Hi there. My name is Ryan Morgan. I'm a pediatric intensivist at the Children's Hospital of Philadelphia, and this talk is on vasoactive agents. I have no relevant financial conflicts. I do have grant support and sit on the AHA's Emergency Cardiovascular Care Committee. Both of those things are related to resuscitation, so only indirectly related to this lecture. By the end of this talk, you should understand the pharmacology of commonly used vasoactive agents, specifically to understand the effects of some pathomimetic agents based on their adrenergic receptor interactions, and you'll be able to understand the mechanism of action of inodilators and their effects on cardiac output. In order to accomplish these objectives, we'll start by going through the general physiologic mechanisms of vasoactive agents and when they're indicated. We'll talk about classes of agents and their actions. We'll spend a good deal of time on adrenergic receptors and signal transduction, then dive in on specific adrenergic agents, vasopressin, and inodilators, specifically phosphodiesterase inhibitors. Let's get started with the case. So a 15-year-old female is admitted with toxic shock syndrome. She's received fluid resuscitation with more than 60 mLs per kilo of normal saline, and an essential venous catheter has been placed. She has bounding pulses, flash capillary refill, a serum lactate of 3.8, and the following vital signs, heart rate 141, blood pressure 85 over 29, respiratory rate of 26, and setting 97%. In choosing a vasoactive medication to initiate for this patient, which of the following physiologic properties are most important? A. Chronotropy, B. Leucotropy, C. Inotropy, D. Augmentation of SVR, or E. Reduction of SVR. Right off the bat, the question stem generously offers us the patient's diagnosis of toxic shock syndrome. We know that she's already received 60 mLs per kilo of crystalloid. She has bounding pulses, flash cap refill, suggesting that she's in warm shock, and her heart rate is still elevated. She has hypotension with a wide pulse pressure, strongly suggesting that vasodilation is her primary pathophysiologic problem. Therefore, in choosing an agent, we should look for one that raises systemic vascular resistance to help us get her distributive shock under control. We'll come back to her. So when we, as intensivists, reach for a vasoactive medication, it's usually to either treat shock or to treat some sort of physiologic derangement that we're concerned could cause shock. So while other lectures in this series are gonna focus on shock physiology in more detail, and specifically on septic shock, it's important that we at least define the problems that we're aiming to treat. Shock, as you know, is really defined by inadequate or mismatched oxygen delivery to the tissues. And oxygen delivery is determined by how much oxygen is in the arterial blood, the arterial content of oxygen, made up by your satin hemoglobin, as well to a lesser extent by the dissolved oxygen. But really what we're gonna focus here on is cardiac output. Cardiac output, of course, is your stroke volume and your heart rate, with your stroke volume being determined by your afterload, your contractility of your myocardium, and your preload. The vasoactive agents that we're gonna be talking about today are really treating these four things, afterload, contractility, preload, and heart rate. And that gets us to the general actions or characteristics of the vasoactive agents that we'll be chatting about. So we have inotropes that improve myocardial contractility, vasopressors that increase systemic vascular resistance, vasodilators that decrease systemic vascular resistance, chronotropes, which increase heart rate, and leucotropes, which improve diastolic relaxation of the ventricle. And for the purposes of this talk, we're really gonna focus on those agents that we commonly use in the ICU. So we're gonna talk about our adrenergics, our catecholamines, phenylephrine, norepinephrine, epinephrine, dopamine, dibutamine, and isoproterenol. We'll talk about vasopressin, which is in a class by itself, and the non-sympathetic inodilators, primarily focusing on the phosphodiesterase-3 inhibitors. And here you can see a breakdown of the adrenergics based on the receptors that they act upon. This table flows from pure alpha through the mixed agents and down to pure beta. And we'll talk about these in a lot more detail soon. So let's just broadly discuss the adrenergic receptors in terms of what they do and where they live. Alpha-1 receptors are predominantly located on vascular smooth muscle. Activation of these receptors leads to contraction of that smooth muscle, vasoconstriction, and increased systemic vascular resistance. Alpha-2 receptors are primarily located on presynaptic nerve terminals of the autonomic nervous system. In the sympathetic nervous system, they really exist as a native negative feedback loop. So binding to these leads to the eventual decrease in the release of norepinephrine, thereby causing vasodilation. Alpha-2 receptors are also located within the CNS, but that's beyond the scope of this talk. Beta-1 receptors are primarily located in the heart. They're also located in the kidney, but that's beyond the scope of what we're talking about here. The net effect of beta-1 activation is to increase contractility with a little bit of leucotropy and to increase conduction throughout the conduction system, thereby increasing heart rate. So they serve as a chronotrope. Beta-2 receptors, like alpha-1 receptors, are located in the vascular smooth muscle of our blood vessels. Activation of beta-2 receptors has the opposite effect that alpha-1 has, though, as it causes relaxation, vasodilation, and decreases an SVR. The alpha and beta adrenergic receptors, which