Vasopressors: Inodilators, Inopressors, Pure Vasopressors, Methylene Blue, Midodrine

What's up engineers? In this video we're going to be talking about vasopressors. If you guys want to follow along with this video, please go down in the link below. We'll have that going to our website which has very comprehensive notes, illustrations of the things that are on the whiteboard that are drawn before and after. It's just going to enhance your true understanding of this topic. All right. Also, if you like this Video, it makes sense, you enjoy it, please hit that like button, comment down in the comment section, and most importantly, subscribe. All right, let's

talk about vasopressors. All right, engineers, let's start talking about the first group of vasopressors. So, I'm going to kind of clump these vasopressors into different types of categories to help us to remember their mechanism of action very easily. So, the first category of vasopressors is going To be what's called our inodilators, okay? So, inodilators, there's two parts to this. Ino is inotropic, right? So, it's going to cause an increase in contractility of the heart. And dilator is just going to cause a vasodilation of the peripheral vessels. Now, how does that help us out? What are

the indications we'd use these in? What are our titration parameters? What are the pros? What are the cons of this drug? How do they even work? That's what we're Going to focus on now. So, the first thing that I want to talk about is the the drugs that are put into this group of inodilators. The first one is dobutamine. Now, what I want you to focus on is primarily just what is their primary receptor that they're working on, okay? Or enzyme. So, dobutamine primarily is a beta agonist, okay? So, it is a beta agonist. It

is going to bind onto beta one receptors, beta two receptors, maybe even a little bit of Beta three receptors. It's also going to have very little alpha agonistic activity, pretty much almost no alpha agonistic activity. So, in a way, we can kind of say that it has very very little alpha agonist activity to almost no alpha agonist activity whatsoever, okay? Milrinone is the other type of inodilator that I want you to remember. Now, this one's very interesting. It Doesn't have any effect on the alpha or beta receptors or adrenergic receptors. It actually inhibits a very

particular enzyme. It's called a phosphodiesterase type three, and it is a phosphodiesterase type three inhibitor. And I will explain how that comes into play a little bit later. And the last one is isoproterenol. Isoproterenol is primarily a beta agonist, a very strong beta agonist at that. Okay, so it loves those beta one Receptors primarily with a little bit of beta two receptor activity as well. How does all of this come into play in their mechanism of action? Let's talk about that. First one being dobutamine. Okay, dobutamine primarily works by stimulating the beta receptors. Well, where

are the beta receptors with respect to the heart and the vasculature? Well, you know you have these structures here called your SA node. You also have this structure here Called the AV node. And then the AV node goes to your bundle of His, your right bundle branch, and your left bundle branch, right? There's beta receptors that are present on those structures, on the SA node and the AV node system. So, if I stimulate those receptors, the beta receptors on the AV nodal system or the SA nodal system, what's that going to do? It's going to

increase the firing. It's going to load those cells with calcium, Increasing the firing of those cells, and that's going to increase heart rate. So, one of the things that we got to remember here is that whenever you stimulate your beta one receptors, when that acts on your nodal system, so here put here our nodal system, that is going to increase your heart rate. What do we call that whenever we get an increase in heart rate? Increased chronotropic activity. So, it's going to increase your heart rate or increase Chronotropic activity, okay? Now, the benefit of having

an increase in heart rate is that this could potentially increase your cardiac output because we know that cardiac output is equal to heart rate times stroke volume. Okay, what else? There's also beta one receptors not on the nodal cells, but on the contractile myocardium. So, if I were to just take a piece of that myocardial cell that doesn't have It's not a part of this nodal system. It's The contractile tissue, those also have beta one receptors. So, if I also stimulate the actual We're going to put contractile myocardial cells, the contractile cells of the myocardium,

that is going to increase their contractility. If you increase contractility, you increase stroke volume. And if you increase stroke volume, you increase your cardiac output. So, when we talk about dobutamine, how does it primarily Work? It increases the a conductive activity, increasing your heart rate, and increasing your cardiac output, and it also increases the stimulation of the contractile cells, loading those cells with calcium, causing more contraction, causing an increase in stroke volume, and increase in cardiac output, right? So, that's a cool thing. Now, here's the other aspect of this. Dobutamine has very little alpha activity,

and instead it has a little Bit of more beta activity. Now, you know there's other cells here, right? You know there's other kinds of like things which are called alpha one receptors. Alpha one receptors, when stimulated on the peripheral vessels, so you have alpha one receptors that are present on the smooth muscle of peripheral vessels, okay? So, here's like a peripheral vessel. Now, whenever alpha one receptors are stimulated, they should cause vasoconstriction, squeezing down On the blood vessel. But what does dobutamine have? It has pretty much almost no alpha one receptor type of activity. So,

because it's technically having very little activity, we can almost say that it almost inhibits the alpha one receptor. And so, because of that, you get more of a vasodilation effect, right? Less vasoconstriction. If you cause vasodilation, you decrease systemic vascular resistance. And if you Decrease systemic vascular resistance, you decrease your blood pressure. Now, the other thing that you have to remember is not only is there alpha one receptors on the actual peripheral vessels, there's also Here, let's kind of denote that there's an alpha one receptor here. There's also beta two receptors on the peripheral vessels.

And what does dobutamine? It's a beta agonist. So, if if I act on these beta two receptors via Dobutamine, that is actually going to do what? It's going to cause vasodilation. Beta two receptors generally cause vasodilation, okay? Alpha one receptors cause vasoconstriction. So, if I have the stimulation of the beta two receptors, I'm going to get a vasodilatory effect, lowering my systemic vascular resistance, and potentially lowering the blood pressure. But the other aspect of this is that this can also decrease what's called afterload, which is the amount of stress that you put on the heart

to have to pump blood out. Beautiful. So, here's the cool thing about this. We've kind of taken and knocked out two of the inodilators already. Dobutamine is a beta agonist. We covered the beta activity, the beta one, the beta two, and the very little alpha Agonist activity. But guess what else we covered? Isoproterenol. We know what it does now. It's a primary beta agonist. So, it's going to increase heart rate, it's going to increase contractility, increasing stroke volume, increasing cardiac output, but it's also going to act on those beta two receptors and potentially cause vasodilation

with a little bit of a decrease in afterload, a little bit of decrease in blood pressure, okay? So, That's a pretty cool thing that we just knocked out two of those mechanisms. Milrinone is a little bit weird. All right, so the next one that we want to talk about is milrinone. Now, milrinone is a little interesting. Its mechanism of action has nothing to do with this actual catecholamines or adrenergic receptors. It's a weird mechanism. So, it It comes down to a very basic concept, and this kind of mechanism is going to happen both within the

cardiac Muscle, okay? And also within inside of the smooth muscle. Now, there's a particular enzyme present in both of these tissues. And this enzyme is called adenylate cyclase. What adenylate cyclase does is in the presence of ATP, it converts ATP into what's called cyclic AMP. Now, cyclic AMP will then go and stimulate a particular enzyme called protein kinase A. Now, here's the difference. Protein Kinase A has different effects within different tissues. So, let's say over here, I cover protein kinase A in the cardiac muscle. In the cardiac muscle, it's actually going to induce a cardiac

muscle contraction. So, it's actually going to stimulate contraction of the cardiac muscle, okay? In the smooth muscle, though, in the vasculature, so in these actual vessels Here, in the smooth muscle, it actually causes relaxation. The reason why is it actually phosphorylates an enzyme called myosin light chain kinase, which inhibits the enzyme, okay? So, it's actually going to induce a relaxation mechanism. Okay? So, here's what's Here's what's very interesting about this. If you look at this mechanism, if you cause the cardiac muscle to contract, it's going to Increase your stroke volume, and you're going to increase

your cardiac output. If you cause the smooth muscle to relax, it's going to cause vasodilation. If you vasodilate vessels, you lower your systemic vascular resistance, lower your BP, and lower the afterload. Now, here's where you're like, "Okay, well, what the heck does Where does milrinone even come into play here?" There's an enzyme In blue here. It's called PDE3, phosphodiesterase type 3. What this enzyme does it tries to inhibit cyclic AMP, and then you lose all of this effect here. If I give a drug that inhibits this enzyme, I can keep the cyclic AMP levels up,

