Okay. Good. So, taking this on for the next one and a half hours, we talk a little bit about the peculiar physiology of blood flow generation during the CPR. And the reason, to some extent, that we picked that topic is that it's very, very different physiology than what happens with the spontaneously beating heart. And the reason that this is not necessarily obvious, you've seen just at the very end of Dan's lecture, you know, where he talked about the compression rate in cats being, people tend to do the same thing as they think the spontaneously beating heart would ask for, right? In a cat with a normal heart rate of around 160 or 70 or 80, they try to compress at the same rate because that's physiologic. But it's really such a different type of physiology during CPR that it is very disconnected from all of those things of the spontaneous heart. So, we want to talk a little bit about that first. And in particular, I'm going to focus on the different pumps that are at work here and how that impacts blood flow generation and how we can manipulate and take advantage of those different pumps, right? In the best possible way. And then Dan talks a little bit about the evidence and I think pressors and those type of things that support the physiology as well. Good. I think I already mentioned that in the history session, but I think this kind of space between life and death is really, really important. And I would say that a significant part for that space to be large is how much blood flow we are actually able to generate during CPR, right? So, if we do really, really crappy CPR, that space becomes really, really narrow. And the opportunity to bring that animal back to life and switch it back to the left side, to the white side and not to the dark side, becomes very, very small, right? But if we are able to generate a lot of good blood flow and keep these organs going, the heart and the brain in particular, then that space actually becomes quite wide. And as we go through that day-to-day, we will see some other methodology by which that window can be opened quite significantly. But generally, the more blood flow, the bigger that opportunity to revive the animal. And so, how can we optimize the blood flow? That is really the key question here. So, first of all, blood flow is really essential. But as I mentioned before, with a normal animal, right, that is running around like that, has a normal spontaneous heartbeat and circulation is very good normally. And we know very much about the physiology, such as like the Frank-Starling relationship, right, that describes very much how preload gets translated into afterload and so on and so forth. But during CPR, things are very, very different, right? There is no Frank-Starling, like the whole preload of the heart thing doesn't really work. So, those things that we all know are not functioning. So, we have to apply different principles. And before we look at the different pumps, maybe we take a little bit of an engineering approach here because that's really what it comes down to. Dan is an engineer. He knows way more about that than I do. But I tried to wrap my head around it somewhat. So, if you think about the circulatory system as a kind of a hydraulic system that consists in a pump on one side and a load on the other side, the load being the circulatory system and composed by the systemic vascular resistant and the compliance of the circulatory system, then we can simplify the whole cardiovascular system for that point. So, normally, during the normal beating heart, during intact circulation, the pump is just the heart, right? And the arterial system here, the vascular part on the right side would be the circulation. And you have the compliance here as well, meaning that that's basically the space that can absorb fluid, let's say, an increase in fluid without having a concurrent increase in pressure in the system, right? So, the venous system, for example, is very compliant. You can administer a large volume to extend that system without really a large increase in pressure while in the arterial system where the compliance is relatively low. If you pump a lot of fluid into that system, the pressure goes up quite quickly, right? So, that's a low compliant versus a high compliant system. And then, obviously, the systemic vascular systems also influences the pressurization or the energy due to the pressure loading of that system as well. And so, those two things together define the load. Good. So, during intact circulation, the pump is normally the heart, right? But what is it really doing cardiac arrest? Because the heart is not really doing anything, right? So, it's not on it in itself pumping. And so, that's what I said. Uncertainty about what the pump is was the background for various models to be developed on what actually generates flow during CPR. And there's many more than those two. But those are the kind of two most iconic ones, I would say. So, there's the cardiac pump model on the left. And there's the thoracic pump model on the right. And you also have those figures that are generated in your handouts. And I'm sure there's some typos there. So, if you find any typos or other things, raise your arm and you get an ITV. And anyhow, so now we're going to go a little bit first through those different systems. And then see a little bit how we can manipulate different aspects of the systems to optimize blood flow, right? Good. So, cardiac pump number one. And that is actually, in a way, relatively similar to the normal spontaneously beating heart. With that system during compression. And so, the big chambers of the heart, the ventricles, the right and the left ventricle, are compressed together without really any increase in intrathoracic pressure, right? So, the model prescribes that those two chambers are compressed in conjunction with the compression of the chest. There's no thoracic pressure increase. Just those two chambers are compressed. And so, that leads to a quite significant increase within the right ventricle and the left ventricle, right? And therefore, also to a significant increase in the intrathoracic arterial system here. But not really... will not really lead to an increase in the intrathoracic venous system because there is... there are valves, right? Here that prevents the pressure to be transduced to the intrathoracic venous system outside of the ventricle, right? So, as a result of that, you will have a very significant pressure gradient between the arterial system within the chest and the venous system within the chest, right? The pressure in the venous system will be really low. The pressure in the arterial system will be really high. So, there's a big arterial venous pressure gradient within the chest during the compression with the thoracic pump. And that leads to blood flow accordingly, right? From the arteriosclerosis to the venous site during the compression itself. At the same time, also during the compression with that system, the intrathoracic arterial high pressure will be transduced to the extrathoracic arterial high pressure, right? So, you will also have a pressurization of the extrathoracic artery system. While the same thing doesn't happen in the extrathoracic venous system. So, you will there also have this big arterial venous pressure gradient, which really generates the blood flow during this thoracic cardiac pump approach. Much the same as you would see with a spontaneously beating heart, right? Does this make sense? During relaxation, those chambers are allowed to re-expand. And basically, venous return will occur. There will also be some negative intrathoracic pressure. Obviously, that further emphasizes venous return and filling of those chambers. But it's pretty a passive process, right? Good. So, thoracic pump in that sense is a little bit more complicated. The driver here is really not so much the direct pressure increase in those two big chambers, but the pressure increase in the thorax itself, right? Yeah, in the thoracic. So, the intrathoracic pressure itself gets markedly increased. And that pressure increase will be transduced to all the other structures in the chest as well. Which includes the veins, the big chamber such like the right ventricle and the left ventricle, but also the intrathoracic aorta, right? So, everything kind of goes along with that intrathoracic pressure increase. Once more, the pressure increase that follows from that in the venous system will not be transduced to the extrathoracic venous system, right? And that's the case because, for once, the pressure increase in the intrathoracic space will also lead to some compression of the veins, of the big veins. This is a low-pressure system. Normally, they're very compressible. You also have those valves here. But also, the little blood flow that goes out will be absorbed. The pressure that results from that will be absorbed by the large compliance, by the really high compliance of the big veins, right? It will not lead to a pressure increase. While, on the other hand, the pressure increase generated in the intrathoracic aorta will be transduced to an extrathoracic pressure increase as well. Because those arteries, first, there's no valves, right? And the arteries are of really low compliance. So, the pressure gets transduced very readily to the extrathoracic artery pressure as well. So, you will have a, while there is not an intrathoracic arteriovenous pressure gradient, right? Because all the structures in the chest go up with the pressure at the same time. You will have an extrathoracic pressure gradient between the arteriovenous side, which generates the blood flow during the actual chest compression with that model as well, right? Does that make sense? All right. From a coronary perfusion point of view, which is one important thing, right? That will clearly not be possible to occur during the compression itself. Because the right side of the heart, including the right atrium pressure, is really high during the compression. The same pressure, basically, as you have on the left ventricular side or the aorta side. You know, everything has the same pressure during the compression. So, therefore, there's no really intrathoracic pressure gradient, right, during the compression itself. So, there will not be any coronary blood flow during the compression itself. Where the coronary blood flow may occur is during the relaxation, right? During the relaxation, there is typically a negative intrathoracic pressure. All those pressures, the intrathoracic vascular pressures typically drop. But, really, the aortic root pressure is maintained to some extent because the aortic valve closes, right? And so, that pressure that has been built up during the previous compression in the aorta remains up to some extent, right? And so, that now generates a pressure gradient between the aortic root and the right atrium, right? And so, therefore, this pressure gradient during the relaxation phase actually leads to coronary blood flow during the relaxation phase. All right? We look at that again many more times. So, it seems a little bit more complicated right now. But you have those figures in your handout as well. So, if you have a hard time right now grasping the concept, then look at it again later. But that's kind of an important thing. So, during thoracic pump, the pressure