The next topic is on vasoactive support, and this is a summary of Dr. Ryan Morgan's talk from Children's Hospital Philadelphia. It's a really excellent talk that he put together, and I'm just going to largely illustrate a few principles. It's really hard to talk about inotropes, largely because there's so much variation in practice surrounding it. And if you come to the cardiac ICU, we think about inotropes a little bit differently compared to patients in the PICU. So these inotropes are commonly used in ICUs. We use inotropes to manage myocardial dysfunction or circulatory dysfunction, both to improve contractility and to provide a perfusion pressure. Most inotropes act through adrenergic receptors. Some have direct intracellular effects, and then there are others such as vasopressin that have specific receptors that they work with that one needs to know. It's really important to know terminology when you're thinking about inotropes. Inotropes increase myocardial contractility. Chronotropes increase heart rates. Vasoconstrictors increase systemic vascular resistance. Vasodilators decrease systemic vascular resistance. Leucotropic agents improve diastolic filling properties of the heart. A good example of leucotropic agent with leucotropic properties is milrinone. And then inodilators have a combination of both leucotropy, increased contractility, as well as offload reduction. Milrinone does that. And similarly, if people are using levosimundone, that is another example of an inodilator. Most inotropes have a combination of many of these properties. There are very few agents that are pure one or the other, but most inotropes, depending on the amount of medication that you're using, actually have many of those properties in a combined effect based on the amount of drug you're using. Most vasoactive agents act through changes in heart rate, changes in offload, and changes in contractility to improve cardiac output. It's very rare that we actually change preload using inotropic agents. One could imagine that if you gave somebody nitroglycerin and venodilator, then that you might actually decrease preload. But inotropic agents, in general, use changes in contractility, offload, and heart rate to improve cardiac output. Mechanism of action for most inotropic support agents is combination with a receptor. The combination of the receptor changes configuration of certain proteins. So those lead to release of other proteins that then have an effect on the circulation. And by and large, most inotropic agents eventually work through releasing or increasing the amount of calcium or decreasing the amount of calcium within the cell to affect either contractility or vasodilation. And so that's kind of really, you know, if you look at inotropic agents and how they work at a 50,000 feet view. There are specific G protein subtypes that exist that is important to know. One is GS, which stimulates adenyl cyclase. And adenyl cyclase pathway works through changing AMP into cyclic AMP. And then cyclic AMP then works with calcium channels to increase calcium within the cells. There's an inhibitor form of it, which is usually, if you stimulate alpha 2 receptors, you get the inhibitory form of G protein, which inhibits adenyl cyclase and reduces cyclic AMP, and therefore reduces the amount of available calcium for cell contraction. And then there's the GQ type of G protein, which is specific to alpha 1 receptors. And also for vasopressin V1A receptors as well. They both use GQ. So if in the exam you're asked about mechanism of alpha 1 or vasopressin V1A, then the messenger there is a GQ protein. And that works through phospholipase. The others work through adenyl cyclase. And this is the only one that works through phospholipase. The receptors are distributed across your body. And it's really important to know where they are. For example, alpha 1 receptors are largely in your vascular smooth muscle. And beta 1 receptors in your heart and your kidneys. And dopamine allergic receptors are also present in your heart, your kidneys, and vascular smooth muscle. And really depending on the concentration of medication you're using, what you stimulate actually changes. And for example, there are very few vasoactive drugs that purely stimulate one receptor but not the other. And the examples of those are, Dr. Morgan put this table together and I kind of copied it. And it really illustrates that there are very few agents that are pure agents. For example, phenylephrine is a pure alpha 1 agent. So if you gave somebody phenylephrine, you're going to increase systemic vascular resistance. And that is the only effect that you would see. Similarly, if you use isopropyl, then the effects are largely on beta receptors. So you will increase chronotropic and contractile properties. So your heart rate will be faster. We commonly use that in patients who have complete heart block as a way of increasing the escape rate. So it's important to know where the receptors are and what type of concentrations of medications actually activate some of these receptors. This is another way of showing where the receptors are and which of the agents strongly are associated with each of the receptors. And this is a good way of thinking about all of your inotropic agents, both for answering questions in the exam as well as in your practice. And the two vasoactive agents that Dr. Morgan had not mentioned was something that we commonly use in the cardiac ICU. One is sodium nitroposide. And sodium nitroposide is a nitric oxide donor that acts by increasing cyclic GMP. And then eventually, through calcium channels, actually affects vasodilation. And the vasodilation associated with niprite is more in the arterial tree rather than the venous tree. So it's a potent arterial vasodilator. And