Hi everybody, my name is Dennis, and I'm talking to you about shock today, which is a very large topic, but a very cool one, and super central to what we do as intensivists. This talk is divided into two parts. The first part has to do with reviewing core physiologic principles of shock, coming up with classification schemes for shock, and talking about the general management tenets for especially circulatory shock. I have no relevant financial or other conflicts of interest to disclose. For this first talk, we're going to focus on three areas. First we're going to go through relevant physiology, and by this I mean a fair bit of biochemistry, but it's not crazy, we're not memorizing enzymes. We're also going to talk about classification that arises directly from our review of the physiology and biochemistry, and finally we'll highlight specific forms of shock with emphasis on types of circulatory shock, and review the core tenets of their management. Take a moment and think about a single cell. This is a cell that has aerobic metabolism capacity, and it does stuff, right? So any given cell has to hold itself together, has to have a membrane, the membrane has to be intact, cells have to make stuff, the proteins that they are made of, as well as whatever proteins or other molecules are related to their function, and then they do things. They respond to stimuli, they cause stimuli, they work together, they send signals, whatever it may be. All of those processes take energy. The easiest thing in the world is for stuff to just fall apart and proceed to entropy. Anything that isn't moving towards entropy requires some source of energy to proceed. Like if you have to send sodium on to the outside of a cellular membrane, then you need some energy available to drive that process. ATP is the main store of energy, it's the currency that the cell uses essentially to purchase these functions, to be able to say, I want to make a protein, I want to have an intact phospholipid membrane, here's the payment for that. Cells need ATP to survive. This is one of those things that is so far in the distance of college and almost so obvious, but worth stating, because the cell has to actually make ATP, ATP doesn't just come from somewhere, you're loading these bonds with high amounts of energy so the cell can make use of it to drive these other processes. So what happens with glucose when it enters the cell is it's split through the process of glycolysis into two pyruvic acid molecules. So pyruvic acid or pyruvate can go into different places. The place we're really hoping it goes is towards the TCA cycle or the Krebs cycle or the citric acid cycle as you see here. And what that's going to do is produce substrate for entry into the electron transport chain, which in combination with oxygen can yield huge amounts of ATP. So what happens if you don't have oxygen around? Then pyruvic acid is not going to just enter the TCA cycle because all of these reactions are going to stall out and back up in terms of those previous substrates, right? I told you we're not going to be remembering specific enzymes, but what you should appreciate is that an enzymatic reaction is not going to proceed to as great a degree if there is a smaller gradient of concentration for something. So that is to say, you're not using the pyruvate, so you aren't going to make more of it. You've got to do something with it, though, because you need to regenerate those other substrates to keep making ATP. So what you do instead is you proceed to make lactic acid. That process of making lactic acid does yield some ATP, not much. It's only a small percentage of what you were getting from aerobic metabolism, but it keeps the cell going. Now you have this lactate around. What are you going to do with that? Lactate that's produced in the cell is going to leave the cell, okay? It's not just going to stick around. Through the circulatory system, that lactate is going to end up in the liver, and the liver can do something that these other sort of tissues can't do. The liver can perform gluconeogenesis, and gluconeogenesis is the process by which glucose is generated, right, as opposed to consumed. This takes energy. It actually takes more energy to complete gluconeogenesis than you get from the anaerobic metabolism that's taking place in the other tissues. So you pay a price. You can't keep this going forever. As an aside, the other thing that happens when you don't engage in oxidative phosphorylation is all those protons that were sitting around to become electron acceptors and take oxygen and turn it into water are also just sitting around. They end up pouring out of the mitochondria and acidifying the cytoplasm. So now you're going to get tissue acidosis, the more that you rely on lactic acid production and not on aerobic metabolism. So what's the result of all this? The cell, remember, is trying to hold itself together, it's trying to make some stuff, it's trying to do some stuff. It's not able to do that as well if it doesn't have as much ATP. So over time, as you start failing to maintain these processes and accumulating potentially harmful substrates, things start to go wrong. And at first that's things just loosen up and don't work as well. But eventually you get disruption to the actual cell membrane, leakage of things that were in the cell outside, leakage of things that were outside into the cell. That causes the cell to swell. That causes the cytoskeleton to change conformation. That messes with the function of proteins, and so on and so forth. Now the cell is just going into a spiral of big problems because it doesn't have enough energy to pay for all the things that it wants to do. That ends up with cell death. So without sufficient ATP, cells die. If enough cells die, tissues and organs are going to die. If enough organs die, guess what? I don't think I have to do that much work to convince you that oxygen is important. The other factor we have to consider is how do we actually get oxygen to the cells? So when we were single-celled organisms, it wasn't really a big deal because our surface area-to-volume ratio was much higher. And so oxygen could just diffuse into those single-cell eukaryotes from the environment and be utilized where it needs to be utilized. As we became multicellular organisms, we actually needed to evolve circulatory systems to allow oxygen to be brought in closer proximity to individual cells and allow oxygen to diffuse down its concentration gradient. So we have a circulatory system into which oxygen is dissolved, yes, but then we also do have a special mechanism for carrying even more oxygen in the form of erythrocytes and hemoglobin. We can get the oxygen into the blood. We need to move that oxygen-loaded blood towards close proximity to the tissues and cells of interest. We need some sort of pump to do that, and we need to circulate the blood. As mentioned, oxygen is going to diffuse from the blood into the target tissues following its concentration gradient. Hopefully everything that I described in words there makes sense, is plausible for the behavior of oxygen in these tissues. Now I'm just going to substitute a few terms, and then we can proceed to put stuff in things that look like math equations. So when I talk about loading oxygen into the circulatory system, I'm talking about oxygen content, or CaO2. When I talk about circulating oxygen so that it can be in close proximity to the cells, I'm talking about cardiac output. And then the product of these two things, how much oxygen, how much am I able to move that blood, that is oxygen delivery, or DO2. So we end up with this familiar, friendly formula that explains a critical concept. The delivery of oxygen to the tissues is a function of how much oxygen is in the blood, and then how much blood, in a minute, you bring to a given tissue. You're familiar with the fact that you need to multiply these formulae by 10. The reason for this is because it's converting the arterial oxygen content units to reconcile with the units of cardiac output, right? So cardiac output is liters per minute, DO2 is basically cc's of oxygen per minute. And so you need to get arterial oxygen content, which is otherwise, because of the way that we express hemoglobin, milliliters per deciliter to milliliters per liter. So you just multiply by 10 to go from deciliters to liters. The oxygen in blood, as we mentioned, can be dissolved directly into blood, but that's not very effective because oxygen is poorly soluble. As a result, we've evolved mechanisms to load oxygen onto molecules that are quite happy to bind oxygen, and then we shove a bunch of those molecules into a bag, and then we move the bag around, and oxygen diffuses where it needs to diffuse. That is what an erythrocyte is. Erythrocytes are way better at carrying oxygen than oxygen is at dissolving in solution. That's why you get this 1.34 number, right? You've seen this expressed probably as 1.31, 1.34, 1.36, 1.39, right? You know, the upshot is that pick your number, it doesn't really matter because you'll get a close enough answer that you'll be able to choose the correct Bord's response. But the reason for the variation is because there are different forms of hemoglobin, right? These other forms of hemoglobin don't have the same oxygen binding affinity. So hemoglobin A, just regular old hemoglobin, has