Good morning, everyone. Welcome to our last day of our Critical Care Congress. I'm Roshni Sridharan. And before we get started, just a few housekeeping items. We just have to make sure that you're aware that the exit doors are behind in the event of an emergency, which will not happen. Also, this lecture is going to be recorded, and it's going to be available to all Congress attendees on Congress Digital. For those of you who would like to listen to it again at home. It is my pleasure and honor to introduce Dr. Raul Gasmiri, this year's Laerdal Award recipient and the presenter of this year's Laerdal Memorial Lecture. Dr. Gasmiri is the Director of Resuscitation Institute and a Professor of Medicine in the Departments of Medicine, Physiology, and Biophysics in the Department of Foundational Sciences and Humanities at the Rosalind Franklin University of Medicine and the Chicago Medical School. He is the Section Chief of Critical Care Medicine and the Director of the ICU at the Captain James A. Lovell Federal Health Care Center. Please join me in welcoming Dr. Gasmiri as he speaks about an ongoing research pursuit for myocardial protection during cardiac resuscitation. Please welcome Dr. Gasmiri. Thank you so much for the kind introduction and for having received the award. I was very surprised, but I was happy to receive that award. So what I want to do today is tell you a little bit of a story of work that I have been doing for many years in the research lab. There's not much clinical here, but it's something that we believe strongly and we're making effort to be able to migrate or translate these findings eventually for clinical management of patients in cardiac arrest. So I have no financial conflicts. I have some research funding, and I have to acknowledge that I started a company with the effort to facilitate the translation of things that we develop in academia to the patient arena. So my talk today will be focused, number one, I want to give credit and acknowledge the person who inspired me in this career and how important it is to have mentors in academia. I'm going to talk specifically about reperfusion injury and work that we have done to minimize reperfusion injury during resuscitation from cardiac arrest. I'm going to talk a little bit about ways of delivering electrical shocks that we believe are going to reduce injury associated with the shocks. And at the end, I'm going to tell you the best way to prevent myocardial injury is not to have the cardiac arrest. So I'm going to pivot from the laboratory to something that we have been doing in our clinical environment, how to prevent the development of cardiac arrest in the hospital environment. First of all, it's important to keep in mind, and we discussed that yesterday, that despite a very, I call it gigantic effort to recognize and treat victims of sudden cardiac arrest, despite all this effort, still, the number of individuals who eventually survive and return back to their lives with good neurological outcome, for sure, is less than 10 percent on the aggregate, probably is less than that. So there's a lot of things that need to be done in order to improve the outcome of sudden cardiac arrest. And you can see here, for example, a very simple slide, if we can prevent, that would be great. But it's not that easy in the pre-hospital environment. It's easier in the hospital environment because we admit the patient who is not in cardiac arrest. So we are going to talk about that later. Roughly, when paramedics arrive, they're able to resuscitate about 35 percent of those victims who suffer cardiac arrest. Some of them are going to re-arrest and then make it to the hospital. And even the hospital, some are going to die. So eventually, best-case scenario is 10 percent hospital discharges with good neurological outcome. So let's jump into this concept of myocardial protection. And I can tell you, briefly, I always give credit to my mentor, Professor Max Garryweil, who was a pioneer of critical care medicine, the first president of the society. And he was my mentor for eight years. And I learned a lot about him. And what I find so impressive is that many of the things that we do today in critical care, you can trace back to what he discovered many years back, and many others that we have to continue working on. So as a research fellow, working with him, I focused on many things. But this was what led to my PhD thesis, was to understand what happened to the heart post-cardiac arrest. So we look at the effect on the heart using pressure-volume loops. You can see here, in the resuscitated animal, there's a rightward shift of the pressure volume, which means dilatation with decrease in stroke volume. And this is the contractility that dropped post-resuscitation. And we published that way back in 1996. But that kind of work inspired me to look option to ameliorate or prevent the development of post-resuscitation myocardial dysfunction. At the same time, in our research laboratory, we had Dr. Fulvio Chieti, who was from Trieste, Italy. And he was a research fellow. And his project was to look at the changes in myocardial pH and PCO2 during cardiac resuscitation and post-resuscitation. And that work was very interesting for what I'm going to tell you next. But I want you to realize that very quickly, after we induce ventricular fibrillation, the myocardial tissue pH dropped dramatically from a baseline