So, I'm going to change focus a little bit. The topic is separated at birth mixed septic cardiogenic shock. I have no disclosures, but I'm going to, can we make this go when I click it as opposed to by itself? So let me go back one. So what I want to do is talk a little bit more about pathophysiology, and I'm going to come at this from the cardiogenic shock viewpoint. So we'll see, but I want to talk about shock pathophysiology in general, and we'll look at that interface between the septic, the features of septic shock and the features of cardiogenic shock. I didn't touch anything. So can I go back here? All right. The scroll wheel will go back. If I go up, the scroll wheel goes back. Okay. Let me try. So here's the definition of shock. It's been around for a while. Samuel Gross in 1862 called it a rude unhinging of the machinery of life. And John Collins Warren some 33 years later calls it a momentary pause in the act of death. This is serious stuff. A better definition, we are a little more scientific about this. So a shock definition is inadequate perfusion. You've heard the word perfusion a couple of times, and you're going to hear it again. An oxygenation of cells leads to cellular and then organ dysfunction and damage. And it's important that there's a time course here, and we'll talk about trajectory as well. It's potentially reversible at first, but may be irreversible if prolonged. So tissue perfusion, again, is a function of flow and pressure. Mean arterial pressure is a function of cardiac output and vascular resistance. And the cardiac output is defined by heart rate and stroke volume, and the classic determinants of preload, afterload, and contractility. We'll figure this out eventually. But the key goal here is perfusion. And that's really what we're going to talk about. So basically, perfusion, as you've heard, perfusion starts with clinical assessment. Clinical signs of organ dysfunction are on this slide. In the CNS system, in the cardiovascular system, respiratory, renal, and then metabolic factors such as lactate and such, and even some hematologic factors. So you're really looking at whether your patient does or doesn't have hyperperfusion, and as you've heard, that's the underpinning of the sky shock classification. Now, the underlying classification of types of shock goes back to this classic figure by Weil and Shubin way back when, the founders of the Society of Critical Care Medicine. And they divide it into these four categories, hypovolemic shock, cardiogenic shock, extracardiac obstructive shock, and distributive shock. Cardiac output is low in the first three, and generally not low in the fourth. Distributive shock is more of a vascular than a cardiac output problem. And ultimately, your blood pressure goes down, you have shock, and this is going by itself. I don't believe it. And ultimately, the blood pressure goes down, you have shock and multiple organ failure. Now, this is a cue for me to say that I'm taking this from the cardiogenic shock. We are not talking about septic cardiomyopathy. That was the last session. And frankly, the number of patients who have septic cardiomyopathy severe enough to cause perfusion failure on the basis of low cardiac output is really rare. So we're going to look at the interface between cardiogenic and septic shock in the more classic sense. And we'll also talk about vascular resistance. So that's part of the notion. You have cardiac output, and you have vascular resistance. And as you can see, you have the systemic vascular resistance, the resistance across the systemic bed, mean arterial pressure, minus CVP over cardiac output. That defines SVR. And pulmonary vascular resistance, again, is the resistance across the pulmonary bed, mean pulmonary artery pressure minus the wedge pressure over the cardiac output. So you have a hemodynamic definition, and then you have a pathogenesis. And here's a relatively complicated slide that Joe Parillo put together way back when about the pathogenesis of shock. And the key things to notice here are that you have a number of cells involved. Once you get shock, I'm going to put my hands up here so I can not. Once you get shock, you have activation of a number of cells, plasma, monocytes, macrophages, endothelial cells. They do all sorts of things that cause cellular dysfunction. And then in septic shock, we talk about cellular dysfunction, and we talk about the effects on the vasculature, the effects on the organs, and the effects on the myocardium. And then patients either succumb to hypotension or multiple organ dysfunction, or they either avoid those things or they recover. So the other thing to think about is that sepsis is clearly a microvascular disease. And we're going to talk about the microvasculature again. So you have problems at the level of the arterial. That's where the regulation of blood pressure happens, vasodilation, and failure to respond appropriately to vasopressors. On the venular side, you have neutrophil aggregation and rolling. And then in the capillary bed, you have endothelial cell dysfunction, a certain degree of capillary leakage. And you can actually see this. This is work of Daniel DeBacker out in 2002, 20 years now, in which they used a sublingual probe to visualize the microcirculation and show alterations in microvascular blood flow in patients with sepsis, both capillary rarification and a decrease in the degree of perfused capillaries and also sluggish flow. And it's even broader than flow. Here's a figure for Peter Sprank, published out in 2004, looking at the components of microcirculatory failure in sepsis, endothelial activation with redistribution of blood flow. So your total blood flow may be normal, but some parts of the organ may be getting enough and some not. Functional shunting at the microcirculatory level, differences in blood flow and perfusion pressures, thrombosis, the interface between coagulation and inflammation, and increased microvascular