a hemoglobin binding affinity of 1.39 cc's of oxygen per gram of hemoglobin. But because of the range and the differences and what kinds of hemoglobin you have, you get some number that's less than 1.39. So my number that you'll see me use is 1.34. Again, hemoglobin grams per deciliter, and then arterial oxygen saturation expressed as a decimal. So that is to say, if you have an arterial oxygen saturation of 94%, you would write 0.94. For the dissolved fraction, that 0.003 is the solubility coefficient of oxygen. And that's quite a bit lower than 1.34, right? So you multiply that by the partial pressure of oxygen in the arterial circulation, PaO2. I'm always happy when I get to talk about my favorite curve in all of physiology, which is the oxygen hemoglobin dissociation curve. So you've seen this throughout your medical and pre-medical careers. This is a curve that relates the partial pressure of oxygen in the arterial circulation with the degree to which hemoglobin is bound by oxygen and existing in its oxyhemoglobin form. You see that it's a sigmoidal curve, which is to say that there's a portion where the rate of increase is rapid, the slope is large, and then a portion where it flattens out. Notice that generally speaking, once your PaO2 is above 90 or so, you're going to be 100% saturated in most cases. And so to be more explicit about this, with a PaO2 of 100, 200, 300, 400, 500, in all of those circumstances, your arterial oxygen saturation would be 100%. But in contrast, when you go below a PaO2 of about 60, you enter the steep portion of this dissociation curve, where relatively small differences in PaO2 will yield a meaningful difference in the arterial oxygen saturation. Gotta talk about left shift and right shift of the curve. When we refer to the curve shifting, we're talking about the affinity for binding oxygen shifting. And so shifts to the right mean that for a given PaO2, the saturation will be lower. So where did that oxygen go? It went in solution and then it diffused down its concentration gradient into the cells. And so right shift occurs or is stimulated by conditions where oxygen unloading into the tissues to a greater extent would be useful. This includes acidosis. Remember what we talked about in terms of the various sources of acid production. This occurs in elevated temperature. And so a warmer site might indicate increased metabolic activity. Conversely, left shift means that hemoglobin holds on to oxygen a little more. And so at a given PaO2, the saturation of hemoglobin with oxygen will be higher. This happens in settings of alkalosis, like for example, might exist in the lungs because you're constantly blowing off CO2, for example, and when the temperature is cool. So this is like my single favorite physiologic pair of effects, which are the Bohr effect and the Haldane effect. So the Bohr effect simply stated is when hemoglobin binds more carbon dioxide, it releases oxygen. It's binding affinity for oxygen is lowered. And so with the release of oxygen that it's available to diffuse down its concentration gradient, there's more CO2 in the periphery in the tissues because of active aerobic metabolism. And so oxygen is being released where there's more CO2, which would be the most metabolically active tissues. That is so elegant and it gets better. So there's all that CO2 in the tissues that binds to hemoglobin actually is a meaningful proportion of the total CO2 content of the blood. But what happens when this blood gets to the lungs, where now there's a gradient for diffusion of oxygen from the alveoli into the pulmonary circulation, as that hemoglobin binds more oxygen, it actually lowers its binding affinity for carbon dioxide. So now carbon dioxide is being released in the alveolar capillary interface. So it can diffuse out down its concentration gradient into the alveolus and out the airways. That is a beautiful combination of effects that allows for continuous oxygen loading in the tissues and carbon dioxide unloading from the tissues. Gotta love that. Let's think about the other piece of oxygen delivery. That's cardiac output. So you've got some amount of oxygen and some amount of blood, and you're pumping some amount of blood to the tissues over some unit time. That's basically DO2. So for the pumping some volume of blood over some unit time part, we want to think about what's the volume of blood, and then how many times in the unit of time are we pumping that volume of blood, right? That's what is expressed here. Take the stroke volume, multiply it by the heart rate. That's your cardiac output, expressed usually in liters per minute. In clinical practice, it's common to index cardiac output by dividing it by body surface area, and this is expressed with the abbreviation CI, or cardiac index. So if you see index used for something, what that generally refers to is dividing by body surface area to provide standardization across patient sizes. You're used to writing things like cardiac output equals heart rate times stroke volume, but if you really sit with the concept of stroke volume and say, well, what's the mathematical equation that explains stroke volume? Stroke volume is actually an end result that arises from an interplay among three independent sort of factors. The first of these, or just a place to start, is preload, by which we mean what is the volume in the chamber of interest? So when you're usually looking at pressure volume loops, they're usually LV pressure volume loops. So in this case, we're talking about left ventricular end-diastolic volume. And that left ventricular end-diastolic volume is associated with an end-diastolic pressure depending on the properties of the left ventricle and the heart in general. There's also how well the heart squeezes. That's called contractility. And then there's the downstream pressure that the heart has to overcome in order to move the volume of blood forward. That's afterload. The Frank-Starling relationship basically says that stroke volume varies in relation to left ventricular end-diastolic pressure. Like, in most cases, if you give preload, your subsequent stroke volume will be larger. The degree to which the stroke volume is able to be larger as a function of increased preload is dependent on the contractility and the afterload. The middle red dashed line, you can think of as a normal curve. If we take one point on this curve and we look at where we are on the x-axis, then that's our preload. If you follow this curve up and over, it changes a fair bit. We start off at, say, 10 or 15 cc's of stroke volume all the way at the bottom, that lowest end-diastolic pressure. And then we end up potentially as high as 80 cc's at that highest end-diastolic pressure, close to 20. If we make the heart squeeze less well, or we increase the downstream pressure it has to overcome to move blood, then we're not going to achieve as high of stroke volume for a given end-diastolic pressure, right? And we end up on this yellow line here. In contrast, if we make the heart squeeze harder, if we reduce the downstream problems that it has to overcome, then we can actually end up with bigger stroke volumes, things to consider in clinical management, as we will discuss. So we've talked a lot about oxygen delivery, what it is, what's in it, how it's accomplished, but how do we know when enough is enough? How do we know the right amount of oxygen to deliver? Ultimately it just needs to satisfy cellular demands, right? So if the cells can do what they need to do, it's enough. Turns out in normal physiology, the DO2 is usually two to three times the VO2. This is why when you're in the unit and the code bell goes off, you can get up and go running and you don't develop shock, like you just compensate because you have plenty of available ability to change and upregulate your oxygen delivery. Heart pump faster, you breathe faster, so on and so forth. So here's DO2 on the X-axis, VO2 on the Y-axis. For a certain portion of DO2, at the lowest portion, the amount of VO2 that can be supported is solely determined by the DO2. And we call this supply dependency, right? So a VO2 above this sort of line of supply dependency can't be accommodated at that DO2. Then you reach a point where the cell just isn't trying to do anything more, it's doing everything that it wants to do. And at that point, any further oxygen delivery doesn't yield a change in the oxygen consumption or the activity of the cell. And we call this condition supply independency. You notice that there's this inflection point between the place where VO2 is supply dependent versus where it's independent. We call that the critical DO2. One way that this is relevant is that as you become limited in the delivery of oxygen, you become limited in the ability to produce ATP and you're gonna shunt more into anaerobic metabolism and lactate generating pathways. And so below this critical DO2 is when you can expect to see lactic acidosis starting. And we'll be talking about other things about comparing the arterial and venous circulations, but just remember this concept about critical DO2. If you're over here, everything's good, you're happy, functioning well, let's say that you get some sort of respiratory virus, you're laid up, it's a big bummer. And you're not functioning as well, but you're okay, right? Like you may be tired, maybe your heart