increase in the chest itself is what drives everything. And for most, the pressure gradient between the aortic compartment and the right atrium during relaxation is what drives coronary perfusion pressure. And the coronary perfusion pressure is a really important determinant of whether an animal is ever going to achieve return of spontaneous circulation or not, right? We look at that a little bit in more detail. So, obviously, all the animals come in different shapes and sizes. And so, there's many different opportunities that allow us to kind of decide a little bit on whether we're going to go more with a cardiac or more with a thoracic pump approach. It's not just a compression site, although I think that's what we try to recommend with recovery, I guess. That if you compress more with the heart, there will be more of a cardiac pump approach to it, whereby you preferentially increase the pressure in the ventricles. And in those animals where this is not feasible, we recommend to maximally increase the intrathoracic pressure by using the thoracic pump approach. And thereby, leading to the blood flow generation as we just discussed previously, right? So, but in reality, there's probably always a little bit both of each present. We don't absolutely know. So, they coexist to some extent, right? So, even if you do the cardiac pump here, there's probably a thoracic pump component to it. And the same maybe to a small extent here as well. The purest form of cardiac pump in CPR as such, where there's no thoracic pressure increase during compression, probably doesn't exist. The only time that it exists is probably with the open chest CPR, right? So, you open the chest and really just compress the ventricles. So, that would be no thoracic pressure increase, right? You just increase the ventricular pressure. So, that's probably the pure form of cardiac pump, which makes it very clear to you now that we always going to have a thoracic pump component to the chest compressions, I would say. Unless you do the open chest, right? Good. A pure form of a thoracic pump approach, where there's basically no ventricular compression whatsoever, exists in a little peculiarity in history here again. And it's the so-called cough-induced cardiac compression, right? So, there was a time when, and that's the, Criley is basically the investigator here and has developed that technique in humans, is that before they underwent some electrophysiologic intervention on the heart, he instructed them on command to start coughing. So, as soon as they, once there was a non-perfusing rhythm intact. So, but he had a very small window of like 5 seconds or 10 seconds to tell them to start coughing because otherwise they would lose consciousness. So, the idea was that he did something on the heart. He sees, oh, the heart is now going into VF. So, you tell, you know, tell him quickly to start coughing before he becomes unconscious. Then, you do this. And that keeps the circulation going because there's just increased thoracic pressure with each of the coughs. And enough so to generate enough blood flow that they will not become unconscious for maybe 30 or 40 seconds. And eventually, they will. But that's long enough for them to take care of the ventricular fibrillation, essentially. So, if you train them a priori, you can prevent them from going into cardiopulmonary arrest as such by coughing, right? And that works actually relatively nicely. That's a pure, you know, thoracic pump thing, right? So, there's no, nobody compresses the heart or anything. This is just fluctuations in thoracic pressures. And they were also able then in a research study, same investigators group, to do that with dogs. Whereby it just stimulated the vagal nerve here. So, you see in this particular graph here on the left the millimeters of mercury. So, that's the pressure in those respective vascular segments. So, the aorta and the left ventricle. And so, you see the fluctuating pressure in the left ventricular segment here. And the aortic pressure has a relatively high diastolic. So, then they induce ventricular fibrillation. And you see how those pressures collapse. The left ventricular pressure comes up until the aortic valve opens. And then all of them go back down together. And then the coughing is induced. And you see this big aortic and left ventricular fluctuations in pressure that that causes, right? So, quite effective. So, this is a pure thoracic pressure thing. But in reality, you know, like you probably have both together. You have a little bit of cardiac pump, a little bit of thoracic pump. But that's a quite neat little thing here. So, then how can you find out which pump is actually actioning, right? And so, there are specific characteristics to those different pumps. And so, if you have all those physiologic measurements available to you, you can figure out a little bit which pump is actually going, right? And that allows us also to repeat what we already discussed. So, for example, the intrathoracic arteriovenous pressure gradient that I mentioned initially is really large with cardiac pump, right? So, with cardiac pump, you have a high arterial pressure typically during the compression, but very low right-sided pressures, right? So, it has a large arteriovenous pressure gradient. While with thoracic pump, there's no such thing, right? So, if you measure intrathoracic pressures in the right atrium and the left ventricle at the same time during the compression, and they both go up at the same time to the same level, more or less, you definitely have some sort of thoracic pump mechanism, right? Otherwise, if the right atrial pressure would stay low, and the left ventricle pressure or the aortic pressure goes up really, really high, that would be more of a cardiac pump thing, right? So, if you have those two measurements available to you, you can already figure out whether one or the other or both, to some extent, are there. Then, the pressure difference between intrathoracic and intrathoracic pressure is also a thing that is quite distinguishing. So, if you measure, for example, have an esophageal balloon to measure the intrathoracic pressure, right? And measure the pressure in the intrathoracic segments, any of them at the same time. And so, if they all go up during your compression, at the same time, it's probably more a thoracic pump thing, right? Versus, if only the vascular pressure goes up, but the thoracic pressure stays the same, that would be more of a cardiac pump thing, right? Relatively easy to distinguish, in that sense. Likewise, with the aortic dimension would typically get larger during the compression, with the cardiac pump, because all that blood goes into the aorta, and the aorta extends to some extent, while that's not happening with the thoracic pump itself. And likewise, with the cardiac dimensions, obviously with a cardiac pump, you would compress the ventricles themselves, so the heart gets smaller, while that's not happening really with a thoracic pump, right? It's purely the pressure increase that generates the flow, and not the actual compression of the ventricles, right? So, if you do an echo, be it esophageal or elsehow, you would see that as well as a distinguishing factor. Mitral valves, oftentimes, but not always, is said to be open during the thoracic pump, because there's not really an arteriovenous pressure gradient, right? So, it just flaps around and is open, while with a cardiac pump, where you have the arteriovenous pressure gradient, it would typically be closed. And then there's some really other interesting things there at the bottom, and I think I want to discuss that a little bit more. That is, how blood flow responds to compression rate, or how perfusion pressures respond to compression rate on one hand, and compression duration on the other hand. So, let me show you some evidence on that. And that evidence is mostly by Halperin. Those are dog studies. And so, he looked at that with direct cardiac compressions, which is open chest, as we discussed before. So, if you really want to have a pure cardiac pump approach, that would be an open chest approach. And then he also did the same experiments with closed chest. So, the experiment first consisted in compressing the heart with 60 beats per minute. And so, another really important variable in the compression characteristics is the so-called duty cycle. So, how much time did you have? Like, for 60 minutes, if you compress with 60 per minute, you have one second for one cycle, right? And so, that's the amount of time that you have for one compression. And then, in that one second, you can use, let's say, 50% for the compression and 50% for the relaxation. So, you would have a half second for each, right? Half a second for compression, half a second for relaxation. And the duty cycle for that would be 50-50, right? 50% for the compression, 50% for the relaxation. So, if the compression rate is chosen really short, as here, then it could, for example, be only 15%, right? A very quick compression versus lung is like, you know, 45% is almost half of that whole cardiac cycle, if you want to say so. All right. And so, what he basically was able to show is that if the animals have open chest and he uses the cardiac pump itself, that the increase, that there was no effect on myocardial and cerebral perfusion if he compressed much slower than faster, right? Same rate. Rate is not affected. It's just the amount of time that he used for the actual compression did not have an impact, right? And that's quite important. But if they used the longer compression time, right, 45%, and increased the heart rate from 60 to 150, it had a massive impact, right? So, meaning that with cardiac pump, compressing slower will not necessarily have an impact, but compressing faster will have an impact. It's like the physiologic tachycardia type of thing, right? So, if the heart beats much faster and the stroke volume is relatively the same, it doesn't really matter so much how quickly it compresses. It's really just the rate that matters. And so, that's a typical characteristic here as well. It becomes important when we think about how fast we shall compress, right? Because if you have mostly cardiac pump, actually the rate, the compression rate may matter to some extent, not necessarily how slowly, not necessarily so much the duty cycle itself, but the compression rate becomes quite important, all right? And so, with open chest, that definitely plays a role. So, then with closed chest, this is the data from the direct cardiac compression. So, you see here that the myocardial perfusion pressure didn't really change when they changed from the short, the 15% to the 45%, but it markedly increased when they increased the compression rate from 60 to 50, right? Same for cerebral perfusion pressure. And the cardiac compression itself stayed exactly the same. With closed chest, it's different, right? With closed chest, it seems that it's not so much the rate that matters, right? So, this is now dogs that are receiving closed chest sternal compressions. You see that if they compress those chests at a rate of 60, but prolong the compression time from those 50% to the 45%, that, for example, the myocardial perfusion pressure or the coronary perfusion pressure increases by 50%, right? Well, if they then increase the compression rate