we use it commonly because the onset of action for niprite is relatively quick. And the offset is also relatively quick. It's a good agent to test in somebody with dilated cardiomyopathy who's presenting in cardiogenic shock. And you want to really get that SVR down to improve your cardiac output. It's a good agent to use. Because if you then cause hypotension and get into trouble, then coming off niprite is a good agent. And if you're waiting for milrinone to act, sometimes using a bridge with niprite actually helps you provide vasodilation to help navigate that elevated systemic vascular resistance to increase your cardiac output. If you think about nitroglycerin, the effects of nitroglycerin are really similar. They are also nitric oxide-related effects. But nitroglycerin largely affects your venous circulation compared to your arterial circulation. And then the other agent that we also commonly use in the cardiac ICU is nicartapine. And these are largely used to control blood pressure in the postoperative states. Like, for example, a patient who has had coarctation repair was hypertensive, one would choose to use nicartapine. Nicartapine is a calcium channel blocker. And compared to all other calcium channel blockers, the effects of nicartapine are largely a peripheral vasculature rather than your heart. So it's a calcium channel blocker which works in arteries, cerebral and coronary arteries, causes arterial vasodilation, and reduces afterload. One thing to remember in patients who use vasodilators, both niprite and nicartapine, is that it has some pulmonary vasodilatory effects. And if you have hypoxic pulmonary vasoconstriction because you have a big area of low-bound pneumonia, you're likely to actually overcome hypoxic vasoconstriction. So eventually, you may actually drop saturation in your patient. So when you're using it, you always have to be cognizant that your oxygen saturations may decrease as you provide vasodilation for these patients. And then finally, to kind of really touch on flow volume loops, I'm just going to go through this in two minutes. Flow volume loops determine a relationship between pressure and volume in a ventricular system. So although these are largely theoretical concepts, there are ways of measuring pressure-volume relationships to measure compliance of ventricles at all. And they can be done in the cath lab. So this is a pressure-volume loop. Volume is on your x-axis. Pressure is on your y-axis. At the end of diastole, we have what's called left ventricular end diastolic volume and pressure. And when your ventricle starts to contract, there's a period of time where there's no change in volume because this is isovolumetric contraction where your ventricle is raising pressure to open your aortic valve. And once the aortic valve is open, then you eject, and therefore your volume in your ventricle drops. And then you reach peak ejection, and your aortic valve then closes as your ventricle starts to relax. You have a period of time when, again, volume is not changed in the ventricle, and this is called isovolumetric relaxation. And then eventually, the mitral valve opens. And once the mitral valve opens, you start filling your ventricle again. And then finally, you have the atrial contraction just before onset of systole that then fills the remainder of the atrial blood into your ventricle. And that gives you left ventricular end diastolic volume. Left ventricular end diastolic volume and its relationship to pressure actually determine the compliance of your ventricle. So if your left ventricular end diastolic volume in a patient is constant, but it's operating under higher pressure, higher end diastolic pressure, then that ventricle is not compliant. Similarly, the left ventricular end systolic pressure volume relationship, which is the point where your aortic valve closes, is a function of contractility of the ventricle. It's a load-independent function of contractility. If your contractility drops, the end systolic pressure volume relationship flattens out. If your contractility increases, it moves towards your right. And the volume in between this loop is your stroke volume. So if you imagine giving somebody phenylephrine, phenylephrine is going to increase your afterload. And it's going to make it more difficult for your aortic valve to open because the pressure, your SVR is high. And therefore, the ventricular contraction has to overcome a higher amount of pressure to open the aortic valve. And therefore, for a same amount of volume that it's going to eject, it has to raise that amount of pressure. So as compared to a normal flow volume loop, you can see that the isovolumetric contraction phase has to be much stronger and the pressure has to be higher before you can eject. So that is what you would see if you increase afterload to your ventricle. Similarly, if you decrease afterload, such as giving somebody dubutamine and using your beta-2 receptors to vasodilate somebody, then what happens here is that with the isovolumetric contraction, you don't have to raise your pressure as high and you can open your aortic valve sooner. And therefore, you're going to eject for longer and more. And therefore, the amount of stroke volume that you're going to create in somebody who has a vasodilator on board is much larger than the stroke volume that you would have in somebody who has an alpha agent on board. And this is kind of one good ways of thinking about how to answer questions on the board is to kind of really go through the flow volume relationships, so the flow volume loops, so that you can understand and answer those questions. Similarly, if you give somebody dubutamine and you're increasing contractility, because the other function of dubutamine acts like beta-1 receptors to