rate's a little higher, you're maintaining, you're not in any sort of danger, you know what a sick person looks like. But what happens if in the course of disease, you actually have a fairly significant increase in your metabolic demand, in your oxygen consumption, right? Well, when you're good, stuff's good, right? So this is why you can exercise and do stuff like that. But when you're sick and you have high demand, it becomes easier to progress into this area of supply dependency, right? It is a lower threshold to be supply dependent for a given DO2. This is a set of concepts. The point here is not that you generate this curve for your patients. The important principle to take away from this is that there is a certain necessary amount of oxygen delivery to ensure cells are capable of doing what they want and need to do. We will talk about the fact that cells may be getting as much DO2 as they could need, but they're not doing what they ideally would be doing. That's a very hard problem to solve, but we are more oriented towards making sure we get the oxygen into the body and make sure it goes to the right place. Let's talk more about this VO2 concept. We talked before about cells needing to consume energy to drive a bunch of important processes, holding themselves together, doing stuff, things like that. The more they're doing, the more oxygen they're gonna require. That kind of makes sense, right? When you think about the blood that's entering a tissue bed and that blood carrying oxygen, as oxygen diffuses down its concentration gradient into those tissues, the oxygen content of the blood leaving the tissue, in other words, the venous blood, is going to be lower. If we know what was going in and we know what came out, then in a closed system, right, with conservation of mass, we know that that oxygen has to be in the tissues. And so that represents tissue extraction. So VO2 is expressed as the cardiac output multiplied by the difference in arterial versus venous oxygen content. That's pretty cool, because basically we can measure these things. We can measure hemoglobin. We can measure arterial and venous oxygen saturation. Cardiac output, we can measure that too, you know, in various ways. And then we can actually figure out what VO2 is. Thank this dude for that. So there's other conceptual mathematical ways that you can kind of relate these concepts of oxygen extraction and oxygen delivery. And one of the ones you see come up a lot is the oxygen extraction ratio. And that's, as you see here, just the oxygen extraction divided by the oxygen delivery. If you think about what we said before, in normal physiology, if the DO2 is two to three times the VO2, then you figure that this ratio is probably around 0.3. And in fact, it is usually around 0.25 or 0.3. So as you know, to calculate these things, you need the cardiac output, you need the hemoglobin concentration, the oxyhemoglobin saturation, the PaO2, that's fine, you can get those things in an ICU. You can also just look at the biggest term that differs between these, which is basically the arterial and venous oxygen saturations. And what do I mean by that? Basically, if you think about arterial oxygen content and venous oxygen content, they're the same circulatory system, right? And so cardiac output's gonna be the same term for them. You haven't changed your hemoglobin level from the arterial to the venous side. You have the same binding constant for hemoglobin oxygen binding affinity. So you save yourself some math. It is an approximation, because especially at extremes of those other values, which we're just saying, oh yeah, they're the same, then the differences might be more significant. But the important thing to take away here is that a bigger oxygen extraction ratio or a larger difference between arterial and venous oxygen saturation suggests that more oxygen extraction is happening at the tissues. It doesn't exactly tell you why more oxygen extraction is happening at the tissues, but that's what you need the rest of the clinical context for, right? It could be due to inadequate delivery, which is kind of what we've been talking about so far. It could also be due to increased demand when there's metabolic derangements and now VO2 is pathologically elevated. That also can result in a larger AVO2 difference. In every shock talk, there has to be a seesaw. So here's the one for this talk. And on this seesaw, you see DO2 on the left and VO2 on the right. And here we're looking at a list of some global factors that can either increase or decrease VO2. Why is this useful? Because when you're faced with a patient who's not doing well, run through this stuff. If you think you have shock, then think about how you can reduce demand. You can sedate patients, you can ventilate them. Paralysis, actually, if a patient is well-sedated has not been well-demonstrated to further reduce metabolic demand, but for sick patients, you might wanna think about it. And certainly for patients who are shivering or things like that, you definitely wanna be thoughtful about the pretty significant contribution of musculoskeletal activity to oxygen demand. Hypothermia, a complicated topic in and of itself. From a first principles standpoint, it makes sense that if you lower an individual's temperature, you lower the overall metabolic rate of many processes. But as you know, the evidence base for this in different applied contexts is heterogeneous. Solely from a first principles standpoint, one can make the statement that it makes sense that you have less oxygen utilization when you're colder. Deep hypothermic circulatory arrest is the most dramatic example of this. We're just going to lightly brush on the fact that all of the things that we've been describing, we've had this underlying presumption that there is some sort of representative global value for each of these things. But the truth is that a body is made up of many tissues and organs, and all of those tissues and organs have different metabolic activity rates, and they have different responses to stress. All of this is to say, the parameters that we tend to look at are global and are essentially, you can think of as weighted averages towards one or the other sort of locations here. As an example, if you're reading a venous saturation off a line situated in the mid SVC, then it may be something like in the low 70s. But if you're reading that mixed venous off of a femoral line, it may be higher. And how you interpret that has to also be weighed with other factors in the patient context. But it's important to know that there is regional variation, and this is to say nothing of microcirculation and the influences at a tissue or cellular level. So here's a little twist on the old Fick equation, right? By which we were able to calculate VO2. If you have, or if you assume you have a VO2 value, then you can also calculate cardiac output. Now, in practice, we already talked about the fact that you can measure hemoglobin, arterial and venous oxygen saturation. VO2 is kind of a pain to measure because you need to know the oxygen going in. Okay, that's fine, you can control that. You need to know the oxygen coming out, which if you're going to do with say, mixed exhaled gas requires you to collect those gases for a period of time, usually a minute. And that's kind of a pain and can't always be accomplished. So instead, there are these old studies that provided norms based on sets of patients, most of whom weren't ill. And basically based on age and heart rate, for the most part, you can look up on a VO2 table what an estimated VO2 would be for such an individual. This is clearly a limited and in many ways, flawed approach to estimating VO2. And therefore cardiac output is also significantly limited in its precision, shall we say. It doesn't mean it's not useful to do this. It just means you have to understand how big of a deal the assumptions might be and in particular, how much those assumptions might deviate from your actual patient's condition. So let's see how this actually looks in a worked example. Let's consider a two-year-old patient who's admitted with ARDS and flu and super infected MRSA. At this point in time, her heart rate's in the 130s. She's breathing in the 30s on a ventilator. Her blood pressure's okay, her SAT's 90%. She has a hemoglobin as you see, ABG with the values as you see in a mixed venous saturation of 70%. For her purpose, why don't you assume a VO2 of 110 cc's a minute? And for the simplicity of the math, ignore the dissolved oxygen contribution to arterial oxygen content. How can you get to cardiac output? All right, so we said that cardiac output is VO2 divided by the difference between the arterial and venous oxygen content. And if we plug and chug, put some numbers in here, I told you to use 110 for the VO2. 1.34 is our memorized number for hemoglobin binding affinity for oxygen. 12.1 we were given up there. 