of 7.2 down to 6.47. And post-resuscitation, it recovers, but kind of slowly. So we have intense intramyocardial acidosis that developed concurrently with the cessation of blood flow through the coronary arteries. No blood flow to the myocardium, a myocardium that is requiring a lot of energy because it's in ventricular fibrillation. So that put, then let me think that maybe there's a way to minimize that. And I remember going to the library to find what could work to prevent this post-resuscitation myocardial dysfunction. And I came across a review article that cited Professor Morris Carmesin from the University of Western Ontario. He was the one who pioneered the concept that targeting the sodium-hydrogen exchange could have a dramatic effect on minimizing ischemia and reperfusion injury. And I got very excited about that work because I thought it would apply very nicely to cardiac arrest and resuscitation, given the fact that there's an intense intramyocardial acidosis developing during cardiac arrest. And I'm going to show you this slide. I'm going to spend a little time here. This is a representation of a cardiomyocyte, but it can be any other cell. So here you have the sodium-hydrogen exchanger, isoform 1, which is expressed basically in every single cell of the body. And the main function is to regulate the intracellular pH. So under conditions in which there is ischemia with anaerobic metabolism, protons would increase, would activate the exchanger, and sodium then comes into the cell, along with other gates for sodium to come in. Sodium bicarbonate co-transports the sodium channels. But this is the main source for sodium entry into cardiomyocytes. The sodium-potassium pump gets disabled very early on for mechanisms that are very interesting. There's an endogenous-like compound, wabi-like compound. It looks like digoxin. I don't know why we have that one, but it inhibits the sodium-potassium pump. Therefore, sodium accumulates and eventually would create calcium entry by prompting the sodium-calcium exchanger to work in reverse mode. Keep in mind that that is electrogenic. So the excess of calcium eventually enters the mitochondria, and that will compromise mitochondrial function, compromise the ability of mitochondria to generate ATP. So this is sort of the core of the work that I'm going to present and what happens when you inhibit the sodium-hydrogen exchanger, NHG-1. The other thing that was very interesting is the following. Because this is electrogenic, there are positive charges moving out of the cardiomyocyte, and that shortens the action potential duration. And that mechanism probably is the reason why there is reperfusion arrhythmias post-resuscitation. I'm going to show you that in a second. So two important things. The damage to the mitochondria and creating the environment for reperfusion arrhythmias. So what we did was to start working with one compound known as cariparide, which is an NHG-1 inhibitor that was developed by Aventis many years back. We did work in a SWIME model of electrically-induced ventricular fibrillation, and the protocol was very simple. We would induce VF and do nothing for eight minutes to simulate what could be a setting of out-of-hospital cardiac arrest without CPR for about 10 minutes. Then at this point, we would administer a bolus of either cariparide or sodium chloride as a placebo, conduct chest compressions for eight minutes, and then give an electrical shock and see what happened after 120 minutes. So that was the basic protocol. And in this experiment, we used an esophageal ultrasound, TE, transesophageal echocardiography, to see what happened to the heart during cardiac arrest and post-resuscitation. So a baseline during diastole, you can see here the septum, sorry, the free wall of the left ventricle and the septum and the cavity here. Then we would induce VF, and after about two minutes of chest compressions, the heart looks very much the same between compressions. But six minutes later, you can see how thick is the left ventricular wall. That thickening was completely or significantly ameliorated when we gave cariparide. So that was the first effect that was very interesting to observe, that the heart did not undergo that progressive thickening of the wall and decreased size of the left ventricular cavity. So in the aggregate, here we are plotting the left ventricular wall thickness that remains basically unchanged during the eight minutes of untreated VF. The heart is sort of hibernating. Then comes the blood flow, and we see the progressive wall thickening that starts to get better post-resuscitation. In the control group, this is associated with progressive decrease in the coronary perfusion pressure. We discussed a little bit the other day about why is that we have a limited time to successfully resuscitate a person, because after 30 minutes, probably we're dealing with similar situations in which the heart does not allow for more accommodate blood returning between compressions. So there's a hemodynamic detriment when we don't treat that condition. In these experiments, the fact that the left ventricular wall did not undergo the same degree of thickening was associated with hemodynamically more effective CPR. There was, this is the aggregate, the time course you can see here in the control group how the left ventricular diameter decreased rapidly, and this is mitigated by the presence of