I can keep stimulating protein kinase A, and I can keep this mechanism here. So, I need to give a drug called milrinone. And what milrinone does is it says, "Hey, phosphodiesterase 3, You out." And it inhibits this enzyme. Then cyclic AMP levels continue to stay up. Protein kinase A levels continue to stay up. You continue to cause increased contraction of the cardiac muscle and increased relaxation within the smooth muscle. And the overall effect is an increase in cardiac output and an actual lowering of the blood pressure and a lowering of the afterload. Same as you

would see with Dobutamine as we talked about above. Now that we know these mechanism of actions of these actual inodilators, what would we be utilizing these for? Think about it. It's really straightforward. If I have somebody who has a low cardiac output because they have something wrong with their heart. Their pump isn't good. So, if I have someone, for example, let's say I have someone with a Particularly like a car- cardiogenic shock, right? So, they have a cardiogenic shock. Let's say that their left ventricle shot. And they're just not able to get a good contraction

of that actual left ventricle. And because of that, they have a low ejection fraction or a low cardiac output because of something going on with their ticker, right? So, because of that, they have a cardio- genic shock. Their pump is not being Able to generate enough contractile force to push blood out of the heart. So, they have a lower ejection fraction, a low cardiac output. I can give drugs like dobutamine. I can give drugs like milrinone very particularly, not as much isoproterenol, but particularly which two drugs? Milrinone and dobutamine would be great in a situation

where someone has cardiogenic shock and You want to recruit as much of the myocardium as you possibly can to have an increase in contractility and increase in cardiac output and then lower the afterload, lower the stress on that left ventricle by causing vasodilation of the peripheral vessels. That's going to lower afterload. That be beneficial in this scenario. Another situation, what if a person is in what's called septic shock? So, they're in septic shock. And when they're in this septic shock, usually it's because the vessels, the peripheral vessels are vasodilating, right? They're vasodilating and they're having

increased capillary permeability. And so, their effective arterial blood volume is low. So, you're like, "Okay, how the heck would dobutamine and how the heck would milrinone help this?" Sometimes if someone has a septic shock, so they have a septic shock, But on top of that, they have a low ejection fraction and a low cardiac output in combination with that septic shock, you can put them on a drug like milrinone or dobutamine because that's going to give you the increase in the cardiac output and the increase in the ejection fraction. Problem is though, it's going to

cause worsening vasodilation by the vasodilation effect. So, you're like, "Holy crap, I could drop their pressure." So, generally, you Give these drugs that are augmenting other medications, which we'll talk about a little bit later. So, these are usually what's called add-ons. So, you're adding on something like dobutamine or you're adding on something like milrinone in combination to something as like, for example, we'll talk about these later, norepinephrine or phenylephrine. These are usually Going to be drugs that'll be add-ons. Okay? So, you're adding them on to vasopressors because those are going to squeeze down on the

vessels in septic shock, but you're going to help to give increased cardiac output through dobutamine and milrinone in those situations. Okay? The last scenario, this drug, isoproterenol, man, this thing could get a heart rate out of a Rock, okay? Sometimes in patients who have very, very bad like AV node dysfunction, maybe they have a significant problem with their their their heart rate and they have just a very, very low heart rate. What is that called? Bradycardia. And they're on the verge of what's called arrest. So, a pericar- a pericardiac arrest, a bradycardic peri-arrest. In that

situation, generally what you do is you give what You put pads on the patient and you'll do what's called transcutaneous pacing until you get a an actual effective measure of what's called a transvenous pacer or a permanent pacemaker. Sometimes pacing doesn't work. And all you're doing is you're just stimulating the skin and giving them a good lick massage. So, sometimes you have to give a drug that'll get in there and really give that heart a good type of increase in Chronotropic activity. And that's where isoproterenol is great. So, when someone who has a very low

heart rate, they're on the verge of being arrest and the what's called peri-arrest from bradycardia, you can give them iso- proterenol. Okay? And this drug may be able to give a quick increase in their heart rate, increase their heart rate enough to be able to hold them over until they get a Permanent pacemaker or a transvenous pacer that they have to float down. So, this is a great, great drug in those situations. Okay, we have an idea of how these drugs work. We know when we're going to utilize them in cardiogenic shock, septic shock with

low ejection fraction and augmented with pressors or a person who's on the verge of cardiac arrest due to severe bradycardia and they're you're trying to stabilize them long enough until you can get them that Transcutaneous transvenous pacer or a permanent pacemaker. Here's the next question. And it's a very important question. When I start these medications, I have to have a goal. I can't just put these medications on and expect them to just work magically. I have to have something that I'm titrating these medications against. And often times we make the mistake of titrating these against

blood pressure. These medications have Variable effects on blood pressure. We don't have a very strong idea about them increasing blood pressure or decreasing blood pressure. So, we should never titrate dobutamine and milrinone against blood pressure. Use it as a way of potentially adding on something else, but never titrate the drug against blood pressure. What should you titrate dobutamine and milrinone against? What do they do? They increase your stroke volume, your cardiac output, increasing Your heart rate. So, you should titrate them to cardiac output. So, you titrate these drugs to the cardiac output. How do I

do that? Well, sometimes we'll put in what's called pulmonary artery catheters, PACs, and that'll help us to be able to identify sometimes like their central venous pressure and other things like that. You can even measure what's called SVO2 and lactate levels. Those aren't really Great, okay? Sometimes the best way of measuring cardiac output is just doing looking at their actual echo. So, having a ultrasound, putting it over their actual heart and looking to see what's their heart looking like. Is their EF increasing? Is there potentially like their stroke volume variation changing? What's it look like?

So, if I have a person's heart and I know what it looks like before I start Them on dobutamine and milrinone and their heart isn't squeezing that good, I put them on dobutamine and milrinone and I slap the echo on and I'm looking to see, okay, is are you recruiting more myocardium? Is their contractility increasing? Is their stroke volume increasing? Is their cardiac output increasing? Use your echo to guide you in that area. Also, use surrogates of cardiac output. If we have an increase in cardiac Output, effectively, you should have an increase like mean arterial

pressure or perfusion to the kidneys. If you increase your perfusion to the kidneys, technically, your urine output should increase as well. So, utilizing urine output also may be a way of being able to determine if your cardiac output is actually increasing. So, again, can't stress this enough, when you are actually titrating dobutamine and milrinone, you don't Titrate it to blood pressure, you titrate it to things like their central venous pressure, SVO2, lactate levels, preferably an echo, looking at what their heart is doing before and after when you put them on these drugs, looking at their

urine output, is that changing? So, there's a lot of things that we have to look at to monitor the efficacy of this drug and continue to titrate it effectively, which makes it difficult to titrate. Isoproterenol, what did I say it's primarily utilized for? Heart rate, right? So, bradycardic peri-arrest. So, you titrate this drug to heart rate. So, if they have a very low heart rate, you're trying to titrate that up to an appropriate heart rate to get them at least a certain amount of time until we can actually get them a permanent pacemaker or a

transvenous pacemaker that we float down. Okay? All right, we covered mechanism of Action. We covered the indications. We covered the titration parameters. Now, the next question is, what are the What are the benefits of utilizing one of these drugs and what are some of the downsides of utilizing some of these drugs? Dobutamine is a great drug. And one of the reasons why it can be actually be relatively effective is it has a very short half-life. And so, because of that short half-life, it's very titratable. Okay, it makes it a pretty easily titratable drug. Okay, that's

one benefit. The downside of dobutamine is that whenever you're on dobutamine for a long period of time or higher doses, these beta receptors, they start to becomes a desensitized. So, the beta-1 receptor starts to desensitize and down regulate, and they start getting taken up into these actual myocardial cells. And so, because of that, you have less Of these beta receptors for dobutamine to bind on to. And so, what will that do? That decreases the efficacy of this drug as you're on it for a long time. And so, that is one of the downsides of this.

It could also be a plus side because it may allow for the person to auto titrate off of it. You can turn the trip off, and eventually it'll kind of auto titrate or wean them off naturally without having to go down slowly, slowly, slowly. So, that's one of the things about dobutamine. So, pro is that it's easily titratable. The downside of it is that if you're on it for a long period of time, high concentrations, the beta receptors start to undergo desensitization, receptor-mediated endocytosis, and their efficacy decreases. One more downside of this is that it

increases unnecessarily a downside, but it's something to think about. It does increase your heart rate, right? So, if you're increasing somebody's heart rate because it has that beta-1 activity, would this be the best in someone who has atrial fibrillation with RVR? No, probably not. So, I would probably stay away from giving this drug to a patient who has very bad A-fib where they have very fast ventricular rates um because it could potentially worsen it. Okay? So, that's dobutamine. Milrinone is a great drug. Milrinone is one of the one of the benefits of milrinone is that

it actually produces more of a vasodilatory effect than dobutamine does, okay? So, you get actually a a more uh of a vasodilation effect. Okay? So, this could actually potentially lower afterload even more, but also lower your blood Pressure a little bit more. So, this might be a little bit better in someone who has very severe cardiogenic shock in comparison to dobutamine, okay? So, that's one of the benefits. The downside to uh to uh milrinone is not it's good at obviously causing vasodilatory effect, which can lower afterload better in certain patients with severe cardiogenic shock, but