permeability and leukocyte adhesion. In addition to the flow problems, there are also problems with ATP generation. Here's a slide that looks at lactate to pyruvate conversion, the citric acid cycle, that sort of big thing that we're just going to call the citric acid cycle. But again, your cells need glucose supplied, and they need oxygen to do aerobic metabolism of that so as to produce more ATP. If they don't, they produce lactate. So lactate production can be due to either decreased flow to the cells, but also failure to utilize glucose and oxygen appropriately. And that's the problem in some of the distributive factors of septic shock. And Mervyn Singer and his colleagues showed in this slide out in the Lancet again 20 years ago that there was an association between mitochondrial dysfunction and the severity and outcome of shock such that tissue ATP levels were much lower in non-survivors than survivors and lower than controls. And in fact, survivors had relatively normal tissue ATP levels. So let's move from septic shock to cardiogenic shock. So here's a figure looking at the classic hemodynamic consequences of cardiogenic shock. You get myocardial dysfunction. That's both systolic and diastolic. The systolic function decreases cardiac output and stroke volume and hypotension. And that causes ischemia. So dysfunction begets ischemia. And ischemia can, again, beget progressive myocardial dysfunction. The consequences of low cardiac output include decreased systemic perfusion and certain compensatory responses, including vasoconstriction and fluid retention. On the diastolic side, your left ventricular end diastolic pressure can go up. And then you have trouble oxygenating, and what blood you deliver doesn't have as much oxygen as it might, again, predisposing to ischemia. And if you get in this cycle and don't get out, it goes down where you don't want to go. And so cardiogenic shock originally was defined by hemodynamic subsets. This is data from the original data in 1976 by Forrester, where they used PA catheters and they plotted pulmonary capillary wedge pressure against cardiac index in patients with MI. And you can see what normal is here up on the left quadrant. Your wedge pressure is low and your cardiac index is high, and those patients are mostly in the green. They mostly survived. Even if your cardiac index is a little bit low, if your wedge pressure is normal, you can hydrate these people. Those will do pretty well. If you have classic congestion, your cardiac index is OK, but your wedge pressure is high. Most of those people do reasonably well, but there are some red. But the real most of the people who die after MI, and that was true then in 1976, and it's true now in 2023, are those with classic cardiogenic shock, low cardiac index, high filling pressures. The shock trial actually has sort of expanded this into different hemodynamic profiles, and this goes into some of the stuff with the right ventricle. Here is the shock trial patients divided by pulmonary capillary wedge pressure on the y-axis and CBP on the x-axis. And so what you can see is if your pressures are low on both sides, that's relatively good. You have either a normal profile, if they're really too low, you can hypovolemic. There are patients with, some of the patients had left ventricular congestion. That is, their CVP was low, but their filling pressures on the left side were high. Right ventricular congestion was relatively where that's, because in the shock trial, patients with RV shock were excluded. So the ones that sort of snuck in there sort of kind of snuck in there and really shouldn't have been included. And what you can see is that there's a fairly high proportion of patients in the shock trial with biventricular congestion, something that wasn't particularly well recognized at the time. And this plays in, as Dr. Jantzer alluded, into the spectrum of mechanical support devices. You can support the left ventricle with the pulsatile or continuous axial or centrifugal flow devices. You can support the right ventricle with axial or centrifugal flow devices, all of this being a story for the other day, for another day. So you get the notion, but the cardiogenic shock has been classified by that phenotype. But it has also been classified by inflammation. And this work started out from the shock trial, this paper from Kosaka, and you can't see the date, it's in the early 2000s, looked at the systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. And I've been quoting, I've been talking about this paper, I finally got back to reading it again. And this is widely quoted as, yeah, yeah, there are people in cardiogenic shock with low SVR. If you look at the paper, that turns out to be true. But look at what they did. They got 302 patients in the shock trial. They looked at 59 patients who they really thought were septic. They thought they had systemic inflammation and suspected sepsis with fever and leukocytosis. And then they compared those, and they actually looked at, they cultured all those people, and they looked at whether they were culture positive and culture negative. So most of the time, you look at table five on the right, and what does table five says? There's an overall association between survival and SERS grouping, and that's true. And there's an association with age. However, if you actually look, the association is in culture positive patients, people who really were septic and had positive blood cultures in the shock trial. And so this paper itself actually looks at sepsis more so than inflammation. But there is a little bit more data. So this is believed. We talked about inflammation forever without really reading the paper. But there is a little bit more. So this has then, this has then been translated into, I'm going to show you a little more data in a second, into the contemporary management of cardiogenic shock statement, in which they talk about, this is a two-by-two table looking