the NHG-1 inhibitor, caripuride. More animals were successfully resuscitated with caripuride, and you can see here, this is the control animal. This is the monophasic action potential post-resuscitation baseline here, and then post-resuscitation. You can see how it's shortening, and that lasts about 10 minutes. In the presence of caripuride, there was almost no shortening of the action potential duration, and that was associated with significant reduction in post-resuscitation ectopic activity. So maybe it's not amiodarone, but caripuride, the drug that we need to give to minimize recurrence of ventricular fibrillation in resuscitation. This is the cardiac function here, cardiac index, and menopausal pressure, post-resuscitation showing better myocardial function in animals that receive caripuride. Then we did another study. This is our BAT model of cardiac arrest, also induced VF model, electrically induced. What we did here differently is that we measure organ blood flow as well as cardiac output using fluorescent microspheres. I can explain the technique later if you want to, but this essence is that we're able to capture what was happening with blood flow during chest compression and in relation to the depth of compression. So these are the caripuride-treated animals, and as we increased the depth of compression, we saw an increase in cardiac index. In the control group, it had no effect and probably a detrimental effect. So we published that and gave the title that there was a leftward shift of the flow-depth relationship associated with administration of caripuride because we prevented the decrease in myocardial distensibility during chest compression, and we preserved the hemodynamic efficacy. And the same effect here that you see in cardiac output applied to different organs. The left ventricle is in myocardium, adrenal glands, kidney, and cerebral hemisphere. So that was very interesting in the sense that we were able to connect pharmacological intervention with a hemodynamic effect of chest compressions. Then we wanted to understand what happened at the mitochondria or at the energy level in this animal. So here we used an open chest, big model of ventricular fibrillation, and resuscitation using extracorporeal circulation. So we were able to open the chest, instrument the heart, obtain myocardial biopsy, measure left LED flow, everything, while maintaining a flow that's low, comparable to the flow that's generated during CPR. And the protocol was very similar, eight minutes of untreated VF, and then we start with extracorporeal circulation, and then we observe the animal post-resuscitation. Here we use a different NH1 inhibitor. This is zonipuride. It was developed by Pfizer. And then what we want to show you here is what happened with certain measurements that point to protection of mitochondrial bioenergetic function. This is the ratio between phosphocreatine and creatinine. This will decrease very rapidly in a condition of ischemia because the phosphocreatinine is used to phosphorylate ATP to preserve ATP. That is phosphorylation of ATP at the substrate level. So the ratio here tells you what is going on with the mitochondria. And you can see in red, the control group, how quickly the ratio drops and recovers only after post-resuscitation. But in the presence of zonipuride, that was mitigated. Less drop in this ratio. So something is happening that is protecting mitochondria under this condition of reperfusion using extracorporeal circulation. At the same time, we measured lactate in the myocardium. You can see in red, once again, very marked increase in myocardial lactate, very quickly, within six minutes of VF. And even though the flow of the extracorporeal was probably better than the flow that you can generate with chest compression, still, the lactate continued to go up. I would like to point to the fact that it's very difficult to reverse ischemia, if not impossible, with the amount of flows that are generated with conventional CPR. And you have to really crank it up with ECMO in order to reverse that, as you can see, post-resuscitation. At the same time, the increase in lactate was less in the presence of zonipuride, the NH1 inhibitor. And there was an inverse relationship, meaning that by protecting the mitochondria, there was less need to generate lactate. So that was a study we did in a swine model. And post-resuscitation animals treated with zonipuride, the NH1 inhibitor, had better left ventricular function through all these indices. Now at the core of this process is the mitochondria. And I wanted to tell you a little bit of what we did with mitochondria in terms of identifying a potential biomarker that we can use clinically to assess whether or not mitochondria had been injured, and whether an intervention that protected mitochondria has some promise moving forward. So we all know how susceptible are mitochondria from ischemia reperfusion. And I'll show you some data, how you can protect them by limiting the amount of sodium that enters the cardiomyocyte during ischemia reperfusion using NH1 inhibitors. Now there's one interesting protein here, which is cytochrome C. Actually, I should go back. I cannot go back, right? No. Hm? You should be able to go back. That's OK. Don't worry. It's late? Huh? OK. No. I wanted to show you. I'm going to talk about cytochrome C, which is located between complex three and four and enables