it also is renally eliminated. So, in patients with very severe chronic kidney disease, this Can actually accumulate and cause uh a very significant negative side effect of it. So, one of the big things to think about is does the patient have really bad kidneys? And if they are having some severe chronic kidney disease, this can quickly accumulate and cause an increased kind of a uh effect on the body causing more vasodilatory effect and potentially increased cardiac output, making it difficult to titrate, Okay? The last thing with isoproterenol, it is a great drug. You know, as

like I said, it can really increase the heart rate. It can really hold you, give you some time to be able to stabilize the patient before they need a permanent pacemaker or trans- transvenous pacer. But, this sucker is extremely extremely expensive. And I know that that shouldn't be a barrier to treatment of patients, but it is very expensive and some hospitals Don't actually have it because of how expensive it is. So, that covers our inodilators. Let's now go ahead and tackle with the next category called inopressors. All right, engineers. So, now let's talk about the

next category of vasopressors called inopressors. Now, inopressors, again, in the name, ino, inotropic, it's going to give you some increased inotropic activity, increased contractility, increased stroke volume, increased cardiac output, increased Blood pressure theoretically. And then, pressor. It's going to squeeze down on the peripheral vessels, increase systemic vascular resistance, increase blood pressure, increase afterload, right? So, those are the mechanisms, and we're going to talk about them a little bit more detail with each one of these pressors uh inopressors. And these categories include norepinephrine, also sometimes termed Levophed in the hospital, epinephrine, and dopamine, Which we will

not be talking too much about dopamine. Um if you are Rob from Germany, who's one of our Discord mentors, you guys will he'll he'll know exactly I am not a big fan of dopamine. Uh we'll discuss it for the thoroughness' sake, but not a big fan of the drug. All right. Norepinephrine. This drug is very, very cool. Probably one of the most commonly utilized types of pressors out there. Now, norepinephrine primarily works through Two types of mechanisms, right? It has a strong alpha-1 receptor agonist activity. Okay? So, it's going to work on those alpha-1 receptors.

It also has a beta-1 receptor agonist activity as well. So, that's going to be pretty cool, and we'll explain how that works in a second. It's kind of We're going to kind of keep building on things consistently. Epinephrine. Now, what I want you to remember about epinephrine is its its effect is somewhat dose-dependent. Okay? So, on lower doses, we'll put LD. On lower doses, it's primarily a heavy beta agonist. What type of beta agonist? It works on beta-1 receptors, beta-2 receptors. So, we'll put beta agonist. On your higher doses, so medium to higher doses, HD,

um this is going to be a alpha-1 Receptor agonist. So, you still keep that beta agonist activity, but as you go up on the dosage, you start adding on alpha-1 receptor agonist activity. Okay. The devil's drug, dopamine. Dopamine is dose-dependent as well, but way more variable in comparison to epinephrine. So, dopamine on lower doses, generally, you know, for example, you can give it like 1 to 4, 4 to 10, and then 10 to 20. Just to give you an example. At 1 to 4, okay, within its dosage range, it primarily has dopamine receptor type of

activity, which it can kind of have a small increase in cardiac output and also a small decrease in systemic vascular resistance. So, by that effect, it actually can potentially cause a increase in cardiac output, a very like Mild, but more vasodilatory effect. So, you can get some hypotension from that. At 4 to 10, you start to get a little bit more of that beta receptor type of stimulation. So, because of that, you may get an increase in heart rate, you may get an increase in cardiac output, okay? And then, as you go up to the

10 to 20 range, you start getting more of that alpha receptor activity, which is going to increase your systemic vascular resistance. So, you see how it these Dosages make it almost literally impossible to titrate effectively. It's just so many different variable effects. That's one of the reasons why this drug isn't great. One reason, it's very difficult to titrate. Second reason, there's multiple RCTs that show that in comparison to norepinephrine in uh patients with cardiogenic shock, norepinephrine was extremely superior. In patients with um uh septic shock in comparison to Epinephrine, epinephrine was extremely superior. And dopamine

was actually associated with higher mortality rates in RCT studies. The other thing is dopamine actually can falsely make it seem like a person's urinary output is increasing because it causes diuresis by working on uh delta-2 receptors present within the kidney causing diuresis making it seem as though urine output's actually increasing, but it's not by perfusion Standpoint. Also, dopamine has the ability to cause malperfusion of the gut. So, it can malperfuse the gut causing more issues there. And on top of that, if this drug extravasates from a peripheral IV, it is a high risk of tissue

necrosis in comparison to a lot of these other types of pressors. So, again, not a big fan of this drug. Don't use it unless you literally have no other choice whatsoever, okay? That's about all we're going to talk about for Dopamine. All right. So, now that we've covered the basic mechanisms uh of like their basic aspects, let's see how that actual uh mechanism that by which they uh work on alpha receptors and beta receptors produce changes within hemodynamics. First things first, let's kind of just categorize this. If you have alpha-1 receptors, you stimulate alpha-1 receptors.

Both norepinephrine and epinephrine do this. What is that going to do? Well, here's what I want you to remember. There is alpha-1 receptors present on two things. There's alpha-1 receptors that are present on arterioles, and there's alpha-1 receptors that are present on venules, our veins. And that's going to produce two types of effects, okay? So, let's think about that. If you do this on arterioles, That's going to clamp down on them, increase your systemic vascular resistance, increase your blood pressure, but also increase your afterload, okay? When you work this on the venules, it's going to

increase the vasoconstriction of the venules, and that's going to squeeze more blood up into the right side of the heart. That's going to increase your preload. If you increase preload, you increase Stroke volume. If you increase stroke volume, you increase cardiac output. So, do you see how we can get kind of a double whammy effect with the alpha-1 receptor stimulation? You can get an increase in systemic vascular resistance, clamping down on the arterioles, increasing blood pressure and afterload, but you can also clamp down on the venules, pushing more blood back up to the right side

of the heart, increasing preload, increasing cardiac Output. Beautiful. What about the beta receptor effect? Let's go back to that beta-1 receptor. You guys should already know this. It shouldn't be too hard now, right? You stimulate those beta-1 receptors. If it's on your nodal cells, the AV node, the SA node, all of that stuff, it's going to increase your heart rate. If you increase your heart rate, you increase your cardiac output, right? It also is going to work on the Contractile cells of the myocardium. If you stimulate the increased contraction by loading calcium into both of

these cells, this is going to increase contractility. And if you increase contractility, you increase stroke volume. If you increase stroke volume, you increase cardiac output. Man, we good. Now, here's the last thing I want to talk about because it's going to come into play When we talk about this a little bit later. Epinephrine, we know is a beta agonist, but it is not just a beta 1 agonist, it also is very interestingly a a pretty strong beta 2 agonist. So, that's the last thing I want to talk about. We're going to do it in blue

here. So, epinephrine, okay? Uh so, we'll kind of put here so that you guys remember that. Epinephrine, we're going to have blue here, is a pretty strong stimulator Of beta 2 receptors, which is very interesting. Why? There's beta 2 receptors that are present um on the lungs, right? Particularly in the bronchioles. And when it acts on the bronchioles, it acts like albuterol. You know albuterol is basically something that we inhale to cause bronchodilation. In the same way, epinephrine will cause bronchodilation. So, it can help in situations where someone's actually having like Difficulty breathing or they're

having bronchospasms like in asthma or anaphylaxis. It also acts on what's called mast cells and inhibits mast cells from releasing histamine, which causes bronchospasm and a lot of bronchial wall edema. But, here's the most interesting part, and this one's going to come into play pretty heavily when we talk about some of the pros and cons. It acts on the liver. And when it acts on the liver, it increases the production of lactate. Why is that important? We'll talk about a little bit later. Just don't forget that. Epinephrine acts on beta 2 receptors, which can give

you bronchodilation and inhibit a histamine response, but also increase your lactate production. And that may sound like a bad thing, but it's not. We'll get to that a little bit later. All right. We've talked about the Mechanism of action of these drugs. We're not going to spend too much talking about dopamine, but we now have a very strong idea about norepinephrine and epinephrine. Now, let's talk about the indications of these drugs. Now, how do these drugs actually work? What are they good for? So, first things first, indication-wise. When we talk about these drugs, we obviously

know from the um the alpha 1 receptor activity first. When we say That someone has a vasodilatory shock, right? So, they have sepsis, right? So, they have a lot of vasodilatory effect. They have a lot of increased capillary permeability that's leaking out. That's lowering a lot of their effective arterial blood volume. So, in a patient with sepsis, okay? Particularly septic Let's actually say sepsis, and particularly in a shock state, so septic shock. In this situation, epinephrine and Norepinephrine are great, great drugs. So, here we're going to put just a abbreviate norepinephrine and epinephrine, where norepinephrine

tends to be more of your first-line drug in comparison to your epinephrine, but epinephrine is also very, very good. Okay? So, in patients with septic shock, these are pretty good drugs to be able to start off with. Okay? Particularly, your first line is going to be your norepinephrine or Levophed. All right. The next one, it's kind of an add-on. It goes back to what we talked about dobutamine and milrinone. Okay? If someone has Okay, let's say that they have cardiogenic shock, right? So, they have cardiogenic shock, some of their actual ejection fraction is affected, right?

