Dr. Nick Ashburn - "One and Done Epi" (12/6/2022)

The CME code is 15342. If someone can write that in the chat because I don't have access to it. 1-5342 and then Eagles is 1-5343.

And we are recording. Thank you Angus for that. So this, this is a going to be a great one because I, I posted this on social media the other day and it got like, you know, tens and tens of thousands of views and a lot of people back and forth. There were some people from North Carolina who were like, yes, we were involved in that study. And so Nick Ashburn is from, as you can see from Wake Forest there and he's a deputy medical director in Randolph county ems, obviously an ed doc and they run a great system up there. And we've kind of been following each other and have known each other through the conferences and through social media. And as soon as I saw this paper I emailed Nick and Jason Stapira and they're like, yes, we'll absolutely come on and talk about this study. So Nick, if you want to add anything else that I miss in your intro, but really can't thank you enough for joining us and take it away.

Great. Well thanks Peter for having me. And certainly this has been a controversial topic, but one that I think deserves a lot of good discussion and looking forward to hearing everybody's perspectives and opinions on this after we get through this. So I will sort of do a brief run through of our study we did and of our findings and really looking forward to hopefully a robust discussion here at the end. So I'll go ahead and get started. So.

So with that in mind, these are basic high level background information points that really we all know cardiac arrest is very common in the United States and current ACLS guidelines are recommending epinephrine every three to five minutes. But really what we did is we called that recommendation of epinephrine every three to five minutes into question. And there is study after study after study after study after study questioning the utility of epinephrine in pre hospital cardiac arrest. And based off of this, we said, hey, there's real equipoise in the literature on the utility of using epinephrine in all of our protocols for cardiac arrest. And so we proposed transitioning to a single dose of epinephrine. So one and done is what we called it. And so with this one and done epinephrine protocol, we really wanted to know, do outcomes change when we use a single dose epinephrine protocol compared to our traditional multi dose epinephrine protocol where patients were getting EPI every three to five minutes. And with this in mind we designed empowered a study to look at survival at a hospital discharge, ROSC rates and favorable and we explored favorable neurologic outcomes in these in these patients.

So we did a pre post study over a four year period where we looked at patients who received care guided by the traditional multi dose epinephrine protocol and then after implementation of a single dose one and done protocol.

We did this in five large North Carolina counties. It was a mixture of suburban, urban and rural areas. And we looked at adult patients who had an attempt, who had resuscitation attempted for non traumatic out of hospital arrest.

For outcomes we relied on the CARES registry and this is certainly a topic of discussion that we'll come back to in a few minutes. But for CARES we use this to define rhythm type survival to discharge favorable neurologic outcomes and roscoe.

And then for our methods this is we, we relied on the intention to treat principle for the analysis. And when we were doing out, when we were working with our statistician, we arrived at doing generalized estimating equations where we were able to account for clustering within each of the five EMS agencies and of course adjusting for traditional cardiovascular and cardiac resuscitation outcomes that we thought would make a difference. So such as age, race, sex. Was the rhythm shockable? Did the person receive bystander cpr? What was the EMS response time? Was an AED utilized, et cetera.

So with this, this is our flow diagram, we had a total of 1,690 patients that were included in the study, 899 in the pre implementation multi dose arm and 791 in the post implementation or single dose arm.

And this is really some of the key results that we had. And I want you to focus on the far right column in the red box. So this is the adjusted analysis. So for survival to hospital discharge our odds ratio was 1 and our confidence interval crossed the point of unity. So suggesting that there's probably no difference in survival to hospital discharge when transitioning from multi dose to single dose. Favorable neurologic outcomes among those who survived similar no difference. Favorable neurologic outcomes among all patients, no difference. Where we did find a difference was with ROSC rates. We found that when using a single dose protocol we actually had fewer patients get ROSC compared to the multi dose protocol. But then going back to the outcome that we really care about survival at a hospital discharge, there is no difference.

This is just showing the same findings, showing it Graphically because I'm a visually oriented person. And so survival at a hospital discharge, no difference. But ROSC rates decreased after implementing the single dose protocol.

