Thank you very much Krista. All right, I guess I'll take the mask off here. There we go. So thank you very much everybody and good afternoon. And so I just wanted to thank you again, the society for honoring us with another Star Research Achievement Award. If it was just me, I'd say there's no accounting for taste, but the international crew that I work with has done a lot of work here and a little unconventional, but this, as far as I'm concerned, this has been one of the biggest advances I've seen in six decades since I started work on the streets of Seattle with Len Cobb and then with Peter Saffer later in some research projects. So with that, let me go ahead and get started. Of course, how's this slide changed by the way? Is there a way to change the slides? Yeah, where is it? I'm sorry. Is this it here? Okay, thank you. Didn't get to see this. Down to advance. Okay, good. Thank you very much. All right, so there's four inevitabilities of life, right? Death, taxes, right? What else? Oh wait, in California here, there's kale. And then there's also disclosures. And so I have, despite all the devices you'll see today, I have no disclosures per se, except that one, I'm not a morning person. So thanks for having this in the afternoon. And I'm also considered an insignificant other in some, let's say some locales. Okay. One person who does have a conflict of interest, just to put it out there is Dr. Keith Lurie, who actually is the creator. And I invited him to be on this because he deserved it from an intellectual point of view. And the rest of us are all either public servants and or academicians at universities. And so we have no disclosures whatsoever. And Joanna Moore, I got to point out, I'm going to talk about in a second, did an incredible amount of work, robust laboratory work that got us to this point. So you'll see as we get on here today. All right. So introduction, sudden out-of-hospital cardiac arrest is by far one of the killers. A thousand cases a day, each day in the US alone, just in the out-of-hospital setting. And of course, many more in the hospital, et cetera. About 80% are non-shockable EKG presentations and with extremely poor prognosis. Two thirds are asystolic when we arrive and with survival chances being less than 1% for the last six decades, to put it bluntly. And that's despite aggressive advanced cardiac life support, epinephrine, airway, et cetera. But one thing that I think has not been well understood has been the, less appreciated anyways, has been the physiological limitations of conventional supine CPR and why it's been limited. So even if it's performed early and optimally, cardiac arrest is only about 15% to 20% normal blood flow and cerebral perfusion pressure, let me put it another way, both in animals and humans, et cetera. And the supine flat chest compressions, you know, do send out forward flowing arterial pressure waves, but guess what else? They also create back pressure, right? On the venous side. And one of the things we found in the laboratory is that really increases great impulses in the intracranial pressure side. And so that's become a problem. It limits, you know, an optimal blood flow in the brain. So you have limited cerebral perfusion and limited cardiac output altogether, by the way. So what's a potential resolution? Well, a couple of decades ago, we started looking at the concept of actually pulling blood out of the brain and back into the chest. One thing is the impedance threshold device, which is the ITD is applied to the airway and on the recoil phase of the turkey baster approach, right? You know, you release, this blocks the air from rushing in. So it prolongs the vacuum just for a second because it's a pop-off valve. That actually in human studies brings you from about an average of 40 millimeters of mercury systolic with conventional CPR up to about 80. But when you combine that with, see if I can get this to, okay, here we go. Combine it with a compression, active compression decompression. So you're actually got a pressure down and then suctioning out. You really enhance that flow significantly and almost double the cerebral perfusion pressure, both in the laboratory and humans. And the NIH funded clinical trial, we showed this proof of concept, pulling the blood out of the brain and into the heart basically does you well. And it gives you a 50% improvement in neuro intact survival, even better in terms of overall hospital discharge. But this has been worked really well, as you probably saw published, you know, 10 years ago in the Lancet. An interesting question came up if we have to go down a stairwell, which way we go, head up, head down. And so we looked at it and it turns out it's not good to put your head down. It increases intracranial pressure further. But if you put the head up too fast, you can't get a good mean arterial pressure. So what we found was you got to prime the pump first with those other devices, get flow going better, and then you could gradually elevate the head. All this work, as I was telling you about, was done by Johanna and the rest of the team in the laboratory. She led it. But we've done a lot of robust and really meticulous work trying to see, should you do the priming