electron transport between complex three and complex four of the electron transport chain. And that cytochrome C gets released, liberated into the cell under conditions with ischemia reperfusion, but also get released to the bloodstream. And we did work in a rat model of cardiac arrest and resuscitation. And this is what happened with the animals that survived up to 96 hours when monitoring the plasma level of cytochrome C. And it never increased above 2 micrograms per ml. We did that using HPLC. The group, the animal that died, have a very rapid increase in plasma cytochrome C. And you can see here the rate of increase and the maximum level, pointing to the fact there was an association between failure to recover, sustain viable myocardial function and the release of cytochrome C, pointing that injury to the mitochondria is critical for compromising the ability to resuscitate. And intervention that can protect the mitochondria may have a clinical value. And I say that because work that we did, actually the work we just helped with, the technique to measure cytochrome C in humans. This is Mike Donino. And what is interesting, he was looking at various markers of mitochondrial injury in patients who suffer out-of-hospital cardiac arrest were successfully resuscitated. And you can see here that the non-survivors had significantly higher cytochrome C levels compared to the survivors. These are the control group. So from the laboratory to one clinical study, it seemed to support the idea that if we were able to measure cytochrome C as we conduct studies in which we would attempt to protect the mitochondria, we might be able to detect a signal by monitoring cytochrome C. So what happened with our caryporide? We were so excited because we did so much. I'll show you a few studies. But we did more. We were so convinced that the caryporide would be a drug that can be used clinically. At that time, Aventis was the laboratory that support us along with other grants. And they were not really prepared to use it for resuscitation in a small market. They wanted to use it first for open-heart surgery. And they conducted this study, the expedition trial, in which they give an infusion of caryporide to patients who underwent open-heart surgery. And it was good for the heart. There was significant reduction of the incidence of post-CABG myocardial infarction. But out of nowhere, there was an increase in the incidence of the stroke. And that basically killed caryporide. The mechanism of the stroke that was totally unexpected is not very clear. It seems to be not related to the mode of action, but to the way the drug was given. Very high dose, continuous infusion, it seemed to trigger an increased risk of thrombotic events. But what happened then with us? Because we were very excited about being able to do that. We don't have the drug. We learned one thing, though, that the drug worked because we're able to protect mitochondria from ischemia reperfusion. So at that time, we wanted to know that maybe there's another drug that's already been used clinically that could produce the same effect as an NH1 inhibitor. And we found that erythropoietin, through non-genomic mechanism, activate pathways that protect mitochondria. So we did a study in a rat model, very simple. We give one bolus of erythropoietin before what happened, one before VF, and we found that there was a signal, very unsophisticated study. And I presented that study at a meeting in Slovenia in the city of Maribor to Professor Germick. And he got so excited, he didn't tell me anything. But he went on to do a clinical trial in the city of Maribor. There you go. And he did a study in which he gave erythropoietin 90,000 units as a bolus at the beginning of CPR. He used to run the pre-hospital emergency system. He was driving ambulance at that point, at that time. So the study was very impressive, actually, even though it was not randomized, because the drug was given only if they have the money to pay for it. Otherwise, they will give a bolus of saline. So this is what happened. There were 24 patients who received erythropoietin. You can see here. And this is the 30 patients who got normal saline. But they were evenly distributed over time. And despite this even distribution, I talked to him and said, listen, I cannot believe it because you're not blind and you're randomizing. Then we decided to do propensity matching with a previous cohort. So this is what you see here. So we have the concurrent controls in blue. And we have the match controls in light green. And there were 48 patients who had cardiac arrest and were treated two years before that were matched with EPO. And in all those groups, despite the concurrent, when EPO was compared with the concurrent, the match, still there was a signal. So with that signal, we started to believe that there was a path for erythropoietin as a drug that we can give early on during cardiac resuscitation. And then we did more work in animal models. And we published that in every single study that we did in rats and in pigs. We found there was a signal in which there was a significant improvement in survival in the animals that received erythropoietin in a weight-adjusted dose similar to the one that was given in patients. So this is the EPO story in which we believe there is a signal. We're working on that. This is one study here in which we used the LUCAS device. The animal