So, they have a low EF. They have a low cardiac output. In these types of scenarios, these drugs Actually could be effective. Why? Think about it. What does norepinephrine do to the beta 1 receptors? What does epinephrine do to the beta receptors? Norepinephrine has a little bit of beta receptor activity, not as much as compared to epinephrine, but it has beta receptor activity. So, it could increase the heart rate, increasing cardiac output, and it could increase the contractility, increasing cardiac output and ejection fraction. So, in patients With cardiogenic shock, these drugs can be utilized, but

guess what? Which one would give you more bang for your buck? If you had a patient with cardiogenic shock, so cardio- genic shock, which one of these two would give you a better bang for your buck? Would you go with the epinephrine or would you go with the norepinephrine? You'd probably go with the epinephrine. So, in a patient with cardiogenic shock, Epinephrine would actually kind of be a really good choice because you're going to get more beta 1 activity. Norepinephrine will also be a good choice. You just don't get as much of that inotropic activity

as compared to the epinephrine. But, generally, you might add these on to your ino- dilators such as dobutamine and milrinone. So, you may give them norepinephrine because it's going to Give you more clamping down, and then give them something like an inodilator like dobutamine or milrinone to increase their cardiac output if necessary. Okay, beautiful. What else we got, engineer? The next one here, this kind of goes back here. Epinephrine is really good at helping to pick up the heart rate. So, in a patient who has maybe something going on with their AV nodal system, they

have something wrong where their heart rate is just not picking up, And they have a very, very low heart rate at the brink of bradycardic peri-arrest. Okay? In those situations, we would prefer to have someone get a pacer, right? Like a transcutaneous pacer. Um we prefer to use atropine, push-dose epis, things like that. And then eventually get them a transcuta- a transvenous pacer or a permanent pacemaker. In situations where you're Trying to stabilize a patient, you may try push-dose epi. Let's say that they're Someone's starting to become bradycardic, they brady down, they go into an

asystole or PEA. You do a push-dose epi. They have a good response to the push-dose epi. It may not be a bad idea to put them on an epinephrine infusion long enough to get them to flow a transvenous down or put in a permanent pacemaker. Or, what was the other drug we talked about whenever you're on the Brink? Isoproterenol is another one if you have them the bang for your you have the money. Okay? So, epinephrine is not a bad drug to give to a patient when they're on the verge of bradycardic peri-arrest. You give

them push-dose epi, they respond well, maybe put them on a little epinephrine infusion and get that heart rate enough to stabilize them to get their their actual definitive treatment that they need. Last thing, It goes back to this what we talked about before. Epinephrine and and a patient with what's called anaphylaxis. Let's say they have a significant anaphylactic response, right? So, there's some type of potential allergen, and they start having lots of bronchospasm. Okay? They start having lots of capillary permeability or bronchial wall edema. And then from that, they start Having lots of this histamine

response that starts causing vaso- dilation. And from that vasodilatory effect, you start seeing signs of hypotension. This is anaphylactic shock. In patients with anaphylactic shock, you know what one of the drugs that you can give is? Intramuscular epinephrine, right? So, you give them something called intramuscular epi. Like a 0.5 mg dose, and you can do It like every 5 minutes, and you can just keep blasting it for a couple Generally, like three doses. If it's not working after three doses, so you try this 0.5 mg, and you try three doses, and they're just not it's

not really giving you the response that you need. Obviously, you're going to hit them with antihistamines. Obviously, you're going to hit them with steroids. But, you know what else? And secure their airway. You can start them on an epinephrine Infusion if they're starting to become hypotensive and having tons of bronchospasm. Why? If I start them on an epi infusion, I have a good titratability now. I can easily titrate this drug. What can I titrate it against? Their blood pressure. I can give them some vasoconstriction effect. I can give them an increase in heart rate. So,

I can increase the heart rate, I can increase The cardiac output, I can cause a vasoconstriction effect. That's going to increase their blood pressure. What else does epi do? It works in the beta 2 receptors within the bronchioles causing bronchodilation. It inhibits the mast cells from degranulating releasing histamines. You get a good effect with epinephrine in those situations of anaphylactic shock. So, pretty cool drug to talk about. All right, we got all the indications, we Got the mechanisms. Now, what are we titrating these drugs against? What do we What do we utilizing? It's so simple.

Blood pressure. MAP. So, you're titrating these blood these drugs against your mean arterial pressure. The question is, what's a good MAP goal? What do I go for? Mean arterial pressure. Mean arterial pressure is basically you take the diastolic blood pressure plus 1/3 of the pulse pressure, right? So, mean Arterial pressure is equal to the diastolic blood pressure plus 1/3 of the pulse pressure. And usually, that's, you know, in a perfectly normal person, 93.33 mm of mercury. Okay? If you take the 120 over 80 blood pressure. But, an acceptable goal in someone with cardiogenic shock or

any kind of shock at that nature is a MAP greater than 65 is enough to be able to perfuse the organs. That's kind Of what we're going for. So, if we can get a MAP greater than or equal to 65 mm of mercury, I titrate my Levophed or my norepinephrine against that goal. Okay? So, if they're at 40, oh, I got to go up a little bit. Oh, they're at 90 mm of mercury. Okay, I can probably come down a little bit. Maybe I can actually come a little bit come down, come down, come down.

So, it allows for us to kind of titrate up and down and determine their responsiveness to that actual drug. Same Thing with epinephrine. When we're titrating epinephrine, we're titrating it against that MAP, particularly greater than or equal to 65 mm of mercury. But, you can also titrate this against heart rate, targeting a heart rate potentially maybe greater than 50 beats per minute um if you're getting a good response out of it, and and titrating it for someone who's in bradycardic peri-arrest. Okay? So, those are the things that we titrate These drugs against. Now, what are

the benefits of these drugs? And what are some of the downsides of these drugs? Potential downsides. So, one of the things to think about with these drugs is that with norepinephrine, it's great. Honestly, this drug is very, very good against patients with septic shock. It's obviously the first-line treatment for septic shock. It's also even good for Patients with cardiogenic shock. It has a very strong track record. Honestly, you just can't go wrong with this drug. The one downside to It's not even a downside, it's just something to think about. What does it do to your

heart rate? It has beta one alpha receptor activity, right? It's going to increase your heart rate. What if I have a patient who has atrial fibrillation with RVR? Their heart rate's going pretty fast already. And I put them on norepinephrine. What do you think that might do? Uh it might increase their heart rate a little bit. What if I increase the heart rate too much and they start going into a rapid A-fib and it actually starts affecting their blood pressure? The whole point is to put them on a drug that's going to increase their blood

pressure. If I give them something that causes them to go into even more faster A-fib, their contractility of the heart's going to go Down and I'm not going to improve their blood pressure. So, it might not be the best choice for someone who is in rapid A-fib with RVR and you may have to go with a different drug that we'll talk about later called uh phenylephrine or Neo. Okay? Epinephrine, this one, honestly, it is uh sometimes we we don't even think to use this one, but it is really good in Septic shock. It's really good

in cardiogenic shock. It again has a very strong track record and even more so cardiogenic shock with a low ejection fraction. It's a pretty good drug. Okay? The other possibility of this is that you get again if someone has some type of underlying like lung disease, COPD, asthma, stuff like that, you can even get a little bronchodilation effect. Pretty cool, right? But, here's the thing with epinephrine. Epinephrine, when we talk about this drug, is you also want to be careful and think about this in a patient who has A-fib with RVR, right? You get even

more beta one receptor stimulation than you do get with get with norepinephrine. So, with this one, you have to be careful because in a person with A-fib with RVR, this can definitely worsen their actual A-fib with RVR. So, potentially be cautious When giving that drug. The other thing to think about with epinephrine is that it can increase the lactate. Let's come back to this. Whenever people have septic shock, one of the things that we try to trend or utilize as a way of a perfusion parameter is lactate levels. Lactates that are usually greater than or

equal to four, Uh kind of like that milli-equivalents per liter kind of tells us, "Ooh, this person may have a lactic acidosis that is due to them not perfusing the tissues." Okay? And that would make us say, "Oh, I got to go up on my presses or I got to give them more fluids. I got to augment their blood pressure and that's the reason their lactate's up." But, epinephrine causes an increase in lactate production. And so, one of the things that you have to remember as a Clinician, if you are giving someone an epinephrine infusion

and you're trending their lactates, be prepared to see their lactate go up. It does not mean that they may not be perfusing those tissues as well. It just means that there's a beta two receptor effect on the liver that's increasing their actual lactate production. It may not have anything to do with you perfusing their tissues well enough. Okay? So, that's another thing to think about with epinephrine. Okay? So, again, that covers a good chunk of what we need to know about epinephrine. Now, what I want us to do is to go ahead and talk about

the next category, which is your pure vasopressors, the ones that are going to clamp down on vessels. All right, engineers, so now we're on the next category called pure vasopressors. So, when I mean pure vasopressors, their primary function is clamping down, squeezing on those peripheral vessels, Right? They don't really provide much inotropic activity. They don't really affect like the heart rate too much directly. Okay? So, their primary mechanism is by clamping down, squeezing on those blood vessels. Okay? The three drugs that I want you guys to remember within this category is phenylephrine, vasopressin, and angiotensin