from 60 to 150, it doesn't have any further impact, right? Meaning that with a thoracic pump approach, typically, as by those studies, the duty cycle is quite important. So, how much time do you take to actually increase the pressure in the chest versus how fast, right? The further increase in the rate really doesn't matter in this particular situation. And so, we've been talking about coronary perfusion pressure and cerebral perfusion pressure and talking about physiology here. It's really important that we kind of wrap our brains around what they really mean because they're somewhat different than in the spontaneously beating heart as well. So, during CPR, the coronary perfusion pressure is typically defined as the diastolic aortic pressure, right, minus the right atrial pressure. And that has to be done during diastole, right, as we discussed before, because there is really no pressure gradient, at least with the thoracic pump model, during systole, right? Good. Other factors are that the autoregulation is typically lost. The autoregulation in a normally spontaneous beating heart really has a big impact on myocardial blood flow, but during CPR, it doesn't really matter that much anymore. It is lost. So, coronary blood flow becomes very proportional to the coronary perfusion pressure. And you can see that here in those studies, whereby here on the y-axis, you see the heart blood flow, and then on the x-axis, you see basically the coronary perfusion pressure or the diastolic arterial venous pressure gradient. And you see there's a really strong correlation between the two, whether the animal receives epinephrine or no epinephrine, what the epinephrine effect is on coronary perfusion pressure. And we're going to talk about it a little bit later when we talk about load. But a very robust relationship during CPR between coronary perfusion pressure and myocardial blood flow. And because of that, the coronary perfusion pressure measurement is a really good surrogate for myocardial blood flow, right? And coronary perfusion pressure is much easier to measure than myocardial blood flow, right? So, it's a nice physiologic endpoint in that sense. Good. And we've also been shown in dog studies again here that the coronary perfusion pressure has to be above a certain minimum level in order for ROSC to occur. And typically, that's considered to be around 20 millimeters of mercury, right, as shown in this particular study here. But it was similarly found in others as well, all right? So, the critical value for coronary perfusion pressure is around 20 millimeters of mercury in dogs and probably in humans as well, all right, above which. And that's the same study here. So, here on the y-axis, or similar measurements here, you see on the y-axis the coronary perfusion pressure. On the x-axis, different groups of animals depending on whether they survived or not. And that's again in dogs. So, you see that in this particular study, animals here, those were all the ones that achieved ROSC but then continued to die. And so, you see they are maybe just close to 20, a little bit less. The ones that survived to 24 hours, their coronary perfusion pressure is very much higher, around 30. But then if you compress even further, which means that you probably get higher interthoracic pressures, therefore bigger AV gradients, therefore higher coronary perfusion pressures, right? Then there is a limit to it, essentially, because the induced injury of those overly deep compressions may become a limiting factor, right? So, they found a subset of animals here that had really, really high coronary perfusion pressures, but they all died from their interthoracic injuries, bleeding, and so on and so forth, all right? So, there's a limit to it. But in principle, it basically means we have to optimize coronary perfusion pressure, do it as good as possible, but not leading to a level where we actually harm the animal, right? So, you have to find the sweet spot. And the sweet spot in this particular study here seemed to be somewhere between 20 and 30, roughly speaking, right? And then the question is, how do we actually arrive at the number, right? So, I said arteriovenous pressure gradient, but let's look quickly at that curve here. So, the blue one here, and that's from our swine lab, is the right atrial pressure, and the red one is the aortic pressure. And you see how, during the compression, and that's sternal compression in swine with a mechanical compression device, you see how the pressure shoots up quite a bit, and then collapses during the relaxation phase. I don't say diastole, but in a way, you know, it's the diastole-like phase, but it's really the relaxation phase, because the heart is not having any systole anyway. And you see, like, it's not a clear pressure. So, if you measure the pressure gradient here or here, it may be very different than here, right? So, different methodologies have been developed to determine where to best actually measure the pressure gradient during the relaxation phase. Some people think that the true mean mode would be to just look at the area, you know, under the curve, because that's the integrated difference between aortic root pressure and right atrial pressure, and takes care of that variability over time. Other things, just in the middle of the diastole or at the end of the diastole. So, wherever you put that line in, right, you get a different coronary perfusion pressure. Utstein currently thinks that that should be the way to go. Just so that you know, when you read different papers about that, make sure that you know a little bit where they actually measured the coronary perfusion pressure, because it may be very much a function of the time of measurement there as well. Cerebral perfusion pressure is more of a systolic thing. So, you see the aortic pressure fluctuation here. And the ICP fluctuation here. And it's pretty much a difference between the mean aortic root pressure and the intracranial pressure. But because they are fluctuating so much, right, so it's not just even the ICP. It's not a constant value. We typically take the time-averaged value of those. And you're trying to hit around 30 millimeters of mercury for that, meaning that you will need around the mean aortic pressure of around 55 to 60, right? Cool. That becomes important a little bit later when we talk about physiology-guided CPR as well, right? Because ultimately, you would like to resuscitate your patient according to those physiologic endpoints. Cerebral perfusion pressure is a little bit complicated. It's not just a function of those pressures. It seems that it's also a function of time, for example. So, in these animals, they all had the same cerebral perfusion pressure here, right? Around 30 by design. And then here in this bottom graph, you see the blood flow here on one side and the duration of CPR on the other side. And this top group here did not have any downtime, meaning that VF was introduced. And then chest compressions started right away, while that bottom group here had six minutes of downtime, meaning that VF was introduced. The animal was left untreated for those six minutes. And then only chest compressions were introduced. Both of those chest compressions were introduced such that the same perfusion pressure was achieved. But you see how big the blood flow difference is, right? So the ones that had no downtime had way better cerebral blood flow. Because there's edema, there is like intravascular clotting. There is various other effects that define a little bit how much blood flow this perfusion pressure generates, right? So it's not that linear of a relationship as it is with the coronary perfusion pressure. Just keep that in mind. And so I think it's a little bit harder to know exactly what to do with that. Good. So back to our previous study, right? We already looked at that slide before. But now you understand a little bit that those myocardial or coronary and cerebral perfusion pressures may be better. Once more, with external chest compressions, it was shown that the compression time is really important, but not the rate, right? So if you want to get better coronary perfusion pressure with a thoracic pump approach, it's important to not have a very short compression time, right, but have like your 50% duty cycle essentially, right? While a much higher compression rate, such as like what's proposed by some for the cats, right, may actually not have that big of a difference, right? That's just kind of important there. And then when we look at blood flow, as in this study here, you just see that that correlates pretty much with blood flow as well. So this is closed chest CPR again. Let's look left ventricular free wall, for example. Let's look at that. And you see that the compression time, prologue and short to long, really improves the flow, right, but not the increase of compression rate. All right. Good. And so that's very much what is mentioned down here at the bottom of that table. And you have the table also in your proceedings. So with cardiac pump, typically the increase compression rate will markedly increase your hemodynamics, right? As such as like with open chest CPR. So the rate may matter. Obviously needs some filling as well, but the rate definitely has an impact, while the duration seems to be more of a thoracic pump thing. All right. Good. So let's go back and ask ourselves, how does that matter? How does that matter? Sorry. So because we can manipulate now the system, right, to take advantage of all of those things. So for example, one thing that has been proposed is abdominal binding, meaning that there is consistently positive pressure applied to the abdomen with just wrapping the abdomen circumferentially, and therefore increasing the intra-abdominal pressure, but also immobilizing basically the diaphragm. And we can then ask ourselves how that impacts things, right? So I guess that has not really been studied with cardiac pump, but you would argue that maybe it would redirect some of the blood flow to the heart and the brain when you do open chest CPR, right, with that approach. Importantly, if you do that with a thoracic pump approach, you will, in theory, increase inter-thoracic pressure, right, because everything gets pushed into the chest. So with each compression, you will have a little bit higher inter-thoracic pressure. But you will disproportionately also increase the right atrial pressure, like the right-sided venous pressures when you do that, so that your coronary perfusion pressure gradient will decrease. So it's generally not recommended to have this kind of abdominal binding placed, all right, for that reason. Interposed abdominal compressions, on the other hand, and that's a little bit how it looks. So if it's well executed, it needs to be quite well coordinated, right? If not, I think if it's not well coordinated, it's not interposed, right, and it wouldn't work well. But that's a different approach. So the pressure now in the abdomen is not continuously applied. It's only applied during the decompression phase of the chest, right? And for those, in principle, I think if it's well executed, it may increase the blood flow. Be careful with some of the injuries that could be sustained. I think we hear a little bit more about that later as well. But in principle, it will increase the aortic