was still on the ventilator. We have an amazing blood flow when the LUCAS, the animal connected to the ventilator that works similar to the impedance threshold device. We measure organ blood flow. And you can see here the survival after 72 hours. And then we did something that looked much more the way we conduct CPR in the field, manual CPR and ventilation with a less protocol. Still there was a signal. So now, and that was one of the reasons why we wanted to have a company that could facilitate moving things that we have developed in the academic environment to the real-world patients. So we're planning to conduct a phase three clinical trial in which the primary endpoint is going to be survival at 72 hours and a whole bunch of other secondary endpoints. So we're working on that process. I don't know when it's going to happen, but stay tuned. If we succeed, we will see whether EPO or erythropoietin can be used for cardiac resuscitation. OK. So that is. Oops. I think EPO doesn't want to go. There you go. So we talked about reperfusion injury. Now I'm going to pivot to another work that we have done in our recent lab, which is to understand the idea that when we deliver an electrical shock, there is some injury to the myocardium. And the question is whether we can minimize that injury by delivering an electrical shock when there's a high probability of success as opposed to giving it every two hours. I'm sorry, every two minutes, as is recommended by the protocol that we currently practice. So going back to the way to do this, once again, Dr. Y was the one who thought about this idea of analyzing the ventricular fibrillation waveform in the frequency domain and measuring what's called the amplitude spectrum area, or AMSA. A lot of studies show that AMSA correlates with the energy state of the myocardium. So if the energy state of the myocardium is good, a shock is more likely to be successful as if it's not. So here you can see one example of AMSA, what happened in AMSA when we induced ventricular fibrillation. It goes down, down, down, and then gets to a plateau here. Now we start doing CPR. This is another model of open chest cardiac arrest with extracorporeal circulation. You can see how AMSA goes up slowly and then tend to plateau at about six minutes. So it takes time for AMSA, in other words, for the myocardium to be in a better condition for successful resuscitation. It doesn't happen immediately. We have to wait a little bit. And then we are in a more favorable condition here for successful resuscitation. So we did a SWIME model, again, of VF-induced cardiac arrest, and develop an algorithm when to deliver the shock. I'm going to explain the algorithm here. One was what we call the AMSA threshold. At any time in which the AMSA was above 15 millivolts per hertz, we will give a shock at the next pulse. We use a BLS protocol, meaning we do compression, we pause for ventilation, do compression, pause for ventilation. And we measure AMSA during the pause so we didn't have to deal with the compression artifact, which is a big challenge. So with that, we got the clean signal, measured, we developed the algorithm in our computer, and the computer will tell us whether or not to shock at the next pulse. That was the protocol. So if the AMSA was more than 15, we give the shock at the next pulse. We also did this criteria based on the initial AMSA, and this has to do with human data that were provided by the Zoll Foundation, sorry, the Zoll Company, we worked with them. So in other words, if the initial AMSA was high, we didn't have to wait much. We set a time to deliver the shock. If the AMSA was very low, we'll get longer. So we have what we call a time threshold. This was an AMSA delta. If the AMSA will jump in very quickly, we'll give a shock. And if nothing applied here, we will give the shock anyway after six minutes. So this is the protocol that we developed, and this is what happened. This is already explained to you that we will measure the AMSA between the pulses. So we have 30 compressions over 18 seconds, six seconds for pulse, and then we read the AMSA, and then we apply the algorithm. This is a business slide, but let me show you a few things. Number one is that this is the CPR duration before we gave the shock. By protocol, we give shocks after two minutes, 120 seconds. With the AMSA algorithm, we have to wait a bit longer, so the mean was about four minutes. And it's a lot of variation because every animal is different. So we gave epinephrine because epinephrine was given at the fourth minute so that animals will get the epinephrine before the first shock more frequently than the other ones that got the first shock after two minutes. The CBP was better in the AMSA-driven. I forgot to tell you the red is the AMSA-driven. And you can see here that the outcome in terms of the initial rusk was better with the AMSA-driven protocol. This is the first shock. We continue to give shock in the other animals. So at the end, we found that the rusk was the same, but fewer shocks were required in the AMSA-driven protocol. Now, we add all the shocks that were not successful, and we develop what we call shock burden. Now, we call it electrical burden. And the electrical burden was much less with the AMSA-driven protocol. And that was associated with better survival, at least statistically here, and less post-resuscitation left ventricular function. So