increase contractility, beta-2 receptors to vasodilate patients. So here, you're going to see an increase in stroke volume. And this ventricle is going to operate with less need for less pressure in the isovolumetric contraction phase as compared to somebody who you're going to give beta blocker, where you're actually going to reduce contractility, where you would reduce contractile force, and therefore, you would reduce stroke volume. So just think about what you're affecting when you're using agents and how it might affect your pressure volume loops. Just go through the basic principles of pressure volume loops as you think about it. So vasoactive agents are common in the ICUs. It's really important to understand the mechanisms of action. And choice of agents is very variable, but it should be based on underlying disease and physiology. With that, thanks very much. Okay, I'll try my best not to go over time, but it was hard to explain everything about congenital heart disease in five minutes. So just to go over the concept of pressure volume loops again, pressure volume loops in the heart measure the relationship between volume loading and pressure generated in a ventricle. Just to go over some of that one more time. So volume is on your x-axis. Pressure is on your y-axis. We start off with end-diastolic. Let's see. Okay, so we're going to start off with end-diastolic volume and pressure. And this is the amount of blood present into your ventricle at the end of diastole. Your ventricle starts to contract. You have what's called the isovolumetric contraction phase, where there's no change in volume. There's just generation of pressure to open your aortic valve. And then the aortic valve opens. You eject. Your ventricle starts to relax. Your aortic valve closes. And then there's a relaxation phase. Again, there's no change in volume. And at the end of isovolumetric relaxation phase, your mitral valve opens, and then your ventricle fills again. And just before end-diastole or beginning of systole, your atrium contracts and fills your ventricle with the amount of blood in the atrium. And so the volume contained within this pressure-volume loop is your stroke volume. We talked a little bit about end-systolic pressure volume relationship, which is an independent measure. Volume in the preload independent measure of ventricular contractile function. The flatter it is, the less contractile your ventricle is. And then your end-diastolic pressure really tells you a little bit about the compliance of the ventricle. Say in a patient with dilated cardiomyopathy who has lots of fibrosis or in a ventricle that's hypertrophic, such as in hypertrophic cardiomyopathy, the amount of pressure a certain volume will generate will be much higher than your normal ventricles. So those ventricles work at a much higher end-diastolic pressure-volume relationship. And that's not good for your ventricle because they consume more oxygen. Because coronary perfusion is from the epicardial to the endocardial surface. If your ventricle pressure is high, then that gradient between the epicardial and endocardial surface is actually decreased, and you may have coronary ischemia. So we talked a little bit about what happens when you increase afterload and what happens when you have increased contractility with ventricle-using agents. But there are other diseases of the heart where pressure-volume loops may be useful. And some of that are really parallel to using increased afterload to your ventricles. So the first figure here is a patient with aortic stenosis. So can you imagine what happens to patients with aortic stenosis, what happens to pressure-volume loop in aortic stenosis? So here you have to use more isovolumetric contraction. Your force of ventricle contraction to open your aortic valve has to be higher because the valve is stenosed. And therefore, similar to giving somebody increase in afterload, you have to have more end-diastolic contraction, and your ventricle has to raise the amount of pressure before it can open the aortic valve. And therefore, you don't have any change in volume until that pressure rises to much higher than what you usually do. So in aortic stenosis, it's just the pressure-volume loops are very similar to somebody who you've given a large dose of alpha agents to. Additionally, the overall stroke volume in these patients is pretty small as well because a small decrease in pressure immediately closes your aortic valve because the valve itself is stenosed. And therefore, your stroke volume is lower, and you have to have a higher isovolumetric contraction phase before you can actually open the aortic valve. So it's like a big pillar. That's the typical feature of aortic stenosis. So what happens in a patient who has mitral regurgitation? Normally aortic valve, but mitral regurgitation. So your ventricle's starting to contract. Your mitral valve's not working. So your volume escapes back into the left atrium, and therefore, you don't have very much of an isovolumetric contraction phase because there's volume exchange during your isovolumetric contraction because you've got mitral regurgitation. So the volume looks something like an egg shape. And the reason why the whole pressure volume loop is wide is because the atrial volume then comes back into the ventricle. So therefore, your end-diastolic volume and the total amount of volume in your ventricle is actually larger. So these are really typical flow volume loops. It's really important to have a visual picture, just like Ira showed you earlier this morning about ventricular desynchrony. It's really important to have a visual impression so that you can answer these questions well. Okay.

inotropes

vasoactive support

cardiac output

adrenergic receptors

pressure-volume loops