pressure during the re-expansion phase of the chest. It will increase the aortic pressure here, and therefore, it may increase the coronary perfusion pressure, right? Because basically, the coronary perfusion pressure is a relaxation phenomenon. And if you increase the aortic pressure during the relaxation by putting pressure on the abdomen, then that may increase coronary perfusion pressure quite a bit, right? And therefore, increase the chance for ROSC, right? And so if it's well executed, at least from the model point of view, right, it would actually improve critical perfusion parameters in the thoracic pump model, all right? Increase the retrograde aortic blood flow during CPP. And some studies in dogs, again, have shown how that goes. So this is with standard CPR here and interposed abdominal compression here. And you have the respective parameter measurements on the y-axis. So you see that the cardiac output in most animals increases. Arterial pressure in most animals increases. Perfusion pressure in some animals not. The issue with there is that in some select animals, potentially, you increase the right atrial pressure quite significantly as well with that process. And maybe that compromises that. But in principle, overall, it may improve circulatory parameters to some extent. The next thing that we can manipulate is airway pressure, right? So the airway pressure can be increased. And generally speaking, the airway pressure already is increased with thoracic pump to some extent because the airways actually collapse as well. And it seems to be mostly in the main stem bronchi. So that's been studied quite well that during forceful thoracic compressions, the airways here actually collapse. And that leads to the inability of air to escape the lungs, right? And so that maintains a higher interthoracic pressure for a longer period of time. And you can see that here on the left side whereby that's in dogs, again, with sternal compressions by Halperin. And so that's basically the sternal force compression. You will see that the aortic pressure goes up accordingly, right, as the compressions are applied. And some air is expressed from the chest, if you want to say so, during the very early compression, right? And then the airway seems to be compressed and it stops. There's no flow anymore. And only when the pressure is taken off the chest, again, the rest of the air escapes. So that's a strong hint for that phenomenon here as well. But generally, that occurs already naturally. And so there's some ways that that can be manipulated further. So, for example, if each breath is given at the same time as a compression, right, you get higher interthoracic pressure as well. And there were some studies done with those simultaneous compression ventilation CPRs where you basically deliver 60 breaths or 60 compressions, right, all synchronized at the same time. And that leads to really high interthoracic pressure. And that has been shown to generate more flow, right, according to the thoracic pump. The higher the interthoracic pressure during the compression, the more flow. And that actually works. The problem is just that you have to breathe like crazy, right? And in an out-of-hospital situation, right, the respective person would have to be intubated. And so it's just not a practical approach at the first place. The other thing is to obstruct the airway during the compression phase of the chest. So similar as this here occurring naturally, you would just further emphasize that approach by basically obstructing the airway, which also would require endotracheal intubation, which is not an easy thing to accomplish, right? So that's why they gave up on that a little bit. The other thing is negative airway pressure. How would that potentially affect the circulation? And that would only then be applied during decompression. So in this particular situation, you would basically occlude during the relaxation phase the airway such that the chest would expand against the closed airway, similar like ITD, right? And so that would lead to more negative interthoracic pressures, and that probably would lead to more venous return here in principle, all right? And so the ITD is one of those implementation methodologies where that could happen, right, and has been shown to improve venous return and therefore cardiac output to some extent. The idea there is that the interthoracic pressure during the relaxation phase is reduced and therefore you have more venous return and then more vascular filling that will be available for the next expression to occur. Another way to accomplish the same thing is this activity compression device, which can be ‑‑ so with those devices, basically the chest gets forcefully re-expanded, typically implemented with some sort of a suction cup. So this is a mechanical compression device, the Lucas, but it also can be done manually such as like here displayed with this ACD device. And with that particular device, the interthoracic pressure during relaxation would be reduced. And though what the key is here is that because the chest gets more expanded, it also has more air in it, right, and it's bigger. So the pressure that it can achieve with the next compression within the chest is higher. So during the compression with those active decompression devices, you can actually generate higher interthoracic pressure with the next phase, which may generate also more blood flow, right? I hope that makes sense. While with the ITD, that's not really the case because with the ITD, actually you have less air flowing into the chest, so the end relaxation volume in the chest may be less, so you can generate less pressure with the next compression and that may compromise blood flow generated by a thoracic pump, right? Another way to maximize interthoracic pressure is by using circumferential chest compressions. In this particular situation, you will not have just one focal compression point in the sternum or elsewhere, but actually the chest will circumferentially be compressed. And that has been shown to increase the interthoracic pressure during compression quite a bit. It's not that easy to implement, at least this particular system here, which is why it has never been applied in the field. But from an animal study point of view, it was shown to be quite effective. So here, it's Halperin again. You see some of the aortic right atrial pressure gradients during manual CPR and with the vest CPR, and you see how much bigger the gradients are that you can achieve, right? And implemented in these days in other devices such as like the SOL thing. But it's the same system. You want to increase and maximize the interthoracic pressure as much as only possible. Then the other thing that it can manipulate in the system is not just the pump, but also the load in the arterial system, meaning the pressure in the arterial system, right? Because that pressure ultimately drives the coronary blood flow, for example, as we've already seen before. And one way to do that is to increase the systemic vascular resistance, such as by using a vasopressor, such as like epinephrine, right? And so the idea there is that this will lead to an increase in the aortic root pressure during the relaxation phase. And that is the driving pressure for the coronary perfusion pressure, right? So if you get your arterial root pressure up while the right atrial pressure is the same, then you have a bigger coronary perfusion pressure. And that is a critical measure for return of spontaneous circulation, right? So it will increase coronary perfusion pressure and coronary blood flow. But it may decrease cardiac output because the systemic vascular resistance is higher and therefore may also decrease your N-tidal CO2 to some extent, which may be one reason why N-tidal CO2 is a little bit inconsistent, because it's not just the quality of chest compressions and those things. It also depends on the vasopressor use, for example. Same with hypervolemia, or the opposite, rather, with hypervolemia. So what we do with hypervolemia is we selectively increase the pressure in the right atrium, right? And therefore, the coronary perfusion pressure may be reduced, right? So if the aortic root pressure is the same but the right atrial pressure comes up, then the coronary perfusion pressure is less. And therefore, we are less likely to achieve return of spontaneous circulation. So it will compromise coronary blood flow, right? Which is why we recommend against that. While hypervolemia also is harmful in that sense, because your aortic root pressure may be less, right? So your right atrial pressure may be all right, but you will not get as much pressure up in the aorta. And if that's not the case, then your coronary perfusion pressure will be less as well. So how to optimize those things in our animals, right? So how can we use what we now learned to our advantage? So if you would only have cardiac pump in a selective way, maybe increasing the rate would be one option to optimize flow within reason. And this will not have, based on the research evidence, any effect when you use thoracic pump. But the compression duration may matter for thoracic pump. And the increased compression depth will also measure for thoracic pump, because whatever helps you to increase inter-thoracic pressure during the compression will improve blood flow. An impedance threshold device will probably help with the cardiac pump, because there will be more filling. With a thoracic pump, as I mentioned before, there may be less end relaxation volume in the chest. And so therefore, the maximum thoracic pressure that you can achieve during your compression may be less. So on the other hand, there's more filling. So it's a little bit of er-er. Maybe one reason why it's not as consistently effective. But maybe ITT together with an ACD used at the same time may overcome some of those issues, because the end thoracic volume that will be acquired will be actually quite normal or even increased. Volume, obviously, is important for both. Compression over the heart is mostly important for cardiac pump, I would say. Not so much will not do very much for the thoracic pump itself. In fact, circumferential CPR, maybe like this, would be better for the maximized thoracic pump approach, because you really want to have a maximum chest volume reduction. But at the end of the day, if you want to have the simplest version of all of it, it is this recent statement. This may be valid. You know, all told, the greater the vigor of the chest compressions, the greater the resulting cardiac output and magnitude of cerebral blood flow. So push hard, in other words. I think it quite matters. In fact, I think you push hard as much as you possibly can, just up to the only limit being the injury associated with it. You know what I mean? Like, obviously, we have a 33% to 50% compression depth is what we currently recommend. But yeah, the harder, the better, as long as you don't generate any injury, really. Except in cats, maybe. And with that, I conclude that session. Thank you very much. Any questions on that? Any spelling errors or other things? No? Otherwise, just come forward and, yeah, and let me know. Thank you so much. And handing over to Dan. I realize I'm all that's standing between you and lunch right now. So we'll be efficient and get through this