in summary, the idea that we're able to be more precise and give the shock when there was a higher probability of successful was associated with better post-resuscitation myocardial function. So we protected the myocardium from the injury associated with shocks. And this is survival curves here. This is the AMSA-driven. There were two protocols for guidelines driven. This is a typical American heart. This is we allow for a shock if we meet any criteria in between, which happens only once. So anyway, so survival was better with the protocol that was guided by AMSA. Then came this paper from Perkins. I don't know if you know this paper. It was very interesting because very large study randomizing almost 4,000 patients in each group and looking at the effect of epinephrine versus saline. What was very remarkable is that the initial ROS was threefold in the groups of patients who got epinephrine. But down the road, there was no benefit. So we realized that maybe we can also apply our algorithm to minimize the administration of epinephrine and therefore prevent the adverse post-resuscitation effects. And we published that a couple of years ago. And to make a story simple, because we have all the data from the first study, we could sort of project what would be the AMSA two minutes down the road. So we developed this algorithm in which if we could predict that the AMSA will increase at a faster speed that will hit the threshold here, the threshold that we decided was 11.4 millivolts per hertz, we will not get the shock. If it's going to come slow, then we will get the shock. And at the end, when we combine both the AMSA algorithm for shocks and the one for epinephrine, there was also an aggregate benefit in terms of less post-resuscitation myocardial dysfunction. So same ROSC, but less post-resuscitation myocardial dysfunction. And that, I think, is supported by, the rationale is supported by the study by Perkins in which epinephrine has adverse post-resuscitation effect. It's probably linked to the effect on alpha-1 and beta-1 receptors, which increase myocardial oxygen demands. Again, survival is better with that combination. OK. Now, I'm going to switch the page. So I told you about what we have done in the laboratory for many, many years. But I also work in the hospital. And I was always impressed, many years back, by the fact that patients that have a cardiac arrest very rarely is a sudden event. And very often, we can see a trajectory in which something happened early on that was unrecognized. And the patient continued to deteriorate and eventually suffered cardiac arrest. And then, because I'm an intensivist, we'll have to take care of that patient in the ICU if the CPI was successful. So looking back, we realized there was an opportunity to develop a system that would recognize early. And the ICU was on board, because at the end, the ICU is going to receive the patient. So many years back, we started developing a system at our facility in which we use what we call it, I call it a single early warning sign. I was not aware of early warning signs. I was not aware of NEWS, which is the National Early Warning Score. So this is the system that we developed. And over the years, got modified, updated, based on what we learned. So basically, what you see here is there are 14 signs. And the only thing we ask to the nurse to call the ICU if one of these signs are met. We're not asking to add points, nothing. We want to have a very low threshold for activation. And if that happens, what typically occurs is the phone rings in the ICU. The nurse pick up the phone, call the resident. And within less than 10 minutes, they are assessing the patient at the bedside. And then they'll call the ICU attending for disposition. That's what it is. Then came NEWS at our facility. This is NEWS. By the way, if you guys know that, you know that there is several signs, not as many as we have. But here, it worked by adding points. So based on the point summation, there is an action. And when it's low, there's not much to do except keep measuring vital signs. In order to activate the rapid response team, the point summation has to be seven or greater. So we compare our system with the NEWS. And we actually presented that at the recent Resuscitation Science Symposium. So we analyzed 182 RRS activations, meaning we went there to see the patient. And we sort of matched what would have happened if we had used NEWS. And you can see here, these are the signs that overlap. These are our signs, the one that will have an element of the NEWS. And these are signs that we have that are not present in NEWS. What is interesting is that besides the mental status change, which is a very common sign for activation, the second most used was condition of concern that doesn't exist in NEWS. So it's very important to acknowledge if a nurse is concerned about the patient, even though the objective data does not meet the criteria, that nurse is encouraged to call us anyway. So we wanted to know what happened with this after that. So in our system, we transferred the patient to a higher level of care in 67% of the time. From that to the ICU in 32%, to the emergency department, 31%. Why is that? Because we have a nursing home in our facility. And those patients don't get admitted, they go to ED first. So in 67% of the time, we're concerned that the patient will benefit from going to a higher level of