So I want to talk about a couple of limitations that certainly some of our colleagues have highlighted with the study. And this was a letter to the editor that was published in pec. And there are great points in this that are certainly limitations to our study and I think indeed to most of the prehospital resuscitation literature. And the big point of it is that we rely on cares and there are several definitions in CARES that we all know are controversial. For example, ROSC NCARES is defined as having at least 20 minutes of cardiac activity without requiring further CPR. That's a controversial definition. And the other issue that we have with our CARES data set is that we were forced to do a intention to treat analysis instead of a per protocol analysis. What I mean by that is that in the multi dose cohort there are some patients who likely received one dose of EPI or no epi, and then in the single dose cohort there's probably a few who may have received multi dose epinephrine. And we don't have a way of verifying that based off of our CARES data set.

So in conclusion, we found that there were similar survival to hospital discharge and favorable neurologic outcome rates, but decreased ROSC rates after we changed our resuscitation protocol from epinephrine every three to five minutes to a single dose of one and done epinephrine. So with that in mind, you know, there's a lot here for us to discuss. I really just wanted to put the core content out in front of us so that we could discuss it further. I'd be happy to answer any questions, take feedback, ideas, and looking forward to discussing this with you all. So thanks Peter.

Awesome, Nick. So if we could start off by just asking a few questions. So how long have you been doing the one and done thus far? What's the timing on that now?

So we started that. So we started that in 2018. So we've been doing that roughly going on four years now.

And just to start with the basic question of when you were trying to get the IRB to approve this. Was that difficult? Just out of curiosity, or did you have the precedent of paramedic 2 and the other studies to help you get through that?

Having the precedent of Paramedic 2 was critical for us getting this through with our IRB. Our IRB was great to work with and of course people have very Raised very reasonable ethical questions with it. But given that we believe there was true equipoise in the literature regarding this and of course paramedic too, we were able to get it approved by our irb. And of course each of the counties that participated asked similar questions and had similar concerns. But I think eventually believe there was merit in conducting this trial. And since publishing this, all the counties have continued with a single dose one and done epinephrine protocol.

Okay. And just to clarify a couple things, so paramedic two, if I recall, was 4,000 people in each group. The group that got EPI had a 24% ROSC rate and only an 8% in the no EPI group. But the neuro attack survival was the same like at one point something or 2%. Right. What was the favorable neuro and tax survival in both groups on a percentage basis and was it similar to paramedic 2? I don't remember seeing that number.

Yeah, let me, I'm going to share my slides again.

Okay. And we have Dr. Beach here today. Thanks Dr. Beach for coming in. And we have quite a bit of cardiac arrest experts on this call. So I'm going to be, we're going to be going around the horn here to the cariboucistas of the world and other people here to get their opinions.

Love it. Now that's great. So here are, you know, I'll read it out loud to everybody, but here are our raw percentages and numbers in the pre post for each outcome. And so for ROSC rates we're at 42 and then 32% respectively.

But the favorable neurologic outcome was 11 and 10.8%.

That's right.

And if I, I mean, I have to go back to my notes on Paramedic two, but are those CPC one and two? Are you, is that how you classified favorable neural outcome?

That's right. CPC 1 and 2 aggregated together.

So I'm wondering.

The paramedic 2 trial had much smaller percentages and I'm wondering why. Maybe I'm way off and someone can correct me here.

I'm looking it up right now.

Peter.

Let's see.

Okay.

All right.

Yeah, go ahead.

For paramedic 2 at 30 days, the Epigroup had 3.2% survival at 30 days and placebo at 2.4% at 30 days. So certainly quite the difference it seems.

Right. So the question is why that difference? Now this is all comers, right? These are all rhythms.

These are all rhythms. The only people who were excluded were traumatic arrest and of Course, people who were DNR were excluded.

So can anyone smarter than me on this call help explain that? Just because I want to make sure that we're, I mean, you know, I think, I think. Yeah, go ahead, go ahead.

Remember, I think paramedic two, what was the time to first drug was? 25 minutes or something along the lines.

From, from the 911 call. It was like 16 and a half from the time of arrival on scene. Yes, you're correct.

Yeah.

Was this, was this sooner?

Good question.

So I will or do you not.

Have that so hours.

So I don't, I don't know time to first drug. But our response interval was right at 8 minutes overall in each cohort. So that would suggest certainly, probably quicker than the 15 minutes you were just talking about.

Yeah, I mean that's one of the, that's one of the, the downsides I thought of paramedic too is that it was such a. Yeah. They were looking at time, they were looking at the drug and the time first drug was very prolonged.