next part. So I'm going to pick up where Manu left off. So he did a really nice job of presenting sort of the theory behind these different approaches to establishing blood flow during CPR. I'm going to review a little bit of the evidence and then talk a little bit about the evidence, both for these different approaches to blood flow and also the evidence for the use of pressors during CPR. No disclosures again. Okay, so compression-only CPR is something that's been proposed in human medicine quite a lot. And I just wanted to briefly touch on it for bystander CPR especially. So obviously, compressions, as Manu just spent a lot of time talking about, are probably the most important part of CPR, generating that blood flow is really critical. And if you look at the meta-analyses that were published relatively recently on compression-only CPR for, again, this is bystander CPR, so out-of-hospital arrests, looking overall at the outcomes, really compression-only versus compressions with ventilation is pretty much the same in people and out-of-hospital arrests. So it looks like you have equivalent outcomes for bystander rescues. And then if you look at this meta-analysis, actually it shows that there's an increase in survival in patients who have compression-only CPR compared to patients who get ventilation along with it. So there has been a big push in lay rescuer training for CPR in people to do compression-only CPR. I think it's important to keep in mind that this is recommended for out-of-hospital human arrests. And so we have to be cautious about sort of applying that to our patients as well. And if you look at the actual ill core guideline, it says if advanced airway placement will interrupt chest compressions, provider may consider deferring insertion of airway until the patient fails to respond to initial CPR and defibrillation attempts or demonstrates return of spontaneous circulation. I think the important part of that statement is the first part of it, which is if advanced airway placement will interrupt chest compressions, which I don't know, I haven't intubated people. I hear it's hard. At least that's what it looks like on Grey's Anatomy. In veterinary medicine, I think it's rare that we can't get a patient intubated while chest compressions are going on. So I think for our in-hospital arrests in veterinary medicine, I would still argue that focusing on airways early makes a lot of sense. Getting patients intubated as soon as possible makes a lot of sense. We don't have good data to show differences in outcomes, but I would argue that we probably wanna, this is one of those places where we may deviate a little bit from the human guidelines. We do have to keep in mind, and Manu has talked about this, is even with good quality chest compressions, we're only gonna get about 30% of a normal cardiac output. So this is just experimental data in dogs. So you can see the stroke volume was about 20 mils at the control condition. And then looking at different compression forces at sort of the optimal compression force right in the middle, we're only getting about six mils of stroke volume in this model. So we're only gonna get a very low proportion of the normal cardiac output with closed chest compressions and something for us to keep in mind as we think about these options for augmenting blood flow. Okay, so looking at the data that we have available for guiding chest compressions in our patients, chest compression position. So unfortunately, this is kind of the sum total of the evidence that we have for what position dogs should be in during chest compressions. And it's not even data that's been statistically analyzed. It's just data that was presented as look at this dog having compressions done on his back versus in lateral recumbency. So here you can see the dog is supine, so laying on his back and doing compressions directly over the sternum as you would do in a person. And here you have a dog laying in lateral, single dog that we're recording these on. And if you look at aortic flow and left ventricular pressures, you can see that in lateral recumbency, they're able to achieve much better pressures. So unfortunately, we don't have a lot of data that would go along with this to say, yes, this is absolutely the way we should do compressions in dogs. I think most of us recognize that given the anatomy of dogs and the shape of the chest, lateral recumbency is probably best, but it is another one of those pieces of very low hanging fruit that we maybe someday we'll be able to answer ourselves to try to figure this out. And I think as we look at the human CPR literature, it's important to recognize that even if it's data collected in dogs, most of the older data collected in dogs is with them supine with chest compressions happening over the sternum, sort of modeling how chest compressions would be done on a person. So we just have to interpret that data cautiously. There was this Hofmeister study, which a lot of us refer to because it's the largest epidemiologic study that has been published in veterinary CPR so far, although we have some more recent ones that we should be looking at a little bit more. But this one, basically, he looked at dogs in lateral recumbency versus dogs that were put in dorsal recumbency and had compressions done over the sternum. And 88% were in lateral recumbency and there was an increased rate of return of spontaneous circulation. This is not a randomized control trial. This is just how the dogs happen to wind up. And whether those dogs that were put into dorsal were more likely those sort of flat-chested breeds like the bulldogs, I don't know. But at least a little bit of clinical data that would suggest that lateral recumbency may be the better option. Compression rates, Manu covered this nicely, but I'll just sort of review again a little bit. This is one of the seminal papers from Circulation published in 1988, looking in dogs at, this was an induced ventricular fibrillation model looking at comparing 60 compressions per minute to 120 compressions per minute. So again, thinking back to what we talked about earlier about the adherence to BLS guidelines now and the fact that there are a large number of veterinarians out there who still think they should be in that 60 to 80 range. But I think we have very, very compelling data in this experimental study that compressions at 60 per minute, much lower likelihood of return of spontaneous circulation and survival than if we go at 120. So huge difference in those two survival curves there. And then, and that's from that same data, looking at aortic pressures, systolic aortic pressures, much higher in the 120 group, diastolic aortic pressures, also much higher in the 120 group. And then looking at the right atrial pressures, you can see there wasn't a big change here in those two as Manu kind of reviewed. So this is gonna obviously improve the coronary perfusion pressure significantly since we've got the increase in the aortic pressures without the increase in the right atrial pressure. So it seems like just this rate is very important. So one of those things that I think we have strong evidence for and we need to make sure we're getting the word out about that. So then more recently, there've been some questions around whether faster than 120 might be better. So this is a registry study out of Hospital Cardiac Arrest, about 3,000 patients looking at chest compression ratios, sorry, chest compression rates plotted against the return of spontaneous circulation. And you can see at these lower rates, we have very poor return of spontaneous circulation. Once we get above about 120, you can see that there's a drop off in this as well. So it does look like we have sort of this sweet spot between 100 and 120 for that rate in this large study. Same for survival to discharge. So unfortunately, these probabilities on the Y-axis are a little sad. So trying not to focus too much on those, but you can see definitely it seems like we've got the sweet spot at between 100 to 120. But there is this data, it's a smaller study, and this is an in-hospital cardiac arrest study, so a different population. But when they looked at the mean compression rates and they were targeting slightly higher rates, they actually found a greater incidence of return of spontaneous circulation in the hospital when they did 120 to 140 compressions per minute. So odds ratio of about four and a half. So four and a half times as likely to get return of spontaneous circulation compared to the 100 to 120. It's a smaller study, but it's maybe a little more relevant to our patients in terms of being in-hospital cardiac arrest where compressions probably started sooner. And this was just published in 2017. So maybe a little bit of evidence that higher rates might be a little bit better. But again, I think it's a very small study compared to those very large studies that show that 100 to 120. And this is certainly not in dogs or cats, it's in people. So I think to summarize that, I think we can all agree that in veterinary medicine, despite the recommendations in human medicine, intubation early is probably warranted. I think that's the combination of the fact that it's easier and also because many of our patients, we think, experience asphyxial arrests as opposed to primary cardiac arrests as they do in people. So early ventilation might be more useful. Most likely doing chest compressions and lateral recumbency in most of our patients makes sense. A rate of 100 to 120 is probably optimal. Although I would say this more recent data would suggest that looking at the possibility of higher rates being useful might be something to think about. Although the experimental data that Manu presented would suggest that maybe it depends a little bit on which method of chest compressions we're targeting, thoracic versus cardiac pump approach. What do we know about pausing chest compressions and its effect? So this is data from way back in 1998 when many of you may not have been born or something, this is just showing from the start of chest compressions, the increase in pressures and arterial pressures. And you can see that it takes a good 60 seconds or so of chest compressions before we reach that steady state arterial pressure. And so this would motivate the idea that more pauses in chest compressions, not going for that full two minutes of uninterrupted chest compressions could lead to suboptimal arterial blood pressures, given that it takes a full 60 seconds from a stop to get them up to that point. This certainly would suggest that we wanna minimize our chest compression pauses. And then this is a study that was just published back in 2011. It was in a registry-based study of out-of-hospital cardiac arrests in people. They collected this data from defibrillators so they could actually get really good timing on when compressions were happening and what percentage of the time during the arrest compressions were happening. And they showed a very nice relationship between the chest compression fraction and pre-hospital return of spontaneous circulation. So again, out-of-hospital, so as soon as they start compressions, the higher their chest compression fraction. So out here, this means that between 80 and 100% of the time, compressions were happening. So their pauses were pretty small. Down here, 40% of the