II. Okay? So, phenylephrine, also known as Neo within the hospital, is a very great drug. It's a very great drug. It's, you Know, it's commonly utilized. Sometimes it's, you know, looked down upon in patients with low ejection fractions, but we'll kind of talk about how that may not actually be a problem in a little bit based upon literature. But, either way, phenylephrine, how does it work? It works on your catecholamine receptors, right? So, it primarily is a stimulator, a very strong one, of alpha one receptors. So, it's an alpha One receptor agonist. Okay? That's its

primary function. Vasopressin, I want you to think about vasopressin like ADH. That's pretty much the name of it. It's basically ADH. ADH works on two types of receptors. There's what's called V1 receptors. So, it stimulates V1 receptors that are present on systemic arterioles and it also stimulates V2 receptors that are present within the kidney. So, to help you guys To remember that, let's actually kind of make a little diagram here that V1 receptors, these are your peripheral vessels. V2 receptors, it's primarily working on the actual kidney tubules, the collecting duct. Okay? The last one here

is your angiotensin II. And this is actually a newer drug. It's called Giapreza. There was a trial called the ATHOS-3 trial that came out a Couple years ago talking about angiotensin II. Now, angiotensin II theoretically sounds like an amazing type of vasopressor, but the data's still limited on it. So, we won't go too crazy on this drug, but we will mention its mechanisms, some of the potential indications when it could be utilized, and potentially the downsides of it based upon that trial. But, angiotensin II primarily works through the angiotensin II types of Receptors. And whenever

it acts on those receptors, these are present in two They primarily works on arterioles, right? And we'll talk about these. When it works on these systemic arterioles, it really causes them to clamp down very hard, but it also works on the vessels in the kidney and we'll talk about that as well. Okay? So, we have a good idea about these three particular types of pure vasopressors. Now, let's talk about how Them working on these receptors actually helps to augment in a way this type of blood pressure or changes in particular types of indications. All right,

first one, alpha one agonist. You guys should be pros at this by now. When we stimulate alpha one receptors, we do it on two types of vessels, right? We either do it on the arterioles or we do it on the venules. So, if I had a receptor here on the arterial, boom, I'm going to have Phenylephrine bind onto this. And if I have it on the venules, boom, I'm going to have phenylephrine bind onto this. When it does this, it clamps down proximal to this, clamps down here, and what is the overall effect? If I

clamp down on the arterioles, I'm going to lower the actual decrease the diameter. If I decrease the diameter, I increase systemic vascular resistance, I increase the blood pressure, and I increase the Afterload. Okay? That's the basic concept. We already know that. We just talked about that. On the venules, it's going to squeeze on the venules and it's going to help to squirt blood up here into the right side of the heart. And if I push blood faster up into the right atrium, I increase my preload. If I increase my preload, I increase stroke volume. If

I increase stroke Volume, I increase my cardiac output and hopefully by increasing cardiac output, I can increase my blood pressure. So, that is the mechanism by which phenylephrine works. It's a pretty cool drug, but one of the primary ways is it's going to stimulate this area a little bit stronger than it does on the venule side. Okay? So, that is going to be our alpha one agonistic activity for phenylephrine. Now, let's go to the next one, vasopressin. So, let's talk about first if I stimulate the V1 receptor. The V1 receptor is particularly going to be

working on the systemic arterioles. If vasopressin works on the systemic arterioles, it's going to cause vasoconstriction. So, if it clamps down and causes vasoconstriction, what's that going to do? That's going to lower the diameter. If I decrease the diameter, I increase systemic vascular resistance. If I increase systemic vascular resistance, I increase blood pressure and I increase afterload. Okay? So, similar effect really as the alpha one agonistic activity. It's just doing it via the V1 receptor. A different type of receptor, but similar effect on the arterioles. Okay? The V2 receptor is where it's a little Bit

different. When it stimulates the V2 receptor, this is present on the kidney tubules. You know the collecting duct? In the collecting duct, there's actually V2 receptors. When uh vasopressin binds onto the V2 receptor, it increases the aquaporins. Right? You know those aquaporins? It increases the aquaporins that are present within the actual lumen Of the collecting duct. That increases water reabsorption. If you increase water reabsorption, you increase blood volume. If you increase blood volume, you can effectively increase your blood pressure. So, you see how vasopressin has kind of two ways by which it can increase blood

pressure. It can cause you to retain more water from your kidneys or it can cause you to clamp down on your vessels, increasing systemic vascular resistance. So, those Are the two mechanisms for vasopressin. Angiotensin II, again, primarily works on angiotensin II types of receptors. So, if I have an angiotensin 2 receptor, we're going to go this way now. Let's say here I'm going to stimulate my angiotensin 2 receptors. When you do this on your systemic arterioles, here let's put systemic cuz we're going to have to focus on renal arteries a little bit afterwards. When it

clamps down, when it binds onto the receptors on the systemic arterioles, it does the same exact thing. You guys already know this. It's going to cause vasoconstriction. When it vasoconstricts the vessels, what's the overall effect of when you clamp down the vessels? When you vasoconstrict vessels, you lower the diameter. When you lower the diameter, you are going to increase your systemic vascular resistance and that is going to Increase your blood pressure and that's also going to increase your afterload, right? Same thing as we talked about with the alpha ones and same thing with the V1

receptors. The other thing angiotensin 2 receptors are going to do is is it's also going to increase aldosterone. If you increase aldosterone, what's the effect of increasing aldosterone? Increased sodium, increased water Reabsorption. So, if I reabsorb more sodium and water, what's that going to do? Increase my blood volume, increasing my blood pressure. It's also going to stimulate ADH release. If I stimulate ADH release, what's that going to do? It's going to reabsorb more water. If I reabsorb more water, I'm going to increase my blood volume and I'm going to increase my blood pressure. So, you

get kind of a double whammy effect where you increase ADH and aldosterone and effectively increase blood volume and increase blood pressure. Very interesting, right? This theoretically sounds like a great drug. Hmm, not yet though. We don't know enough about this drug. But, here's the other effect. It also works on the efferent arterioles within the kidneys. And when it acts on the efferent Arterioles in the kidney, it actually clamps down on them and will cause more filtration via the kidney, effectively increasing your glomerular filtration rate and increasing urine output, which again sounds great. But again, the

data just doesn't show much of an actual like overall benefit in mortality with this actual drug and potentially even more negative connotations associated with this drug. But theoretically, it should be the perfect vasopressor. But again, that covers the mechanism of action of these drugs. What are the actual reasons or indications we would put someone on one of these drugs? Okay. First one is whenever someone is in what's called a vasodilatory shock, okay? The best type of example, the most common type of vasodilatory shock is septic shock, Right? So, these vessels are getting really leaky, okay?