Right, right. So. But, but there is a signal here of the same thing which is more rosc. Right. In EPI group. But no, no difference in neuro attack survival which is really the big question here. So. And I want to bring in Jim Roach here. So Jim, I'm going to pick on you because I know that you now at BSO for over a year, maybe a year and a half and I know you have some prelim data have moved to something that I love, which is intra arrest epi drip. So perhaps it's that 1mg is too high of a spike and perhaps it's causing. You're not protecting the brain. The neuroprotective CPR that we're now talking about.

And Jim, would you mind talking about your algorithm? And perhaps there is a Goldilocks zone that we still haven't found yet. The sweet spot of either the EPI administration, how it's given the frequency we're talking about now, obviously. But.

Let'S consider the actual dose of epi. So Jim, you want to comment on that?

Sure. Pete. Yeah. Good morning everybody. And this is great stuff. When I saw the title of this lecture today, I was like, man, I got to check this out. This is great. So I applaud your work here. As Pete said, we do for the same reasons. Looking at paramedic 2 and other trials, thinking about epinephrine and neurologically intact survival, you know, our thoughts was pretty much like we need EPI on as early as possible. But the Amount of epinephrine, that's the question. So we started a EPI drip and the EPI drip is set. So it's very simple and it's in line with what the firefighters are already doing on other drips. So they get approximately 2 milligrams of epinephrine over a 16 minute period. So it's much less than the typical.

You know, three, you know, every three.

Minutes, one milligram every three minutes. And we've, we've seen. I don't have that information right in front of me. I presented that at Eagles, we had an improvement in neurologically intact survival and our, and our ROSC rates stay about the same. And I think Paul puts it best, you know, just looking at these things, it's a bundle of care, not, not any one thing. So I don't really know the answer to why that's the case in terms of, you know, our ROs staying roughly the same despite not having the same amount of epinephrine on board. But it is what it is. But I, but I also think about this in terms not just, you know, outcomes, but, you know, for the ease of work. So the EPI drip is meant to be, you know, simple. They come on scene, they hook up the drip and they sort of start, they don't have to think about it again every three minutes. But, you know, this is even, probably even easier just doing one dose of epinephrine and not repeating the dose, probably even easier than an epidrip. So that's great.

And so, Jim, you have a signal towards increased neuro attack survival. Scott Youngquist, who we had on the webinar talking about this is last year now he in Salt Lake did 5mg IM EPI 1 to 1000, and he found no difference in survival. But again, the problem here, as I see it, and I would love to hear some other comments here, but the numbers are effectively small. It's almost like a TXA study, right? With TXA the improvement is about 2 or 3%. So in order to see a signal, you have to have tens of thousands of patients. And here we're talking in Nick's study of, you know, 900 in one side and 791 in the other. Scott Youngquist probably had small numbers too. And the question is, how do we answer this question effectively without throwing the baby out with the bathwater? So anybody else want to throw in a comment here? I'd love to hear from.

Some other people. Dr. Pepe, go ahead.

Okay, if you'd like me to speak. So first of all, the CME code for today is 1-534-215-342. So there's a couple things. Thank you very much for the presentation. So a couple questions I had about your study is that one, did you stratify it by time? And it sounds like from what I heard you say is that you actually didn't look at the time of epinephrine administration. Especially in non tiered EMS systems, the delivery of the drugs are usually pretty delayed because of the delay in getting intravascular assets in or whatever it might be. That's one of the reasons why you see the IM working. But there's some other reasons for that as well. And so what happens cardiovascularly, the hemodynamics has changed so much at that point in time, the EPI wears, you get a pulse, then it wears right off. That gives those advantages a little bit to the drip system you heard about. But the main thing is that is, is the time factor. So one of the things that Paul Banerjee did up in with his pediatric study, which was really pretty cool, was went right to the epi and got, got, came down from 17 minutes to what, seven minutes and then finally onto five minutes by having it all prepared before he got to the scene. And so the point is, time is a big issue because I mean the paramedic study was a joke for many of us to see how that was done. The other question is did you apply propensity score matching which is really probably more appropriate for cardiac arrest studies nowadays than they had to head clinical trials because of all the confounding variables. So those are started to throw a lot of stuff at you, but those are just, I can go into this much more detail, but those are the things that would be bothering me right away about how to interpret the results. And most importantly, did you divide out and stratify by whether it was a ventricular fibrillation or a non shockable presentations? So sorry. So the two main questions I wanted to get from you is one, did you time stratify? Two, did you apply propensity score matching? And then third, you know, did you break it up at least by very least by non shockable versus shockable rhythms?