0.9 is the decimal expression of the arterial oxygen saturation, the SAO2 and the blood gas. Remember that arterial oxygen sat on a blood gas is generally more accurate than a pulse ox saturation, especially for low values of arterial oxygen saturation. For the venous side, we use the same oxyhemoglobin binding affinity. We use the same hemoglobin concentration and we use 0.7, the decimal expression of the venous oxygen saturation. We have that multiplied by 10 there so that we convert to the appropriate units so that all the units reconcile in the end. And then if we just finish out that math, what we get at you see at the bottom, 3.38 liters per minute. We can actually now anticipate types of shock or sources of problems that lead to shock arising directly from this physiologic framework that we've developed. We've talked about DO2 and we talked about VO2. For the DO2 side, hypoxic shock is just another way of saying you don't have enough oxygen going to the tissues. For anemic shock, if you don't have oxygen carrying capacity, then you're not able to bring enough oxygen content to the tissues and that can progress to shock. So this might occur, say, in someone who has significant hemolysis, for example, in the setting of a hemolytic transfusion reaction or in the setting of certain disease processes or malignancy, or hemorrhage, for example. Circulatory shock is often what people go to first when they think about shock. There is this very substantial coupling of hemodynamics in people's minds with shock, but as this sort of classification, what it helps you to remember is that hemodynamic reasons for shock are only one of a set of reasons for shock. And finally, and most challengingly, is histotoxic shock. So this actually, although we've listed it as a DO2 side problem, is really not a DO2 side issue so much as it is a cell function issue. This refers to the situation where the cell is actually just not capable of utilizing the oxygen that's around, and so actually its oxygen extraction might be significantly diminished. And this still leads to problems, it's just way harder for us to fix because even if we do deliver a whole bunch of oxygen to that tissue bed, it's not able to make use of it. This usually leads to irreversible shock and is a bad problem. So hypoxic shock, as we said, not enough oxygen in the blood being delivered to the tissues of interest. This happens if the lungs are not good at loading oxygen into blood due to V-cubed mismatch, diffusion issues. This occurs when there's right-to-left shunt, such that blood does not have an opportunity to participate in gas exchange, then you are essentially bringing the venous saturation back to the arterial side. This also does happen if the inspired partial pressure of oxygen is low. Altitude is one setting in which the partial pressure of inspired oxygen is low. This is why in extremes, for example, mountain climbers, they bring supplemental oxygen. So here, arterial oxygen content is low because arterial oxygen saturation is low. As with other types of shock, there's a compensatory increase in cardiac output so that you can circulate blood with oxygen in it to the tissues to the best degree possible. If you maintain in a chronically hypoxemic state, among the different adaptations your body undertakes in addition to that increase in cardiac output is an increase in erythropoiesis. And so your red blood cell mass increases such that you can try to improve arterial oxygen content through increasing the hemoglobin concentration. There's many different rules of thumb that are available for what is a problematic level of hypoxemia. I think in general, if you are seeing a PaO2 less than 30, you can be certain this patient is going to be experiencing some degree of compromise. They're certainly not going to be able to upregulate their activity acutely. So anemic shock is now talking about the red blood cell mass side of things. Here, even if every single red blood cell in the circulation is appropriately saturated, there's just not enough of them. And remember, the bound fraction of oxygen is the major determinant of arterial oxygen content in most cases. If you have loss of red blood cells, inadequate production of red blood cells, both, then you can end up with not enough to provide the critical DO2 like we talked about. So again, maybe 100% saturated, but still below critical DO2 because you just don't have enough arterial oxygen content because the bound fraction is low. Here, we actually need to make sure to pay attention to the dissolved fraction of oxygen because proportionately, your total arterial oxygen content is now much more independent on that. And so even though solubility of oxygen remains low, if you drive a large enough gradient of oxygen, you'll get some to diffuse in. And so this is where you might have the patient who comes in with a hemoglobin level of 2 or 3. And you put them on supplemental oxygen, even though they're 100% saturated because you want the PaO2 to be as high as possible. This is also a patient in whom you need to think about the VO2 side, reduced demand. So these patients very commonly have a compensatory increase in cardiac output, as we talked about, similar to patients with hypoxic shock and many other kinds of shock, when possible. Cardiac output will be increased in order to increase the oxygen delivery to the tissues. To have another number to start with, a hemoglobin less than 5, similarly, you should consider the patient at continuous risk of experiencing an acute problem from a critically low DO2. Does this mean that everybody with a hemoglobin of 2 is going to arrest? No, right? Some patients develop severe anemia over enough time that other compensatory mechanisms establish. Kids are really robust, frequently able to upregulate their cardiac output. And so, similarly, you can be surprised at how well patients can tolerate this. It doesn't mean it's not high risk. It doesn't mean that they're not at continuous risk of some acute thing happening. So got to respect it. At some point in this lecture, we have to talk about types of circulatory shock. You've all seen tables something like this that have arrows going up and down for cardiac output and SVR and things like that. So you do have to have some sort of working understanding that such classification schemes are appreciated by people. But it's super, super, super important to remember that these categories in patients are not mutually exclusive. Patients can have more than one problem that is leading to shock. It's helpful to think about these patterns so that we can think about how they might manifest in a given patient, and therefore how we might recognize and the major point being address them. But don't get overly anchored on the importance of selecting the correct classification of shock. The important thing to do is to recognize that shock is there and deal with it appropriately. Hypovolemic shock or inadequate circulating volume can occur either because you're not getting enough volume in or because too much volume is going out. What you usually see is a low CVP and low cardiac output. Sometimes compensatory mechanisms, especially in children, can be so robust that the cardiac output is not necessarily that low, but you still might see signs of stress on an organ function level. Usually the SVR is increased as a compensation. If it's not, that can also add to the problems of hypovolemia, both in terms of maldistribution of cardiac output as well as venodilation and increased venous capacitance serving as a sink for whatever volume you do have there. So what do you do about it? Stop the losses and fill the tank, right? So if the patient is bleeding, control the bleeding. If you can stop the GI losses, then stop the GI losses. If the patient is losing blood, remember that you should be giving red blood cells and the coagulation and clotting factors, especially if there's a large amount of blood loss. And accompanying especially large volume resuscitations, you can get electrolyte derangement. So anticipate it and deal with them. Cardiogenic shock is a pretty complicated topic in itself because there's a lot of ways that the pump can have problems. Classically, people are talking about a situation with low cardiac output, high CVP, because basically you have stagnation and the blood is not able to move forward very well. This can also be associated with high SVR as a compensatory mechanism to just drive afferent blood flow. One of the biggest things to look for and to be alert for is an increase in this ABO2 difference that is very common in cardiogenic shock. Another phrase that's used is stagnant shock, and this I think is really evocative of the notion that the blood is just not moving as robustly as it should, and so therefore the tissues have no choice but to extract more oxygen. Remember the determinants of cardiac output, and also remember the other things that matter for the heart. A heart that contracts okay but has an abnormal rhythm might have a poor stroke volume. Also, the presence of things like valvoregurgitation or shunts may decrease the efficiency of even a well-contracting heart, and over time, volume loads, for example, can lead to dilatation and further worsening. But in the acute situation, what do you do? You want to optimize preload because if the left ventricular end-diastolic pressure is too high, you're not going to get more stroke volume. You're just going to drive back pressure into the pulmonary vascular bed. That's where you get your pulmonary edema, your left atrial dilatation. It's not helpful, so you want to optimize the preload in relation to the available contractile state, and then you want to also think about the afterload, right? Because even if the heart is not contracting very well, if you reduce