time, compressions were happening. So you can see a significant increase over time, over increases in that compression fraction. And what they found was there was about a 10% increase in return of spontaneous circulation for every 10% increase in compression fraction. So the less pauses and the shorter the pauses, the more likely they were to get a return of spontaneous circulation. So it does seem it's important to continue those compressions and minimize those pauses. Unfortunately, it's an out-of-hospital study. The number of survivors were actually too small to actually look at survival to discharge. So this only included data for return of spontaneous circulation. So how that translates to survival to discharge, not really sure yet. So I think overall, we can say we wanna maximize our chest compression fraction in patients who wanna minimize those pauses. And then Manu touched on this, so I'm not gonna belabor it too much, but this is similar to the data he showed. This is a study from 1995 comparing open chest to closed chest CPR. So this is closed chest cardiac massage. This is open chest cardiac massage. The dotted line is the aortic pressure, and the solid line is the right atrial pressure. So as Manu said, the difference between those two, especially during that relaxation phase or diastole, if you wanna call it that, that difference, that gray shaded area is representing coronary perfusion pressure. So a minimum target coronary perfusion pressure, Manu said 20. This is a little more, I guess, conservative at 15, but roughly that same rate that Manu commented on. If we look at the closed chest massage, you can see we're rarely even getting above this 15 level, whereas with the open chest cardiac massage, we're very consistently getting above that 15 millimeters of mercury of coronary perfusion pressure. So no question that with open chest cardiac massage, we're gonna get better blood flows and better coronary perfusion pressures, which is probably why those outcome studies have suggested that they're better. So this is a little review article that was published back in 2005 in Resuscitation, just looking at comparison between open chest and closed chest CPR. And I think you can see that arterial pressures are higher and venous pressures are lower, as Manu commented earlier, which means our coronary perfusion pressures are gonna be better in these patients. So this lower venous pressure is probably as important as the increased arterial pressures that we're getting in terms of our coronary perfusion pressures. Manu made a comment about getting free ITDs if you find mistakes in his proceedings. This is a published paper in Resuscitation and there's a typo in this one as well. So like it says, right arterial pressure peaks, these should be atrial, both of these. So it's always fun to read papers closely and realize the problems, but just to summarize what we said before that with open chest cardiac massage, we're gonna get increases in coronary perfusion pressure because with closed chest cardiac massage, we do increase those right atrial pressure peaks more because we're increasing overall intrathoracic pressure by doing it with the closed chest. So definitely lots of good evidence that open chest cardiac massage is gonna improve your coronary perfusion pressure and just your blood flows in general. So what do we know about open chest CPR and its impact on outcome? So this is a meta-analysis published just last year in 2019 looking at clinical trials. Interestingly, so when I was thinking about open chest CPR, it seemed to me that trauma cases would be the ones that would be most likely to benefit from it, blunt trauma, especially if there were rib fractures and things like that. But if you look at this data, it's interesting. So overall, they saw no difference in return of spontaneous circulation between open and closed chest. And again, these are clinical studies. If you look at the subset of patients who were non-trauma cases, they actually did have a significant improvement in outcomes. So over here, favors open chest. As opposed to the ones who had blunt trauma, they actually did worse with open chest CPR. So interesting. So it does seem like maybe for the non-traumatic cases, maybe we'll have better luck. You can also see, however, that there's only one study here that was done with the non-traumatic because most likely it would be the trauma cases that would get open chest if anybody's gonna get them. So I think this is a little dicey right now to try to interpret this too accurately. But unfortunately, overall, it doesn't look like we've got great survival, improved survival with open versus closed in these studies. And then this is survival to discharge. A smaller number of studies looked at it, but again, no difference in survival to discharge between open and closed chest in this case. So looking at the clinical studies, we're not seeing the benefits that we see in the experimental studies. Again, I think all of these have to be taken with a grain of salt. These clinical studies, you don't have the same kind of control. The question is, if you had really similar patient populations, would you be able to demonstrate a difference? Who knows? But right now, certainly don't have strong evidence from the human literature that it's better. So IllCore did not update their closed chest versus open chest recommendations in 2015. So they just stuck with their 2010 recommendations. Most of the data was available at that time. So their recommendations are basically that open chest CPR can be useful if cardiac arrest develops during surgery when the chest or abdomen is already open or in the early postoperative period, specifically after cardiothoracic surgery where closed chest compressions would probably not be a great idea. And then a resuscitative thoracotomy to facilitate open chest CPR may be considered in very select circumstances of adults and children out of hospital cardiac arrest from penetrating trauma with short transport times to the hospital. So penetrating thoracic trauma would make sense that you would have to go to open chest. But in general, their recommendation is maybe to consider during surgery, maybe not around that. I thought this is an interesting paper that was just published in VetSurge last year about the approach to doing open chest, quote unquote open chest, but direct cardiac massage during abdominal surgery in dogs. So this was a cadaver study where they basically took cadavers and they were measuring the amount of time it took to get to the heart via an abdominal, an incision through the diaphragm if the abdomen was already open versus a lateral thoracotomy, which would be the standard approach to take. And this is just an example of the diaphragm opened up and a star on the heart right there, as you can see. And what they found interestingly when they looked at the time to access the heart is that there was no significant difference. It was almost identical in terms of the amount of time it took to get into the heart statistically. And if you look at the means, you can see they're pretty similar. So it didn't take a longer time to get there. The time to close the pleural space, it took a little bit longer for the thoracotomy. So I think people have been concerned about doing this approach because they think it's gonna be hard to actually get up there and access the heart through the diaphragm, whereas with a thoracotomy, you just slice it open and the heart's right there. But I think this is, you know, it's cadaver data. It's a very small number of cadavers that they looked at, but at least it seems that it doesn't actually take that much longer to get to the heart or any longer at all. And so this may be a viable approach for the patient with the open abdomen who arrests during surgery. So to summarize, I think the evidence suggests that open chest CPR certainly results in superior hemodynamics, but we don't have good clinical outcome data that would suggest that it should be our go-to in all cases. Hard to know how to interpret that, but right now it's a little bit tough to make that argument. Okay, so talking about pressors. So whenever I give talks, I'm always looking for pictures to put in there to try to enliven things up. And I thought this is the coolest thing ever, that like the Marvel Universe does pressors, which is so cool. So Iron Man is epinephrine, and Bucky, the best friend of Captain America, is vasopressin. So kind of an awesome thing to start with. So we're gonna talk both about epinephrine and vasopressin, what evidence we have for them during CPR, and whether we should be using them or not, and how we should be using them. So taking a look at our recover CPR algorithm here, we have our shockable rhythms on the left and our non-shockable rhythms here on the right. Pressors, in our guidelines, we recommend considering epinephrine or vasopressin every other cycle for shockable rhythms if they're prolonged. So if, and our general rule of thumb in the guidelines are, if it's more than 10 minutes, so more than five defibrillations, you can consider giving a pressor to a patient with a shockable rhythm. For the non-shockable rhythms, we do recommend low-dose epinephrine and or vasopressin as early as possible. So as soon as you have your diagnosis of your shockable rhythm, and then with prolonged cardiopulmonary arrest, you can consider high-dose epinephrine in those cases as a last-ditch attempt. So that's how the guidelines are written now. We're gonna take a quick look at the current evidence we have around the use of these pressors, both low-dose epi, vasopressin, and high-dose epi. So epinephrine, probably the most studied drug in CPR. It's the one that's probably been used the longest when it gets to ALS. It acts via alpha-1 receptors on peripheral vascular smooth muscle, activating phospholipase C. We get production of diacylglycerol and IP3. IP3 causes release of calcium from the sarcoplasmic reticulum, and that's what leads to our peripheral vasoconstriction in these cases. We also get activation of protein kinase C from the diacylglycerol, and that will also stimulate peripheral vasoconstriction. So two different mechanisms, but via the same receptor within peripheral smooth vascular smooth muscle. Beta-1 stimulation also happens with epinephrine, and that triggers adenylacyclase, which breaks ATP down to cyclic AMP, and then through second messenger systems, that'll lead to increases in chronotropy and increases in inotropy. So this is mostly in the nodes in the heart and in the myocardial cells in the heart, increasing chronotropy and inotropy. And then we also get beta-2 stimulation also via cyclic AMP production, which leads to a different set of second messengers that cause bronchodilation. So epinephrine, I think of it as a dirty catecholamine. It hits pretty much all of the adrenergic receptors, has many effects. During CPR, we're mostly giving it, though, for these alpha-1 effects, causing that peripheral vasoconstriction and redirecting blood flow from the periphery back to the core, as Manu mentioned earlier. So catecholamines are recommended in most CPR attempts, remembering that external compressions, again, we only get about 30% of a normal cardiac output, so that alpha-1 causing that peripheral vasoconstriction. In theory, when the catecholamines