is it. Right? Good. Thank you so much.

Are you still sharing?

Yeah, I am. Okay, here we go. It looks like it's exiting it. Let me see what it says now. Okay. Huh. I tell you, close here.

You're good, you're good, you're good. Here we go.

Yeah. Dr. Daya, go ahead. I want to hear the comment from Dr. Die up in the Northwest.

Yeah. So we've actually implemented this basically since we were part of the Rock Dxabi trial. So we actually added 2 grams, and we now use it also for postpartum hemorrhage. So we have three indications. Postpartum hemorrhage, it's not responding. We give it for tbi and we also give it for shock. I think we also, when I take transfers to our trauma center, if I have a head bleed that's confirmed from another facility, I don't often get it within the hour, but it'll at least be within the three hours I will give it as part of the transfer package. And we also give it an our ED on arrival if we have a significant tbi. So we've added it. I think a couple of things that have come up a lot in the Siren Network. They've been talking about doing another trial, but they want to wait until looking at the tag studies that are done in the hospital. The problem that Marty will also tell you is that when you look at the tag, there was no differences in the tag in the three groups that got txa. So waiting for a tag really was not really helpful at all. So that's the policy we've used. The harder part has been changing culture. When you have tbi, there's a lot of stuff that has to be done, including airway and other things that are in priority. Same with shock. So reminding people to give the TXA is probably our biggest challenge. That's the biggest thing that we've seen. And seizures are one contraindication. So sometimes you will see post traumatic seizures with a head injury. So that's something to keep in the back of your mind.

But people, that's the whole point, they have them anyway, so you got to be prepared for a period. And the difference wasn't that much in the long run in these studies. So my bottom line is, if this is my family member, I know exactly what I'm doing there, you know, for them.

And the question is, in Palm beach county, we're putting the two grams in a 50 bag. One drop every two seconds. It's going in over two minutes. Dr. Dyer what is your process for giving the two grams up in your neck of the woods?

We just push it, we don't drip it.

Right. And I wonder, does anyone know if those seizures are caused by the speed of administration or is it just kind of an association? That is unknown how that happens, the mechanism.

So the mechanism of the seizure is well known. It's studied in animals. It's actually an anti GABA effect in the brain. So it's been shown that the molecule actually inhibits gaba and so that's why you get seizures. So that's why seizures is a relative contraindication. So that's the only thing. We've only used it maybe 10 or 20 or 30 times. So be fun to actually look back at our experience. We implemented this work on I think the start of 2022. So it's been about 15 months.

And then the last question I have, isn't it true that in order to determine a difference giving TXA, even with these huge studies, crash 2, crash 3, etc. That there's only really a small difference that TXA could make, that the only way to really tell if this new implementation of early higher dose is going to make an impact is to do another very large study? Do you agree with that premise.

Or.

Do you think we'll see data with smaller sample sizes?

So just to be honest, you should know that there wasn't. There's another study from Thailand that actually looked at the 2 grams. That's actually what drove the txntbi study. That Thai study was done and showed a benefit in a group of I think 400 patients.

So that's where we actually got the idea of the 2 grams or even people talked about 4 gram boluses because again, the upper limit is not necessarily known. If you look at what's given to women.

With dysfunctional bleeding, it tends to be pretty high doses. So just keep that in the back of your mind that the dose, upper dose, we don't know yet.

Last question, Peter. Are we, are we blocking it from getting to kids? Are we not, not keeping it from kids or what do you think?

No, no, no, no. We're giving it to kids and we're happily giving it 15 per kilo. But my last question is, is you had mentioned Im earlier and a few people have been asking about intramuscular. What is the kind of the party line on that?

Well, what I've heard so far in the party line, both from say people like Marty or John Holcomb etc, is that they don't know about the pharmacokinetics of this IM in that it won't distribute very well as the IO or iv. So go that route and we hopefully we've got the IV in for the blood and all that kind of thing right now, having said that, if we don't have the blood, maybe something I would still be considering if we didn't have the blood, that's number one. And number two, for the tactical people who are out and they don't have anything else there where they could do it as self administration. We wouldn't rule out the IM under those circumstances and it may not be as effective, but at least you're getting something on board. So that's the context under those circumstances.

Okay, awesome. All right, well, I know that you have to run, so I really appreciate.

I hope this was this helpful to you.

Yeah, it's hugely important because I mean, understanding that data and knowing that the pre hospital arena is where it needs to be given where the trauma folks for a while were just telling us, no, don't give it.

And I said once when I presented it like this, a lot of them went over, you know, and really positive and I mean, but the T triple C people were already doing it, you know, at the same time the people in San Antonio were doing it for years now, for example, that's where I first got on board with doing this with Craig Manifold of all people. Right. So. Which is really cool. All right. And that was before the studies were published. All right, well, listen, I got to get over and run the other meeting, so. But thank you for being here. I wish you all luck and hope this was good for you. I don't like to bore you guys either, so.

All right, that was great. And by the way, Joseph Zalkin is going to be nice enough to restream so he'll be on the Eagles. You'll see him on the other side restreaming for us. I'll be. I'll be mobile my phone.

All right, got it. Okay, thanks. Bye. Bye.

Thanks everyone for coming on. Appreciate it.