All three of these are fantastic questions on the covey. And so for the first one, do you we time stratify? So we do not have data accessible to us on time to first drug to first drug. So that's certainly a limitation. Okay, for the second one on the propensity analysis we did not do propensity scores for this one. And then for the third one in our adjusted model, we did adjust for shockable versus non shockable rhythm.

Okay.

Future subgroup analysis that we're working on right now that will published shortly, looking at shockable versus non shockable. And the short answer, there is same results, decreased rosc, no changes in survival to discharge.

Oh, and then you're thinking, there is one other sidebar. Did you guys control for how ventilation was delivered? Actually physically, how it's delivered and so on? Did that get control?

No, we did not adjust for that.

All right, got it. All right, thanks. That's okay. We'll leave it at that.

Yeah, those are great questions.

Really. It also brings up, it also brings up the other question, which is, should EPI even be used in shock or rhythms to begin with? Right. And.

You know, I'm looking at your numbers here. You had 16% in the pre shockable and then 22% post. So you had a 16 and 84 and then a 22 and a 77.

And you know, again, I know that there are lots of agencies now who have removed EPI completely from the shockable rhythm protocol and only have it in the non shockable rhythms. And there are agencies now who have extended their epi doses to five or 10 minutes. Some are using half a milligram instead of a milligram. So what. I feel like it's happening. And if somebody wants to comment on this, but it feel, it feels like there's absolutely no standardization for EPI at this point in time. Nobody has any signal as to what to do. And we're all kind of floating in the ocean, you know, waiting for the Coast Guard to come pick us up, like the guy from Alabama. But does anyone want to comment on, like, what is the future here? Based on what we're. What Nick presented today and other studies.

That are out there, Peter, I want to concur with that. I think, I think your shockable rhythms is kind of. Is where I think separating your epidosing between shockable rhythms and non shockable rhythms is where I think the future is going. I think that your shock algorithms, of.

All people, I should ask you, maybe this can be obviated altogether in an unnecessary question. If you can completely restore normal blood flow.

Yeah, well, that's the question.

Yeah.

If you can get to normal hemodynamic blood flow or something close to it, then you really don't need epi. I mean, if you see some of those studies, you can put somebody with some of the Heads up. Stuff we've been doing. You could do CPR on, on, on some of that for half hour, 45 minutes, no epi.

Okay, so carries nothing. One shock. Okay, but is your, is your marker for that, an end tidal? An appropriate end tidal. Obviously we can't, we don't, we don't have an A line. We're not going to check someone's diastolic.

Blood pressure during I think, end tidal and maybe cerebral.

Oxygenation.

Oximetry.

Yeah, yeah, oximetry. If you can, if you can gather that, if you're, if you're slick enough to be getting those two things.

What's fascinating is about the latest, that this has got to go through peer review yet, but the results, we got pretty much the results in on the latest stuff Carrie's doing, for example, with non shockables and they're restoring not only, you know, really good blood flow to the brain, but the, the Ross rates are about the same when you compare it to the controls, which is interesting, is that. But then what happens? The neurologically intact outcome, which is what you're really looking for, is dramatically improved, especially if you do it early on. So. But that's just a hint of the future. We'll leave it at that. I don't want to get across from the main thing, but that's part of the issue is, is restoring the hemodynamics and getting this stuff on really early on, you know, that kind of thing. And I don't think it's. Getting. That's not happening is what I'm getting at. And particularly fibrillation cases, you know, which was, I think, Peter, I'm sorry, Paul Banerjee enjoyed such success with the children.

Right. And I'll throw this in for the pediatric side of it, where most of the cases are asystole and it's nearly impossible for people to be able to detect a pulse with their two fingers. Right. And oftentimes you have a kid, let's say, who has PEA and you're just jamming more EPI in. And so obviously in Palm beach county, we had a case recently where we used ultrasound on a kid, a one year old, who had cardiac wall motion. We withheld the epinephrine. The kid made a full recovery. Right. But then ILCOR comes out on November 3rd, it's in circulation, the 2022 updates where they say we do not recommend ultrasound in EMS because it's too haphazard and not many people know how to do it. And it's, it's, it's all Variable when it, when in fact.