for three minutes? Should you do it for one minute, four minutes? And then how fast should you elevate the head and when should you do it? So all that's been worked out really well and now we're kind of bringing it to the clinical situation. But let me just give you the laboratory data. These are in, by the way, VF models, but they're prolonged VF in which we're doing it. So you see here on the, I guess I better do this thing here. It's not showing up. But on the left axis is cerebral perfusion pressure. And so you could see pre-arrest that the start of CPR goes way down and you get it up a little bit. But one interesting thing is that it kind of falls off over time for various physiological reasons that I will not go into today. The one thing cool about the active compression decompression ITD combination is that you not only improve cerebral perfusion pressure even in supine, but it's actually more prolonged. But what was striking, we already had the proof of concept, but then, hey, let's just add in this supplement. It was synergistic when we started doing the head elevation. We did it right. We're normalizing not only cerebral perfusion pressure in animal models, but even when I've got some correlative studies that we're doing right now in terms of end-tidal CO2, you're getting end-tidal CO2s in the 50s within five minutes of applying all this. So we think that it's out there to, plus we're getting people who are waking up, which is the whole thing. So this concept of a neuroprotective effect is probably there, as we're seeing in the laboratory, and we think it's there in humans, as I want to try to point out here. So I went the wrong way here. Thanks, Sergio. All right. So this thing, again, creates gradual automated elevation. It's another device that we put on, as you can see there. But remember, these are all FDA cleared now. They were convinced also with the data we had. And remember, it requires all these things to make it work. You've got to prime first, and then you start elevating the head in a gradual manner. So our study purpose here was basically to see if such robust outcomes in a lab are also applicable for patients with non-shockable presentations. Take the defibrillator out of there. These are our classic ones that have really poor outcomes here, PEA and asystole. All right. The methods were, I'm oversimplifying here so we can get through this, but it's a comparison in the neurointact survival, not hospital discharge. We're really going for neurointact survival for patients presenting with asystole and PEA with unadjusted head-to-head evaluation and then propensity score matching, because we know all these well-established variables that impact out-of-hospital cardiac arrest outcomes. So we thought this is a good way to be able to look at that in this particular kind of clinical scenario. So the Head Up Registry was started a couple of years ago of people who were early adopters. We've only collected, well, we decided to end the analysis last year at the end of the year, so 2021. And we looked at those enrolled over those two years, and we got 380 patients of about 400 or 500 that had all cardiac arrests that had non-shockables. And it was a pretty diverse group of people that were doing it at first, and they collected all these data as well. The conventional group, where we got the control group was interesting because we used on purpose two NIH-funded clinical trials that, for example, a large part of it, in order to get into the trial, you had to demonstrate that you're doing quality CPR. They actually had gadgets on that measured the quality, the rate, the depth, interruptions, recoil, all that stuff. And you had to demonstrate to get into the trial, you had to demonstrate for them that you're doing quality CPR. So we purposely did this to have a stringent control group as best we could. And you'll see later, reason why it's not contemporaneous, but nothing's changed over all these years. But also, we were doing our part during COVID, which actually changed the game a little bit. So what were the results? Well, both the unadjusted, of course, the adjusted data show equivalent age, sex, response times, blah, blah, blah. But when we looked at this, this is interesting, and it's important to what I'm going to show you in results, how we decided to present the data. The median time from the 911 call receipt, going through the dispatch or everything else, to the EMS-initiated CPR, not just the scene arrival, but when you started CPR, was actually eight minutes for all those many patients in all the groups. And so I thought that was kind of cool. And the median time to the AHEP application, which is pressing the button on this thing, was about 11 minutes. And I purposely, there was a lot of outliers here that we had a response time of like 20 minutes, 25 minutes, and so on and more. So I purposely wanted to look at 15 minutes seems like a reasonable response time. And it turned out 80% got it done within 15 minutes. So again, I can't show you this very well because there's no real pointer system here. But if I can, I don't know. The left axis is good neurological outcome. And you're comparing gray as the unmatched sample. Gray, 26 of 1852 survived. And