at the classic wet, dry, cold, wet. And again, classic cardiogenic shock, as I told you, has high wedge pressure, low cardiac output, wet and cold. There's euvolemic cardiogenic shock. They're dry and cold. There's the vasodilatatory shock isn't cardiogenic. They're warm and dry. That's a different, that's distributed shock, if you will. And then there's this vasodilatory cardiogenic shock. They're warm, but they're wet. And it's a mixed shock. It's somewhere in between combined cardiogenic and septic shock. So where does the inflammation come in? Well, I'm going the other way. So the cardiogenic shock paradigm was adjusted, or at least added to, by Judy Hochman in a paper out in circulation. What she called the stuff on the right was the classic paradigm, by which she meant the outmoded paradigm. And then she put in systemic inflammation with inflammatory cytokines and inducible nitric oxide synthase that caused additional vasodilation, worsening the systemic perfusion, worsening the coronary perfusion, and worsening all the outcome. This led to a trial of nitric oxide synthase inhibition in cardiogenic shock, which unfortunately, although it raised blood pressure, did not improve outcomes. But it did stress the role of inflammation as worsening cardiogenic shock. And then we have a little bit more data from my colleague, Dr. Jentzer, over here, who looked at systemic inflammatory response syndrome associated with increased mortality across the spectrum of shock in cardiac patients. And again, this is a similar analysis. They took 9,000 patients in the Mayo Clinic CICU and looked at the association between SERS and mortality. And as you can see, after multivariate adjustment, SERS was associated with higher hospital and one-year mortality among basically all stages of sky shock, stages A to D, not sky shock to age C, because you're in so much trouble that it doesn't really matter whether you have SERS or not in extremis. So I think that was just failure of being able to show an effect that's clearly true. So I showed you a slide that said that sepsis is a microvascular disease, but I'd argue that shock is a microvascular disease. By the time you get to the final common pathway, you have vasodilation, you have vasopressor hyporeactivity and neutrophil aggregation and endothelial dysfunction. The endothelium doesn't know why it's sick. It just knows that it's sick. And the mechanisms of vasodilatory shock have a certain commonality, too. This paper is out from a review of Donald Landry in New England Journal of Medicine in 2000. And they were interested. This is early in the vasopressin era, and on the right side of the slide, you can see all the stuff about decreased vasopressin stores and decreased plasma vasopressin. That's more prominent in septic shock than in cardiogenic shock. However, if you look on the left, you have opening KATP channels by deficiency of ATP and inflammatory mechanisms such as nitric oxide to open KCA channels, and that affects cytoplasmic calcium and causes vasodilation. So you could see how at the basic level you might have a similarity between vasodilation from simply decreased flow in cardiogenic shock or a combination of decreased flow and inflammation in septic shock and maybe in septic shock and cardiogenic shock. So this paper, published out in Critical Care, is sort of a position paper looking at evidence for both microcirculatory and macrocirculatory dysfunction. I won't go through all of this, but just to show you sort of the basic, if you will, the ultimate concept of this is you got the macrocirculation on the left and the microcirculation on the right, and you have deterioration in both in cardiogenic shock. And down on the bottom, you got treatment strategies, and maybe you have some that mostly work on the microcirculation on calcium and nitric oxide, and maybe revascularization is mostly macrocirculation, but even revascularization has some microcirculatory effects, and the support and the balloon pump and the butamine, they have effects both on the macrocirculation and the microcirculation, suggesting, again, at some ultimate level, at least similarities in pathogenesis. So and you saw this three-axis model just in the last talk by Dr. Jentzer. And it's in the cardiogenic shock patient. It's part of the SkyShock paper and the SkyShock paradigm, but I'm not so sure that it doesn't apply to all sorts of shock. I mean, think about it. You've got the shock severity as a dependent of outcome. You have the phenotype and etiology. This particular phenotype is specific to cardiogenic shock, but you can imagine there are different phenotypes of septic and other forms of shock. And then you have risk modifiers. Cardiac arrest is often arrhythmic in cardiogenic shock, but you have organ failure and systemic inflammatory response and frailty. So the title of the talk was Separated at Birth. By the way, you did know. You have seen this, right? This is where the title comes from. This is a whole book of people who look like they're separated at birth. What you have in the big picture is Mick Jagger and Don Knotts and George Shultz and the Cowardly Lion. So are they separated at birth? Well, not so sure. You have stages of shock. You have compensated shock, tachycardia redistribution of blood flow, but perfusion is maintained. You have decompensated shock, hypotension, oliguria, acidosis, and perfusion is compromised. And then you have irreversible shock, refractory vasodilation, and multiple organ failure. So I'm not so sure that cardiogenic shock are separated at birth. I think at some point, at some final level, there is convergence, maybe inflammatory mechanisms, but also mechanisms at the mitochondrial level. And that suggests a certain similarity in pathogenesis and also that strategies to treat shock may have a commonality across etiologies. Thank you very much.

cardiogenic shock

septic shock

inflammation

microvascular dysfunction

treatment strategies