They're vasodilating, they're getting leaky, you're having a decreased effective arterial blood volume and you just have a very significant vasodilatory shock. Again, what kind of vasodilatory shock would be the most common? This would be septic shock. So, in septic shock all of those agents can be utilized. All of them. Generally, your first one is what which one? Do you guys remember what was the first-line agent? Norepinephrine. What was another one? Epinephrine. There is data that shows that phenylephrine is able to be utilized and is very effective in patients with septic shock, okay? Even if they

have low ejection fractions, I'll explain here in just a little bit, okay? Cuz it's pretty Honestly, phenylephrine is almost like norepinephrine. It just doesn't have that little extra beta 1 receptor agonist activity. The other one that you can utilize is vasopressin. Vasopressin is kind of a second-line agent though. So, this could be considered as a first. This would come down to more of a second-line agent. We don't utilize vasopressin at first. It's usually going to be norepinephrine, maybe phenylephrine and A little bit later, if you need an extra one, you may add on second, third-line

vasopressin. Angiotensin 2 is kind of a last-ditch effort, okay? This Because it's kind of a newer drug, we don't know enough about it. You kind of use this as kind of like a last- ditch effort, okay? It's like, "Ah, well, nothing else is working. I have them on three vasopressors, four vasopressors. They're not really Responding. Let's give it a shot and see what happens." Okay? So, these are the drugs that you would utilize here. Okay, the next one. This is the sad one, the one that I see a lot unfortunately in the neuro ICU is

you can deal you can give a particular type of drug called vasopressin whenever someone has what's called central diabetes insipidus. And this can actually cause them to quickly hemodynamically collapse. So, in a patient who has impending herniation, okay? Impending herniation or near the point of brain death. Their hypothalamus says, "All right, I ain't releasing any more ADH, baby. I'm done." And it stops releasing ADH. If it stops releasing ADH, now your kidneys don't hold onto any water. It just says, "See ya. And then let the floodgates open." All of this urine just starts pouring out,

tons and tons of dilute urine. If you drop out tons and tons of dilute urine, I mean a lot. Like almost like a liter an hour. You're going to effectively lower your blood volume significantly and lower your blood pressure significantly. And so, the whole goal of this, the whole reason that the body does this is because if you get rid of dilute urine, What would you have left over if you get rid of all water? Sodium. And if you have a your blood is really rich in sodium, what would you do? Pull water from the

brain wherever there's edema and high intracranial pressure. But in something what's called central DI we can use a drug called vasopressin. Why? Because vasopressin is basically ADH. It's going to act on the V2 receptors and reabsorb all the water that your actual kidneys are trying to Get rid of, okay? The other type of condition that we can utilize one of these vasopressors for is what's called hepatorenal syndrome. So, what's called hepato- renal syndrome. This happens in patients with cirrhosis who have really bad livers. And whenever they have these bad livers, the liver starts releasing lots

of like cytokines. And what these cytokines do Is like nitric oxide and other types of molecules is they cause the renal vessels to undergo a vasoconstriction. They really squeeze down on them. And as a result, you don't get much blood flow going into the kidneys and you kind of develop what's called an acute kidney injury where you don't really make a lot of urine. What happens is vasopressin is actually believed to be very beneficial in this. And the reason why is vasopressin may also cause vasoconstriction of the efferent arterioles, increase your glomerular hydrostatic pressure and

cause an increase in actual perfusion, an increase in urine output. And so, that may help to save the kidneys in a patient with hepatorenal syndrome who also has some type of underlying hypotension. So, it's another benefit to vasopressin. Okay? Last but not least, kind of comes back to this angiotensin 2 discussion. Angiotensin 2 can be utilized in a patient who has very, very bad shock. But particularly, one of the the there was another trial besides the ATHOS-3 trial. And there was a there was a gentleman who kind of did an article that showed that angiotensin

2, there can be particular times where it may be beneficial to start it. One of the reasons why is if someone has a renin level that is greater than 200, greater than or equal to 200. So, the reason why is whenever your blood pressure is low, your renin-angiotensin-aldosterone system tries to kick in to increase the blood pressure for you. But there's only so much angiotensin-converting enzyme. So, if you check their renin levels, they'll probably be pretty high. These are People that may actually respond well to angiotensin 2. Another thing is if a person is on

renal replacement therapy. So, they're septic and they're on renal replacement therapy, there might be some degree of renal dysfunction and patients may respond well to angiotensin 2 because it helps to increase urine output. And the last thing is if the patient was on a pre- illness ACE inhibitor, they may have some degree Of renin-angiotensin-aldosterone system dysregulation and may respond well to angiotensin 2. So, in these situations which a patient is in what's called septic shock and you have them having a renin greater than or equal to 200, they're on renal replacement therapy because they have

severe kidney dysfunction, or they were on an ACE inhibitor before they developed septic shock, they may be a candidate for angiotensin 2. So, I just Wanted to mention that. Again, that was another article that came out that potentially finds one of the nooks or crannies of when that this drug could be utilized. That covers the indications, okay? So, the big one that I want you to remember is septic shock or vasodilatory shock. All of them can be utilized. If you want to know kind of when this one would be utilized, it's based upon those three

parameters. And then the other two Things to mention is vasopressin may be beneficial for a person who is in septic shock and also has central diabetes insipidus or this alone or hepatorenal syndrome. Okay. Titration parameters, it's actually very, very simple. Thank goodness, right? Phenylephrine, we're titrating it to MAP. MAP greater than or equal to 65 mm of mercury is an appropriate goal, okay? Vasopressin, you titrate this to a MAP greater than or Equal to 65 and also to urine output, okay? You expect hopefully putting them on ADH may actually help to put vasopressin or ADH

will change the urine output potentially kind of lowering their urine output a little bit. Okay? But, again, that's going to be one of the big things here. Okay? So, again, vasopressin potentially is going to cause a map you want to titrate it to a map greater than or equal to 65. Angiotensin II again, you're titrating this to a map greater than or equal to 65, but you also have to look at everything else with this drug. You want to look at a bunch of stuff. What's their heart doing, you know, before you started then after

you started this drug? What's their urine output look like? What's their maps look like? What is their overall just clinical physical exam status look like? Are they perfusing limbs? What's their you know, Some of the potential cause that we'll talk about this? Is there any signs of that that we need to turn the drip off or what are you know, so on and so forth? So, again, big thing to know about these drugs is that you're titrating them against blood pressure particularly map having a map goal of greater than or equal to 65 is that

goal. Okay? Now, what are some of the pros of Phenylephrine, vasopressin, and angiotensin II and then what are some of the potential cons? So, one of the beautiful pros about phenylephrine is that this is great in a patient with A-fib with RVR. This is a good one to give. So, remember how we said that norepinephrine, epinephrine, those probably aren't good. Dobutamine probably not good. A-fib with RVR, phenylephrine is actually going to be probably one of the Good ones. And the reason why is you got to go back to this, right? So, you got to remember

kind of your basic physiology. Phenylephrine will cause your vessels to clamp down. It'll increase your blood pressure and that'll try to produce what's called a reflexive so, what's called a reflex bradycardia. Because the whole concept is that if you increase your blood pressure by clamping Down, activates the baroreceptors, baroreceptors go to your medulla, stimulate the parasympathetic nervous system, they cause the vagus nerve to go and release acetylcholine on the SA node and AV node and lower your heart rate. So, it produces a reflexive bradycardia which is beneficial in patients with A-fib with RVR. The other

thing is if a patient has what's called aortic stenosis, they already have a fixed afterload that they're super used to and So this would actually be okay if you're worried about potentially like having lower EFs and stuff like that associated with some cardiac issues. If a person has a aortic stenosis or even a critical aortic stenosis, this is actually a drug that their their their left ventricles already accommodated for this high afterload that it would still be a good drug to give. Now, here's the potential downside of what we talk about with as a potential

Con to phenylephrine. There's this question of what if a person has a low ejection fraction? Can we utilize this drug because it's supposed to clamp down on the vessels and increase the afterload? That may be true. It may be a problem where if a person does have a low ejection fraction and you increase their afterload enough, it makes it harder for that ventricle to be able to push blood out especially if the EF is already low. But, one of the things that you have to remember is not only does it actually increase afterload, but you

have to remember it also increases your preload. And if you increase the preload, that should increase the stroke volume and that should increase the cardiac output. But, here's the big thing. They have to be volume responsive. So, if you have a patient who has a very very like severe systolic heart failure, they're probably Not going to be they're not going to help them by increasing the preload. So, if someone does have a severe ejection fraction that's very low and they're just not volume responsive that would come from that increase in preload that you get from

phenylephrine causing the venoconstriction on the alpha receptors pushing blood back up to the heart, increasing preload, increasing stroke volume, Increasing cardiac output. In a patient with a systolic heart failure which is having a low EF, it may not be the best situation for them because they're not going to be super volume responsive. Okay? So, again, phenylephrine great in a patient with A-fib with RVR because of the reflex bradycardia. It's good in a patient with aortic stenosis because they're already having a fixed afterload that they're used to. And the question always comes is does this actually

Affect can we still use this drug in a person who doesn't have a great ejection fraction? You still can. Okay? You just have to kind of be careful. At the end of the day, phenylephrine is almost equivalent to norepinephrine. It just doesn't have that little extra beta 1 activity in comparison to epinephrine and norepinephrine. Okay? But, phenylephrine still a great drug. Vasopressin, what are some of the pros Of this drug? One of the pros is that it actually acts on the efferent arteriole. Okay? And it actually causes vasoconstriction of the efferent arteriole which increases your

glomerular hydrostatic pressures. And so that may actually help to increase your urine output a little bit. Even though it actually acts at the distal the collecting duct causing water reabsorption, you still may get at least somewhat of an increase in urine output. But, again, you do have it acting on those V2 receptors and so that is going to increase the reabsorption of dilute urine particularly like water. Okay? It also can act on the pulmonary vessels and cause the pulmonary vessels to undergo vasodilation. If you vasodilate the actual pulmonary vessels, that lowers the pulmonary artery pressure.