again, this is all people, including the outliers. And that gave you about an odds ratio of about threefold. If we did the propensity matching, which had all those things in there, it actually bumped it a little bit up to like almost fourfold. But the most important thing that I did learn is that we said, well, we really do need to look at how response intervals change that just like AED. So it'd be the same thing. And it was like, duh, the earlier intervention, the better results, and all these were statistically significant. But it actually becomes really interesting in that if you break down the median time, 50% of the cases, and then the other one, the people who got there pretty quickly were people who had designed these bat packs. And they had this thing. It's a true pit crew approach. So in other words, they don't just get to the scene fast. They get the patient treated fast as well. And they're the ones that had the best times, by the way. So we're going to be recommending that at the end of this talk. They just did it by themselves. It was very cool. So let's show you that. So on the right now, we're seeing that 1059 at the top. That's the odds ratio when you're looking at less than 11 minutes, the median time. So half the people could get it there, and the odds ratio is way up there. And then if you look at less than 16 minutes, there were no more survivors on their end, and we had a few more on our end, so to speak. And look what happens there. It's like almost 14-fold odds ratio. And by the way, I've never seen a confidence interval over 100. That's actually an artifact of, by the way, statistics, just small sample size. But still, it's pretty cool looking to see that. All right. So just as an FYI, PEA presentations did have a higher odds of both hospital discharge. But I think the most important thing is just looking at the, this is unadjusted. It just almost 10% went home versus 3% in the control groups and so on, even when you matched them up. And also, this is, I think, the more striking thing. Normally, in many EMS systems, unwitnessed arrest with an asystolic presentation is futile, and most people actually pronounce them dead. But when we specifically examined those cases, which are almost half of all the non-shockables, it had a higher odds of both hospital discharge. Look at that. If you had the old days when we looked at hospital discharge, 5% for unwitnessed asystole. It's unheard of. But we were also wanting to look at neurological outcomes. It's still 2%. You might say, well, that's awfully low. But there's 350 cases a day in the United States, let alone what's happening worldwide. So this could have a significant impact there as well. The limitations in discussion here is that it's a relatively small sample size to date, because we prospectively decided to cut it off at that date. However, despite the current sample sizes, the statistics are already pretty compelling. Also, especially because we purposely compared to this neural protective group to the high performance EMS agencies that closely monitored CPR quality outcomes, et cetera. People say, oh, it's not a traditional randomized clinical trial. In fact, where we're submitting it, they called it a non-randomized clinical trial. They see it as an acceptable approach. However, we've already done the clinical trial in terms of proof of concept. And this, again, was just something we added into the laboratory. It just had a very good synergistic effect. So I think we're fine with this now. And the FDA thinks so, too. Also, you might raise the issue that this is, again, non-contemporaneous, as I said. But the survival rates have not changed. If anything, they were better with the control group compared to past and national databases. And also, the registry data were collected during COVID when we had PEA and asystole cases skyrocketing with futile efforts, really true futile efforts under those circumstances. So I think the results were attenuated. And they're going to be a lot stronger, especially if we look at time under 15 minutes. Either way, the raw data really make a difference, et cetera. So in conclusion, rapid initiation of this neuroprotective CPR is associated with markedly improved outcomes, regardless of the initial EKG presentation. And it can be viewed as, I think, the AED equivalent for non-shockable cases. But even better, you have a larger window. And it even helps shockable cases, by the way. And the neuroprotective CPR is not advised if you do it incorrectly. Just don't put the head up, that kind of thing. And it's for that. But if it's done right, it's strongly recommended for all basic responders, first in responders, firefighters, paramedics, whoever. But as long as they're in your ICU, I know that there are several ICUs that are now going to be putting this in across their system, because they could do it right away and get really good blood flow again. So with that, that's what I'm thinking that we're going to see here. I'm Paul Pepe, and I approve this message. So thank you, everybody. Any questions, let me know.

neuroprotective CPR technique

head elevation during resuscitation

blood flow to the brain

non-shockable cardiac arrests

improved patient outcomes