care. You can see here that for all the 182 activations, if we had used NEWS only for 5.5% of the time, we would have reached the threshold for activation and go and see the patient. These are patients that were admitted to the ICU. And the seven point score for NEWS to be activated occurred only 10.3% of the time. So we believe that our system has a much lower threshold for activation and a broader scope. And by acting very early on, we're able to change the trajectory of clinical deterioration. And in order to get some understanding whether that was impactful or not, this is I think my last slide. But I found this paper was very interesting. There was a study published in 2017 looking at in-hospital cardiac arrest mortality per 1,000 hospitalization. And in the study, based on data that was a bit earlier, from 2008 to 2012, the median was 4. The lowest was 1.4. The highest was 11.8 cardiac arrest per 1,000 admissions. And we're so proud because ours, we were off the chart. It was only 0.8 cardiac arrest per 1,000 hospitalization. So we continue to enforce our rapid response system because we believe that the best way to deal with in-hospital cardiac arrest is to recognize as early as possible a patient who is deteriorating. You can change the trajectory, treat the patient, and avoid a whole bunch of complications. And I wanted to share with you this title, at least, that there is a lot of interest now on in-hospital cardiac arrest. And this is a paper that was published a few weeks ago, I believe, or at the end of last year by ILCOR talking about 10 steps toward improving in-hospital cardiac arrest quality of care and outcomes. And the effort is divided in four quadrants, and one quadrant is the prevention of cardiac arrest in the hospital. So I think it's very good that we are paying more attention now how to minimize in-hospital cardiac arrest, which I think that's totally doable. So in summary, I told how important are mentors in our lives. And I can tell you that Dr. White inspired me to create a vision that I continue to follow. And I don't think I'd be talking to you today here to you if it was not because of Dr. White. I believe that targeted reperfusion injury is a valid target that we need to develop, especially we can give a drug as early as possible. We call it first drug in before epinephrine in order to. So we're working on that. Erythropoietin is first in line in terms of our clinical development. But we want to follow up with an NH1 inhibitor. And we also want to use a vasopressor that does better than epinephrine. And there's some work in the past using alpha-methylnorepinephrine, you might know that, in which it selectively activates the alpha-2 receptor and does not activate the other receptors that are associated with worsening myocardial function. We talk about that we can reduce the burden on the heart by being more precise how we administer a shock and try to minimize the use of adrenergic agents. And finally, we can prevent the cardiac arrest as the best way to protect the myocardium. Thank you. Thank you, Dr. Gasmeri. Any of you who have questions, you can walk over to the microphones that are there on both of these sides in these pathways. Dr. Gasmeri, I had a question, just curious about the choice of the eight minutes in the first study that you had done for the karyoporide. Because most of the time, I mean, intuitively, it feels like the defibrillation occurs much earlier than the eight minutes. I'm curious about the thought process between choosing eight minutes initially for chest compressions and then eight minutes. Yeah, that's a very valid point. If we have a very effective system, you would expect that somebody is going to attempt to defibrillate for sure. Eight minutes is, I think today, more of the average time for an average CT for paramedics to arrive. We wanted to emphasize more of a worst-case scenario as opposed to a better. So that was the main reason to use eight. Oh, yes. Yeah, to make it more. And the other thing that we don't measure, but all the animals are anesthetized. So maybe that also creates some protection. Wonderful. Yeah. But the idea was to create a more challenging scenario as opposed to make it simpler for the drug to act. Absolutely. Any other questions from the audience? Hi. Sorry. Hi. Ernie Saxton, University of Michigan. Question about when you lowered the threshold or your news comparison and had more patients identified as needing advanced care. We're trying to implement something similar in our institution, but a lot of times we have pushback from transferring someone to the ICU sooner because they're not presenting themselves with all the objective data that you mentioned to say that they needed a higher level of care. So how did your institution deal with that issue of sometimes it's capacity or just the belief that the patient doesn't need that higher level of care, even though there are those other things present? Yeah. No, that's a very good question. And I can tell you every time I present the data, that's the questions that come. You say, we cannot do that. You're going to overwhelm the ICU. And I think that's true. It's a challenge. In our institution, there's a buy-in by the ICU. So when we started very early, about 20 years ago probably, the nurses understood that that was good for everybody, including the ICU, because we can treat with less resources that patient. I think you