the downstream resistance to it emptying, you're going to get a larger amount of emptying. In other words, a larger stroke volume. The end-systolic volume is going to be lower, and so what you see on this bottom graph is that you start off with a relatively small difference between the end-diastolic and end-systolic volumes, and here you haven't changed the contractile activity of the heart at all. All you've done is reduce the resistance to downstream flow, and what you see is that progressively from beat to beat, the left ventricular end-systolic volume is lower. The left ventricular end-diastolic volume is not that much different, right? But the end-systolic volume is much lower because you drop that afterload, and the stroke volume, which is the difference between those two, is larger. So this is just a illustration of the importance of managing afterload, particularly for patients who have poorly contractile hearts. For patients with healthy hearts, they can tolerate more afterload. You don't see as dramatic an impact on stroke volume either of high afterload or afterload reduction within a reasonable range, right? So even a healthy heart with crazy amounts of hypertension, that afterload can cause problems. If you think about a situation like negative pressure pulmonary edema where there's very acute afterload on the LV, and that just causes that flash pulmonary edema, it's just an illustration of the concept. Even a healthy heart can experience that at extreme enough values, but the values are more extreme than they are for, for example, patients with congenital heart disease. Think of distributive shock in accompaniment with the term pathologic vasodilation. So the issue here is not necessarily that you don't have sufficient cardiac output. It's that it's not going to the right places. In this case, you would want to make sure that organs like the brain and the heart and the kidneys are well perfused, but if you have significant vasodilatation of a large vascular bed like, for example, the skin, that's going to serve as a sink for the available cardiac output. So these patients, although they may have a normal or even high cardiac output, especially if compensatory mechanisms are activated, are characterized by low SVR and usually low CVP, but that can vary. Again, the problem here is maldistribution of cardiac output due to vasodilatation. So the management of this acutely is going to include giving volume for patients who are showing overt signs of shock. You're going to administer agents that will help increase the SVR, and you're going to deal with if there's a primary cause of this problem, such as exposure to an allergen, by giving things like epinephrine or other agents. Obstructive shock is what we call it when the heart is not actually able to either receive volume that it can pump forward or pump forward due to some physical obstruction in either case. There's many different potential causes for this. Some of them are listed here. Remember also that significant vascular resistance can actually contribute to obstructive shock in terms of the phenomenon having to do with inability of blood to move forward still fits in this category. Examples of this might include pulmonary hypertensive crisis, really acute development of systemic hypertension. So in general, obstructive shock is going to manifest as a low cardiac output state where there's back pressure detectable, and so in the case of, say, massive PE, you might actually have a very high CVP because of acute right ventricular dilatation and failure. As far as obstruction on the left side, let's say you had critical AS and you had obstruction of left ventricular outflow, that back pressure absolutely could be transmitted back to the left atrium and to the pulmonary vascular bed. What you do about it is relieve the obstruction. That requires diagnosing or having a sufficiently high index of suspicion as to where the obstruction is so that you know what to go after. Neal decompressing? Are you doing a pericardiosynthesis? Bringing the patient to the cath lab? Are you pursuing something like TPA? All of these things would be on the table depending on the nature of the obstruction. We've saved sepsis for last on purpose because sepsis is a distinct clinical entity that can be very challenging to manage because of the variety of problems that can occur when you have a dysregulated host inflammatory response. Many taxonomies place sepsis in the distributive shock category because of the classically described, you know, flash capillary refill and bounding pulses of vasodilated septic shock. Working with kids, we certainly know it's the case that vasodilated shock is not the exclusive or even necessarily the common way kids in shock present. Sepsis is common, you know this. Sepsis is deadly, you also know this. Even though there was an update to the adult septic shock diagnosis guidelines which brought increased emphasis on organ dysfunction as opposed to just being infected and inflamed, technically we're still working with the expert consensus definition developed in 2005 by the IPSCC. And I've highlighted the salient points here as far as the terminology you can expect to see. SERS is a dysregulated distributed host inflammatory response. Sepsis is when you have SERS and a suspicion or proven infection. Severe sepsis is when you have sepsis and stuff's messed up. If the cardiovascular or respiratory system is among the things that are messed up then that's enough to classify severe sepsis. If neither of those things is messed up and you have two of these other ones, neuro, heme, renal, or liver, that's enough to call it severe sepsis. And septic shock is when we have cardiovascular dysfunction, certainly when we're doing things like using vasoactive agents, when we have lactate elevation, and so on. And so one thing to point out here is that you do not have to have hypotension to diagnose somebody with septic shock, right? If they are receiving support of the cardiovascular system or they have evidence of low cardiac output, they have septic shock. If you have a suspected or proven infection, of course. Pathophysiologically, this notion of the dysregulated and distributed host inflammatory response, that's really what we're talking about with the systemic inflammatory response syndrome. It's normal and appropriate for the body to respond with inflammatory stimuli to localized phenomena. There's some area where bacteria breach a barrier, there's a location where there's been trauma or disruption of tissues for one reason or another. Recruiting inflammatory cells to that location and allowing for control of these foreign invaders and subsequently repair of those damaged tissues, that's appropriate. That's good. That's good inflammation. But what happens with systemic inflammatory response syndrome is that you have activation of these same processes in areas where they're not warranted. And these inflammatory cells and the mediators they release in the form of cytokines or chemokines, which in turn the latter recruit more immune cells to the location, these inflammatory cascades being set off cause harm to tissues. To get more specific about the kinds of problems you can see in sepsis, one of the biggest categories of dysregulation is to the vascular endothelium in a distributed fashion. So the endothelium becomes leakier. There's more recruitment of immune cells as we mentioned. There's going to be activation of clotting and coagulation cascades because of the release and exposure of tissue factor. This is going to lead to micro circulatory thrombus formation and that's going to cause disruption to tissues to go organ by organ. This can manifest as myocardial dysfunction if it's the heart. This can manifest as disruption of the alveolar capillary interface if it's in the lungs. And at an extreme actually sepsis can be associated with ARDS as you know. This can lead to disruption of the gut barrier and bacterial translocation can further exacerbate the inflammatory process. In the liver this may be associated with worsened liver function in which case we're talking about metabolism and clearance of especially pathogenic lipids. This can actually also lead to worse inflammation because you're having more substrate for immune activation. In terms of the kidney it's probably not just perfusing pressure in sepsis that causes AKI. There are patients who actually maintain acceptable hemodynamics who still develop significant AKI. Very likely the circulating mediators that are carrying out these processes are also affecting the kidney in certain ways. In terms of the CNS you disrupt the permeability of the blood-brain barrier then you're going to get all sorts of sequelae in terms of brain function. To say nothing of the fact that inflammatory processes in the brain itself can be very disrupting. In terms of effects to the marrow or the hematologic system one of the most interesting areas of active sepsis research has to do with immune phenotypes or the categorizable behavior of people's immune systems in response to infection. Because inflammation at some point has to be accompanied with a counter-regulatory response, which is in effect an immunosuppressive response, the magnitude and duration of that immunosuppressive response is a potential source of variation in terms of outcomes following sepsis. When