Okay? Which can make it easier on that right ventricle. Okay? The last thing in the potential con of vasopressin. Okay? Because the good things is that it can help with urine outputs particularly by acting on the efferent arteriole, but again, do remember it does reabsorb water at the collecting duct. It also can lower your pulmonary artery pressure by causing pulmonary artery vasodilation which can put less stress on the right ventricle. But, one of the big things is that If you were having an IV okay? If you have an IV okay? Let's say here's your IV

and the IV is you know, running in through a peripheral vessel. Okay? And somehow that drug that you deliver the vasopressin, right? It somehow leaks out. Okay? Extravasates out of the vessel or through the IV and it gets into the nearby tissues. It can cause tissue Necrosis. Like no joke, you can actually like lose digits, lose fingers and toes if this drug actually does extravasate. So, it does have a very high risk of tissue necrosis and digital ischemia if this drug extravasates. So, that's one of the potential things that you'd really really want to be

careful of if you're running this this drug through a peripheral IV. Okay? The last thing that I want to talk about As the potential cons of angiotensin II and it does have a lot and that's why we don't think that it's this beautiful wonder drug. It's been shown that it can increase thrombosis. Okay? It may increase the activity of the coagulation cascade. And by increasing the activity of the coagulation cascade, it can lead to a prothrombotic state and increased risk of clots. That's not great. The other thing is that it's also been shown to be

able to stimulate potential immune system cells increasing the production of interleukin 6. Interleukin 6 causes one of the one of the big contributors of cytokine storm and which leads to multi-organ system dysfunction. And so in the same way, if you have someone on angiotensin II and they already the person is already having some type of multi-system organ dysfunction, you can potentially worsen That because angiotensin II has been shown to have higher levels of interleukin 6 in these kind of studies. So, one of the big things to remember is that angiotensin II it looks like the

perfect vasopressor, but there is an increased risk of clotting, there's an increased risk of pro-inflammatory states, and some studies even showed with an animal models that whenever angiotensin II gene was actually knocked out, they had Actually like lower mortality rates. So, again, not quite sure about this drug, need more evidence, but it can be a last ditch effort in patients that are on the verge of dying. All right, that covers this group. Let's talk about the next drug which is called methylene blue. All right, engineers, now let's talk about the last part of kind of

like the IV kind of like vasopressor drugs and that is methylene blue. Methylene blue is that kind of Like this is the official like okay, the the person is literally dying. We have them on tons of pressors and we don't have anything else to do at this point in time. But, oh, hey, let's try methylene blue. Methylene blue is good for refractory vasoplegic shock of any type of etiology whether it's septic, cardiogenic, maybe even a person after they had like some type of cardiothoracic surgery, we can utilize this drug. So, really is kind of like

That refractory vasoplegic shock of any etiology, you can utilize this drug. How does this drug work? It's really interesting. How methylene blue works is you have an enzyme. Okay? This enzyme inside of the okay, so it's going to be particularly right here in your vascular smooth muscle. It doesn't really have much of an effect on the heart at all. It's primarily within the vascular smooth muscle. So, in a way, methylene Blue is a pure vasopressor. If you want to put it in that category, it's just a weird way it does it. It's a pure vasopressor.

I just wanted to have this one separate. What it does is if we were to zoom in and kind of look at the enzyme that it affects, there's an enzyme called nitric oxide synthase. What does it do? It synthesizes nitric oxide. So, when you synthesize nitric oxide nitric oxide helps to stimulate the Conversion of what's called GTP into cyclic GMP. Cyclic GMP then helps to stimulate the entry or the pushing of calcium back in to what's called the Okay? So, it pushes the calcium back into the sarcoplasmic reticulum of the muscle. Okay? Now, here's where

it's really interesting. You give someone methylene blue. What methylene blue does Is it inhibits this nitric oxide synthase. That decreases the amount of nitric oxide. It also inhibits the activity of nitric oxide on being able to stimulate there's an enzyme. You know there's an enzyme right here that can you know triggers this step of GTP to cyclic GMP. It's called guanylyl cyclase. And nitric oxide is involved in this step. So what it does is methylene blue Inhibits nitric oxide synthase lowering the nitric oxide. Less nitric oxide means less conversion of GTP into cyclic GMP. So

now I have low cyclic GMP levels. If there's low cyclic GMP levels, there is less of calcium being pushed into the sarcoplasmic reticulum. As a result, the calcium in the actual cytoplasm increases. Because now we're not pushing as much of it into the sarcoplasmic reticulum. Cuz Again, what does methylene blue do? Inhibits the nitric oxide synthase, less nitric oxide, less conversion of GTP to cyclic GMP, less calcium pushed into the sarcoplasmic reticulum, more calcium in the cytoplasm. And then you're going to have more calcium binding to the actual components of the sarcomere and increasing the

contraction of that smooth muscle. And what's going to be the results of that? If I contract the smooth muscle, I'm going to cause Constriction. If I cause vasoconstriction, I increase systemic vascular resistance and effectively increase the blood pressure. That is how this drug works. So again, methylene blue inhibits nitric oxide synthase, inhibits the conversion of GTP to cyclic GMP, inhibits the calcium being put into the sarcoplasmic reticulum, keeps the calcium in the cytoplasm, binds to more sarcomeres, increases more contraction, causes vasoconstriction which leads to An increase in systemic vascular resistance, and increases your blood pressure.

And what kind of patients is this beneficial? This is beneficial in someone with what's called refractory vasoplegic shock of any etiology. Okay? That is something that I really want you guys to remember. Now, how do we titrate this drug? This drug is very interesting. Generally we Kind of base it upon its response. If it works, good. Let's try to keep using it. If it doesn't, we're not going to use it. We'll try something else. So what we do is you kind of give this one. I don't want you guys to focus too much on dosages,

okay? Because it varies from institution to institution. But generally what you do is you give 2 mg per kilogram of the methylene blue and you look at the response. Okay? Was the response good? It wasn't. Then we're not going to eat we're not going to use the infusion. If the response was good, then we're going to put them on an infusion and we're going to titrate that infusion to an actual map goal, okay? So we'll titrate the infusion to a map goal of greater than or equal to 65. And we'll do that generally, you know,

for about 48 to 72 hours, okay? Because there is some really negative effects of this drug and you'll titrate it for About 48 to 72 hours until you start seeing improvement in their hemodynamic status and then see what happens when you pull the drug off, okay? So we have an idea of how it works. We know when we use it. We know how we titrate it to determine even if we want to titrate this infusion. Again, hit them with this dosage, see the response. If they do have a response, put them on an infusion, target

a map greater than or equal to 65 over 48 to 72 hours, Start trying to titrate down on it and see their hemodynamic response. Boom. What are the negative things that you have to be looking out for with this drug? This drug does cause vasoconstriction of tons of vessels, not just systemic vessels. It also clamps down on your peripheral I mean on your pulmonary vessels. So it actually causes vasoconstriction of your pulmonary vessels. If you vasoconstrict the Pulmonary vessels, this increases the pulmonary vascular resistance, increases pulmonary hypertension, and as a result puts stress on the

right ventricle of the heart. Okay? So increases your right ventricular stress. So that's something to think about. On top of that, if you increase the the pulmonary vascular resistance and you clamp down, less blood is going from the right ventricle to the actual pulmonary vessels. So as a result, this can also Lower the oxygen saturation as well on your patient, okay? Not just that. Not only does it lower the oxygen via this mechanism, but it actually if you put a pulse oximeter on the patient, it's interesting. You give someone methylene blue. You put the pulse

ox on, all of a sudden they're going to have like a pulse ox of like 52% and you're going to be like, "Oh my gosh, this person's dying." It's actually not because of that. It's not Because they're not oxygenating maybe properly. It could be, but it's actually the methylene blue actually alters the effectivity of the pulse oximetry to determine their true pulse their true saturation of oxygen. So that's another thing to be thinking about. When you give someone methylene blue, be prepared for their O2 saturation on the pulse ox to say that they have a

very low O2 saturation, okay? All right. So we know that it increases Pulmonary vascular resistance, causes pulmonary hypertension, causes more stress on the right ventricle, can cause a lower oxygenation status, and big thing to remember, it can actually cause an inaccurate reading on the pulse oximeter. All right. What's another potential con to this drug? Another potential con is it is what's called a mono amine oxidase type A inhibitor. So what that means is is going to inhibit the monoamine oxidase A enzyme and Because of that it increases the level of 5-hydroxytryptamine within the synapses, serotonin.