were first recommended for CPR, there was thought that the beta-1 effects actually could be beneficial as well if the heart's not beating. Maybe if we hit those beta-1 receptors, it'll magically start beating. It turns out that probably doesn't work, and maybe actually has some detrimental effects as well. The goal of giving them, though, is to increase that coronary perfusion pressure and cerebral perfusion pressure. I noticed during Manu's lecture, he used CPP for coronary and CEPP for cerebral, and I do the opposite, so I apologize for the confusion. The two CPPs are a real problem. Just make sure you know which one you're talking about when you're looking at literature. Often, if you're looking in hemodynamic literature, it's gonna use CPP for coronary perfusion pressure, and if you're looking at the head injury literature, it's gonna use CPP for cerebral perfusion pressure, so just be careful and make sure you know which one you're talking about, because there could be different effects on the two systems. Yeah? Oh, no, where? What did I do? Oh, positive, all right. You get a... Woo! They were supposed to be for my news typos, but I'm just gonna claim that. Enjoy, enjoy, it's on my new. All right, so as I mentioned, the beta effects, initially, it was thought that maybe the beta effects were actually useful. They may increase coronary and cerebral blood flow, so COPP and CEPP, but the detrimental effects, there are many potentials, so once you get return of spontaneous circulation, they'll lead to increases in cardiac contractility and heart rate, potentially increasing myocardial oxygen consumption. They have the potential to worsen ventricular arrhythmias, again, in the post-cardiac arrest phase, because of all that beta stimulation, and that can especially happen in acidemic patients, because that's gonna sensitize the myocardium to these arrhythmias. They can decrease hypoxic pulmonary vasoconstriction, which can actually worsen hypoxemia by sort of taking away that normal measure that should decrease blood flow to poorly ventilated areas of the lung, and they've been shown to potentially impair the microcirculation as well, so lots of reasons these beta-1 effects may not be so great, and really, there are nice studies now that have demonstrated that it's the alpha-1 effects that predominantly help, although maybe the beta-1 effects help just a little bit. So looking at the experimental studies of the use of catecholamines, so this is very similar to what Manu was talking about, so in this canine cardiopulmonary arrest model, you can see where the epinephrine is injected here. Right atrial pressures don't really change very much, which is what we're hoping for, because we don't wanna decrease the coronary perfusion pressure by that, but you get increases in carotid pressures and increases in aortic pressures, both systolic and diastolic aortic pressures, which is beneficial because it's that diastolic aortic pressure minus the right atrial pressure that will tell us what the coronary perfusion pressure is, so by raising both of those without really having a big impact on right atrial pressure, we get improvements in our coronary perfusion, and then looking at studies, these are experimental studies in dogs that are comparing different types of potential vasopressors and other drugs. During CPR, there's consistent signs that we have increases in return of spontaneous circulations and increases in coronary perfusion pressure with the use of epinephrine, so in this first study, you can see comparing epinephrine to isoproterenol, a beta agonist, 10 out of 10 of the dogs got return of spontaneous circulation when they were given epinephrine, none when they got the beta agonist. Looking at this asphyxial arrest model, again, dogs that got epinephrine, nine out of 10 had a return of spontaneous circulation, none that didn't get epinephrine that got placebo, and then methoxamine versus saline, so methoxamine is another alpha-1 agonist. You can see 10 out of 10 that got methoxamine got back, two out of 10 that just got a saline placebo, and then finally, comparing epinephrine to methoxamine, again, more alpha-1 specific, same, all of them got return of spontaneous circulation, so it definitely seems, looking at sort of the dog studies, the experimental studies that have been done overall, we can get increases in return of spontaneous circulation with the use of epinephrine. So then the question comes to this high versus low-dose epinephrine. We know that high-dose epinephrine in clinical studies in people is associated with an increase in the rate of return of spontaneous circulation, so this is a meta-analysis published back in 2000 now. If you look at these studies overall, and this is the overall effect, you can see that there's a relative benefit of high-dose epinephrine in terms of return of spontaneous circulation, but then if you look at the survival to discharge, unfortunately, it's the opposite effect, so you get more of them to get a pulse back, but then fewer of those patients actually survive to leave the hospital, and that's likely because some of those detrimental effects that we talked about with those beta effects, especially at the high doses, and there are many possible mechanisms that have been suggested, so maybe the vasoconstriction is so severe that we start to get a more severe acidosis in the periphery, maybe increases in matricular arrhythmias, the myocardial oxygen consumption we talked about. We can also get hyperglycemia with these high doses of epinephrine, and maybe that impairs neurologic recovery as well, so lots of potential reasons, but at the end of the day, high-dose epinephrine gives you a short-term gain, but at the cost of a long-term worse outcome. Looking at the clinical studies, it always surprises me that clinical studies are still being done, and there are still randomized placebo-controlled trials being done with epinephrine, which is great because there's definitely not a consensus 100% on the use of this drug, but there have been multiple clinical trials in the last few years, and then these are some meta-analyses on this, so looking at the use of epinephrine in these patients, you can see overall there's an increase in survival to discharge in patients who receive epinephrine versus no epinephrine, and again, a meta-analysis at a bunch of individual clinical trials. Unfortunately, you also see an increase in the proportion of patients with poor neurologic outcome among the patients who get epinephrine, and this has been one of the things that's driven more research and discussion about whether epinephrine is a good idea or not. Now, the question you have to ask yourself is do we see more poor neurologic outcome because we have more survivors who maybe they survived because they got the epinephrine and we got them through CPR, but they were the ones who were in worse shape that we got through, as opposed to the ones who didn't get epinephrine who maybe didn't survive, who would have gone on to have poor neurologic function, but there is this concern that maybe we get more patients with poor neurologic function and for us, that probably means losing the patient because it's unlikely that we're gonna get through the post-cardiac arrest period in a patient with severe neurologic dysfunction after CPR. The PARAMEDIC-2 trial was just published in 2018, and this was a large randomized placebo-controlled trial, and if you look overall at the outcomes here, survival at 30 days for patients who got epinephrine versus patients who got placebo, there was a statistically significant improvement in 30-day survival, so an odds ratio of 1.39, so about 40% more likely to survive to discharge if they got epinephrine than if they didn't get epinephrine in this study. Looking at favorable neurologic outcome at three months in this study, they showed no difference, so pretty much if you look at these confidence intervals, they include one, so we don't have that same problem with the poor neurologic outcome in the patients that got epinephrine compared to the ones who didn't in this large randomized controlled trial. So, sorry, survival and then the favorable neurologic outcome, so looking a little rosier for epinephrine based on this. The other question people have asked is, does timing matter when it comes to epinephrine? Do we wanna get it on board right away or do we wanna give chest compressions a chance for a little while before we think about going to epinephrine? And this is an observational study published in 2018 in circulation for out-of-hospital arrests, so that's why you have such a wide range in how long it took to get epinephrine on board because it'll depend a little bit on how long it takes the paramedics to get there to give it. But if you look at the number who received epinephrine, you can see most people got it within 10 minutes in these out-of-hospital arrests, but some were way out here, close to 30 minutes. But then the black line is survival to discharge, and you can see that there's this statistically significant drop in survival to discharge based on how long it takes to get the epinephrine. Is that just because that's how long it took to get the epinephrine or is that because that's how long it took CPR to really get started by someone who's trained in it and really knew how to do it? Hard to tease those out, but it does provide some evidence that early epinephrine may be beneficial rather than waiting until later in the course of the scenario. So what does ILCOR recommend? So ILCOR did update their epinephrine recommendations in their mini update in 2019. So ILCOR has stopped doing every five-year giant updates. They're doing rolling updates now. So every year, there's some new things that come out. So just in 2019, they updated their recommendations. They're not that different. There are a couple of little changes. So the first one is epinephrine should be administered to patients in cardiac arrest. So pretty straightforward. It's reasonable to give it every three to five minutes, which is what we recommend as well. So sort of every other cycle of basic life support if you're doing two-minute cycles. High-dose epinephrine is not recommended for routine use in cardiac arrest. So they are basically saying don't do it. For non-shockable rhythms, you should give it as soon as is feasible. Interestingly, I think this is new. I know you can correct me if I'm wrong, but it actually says for shockable rhythms now, they recommend waiting until you've tried defibrillating a few times before you give epinephrine. I'm pretty sure the 2015 guidelines said give it right away. So this seems like a little bit of a shift in their recommendation. And this actually now matches up a little bit more with the recover recommendations, which are to give defibrillation a chance before giving epinephrine. So anyway, I think it is a little bit of a change. Maybe they read our guidelines and decided that we were right, I don't know. But yeah, and our recommendation for that is based mostly on, it's really expert opinion, but mostly based on, or someone's opinion, I don't know if they're experts, about the potential that catecholamines could, if you have a dysrhythmia like pulseless VT or like ventricular fibrillation, that there's the potential that the epinephrine could actually make the