we're talking about organ dysfunction it's really important to recognize that the age-related variability and what constitutes normal is a big complicating factor in the pediatric domain moving towards rigidly defined thresholds for degrees of severity of organ failure as you've seen happen in the adult sepsis definitions. Nevertheless there are thresholds that are provided and you'll notice that many of the thresholds are provided as age- related norms as well as provided as changes from baseline for an individual patient. And you see this reflected in things like the SOFA score as well and so I think this is sort of sensible and will likely appear in the next iteration of pediatric sepsis definition which is being actively worked on. Okay so frequently in didactic settings like this we pay a lot of attention to terminology and definitions and making sure that we have clearly explained the difference between like sepsis and severe sepsis and SERS but you know from your clinical practice that the really important thing to do is recognize that sepsis is occurring in patients so you can do something about it. Picking the right term for what the magnitude or severity of their sepsis is is definitely not the priority compared to saying this patient needs prompt management and there are specific goals I should be moving towards to maximize their chances of a good outcome. As pediatric intensivists it's necessary for you to be aware of the latest state of the consensus relating to how we should be treating especially very common diseases like sepsis and so we look to the surviving sepsis campaign guidelines that were updated in 2020. This is the pediatric version of those guidelines. One thing to recognize about these guidelines is that they're trying to be helpful to as many people as possible and so what you see as a result is a very broad basis of potential context for where you might be implementing these guidelines. You'll especially see that on the next slide. My takeaway from this slide is that it's really not that different from the ACCM PALS guidelines that preceded this set of guidelines. Recognize that sepsis is there. Have some sort of systematic way of doing that you know recognition bundles sepsis huddles things like that. Once you decide that sepsis or septic shock is present you've got some time-sensitive priorities to achieve. You need to get source control on board right that's the start empiric broad spectrum antibiotics. You gotta tend to your ABCs. You gotta get access. Ideally you're getting a blood culture so you can actually make a diagnosis narrow your broad-spectrum antibiotics but ultimately you're prioritizing administration of antibiotics and support of the ABCs. Lactate is a well recognized marker that tends to go up in patients who are sicker with sepsis and tends to go down as you are managing sick patients with sepsis and so it can be useful in context of your entire clinical assessment. In terms of therapeutic imperatives the two things you see here are the same things you saw in the ACCM PALS guidelines. Give fluid boluses, start vasoactives. One distinction here is that they're essentially presented in parallel as opposed to in series so the ACCM PALS guidelines had this more on the order of give fluid, give fluid, give fluid. Fluid's not working, start pressers. Start another presser, pressers are not working, think about giving steroids. Steroids are not working or you didn't give steroids, think about ECMO. Here you're kind of seeing everything presented in the same tier and this I think is actually more reflective of clinical reality which is we're doing all these things all at the same time. I think another benefit of this modification is that you're thinking about fluids and vasoactives in parallel. You're not necessarily gating vasoactives behind some threshold of fluid and I think we should always be emphasizing what the response to our interventions is in terms of deciding what the next step should be. So if you give fluid and nothing happens then your two possibilities are either you didn't give enough or fluid is not the solution. You give more fluid and things get worse, now you should be thinking okay, fluid clearly does not seem to be the solution, it's time for me to move on to something else, start vasoactives. These guidelines do not recommend the 20 per kilo, 20 per kilo, 20 per kilo. They recommend frequent reassessment and thinking about starting with the volume of 10 per kilo. That should be dosed as ideal body weight. One thing we have to point out here is how steroids are represented. Plus minus steroids for refractory shock. Hydrocortisone may produce benefit or harm. This is basically just a statement of the state of the evidence at the time that they developed these guidelines. This is unfortunately not particularly helpful in terms of whether you should give steroids to your patient but it is at least intellectually honest and the truth is that in pediatrics there's evidence that you could construe as supporting the use of steroids and evidence you could construe as being against the use of steroids. In terms of the fluids and the vasoactive management for kids, there's a couple of differences from the ACC and PALS guidelines. The first difference is that you see there's this distinction between whether you're working within a healthcare system that has access to critical care versus not. Healthcare systems without access to intensive care does not mean your particular hospital does not have intensive care services. It means that you cannot plausibly send this patient to a pediatric intensive care unit. That is generally not the case for most regions within, for example, the United States. If you are in a setting with access of some kind to intensive care, even if that's not a different floor of your particular healthcare institution, then what that means is you can support patients in greater degrees of respiratory distress or failure and you have more technologies available mechanical ventilation, reliable oxygen supplies, monitoring both non-invasive and invasive, skilled personnel, so on and so forth. The other factor about these settings where these various intensive care resources may be available is that there are different patient demographic factors, especially relating to nutritional status and endemic diseases. And so if we look at the green side, this is healthcare systems without intensive care. The upshot here is that you're going to be very, very judicious in giving bolus fluids. You're going to give bolus fluids if patients have obvious losses of large amounts of fluid. You're going to give fluid boluses if patients are obviously very hypotensive, right? But otherwise, you're not necessarily going to give fluid boluses. You may give fluid, but you're not going to necessarily bolus it. And this is mostly on the basis of what's called the FEAST trial, which was performed by Kath Maitland and her group. This was a really well-designed, rigorous, prospective study, which sought to evaluate the impact of bolus fluid management for children presenting in shock in sub-Saharan Africa. And these figures tell a really important story, which is that the patients who got bolused with volume did worse. They died more than the patients who did not get bolused with volume. And so this is the main study that has led to the circumspection that you see introduced in terms of the current surviving sepsis campaign guidelines. I think that this is appropriate because this is the best data that we have for this population. And so with that in mind, we should consider it and potentially practice differently. It's, again, a well-designed, well-powered trial with very clear differences in the outcome of interest. So we've taken a great tour through recognition, classification, pathophysiology, all these things of shock. But now we got to get down to actually caring for a patient who has shock. And before that, we have to even recognize that a patient has shock. How do we do that? What are some things that can assist us there? And how do we know that we're winning? That's going to be the topics of the next talk. All right, so the second part of this talk is about recognition and monitoring of shock. So we know why shock happens. We know what's involved on a molecular level. We appreciate the patterns of pathophysiology that we can see. But now we actually have to make sure we recognize shock, and we have to deal with it, and we have to see if we're winning or not. And monitoring basically helps us both to pick it up and to deal with it. I still have no relevant financial or other conflicts of interest to disclose. So in terms of monitoring, it may feel a little unusual to see vital signs and clinical exam here. But these are the monitor you can apply any time as often as you want. And you can learn quite a lot from them. And then we do have to talk about data that you can get at the bedside. You guys are all familiar with the incredible variety and volume of data that you receive in an ICU. But you need to be able to hone in on some things that can tell you something you can act on. And so in the case of shock, we're going to look at three potential measurements or monitors that can tell you things about the nature of your patient's shock. And those are lactate, SVO2, and NEARs. Think about shock of any