You know what that can lead to? Serotonin syndrome. So it can lead to serotonin syndrome. It actually may not be a bad thing in a patient with significant hypotension. It actually may increase their blood pressure, increase their heart rate, all of that stuff. But either way, it's not a great thing to have. But it is a possibility of Serotonin syndrome with this. Another thing, because it acts as an oxidizing agent, in patients with what's called G6PDH deficiency, okay? It can act as an oxidizing agent and cause more damage to their actual red blood cells, increasing

the Heinz body production. And this can lead to an increase in their hemolytic anemia. So you can see an increase in their Hemolytic anemia because of the oxidizing effect, especially in these patients with G6PDH deficiencies, serotonin syndrome, potential O2 desaturation, increased stress on the right ventricle, inaccurate reading of their pulse oximeter, and what else? It also interferes with the cytochrome P450 system. It's an inhibitor. So because it's a cytochrome P450 inhibitor, it increases the drug Concentration of other drugs. So increases drug concentration of other drugs. So if you give someone warfarin, if you give someone

fentanyl, if you give something digoxin and you give them methylene blue, all of those drugs are going to be in higher concentration than they should be because this drug methylene blue inhibits that cytochrome P450 system. The so the metabolism of those other drugs are affected in that sense. So you See how it can be a very powerful drug, but there is a ton of different cons associated with it. Okay. The next thing that we have to talk about is when we give these drugs, can we run it through a peripheral IV? Do I absolutely need

a central line? And do I need an arterial line to monitor these actual drugs? All right. So now the next question is, okay, we got a patient crashing, all right? Their pressure's Like 40 over dead and and we got to run some vasopressors in there to get their pressure up. What do I do? Can I Oh, Zach, I don't only have a peripheral IV. All right. Run that sucker through the peripheral IV. It is okay in a crashing patient. You need to support their hemodynamics. So peripheral IV So peripheral vasopressors are safe for a very

short period of time. There is particularly ones that we should be very very careful of, but it Is okay. So whenever we have peripheral IV, yes, this is okay. You can run these through a peripheral IV safely. There's a couple things that you have to be careful of. So hold on real quick. Peripheral IV, it is safe, but you have to be very careful. You have to have a lot of parameters that you're monitoring for. First thing I always tell some of my nurses is that, okay, if you're having a person running you're Running vasopressors

through a peripheral IV, let's make sure that that peripheral IV is easily able to be kind of monitored. I don't want any kind of like deep ultrasound guided IVs into the antecubital fossa, none really in the hand. I want that somewhere in an area like a vessel where you can actually kind of monitor any surrounding tissue necrosis. That's an important thing to be able to do. So try not to have deep ultrasound guided IV because then it's Going to be difficult to be able to discern is there any kind of extravasation or tissue necrosis, okay?

Second thing is, if you're running a particular type of vasopressor, make sure that there is some type of counteracting agent that you can utilize in case it does extravasate. For example, there's a drug called phentolamine. So in patients who are taking some type of catecholamine type of vasopressor, phenylephrine, Norepinephrine, epinephrine, those kinds of drugs we can actually utilize phentolamine against. The ones that I would say be very cautious and probably not try to run through peripheral IV for very long whatsoever is vasopressin. And you shouldn't be using this drug anyway, but dopamine. Okay? These ones

you got to be cautious because these ones if they do extravasate, there is risks of tissue Necrosis. Norepinephrine, you shouldn't do this for a super long period of time. Eventually, if you're going up on dosages, you should put in a central line. But, phenylephrine, as well as epinephrine, those ones have had pretty safe There's almost like no case reports of any kind of like extravasation tissue tissue necrosis associated with those, okay? But, peripheral IV, if someone's dying actively in front of you, you should run Those vasopressors through peripheral IV until you get them a little

bit stabilized, and then you can put in a central line. So, central lines is kind of like the best thing that you should try to do um if you need it. So, whenever you have to put in what's called a central venous catheter, this is because you're pushing maybe higher dosages of the drugs, you have a high risk of tissue necrosis with the type of agent that you're using, you're trying To push tons of fluids, uh whatever it may be, central venous catheters are kind of the designed go-to. And so, generally, you can use what's

called an internal jugular vein, you can use what's called a subclavian, or you can utilize what's called a femoral vein. These are just larger veins that, you know, they're you're able to push some of these actual uh sclerosing or kind of like really caustic types of Agents through, okay? As well as push large volumes of fluid. So, central venous access is kind of going to be It should be the, you know, the gold standard type of thing that you're doing for a patient whenever you're running high-dose vasopressors. You don't want to have all of these

things running through peripheral IVs for a long period of time, and you also just want to be very cautious, okay? But, if you're having on someone on a very low dose of A vasopressor, and you're running it through peripheral IV, that is okay. Okay? The last thing is should we have arterial lines whenever we're having a patient on a vasopressor? The reason why is arterial lines will give us an adequate kind of like a particularly, you know, sometimes a very accurate kind of measurement of the mean arterial pressure. So, arterial lines are good to use

if you're trying to get maybe an accurate MAP on someone who maybe has a problem or a decorrelation within their their their cuff pressures. So, if you have someone who has issues with their cuff pressures where maybe they're just a vascular path and you're not very getting very good kind of cuff pressures, it doesn't really make sense, or they have like a subclavian stenosis or an aortic dissection of some kind, and you're getting inadequate or Differences in their their cuff pressures, it may not be a bad idea to put in arterial line. Arterial lines are

going to give you a little bit of a better idea of what their mean arterial pressure is, especially if you lose a pulse in a patient who is significantly hypotensive, at least arterial line will be able to give you a very good representation if they still have any types of pulse pulsatile activity on monitor as Compared to trying to palpate and find a pulse. So, not a bad thing to have arterial lines. Okay? So, that covers that aspect. The last thing that I wanted to cover um is there is a type of oral vasopressor if

you'd like to consider that, and it is called midodrine. Midodrine's primary mechanism of action, you can literally think about this as a oral type of phenylephrine. It's Primarily an alpha-1 receptor agonist. And so, it's going to cause an increase in vasoconstriction, increasing your systemic vascular resistance, increasing your blood pressure, and potentially increasing afterload. But again, it's also going to it's going to do this on the arterioles, but it's also going to do this on your venules. So, you're also going to get an increase in preload within the venules, you're going to get an increase in

stroke volume, and you're Going to potentially get an increase in cardiac output, okay? So, it has receptors on the arterioles, and it has receptors on the venules, okay? So, you can get a little bit of a clamping down here, increasing your systemic vascular resistance, and you can get a little bit of a clamping down here to increase the actual return of blood to the right ventricle. So, pretty much similar to Phenylephrine. Now, what are the indications for this drug? This is where it's commonly utilized in an ICU. You have a patient who's been on some

phenylephrine, they've been on some Levophed, they're on a really low dose. Maybe they're on like, you know, 30 of phenylephrine, maybe they're on like two or three of, you know, norepinephrine, and you're trying to get Them off of that vasopressor so that you can, you know, get them out of the ICU, okay? In those situations, sometimes this drug is utilized to wean vasopressors the IV, okay? To wean off the IV vasopressors. There is a trial called the MIDAS trial. And the MIDAS trial said that it is not actually that effective um in utilizing midodrine to

be able to Wean off vasopressors. We still utilize it, though, um because it does have this alpha-1 agonist activity. Again, the data says it's not really that great at being able to wean vasopressors, but again, we still utilize that in that kind of manner. The other utilization of this drug if someone does have is they're on a vasopressor, and you're trying to wean them off where it may be actually beneficial is if a Person has what's called hepatorenal syndrome. Because it may actually cause um some effects particularly to the renal vessels um in in helping

to particularly causing some particularly in a person who has hepatorenal syndrome, it may actually work by causing some some splanchnic vasoconstriction, helping to increase kind of the flow through the actual Portal vessels. So, in that situation, it may be somewhat helpful in a patient who has hepatorenal syndrome. You should give something like midodrine and octreotide as well. Uh but again, indication-wise, sometimes we utilize this to wean vasopressors off, the IV ones. The MIDAS trial says that it's maybe not that effective, but you can also give this to patients in hepatorenal syndrome. What are the cons

of this drug? The cons of this drug is that it is actually renally excreted, okay? So, if a person has significant CKD or renal dysfunction, it may actually accumulate. That's one particular thing. And then, the second thing is that it actually, just like phenylephrine, can produce a reflex bradycardia, okay? So, that's something to think about. Generally, whenever people are weaning This drug trying to wean IV vasopressors, you can start something like midodrine like 10 mg Q8 hours, and you can titrate up to about 40 mg Q8 hours. Um if you're trying to wean them off

these vasopressors, just have to be again considerate of their actual underlying renal function, and again, realize that there is a potential for it to produce a little bit of a stress on that heart if Someone has a very significant low ejection fraction and a bad systolic heart failure that wouldn't be responsive to an increase in preload. But, that covers our vasopressors. All right, engine nerds, in this video, we talked about vasopressors. I hope it made sense. I hope that you guys did enjoy it. As always, engine nerds, until next time.