It'S my guess that in kids, people aren't looking at this sudden bump in end tidal to say, hey, maybe we should get push pressure Instead of the 0.01 full cardiac arrest dose of epinephrine. So.

You know, I just think that there's some clinical nuance here that we may need to be teaching, right, Such as this, the end title, et cetera. But I just don't think that it's so binary. Paul, like you always say, things are never binary. It's not just EPI or no epi. There's other things that, there's other quantitative measures that we need to be utilizing. Maybe downtime, initial rhythm, end tidal, CO2, other things to help us figure out who gets EPI, how much they get, and then we have to figure out what is the dose, what is the frequency, should it be a drip or not a drip? Does anyone on the call here feel like we should just be removing it all together? Because I know a lot of people are on that in that bucket of.

The future.

I think is algorithmic and I think the first branch is, well, depending of course on what other adjuncts and other things you're doing. But I think the first branch is shockable or non shockable.

Okay, Yeah, I agree with that. All right, well Nick, we're reaching the bottom of the hour and we always like to give our speakers the last word. So after hearing our conversation, and I know that you have some other analyses coming through, what is your recommendation for us, number one? And what do you have in the pipeline, if anything, to help further answer the questions that we have?

I think.

Well, I used to start with Peter. There were a couple of questions in the comments that I wanted to take a second to address. And so one was I believe patients were only randomized in paramedic two, once they reached a point where parenteral meds were needed. Does this cohort include patients who achieved ROSC after one or two shocks and did not receive epi? So yes, this was a.

Per intention to treat analysis. And so all the patients in each cohort were included pre vs post, whether they got epi or no epi, 5 doses of epi, etc, etc. So unfortunately we don't have the ability to do a true per protocol analysis, so they would have been included. And then Larry, you were saying, do you know the average number of epidoses in the pre implementation group and similar concern there? We do not, we do not have the ability to know the number of doses in the pre implementation Group certainly a major limitation of this trial.

So I think going back to your original questions, Peter, is First of all, thank you all for letting me join you all this morning and the discussion we've had here. And I think that our practice in Randolph county and in this area of North Carolina is certainly reflective of what you all are discussing. It's not binary. Nothing is ever easy. And really we're, you know, utilizing end title. Some of our counties are using end title to dose their EPI and when to give repeat doses of EPI after 10 minutes of entitled monitoring. We have not done that in Randolph County. We're still on one and done. But certainly our, the county that we're in now for Scythe county does one dose of epi up front 10 minutes later based off in title. Redose FE based off of that. None of the areas in our, none of the counties in our area are doing an epidrope. I think that's certainly an intriguing idea and I'd love to, to learn more about that and. But I, I'm waiting on the Coast Guard like you all are, so. I love that analogy.

Peter.

Hey, Nick, I just want to say please feel free to give me a call anytime to just go over things just sort of generically, if not on specific issues. And I just want to congratulate you and thank you for like looking into this and doing it because it takes, it's a lot of work to do what you just sort of summarized in 10 minutes. Not underappreciated. Thank you so, so much. You know, sorry I got so much background as everybody's getting me on the. But it was leave off again for everybody else. But what?

Hang on.

Oh yeah.

Make sure we got this right. 1, 5, 3, 4, 2. I'm sorry, did I have it right?

Yeah.

Okay, we're gonna pop over in a minute. But I, I would echo what Paul said, Nick. And you know, I think that.

You.

Know, there are a lot of people doing a lot of great work and their work really sometimes goes unnoticed. Yours didn't. And I think webinars like these where you come in and present your work or we could talk to the author himself. Obviously you have the other authors behind you, which thank them as well. But again, thank you so much. This will be recorded. We'll put it on our YouTube channel for others to see. And anyone have any last minute questions or comments for Nick before we head over to Dr. Pepe's webinar?

That was very good.

Awesome.

All right. I gotta tell you, that was great. That he did it in 10 minutes, too.

Yeah, exactly. I think the first time we ended on time. Yes. All right. All right, Nick, thank you so much. Feel free to stick around if you like. If not, we'll see you on the other side. Thanks, everyone. Appreciate you.