kind. There's usually a period of time where the patient is not totally in a normal condition, but all the different organs are working, they're making urine, their mental status is okay, they're not distressed, their human dynamics are okay, right? But something's wrong, something is affecting them. We call that compensated shock. Then you cross over into a situation where now you're starting to see some dysfunction, you're starting to see some biomarker elevation, you know that organs are actually getting affected by the DO2 VO2 imbalance. That's called uncompensated shock because that means increasing cardiac output, redistributing blood flow, attempting to increase oxygenation didn't help enough, right? And now organs are actually experiencing supply dependency. If you let that go on long enough, and as we talked about before, if enough cells fall apart, that the organ starts to fall apart, you can enter a situation where even if you do deliver oxygen to all of those cells of the body, it doesn't matter. They're not able to function anymore. Things have gone too far. We call this irreversible shock. We're really trying to avoid this because we're trying to avoid situations where patients are at risk of dying and patients with irreversible shock are at very high risk of dying. So vital signs are vital, right? This is something that I remember hearing in medical school, and I still strongly believe the way to leverage vital signs to their greatest benefit is not just to think of them as a point estimate of some phenomenon, but to look at their trends over time, right? And so your institution may have different options for doing that, whether within the EHR, or via third party tools, things like that. At our institution, we have a tool called T3. T3 allows us to basically graph various parameters over intervals of time that we specify. And just visualization like that can give you so much insight into patterns of things that are happening. So strongly encourage you actively evaluate trends of vital signs in your patients. It's also important to just be straight up about what the clinical exam of somebody in shock looks like. Because those hungry organs, those organs that have high oxygen extraction, or those organs that are very dependent on afferent perfusion, in the case of the kidney, you're going to see those start to alter first, and you're going to see cardiac output increase in response. And then you reach a point where stuff is not going well, body's not working well. And that's where you start to see derangements of organ function. Hypotension is a derangement of the cardiovascular system's function. And kids are pretty robust, they have pretty significant ability to compensate with increases in cardiac output in the setting of stress and so if a kid is in shock and hypotensive they are super sick. So you got to respect that and you got to address it. Continuous monitoring of these vital signs and frequent reassessment in terms of the clinical exam allow you to assess whether things are going well or not going well and if they're not going well in what ways are they not going well. So never let go of just straight up going to your patient's bedside looking at them and looking at the monitors you will learn things and those things will help you make better decisions. All right mixed venous oxygen saturation you're all familiar with this from your clinical practice usually you're interpreting this in the context of somebody who has an IJ central line and is being managed for shock or maybe you're in the cardiac ICU and the patient is post-op from a congenital heart surgery and you're monitoring this along with other sort of pressures and saturations but regardless mixed venous oxygen saturation is the saturation of the blood that returns to the right side of the heart. Once all of the different sources of systemic venous circulation join together in the right ventricle and get ejected to the pulmonary artery that's mixed venous blood. So when we were talking about the Fick principle and oxygen extraction of the tissues and the AVO2 difference the wider that AVO2 difference the lower the venous oxygen saturation is then you can extrapolate that cardiac output has been impeded to some significant degree. In terms of where you're acquiring a mixed venous oxygen saturation the location matters we talked about regional circulation we talked about differential oxygen consumption by different organs and so you can imagine that where you draw this sample is going to affect what the oxygen saturation will be because if it's coming from the IVC blood the organ extraction may be lower and so the venous saturation may be higher but it may not be representative of what's going on in the head and the upper third of the body and so usually the SVC sat is what you're obtaining in the ICU. If you're in the cath lab you're using the PA saturation because everything is definitely mixed by that point that it's going to the lungs. There's lots of caveats you have to think about in the cath lab as far as interpreting saturations and the presence of shunts but for the most part we're not sitting in the cath lab doing this we're sitting in the ICU managing someone with shock looking at mixed venous saturation using the SVC sat as a proxy. This figure that you see on the right is nice just to have some sense of how this relationship between mixed venous saturation and cardiac index may look. The big takeaway for me from this figure is that it's nonlinear and so you know that there is a degree of direct correlation between change in mixed venous saturation and change in cardiac output but you don't know precisely how related they are. Nevertheless trends are useful and that's something that we're going to keep saying over and over for actually all of these monitoring modalities. This is just a picture of normal pressures and saturations in a structurally normal heart that you may observe during cardiac cath. It's kind of hard to find some of these images sometimes so here you go. And I just thought this was like a cool picture so I thought I would put it up and that way you could have it you could pause the video you could check it out. Okay so mixed venous saturation when we say that technically what we should be talking about is the saturation of the blood entering the PA what we are usually actually talking about is the saturation of the blood entering the SVC and so we're not getting input so to speak from the IVC from the coronary sinus right. There have been studies that have looked at the degree to which mixed venous saturation and central venous saturation agree with each other. The upshot is that they don't agree with each other fantastically well in terms of any particular point estimate and that is the figure that you see to the right which is that for any given average of mixed venous sat and central venous sat the actual point value can differ by as much as plus or minus 13 according to this figure. Of course we have to talk about lactate. Of course we draw lactates in patients with shock. There's plenty of literature that's been developed over the last 20 plus 30 plus years that has shown that in certain circumstances and when used judiciously lactate can be a useful biomarker for trending the progression of a patient with shock. You weave things together from all of the different data points you have available and lactate is another one of those. You know where it comes from because we talked about this talked about anaerobic metabolism and the Corey cycle and how lactate is how you just keep things going so the cell doesn't straight up start falling apart even though this eventually will not be enough to keep things going. Lactate is a serum biomarker that we use because it's a surrogate for tissue hypoxia right. The presumption is that if you're producing more lactate in the tissues because of local hypoxia then eventually there's going to be lactate that leaks out of those cells either because they die or whatever happens and ends up in the circulation and then you draw a blood sample from somewhere else in the circulation and you can see that oh there's more lactate in the body right. So lactate is a lagging indicator. It's something that's only going to become elevated after tissues have reached a certain threshold of being jacked up from not having oxygen. And so you already have a problem to deal with if your lactate is significantly elevated and the threshold for significant elevation differs depending on the studies you look at and their goals. Greater than two is like a threshold that many consider abnormal. Greater than four more certainly abnormal. Greater than eight you really have problems now. And actually as lactate gets worse outcome gets worse and that's across a variety of settings. Lactate for some population of patients who have shock when they're sick it goes up and when they get better it goes down. And that's actually quite useful if it does that in a predictable fashion because it's another way for you to reconcile other pieces of information you're getting from the physical exam or the trend in the urine output or whatever it may be. So definitely still very useful. You can obtain it as often as you're willing to do blood draws. So that's pretty cool. It's easy. One thing that we will talk about in a little more detail is that there's