have to make the case that perhaps the return on investment justifies it. Because if the patient gets to the point, let's say, needs to be emergently intubated of cardiac arrest, that patient is going to end up in the ICU no matter what. But he's going to use more resources. So it would be interesting to do a study on that in terms of the relationship between the time of activation and the resources utilized. And maybe that would be data that would justify, not justify, but at least make a stronger argument. I mean, if you step back, at the end, why do we go to the hospital, right? We want to save lives, and we want to do it the most efficient way possible. So sometimes those metrics that would measure something that is not directly connected to the patient care need to be retired, like somebody recommended for some other metric or processes. I think the best way to do it is the ICU to drive the process. If you don't have buy-in from the ICU, it's not going to work. But if you create a team, because they experience what happened when the patient is not recognized early on. So if there's a way to recognize early on, I think you're going to have a buy-in by the ICU team. And maybe you can do a pilot, see what happens. And you can show if you, at the end, use less resources and save more lives with less complication, you have a winner. Thank you. Yep. I have a question to follow up on that particular question, Dr. Ghasemiri. When you implemented the protocol, you, of course, got buy-in from the ICU. Were there any barriers to implementation of the protocol? Any barriers to implementation, any pushback that you got as far as increasing the number of calls from the nurses, even if the patients didn't meet any specific objective criteria? Not in that regard. There's only one, sometimes, pushback. It's from other providers in the medical floor. They get annoyed if the nurse activates the rapid response system without letting them know. And we've been pushing for that over and over. We said no. If somebody tries to tell you not to do it, you talk to us. We have to create an environment, a culture, in which there's no reprisal. And it's interesting, because that is written in that document. So it's good to make sure that nurses are totally comfortable to act. And that was the only thing I would say. And the other thing, which is important, we develop those signs. And I think every institution is different. For example, one of our signs is if the patient needs non-invasive ventilatory support. That is new. Not the patient that come home for another reason, just sit up at home. The one in which somebody decided to put on BiPAP, for example. That is a criteria for activation. Why? Because we don't use BiPAP in the medical floor, because the medical floor is not comfortable. We would assess that patient. So the signs got to be flexible and reflect what is your patient population. Thank you. It's not fixed. Yeah. Thank you. Please go ahead. The ICU is a very expensive resource. Have you considered stratifying your markers to move people to the ICU or to a step-down unit where they get more than the floor, but less than the ICU? Yeah. No, that's a very good idea. In fact, what happens is that we are a relatively small hospital. And the quote-unquote step unit is inside the ICU. So when the patient comes to the ICU, it's going to be labeled as critical or intermediate. Intermediate for a step-down. And I have the same idea. In another facility, I would say, why not bring it to step-down? Because I think that the value in which you have physician and nurses who deal on a daily basis with people who need critical care. And they're, I think, best equipped to recognize the importance of early deterioration. One of the things that I'm going to tell you that also, in connection to this, we realize that very often patients have a respiratory problem in the floor. And the usual response to get a blood gas, the blood gas looks good. And half an hour later, there's a cold because the patient stopped breathing. We realized there was no tools to recognize increasing the work of breathing. Oxygenation does not measure work of breathing. So many years back, we developed what we call a web scale, a work of breathing scale. We publish it. We use it. So we have a more objective way of recognizing a patient who is suffering progressive increase in the work of breathing based on respiratory rate and activation of accessory respiratory muscle. And this is included in our early warning signs. If the work of breathing is more than three, we want to be notified. We can assess the patient earlier. So I think a lot of things that can be done when we focus on how to recognize early on clinical deterioration. But you're absolutely right. The right place for the patient, I think, is to move it to the higher level. But the higher level needs to be defined. And a step down, I think, would be a step up into a step down, right? Absolutely. Any other questions from the audience? Well, thank you, Dr. Gasmiri, for giving us some hope that there are possible targets from a pharmacological therapy, from electrical therapy, and most importantly, prevention of cardiac arrest. You're welcome. Thank you very much.

myocardial protection

cardiac resuscitation

reperfusion injury

sodium-hydrogen exchanger

cariparide

erythropoietin

amplitude spectrum area

rapid response system

cardiac arrest management