myocardium even more irritable through that beta-1 stimulation and maybe make it a little bit less likely you'll defibrillate them successfully. And that was based on our discussion that we felt that in our patients, we much more commonly saw the non-shockable rhythms. And when we saw the shockable rhythms, it was often later in the course of CPR after they had had multiple doses of catecholamines. And so to keep the guidelines simple, we just figured epinephrine hasn't necessarily been shown to be as beneficial in the shockable rhythms. We know that defibrillation is the best option, so we would start with that. So it will be interesting to see, we're ramping up now to, this will be one of the questions we'll be looking at freshly in the next few months. And we'll see, looking at the literature, whether we support our current recommendations or if we would recommend making changes. So interesting though, that that's coming more in alignment with us. So really our epinephrine guidelines are the use of low-dose epinephrine every three to five minutes early in CPR as recommended is how our guideline was written. And that was for the non-shockable arrest rhythms. And then the use of high-dose epinephrine could be considered with prolonged CPR. And that may be one that we're gonna have to revisit as well looking at the new literature and trying to decide whether it makes sense to even have it in our algorithm anymore. My general recommendation to folks based on the meta-analysis has been, I only give high-dose epinephrine if I'm about to give up. If I think there's a chance I'm getting this patient back, I don't give it. But if I'm really to the point where I'm about to call it, I may do it as just a last-ditch effort. So the guidelines, a lot of people read the guidelines and think that they're supposed to give epinephrine 10 minutes in always. It's not what the guidelines say and I wouldn't recommend it. If you have a patient that has an acute reversible cause of arrest, CPR is going well, your end-tidal CO2s are pretty good, I would not be giving high-dose epinephrine to that patient 10 minutes in. I would give them more time and see if you can get them back. Okay, vasopressin. How many of you guys still have access to vasopressin in your practices? You have, there's so many rich people in the audience. That's so cool. So we used to have it in our crash cart and our pharmacist said, oh, no, no, no, not anymore because of its cost. Are you guys really paying like 200 bucks a vial for it or are you guys getting it cheaper somewhere now? I see a head shaking up and down. So you are all wealthy people, that's good. I'm glad there are rich people out there who can do that. Yeah, so vasopressin used to be really cheap and then all of a sudden, like many generic drugs these days got very expensive, which is frustrating. I keep hoping that it's gonna come back down in price. But vasopressin has been studied pretty extensively in CPR as well as an alternative to epinephrine. So remember it acts via peripheral V1 receptors that causes activation of phospholipase C, same kind of mechanism as the epinephrine but through a different receptor. And then that causes release of calcium from the sarcoplasmic reticulum that causes peripheral vasoconstriction. So different receptors, different functions of those receptors but similar mechanism to epinephrine. It does not have the beta effects though, right? So it acts via its own V1 receptors, no adrenergic receptors are involved at all. And that may be beneficial thinking about those beta one effects of epinephrine that may not be good. So it does have a longer half-life so it sticks around a little bit longer and may have its effect for a longer time. It doesn't act via those adrenergic receptors so we don't get those pesky beta one effects that may be detrimental and we don't get hyperglycemia with it. And the other thing that's nice about it is alpha one receptors do become unresponsive in the face of an acidemic pH, whereas V1 receptors stay responsive even in the face of acidemia. And obviously as CPR progresses, it's likely these patients are developing more and more severe acidosis, metabolic at least and probably in the periphery, also respiratory acidosis. So there's the potential that this would be a more effective vasopressor in those types of patients. So if we look at the experimental evidence, there certainly is decent experimental evidence that compared to epinephrine, we can get increases in myocardial and cerebral blood flow with vasopressin compared to epinephrine and then that effect lasts longer. So this is coronary perfusion pressure here. You can see significantly higher, close but significantly higher. But then as time goes on, this is five minutes after administration, the epinephrine is starting to drop already but the vasopressin is still having a pretty good effect. Same effect on cerebral perfusion pressure, looking at left ventricular blood flow again, similar although bigger differences here and total cerebral blood flow, it doesn't matter. But you can see that the major point here is that it does seem to have a better effect and it does seem to last longer than the epinephrine does. We also have some evidence that it has increased efficacy with these prolonged arrests. So again, these are all the drug administrations here. This is time. So ventricular fibrillation, four minutes after VF, this is induced in dogs. They start BLS and then they start ALS seven minutes in. So you can see the first drug doses administered here, looking at coronary perfusion pressure of the vasopressin versus the epi, you get a better effect. And you can see that even with these repeated doses, you're getting a better effect of the vasopressin. So this can't be just the longer half-life. It also has to be that it's having a better impact maybe because these dogs are developing some acidemia and these other potential causes. But you can see that's true for coronary perfusion pressure and it does seem to have a good effect. So it does seem like it has these magical properties in these experimental studies. The problem is when you try to translate that into clinical practice, it just hasn't been able, we haven't been able to document that this is the case. So there have been many studies of epinephrine versus vasopressin or the combination of epi and vasopressin. And this is a meta-analysis published in 2012, comparing vasopressin to control and control could be either epinephrine or epinephrine plus, sorry, just epinephrine, this is just compared to that. And if you look sort of overall, sustained return of spontaneous circulation, no difference in outcome. Survival to discharge, no difference in outcome. Favorable neurologic outcome, no difference. So although experimentally, it looks like it has some benefits when you actually put it into a clinical patient, at least in people, it doesn't seem to make a difference. So it's interesting that you can have something that looks so promising in an experimental setting and fail to translate it. So overall, it's generally been shown to be equivalent to epinephrine. What do we know in veterinary medicine about these two drugs opposed to each other? There was a prospective pilot study that came out of Tufts, a very small number of dogs. Well, 60, it's not that small, but 60 dogs that were randomized to either get low dose epinephrine or vasopressin. 32 of those achieved return of spontaneous circulation within six minutes. Frustratingly, more dogs in the epinephrine group survived to one hour than in the vasopressin group. So Epi actually did a little bit better here. Because they had so few dogs that survived to discharge, they couldn't comment on survival to discharge. They just didn't have enough to do statistics on. But in this case, at least, they weren't able to document a short-term improvement with the use of vasopressin. And then again, that Huffmeister study looking retrospectively, they did find that nine animals that were treated with vasopressin, if you looked at those nine, they had an odds ratio for return of spontaneous circulation of 13 times. The ones that got epinephrine, but look at those confidence intervals. They're whopping, because it was a very small number of animals. So I don't think it's 13 times more likely that you're gonna get ROSC. This is probably more one of those equivocal things, but again, a little bit of data that would contradict it. But keep in mind, this is an observational study. This is actually a controlled clinical trial with arguably a larger number of patients. So I would probably go a little bit more on the Tufts data at a minimum saying that I certainly don't think we have a preponderance of evidence that says vasopressin is better. So the 2015 vasopressin human CPR guidelines from Ilcor say the combined use of vasopressin and epinephrine offers no advantage to standard dose epinephrine and cardiac arrest. And vasopressin does not offer an advantage over the use of epinephrine alone. And so their response to that was therefore to simplify the algorithm, vasopressin has been removed from the adult cardiac arrest algorithm in 2015. I think it's really important to keep in mind that the only reason they did this was to simplify the algorithm. It wasn't that there was evidence that epinephrine was better. It was just that they didn't wanna have two drugs for the same indication on the algorithm. And I think this is important for us to consider because I think there are cases where if you have access to vasopressin, it would make sense to consider it, right? So you have a really bad DKA that arrests. You know that patient is severely acidemic at the time it arrests. If you have vasopressin, we can't say that there's clinical evidence to support it, but certainly experimentally and based on the physiology, you could make the argument that it might be the better choice. So think about your individual cases. If you have access to it, I would argue there may still be a place for it. And I would hate to think about taking it out of the algorithm just because I wanna make the algorithm simpler. So we'll see what comes out of the 2020 guidelines. I don't, I'm not a big fan of thinking about taking it out right now. So our guideline basically says the use of vasopressin as a substitute or in combination with epinephrine every three to five minutes can be considered. So this is one of those things where epinephrine is recommended. You can consider subbing in vasopressin or doing it in addition as well. So we'll look at the literature that's come out since and we'll hopefully have some new recommendations in another year or so for a cover. So just to summarize epinephrine for non-shockable rhythms, low dose is a good idea early and every three to five minutes. For shockable rhythms, we, I think, are in alignment now with the human guidelines which say give defibrillation a chance and then think about epinephrine later. For vasopressin, no demonstrated clinical benefit either alone or in combination and we definitely need more studies with prolonged arrests and with patients with significant acidemia before we can say for sure one way or the other.

physiology

blood flow

CPR

cardiac pump

thoracic pump

compression rate

compression depth

abdominal binding

airway pressure

vasopressors

epinephrine

vasopressin