more than one pathway by which the serum lactate can become elevated. One of them is basically DO2 VO2 imbalance or shock but there are others and we'll point those out. Ultimately it's also really important to remember that the serum lactate is a global value that is in one compartment and so it can only to a limited extent speak to what's happening in the actual tissues. So the serum lactate may not be abnormal even though the tissues may be experiencing significant derangement. So don't anchor too much on a normal lactate value right. If every other detail of your assessment of the patient suggests they're in shock but their lactate is okay, you got to think about how much you want to hang your hat on that lactate. Okay so one classification scheme that you may have come across has to do with the type A versus type B lactic acidosis. Type A lactic acidosis is just shock right. It's a DO2 VO2 imbalance. Type B lactic acidosis in this classification scheme is pretty much everything that's not shock that can result in the lactate being higher. So that could be increased lactate production, decreased lactate elimination. So there's a big list of those kinds of causes and we'll go through them in the next slide. There's also you may have separately talked about this entity called D-lactic acidosis. This specifically has to do with glucose fermentation in the gut by bacteria and so that actually results in production of the enantiomer of the usual lactic acid we're caring about L-lactic acid. D-lactate is a problem too because we absorb D-lactate and that can cause dysfunction in various organ beds including CNS dysfunction. The main thing here is just to deliver less substrate to the bacteria that are fermenters in the gut and so usually adjustments in enteral intake are the main way to solve a D-lactic acidosis. Here's the slide that I promised you. This comes from Deranged Physiology which is an absolutely amazing website that describes in incredible and engaging detail a lot of core critical care principles. So Alex Yartsev presents this mechanism-based classification of lactic acidosis. So just sort of absorb the vibe of these different categories. You have increased rate of glycolysis due to lack of ATP. That's shock. And then you have increased rate of glycolysis due to exogenous pro-glycolytic stimulus. That is when glycolysis is stimulated by something else. So epinephrine does this, albuterol does this, and so that's something to be alert to is when you have a patient on these medications and the lactate is bumped, if that's the only thing that's off and everything else is fine, consider whether your catechol administration might be contributing to that. You have unregulated substrate entry, pyruvate dehydrogenase, so metabolic stuff, oxidative phosphorylation, look at propofol here, look at metformin here, look at tylenol and salicylates here, look at cyanide now. Cyanide poisoning is not necessarily a common clinical entity, but nitroprusside use is relatively common, especially in the cardiac ICU. And so this is why you want to limit the use of nipride. You have decreased lactate clearance as you would expect if you have liver or renal dysfunction. The liver metabolizes lactate, the kidney clears lactate, okay? And anything that affects gluconeogenesis in the liver is also going to affect your lactate levels because now you can't actually consume that substrate and allow for the regeneration of glucose. Let's break down near-infrared spectroscopy. When you apply NEARS to the brain, that's cerebral oximetry. NEARS is a monitoring modality that is non-invasive and based in the optical transmission of near-infrared light. So like the pulse oximeter, you have one side that's emitting light and another side that's receiving that signal after it's passed through some tissue bed. In a pulse oximeter, what it's doing is essentially subtracting the pulsatile signal and the non-pulsatile signal, but in the case of a NEARS monitor, you don't actually need pulsatility for this to be able to read differences in the concentration of different wavelengths of hemoglobin. So that's good for vascular beds where there isn't like a large amplitude pulsation of blood flow. That could be in the brain, for example. That could be in the somatic bed, in muscle or kidney, things like that. That's called somatic oximetry when it's applied to those other locations. But we're mainly talking about cerebral oximetry here because it would be really useful to know what the oxygenation status is in the brain. And it'd be super, super useful to be able to do that non-invasively because you could put like a microdialysis catheter in, you could sample from the jugular bulb, but those are pretty intense things to do. It's unclear if they actually help a patient get better, do better, experience less morbidity. And so non-invasive approaches are compelling. So NEARS is basically like being able to detect the percent of hemoglobin that's saturated with oxygen and to be able to do that in this sort of amalgam of all the different vascular beds within the area of the receptor. And so in the case of the brain, this is going to include a bunch of vessels, right? A bunch of small capillaries, a bunch of larger vessels, the surrounding tissues. And so we use the NEARS as a reflection of the venous oxygen saturation essentially in that region of the brain that is covered by the receptor. So it's superficial, right? It's like the cortex that's near the forehead is like usually what we're sampling. So it's a local statement about that tissue that we can choose to extrapolate. And it turns out that when the NEARS goes down, it is usually some time where cardiac output is lower and extraction is higher. So it actually is helpful. You see this applied frequently in the cardiac anesthesia, cardiac intensive care settings for patients who are experiencing derangements to their hemodynamics in a predictable fashion and especially neonates. Here's just some normal values for RSO2, which is that regional oxygen saturation in the area of the cerebral cortex that we talked about. The upshot is like high 60s to low 70s seems pretty reasonable, which is pretty reasonable for a mixed venous saturation anyway. So it kind of feels, and it actually does more or less respond like a mixed venous does. As long as you can pick up the signal, you then have a continuous approximation basically. One very important and appropriate question you could ask is how good of an approximation is the NEARS for the mixed venous. Just like when we talked about central venous oxygen saturation and the true mixed venous oxygen saturation, any individual point value is not well correlated between these two modalities. But the graph on the right shows that trends are useful in both. The trends don't behave exactly the same in both. But if you look at box two, the cerebral NEARS experienced a big dip, but the point value for central venous oxygen saturation, it's not really greatly visible here. The gray circle actually went up. So they just definitely did not agree at that moment in time. But in general, you see that the way in which mixed venous or central venous oxygen saturation goes up and down and the way in which the cerebral NEARS goes up and down are like kind of similar in enough places for this to be useful. So go see the patient, go put your hands on them, examine them. Look at the vital signs. Look at the stuff connected to them. Do that, especially when patients are sick frequently. Vital signs are always going to be vital. Your clinical assessment is always going to be vital. Yes, interclinician reliability for a lot of components of the clinical exam is low. That's fine. When you are responsible for a patient, you need to know how they're looking and how that's trending. Always, always remember that there's no single monitor that will tell you the whole story. You need to integrate all of these different points of data into a considered assessment. So you can't just say lactate's down, so we're not in shock anymore. You can't just say, oh, well, the blood pressure is fine, so that means everything's fine. You have to put it all together. You always have to think about these modalities of monitoring and measuring things for the patient in the clinical context of that patient. And knowing the limitations and the flaws of these monitoring modalities will help you calibrate how much weight you give them in coming to a conclusion about a patient. And as we saw throughout all of these modalities, trends are often way more illuminating than individual point estimates. But of course, especially in rapidly evolving situations, point estimates are really valuable and really useful. So just to be clear there. This is a philosophy that I would advocate that we all try to live. And this was relayed to me by my division chief, Jeff Burns, when I was a fellow. A good intensivist is one who is there. I think this is exactly right. I try to live by this. And I hope you will, too. Your patients are going to need you, too. Thank you so much for your attention. I'm more than happy to be emailed with any questions you may have.

management of shock

afterload management

poor cardiac function

distributive shock

obstructive shock

septic shock

vital signs monitoring

lactate levels monitoring

NEARS monitoring

patient care

timely care