we now know there are multiple subtypes and even sub-subtypes are, are transmembrane proteins that live in the cells of the tissues that we just mentioned. The protein structure is depicted here. It consists of seven membrane-spanning alpha helical domains. The N-terminus is extracellular. The C-terminus is intracellular. And the most important characteristic of these receptors is that they're tightly coupled with membrane-bound G-proteins on the intracellular side. We're gonna talk about those in a lot more detail. So these G-proteins are also membrane-bound. They're so named G-proteins because they're closely associated with either GDP or GTP. GDP when they're in their inactive or unbound state, and GTP after ligand actually binds to the extracellular side of the receptor. They are heterotrimeric with alpha, beta, and gamma subunits. And the specific subunit composition, particularly of the alpha subunit, determines what the downstream actions of a particular G-protein are going to be when a ligand binds to the associated receptor. These compositions and these actions vary depending on the type of receptor and they vary depending on the type of tissue that the receptor and the G-protein are located in. So what actually happens when one of these receptors is bound? Regardless of the ligand, regardless of the receptor type, and regardless of the cell type, there's a common series of events involved in G-protein activation in all of these cells. So we have our G-protein coupled receptor, which for us are our adrenergic receptors, associated on the cell membrane with a heterotrimeric G-protein. Here in its inactive state, it's bound to GDP. Binding of the signaling molecule to the extracellular portion of the receptor causes a conformational change in the intracellular portion, which then causes the alpha subunit of the G-protein to exchange GTP in place of GDP. This activates the alpha unit, which then can separate from the beta and gamma subunits, which then triggers a downstream response that again varies depending on the type of receptor and the type of cell. GTP is then hydrolyzed back to GDP. The signaling molecule comes off the receptor. There's a reassociation of all of these proteins back together, and it's ready to be activated again. The alpha subunit structure determines what it does and what other proteins it acts upon after it dissociates from the other subunits of the G-protein. For adrenergic receptor associated G-proteins, we classify these alpha subunits and the G-proteins themselves as one of three subtypes. So GS is for stimulatory. These proteins stimulate adenylate cyclase. GI is inhibitory. These inhibit adenylate cyclase. And GQ proteins stimulate phospholipase C. And we'll go into detail on what this means. How do these G-protein subtypes match up with the types of adrenergic receptors that we already know about? So beta-1, beta-2, and DOPA type 1 receptors are all associated with GS or stimulatory G-proteins. Alpha-2 receptors are associated with GI or inhibitory G-proteins. And this actually makes intuitive sense because you'll remember that the alpha-2 receptors are located on presynaptic nerve terminals and binding to them actually inhibits the release of norepinephrine. And finally, alpha-1 receptors have the GQ subtype of G-proteins all to themselves. You'll also see D2 type 2 dopaminergic receptors are on here. We're not gonna talk about the brain today, but you'll remember that D2 activation in the brain inhibits prolactin. So unsurprisingly, D2 receptors are associated with an inhibitory GI protein. Let's get back to our patient with toxic shock syndrome. So remember, she's gotten her fluid resuscitation. She's got bounding pulses. We've said she has warm shock. And we've decided that we wanna start an infusion of a vasoactive medication. Which of the following cellular signaling mechanisms should we be seeking to activate with our choice of medication? Take about 15. The best choice here is C, GQ protein activation to increase the release of 1,2-diacylglycerol and inositol triphosphate. Getting to the right answer here was a multi-step process that incorporates a lot of what we just talked about. With the first question that we asked about this patient, we had already decided that what we needed to do for her vasodilatory shock was pick an agent that increased systemic vascular resistance. Maybe we have an agent in mind, but what we really need to know is what kind of receptor do we want to act on. And of the ones that we've learned about thus far, it's an alpha-1 that we want to activate in order to induce vasoconstriction. Then we need to remember what alpha-1 was associated with in terms of the subtype of G protein. And alpha-1, as you'll recall from the last slide, is associated with the GQ protein. We haven't talked about the downstream effects of GQ activation, but we're about to. When phenylephrine, norepinephrine, epinephrine, or dopamine bind to an alpha-1 receptor on smooth muscle tissue, it causes conformational changes in the protein, which triggers the alpha-Q subunit of the G protein to drop GDP in exchange for GTP. This activated alpha-Q subunit then dissociates from the rest of the G protein, heads down the cell membrane, where it activates phospholipase C. Activated phospholipase C then hydrolyzes phosphatidyl inositol bisphosphonate, or PIP2, to inositol 145 triphosphate, IP3, and diacylglycerol DAG. IP3 binds to specific receptors on the endoplasmic reticulum, triggering calcium release into the cytosol. It also has effects on the efflux of extracellular calcium into the cell as well. The combination of diacylglycerol and increased intracellular calcium allow for the activation of PKC, protein kinase C, triggering additional calcium influx. And the net clinical effects of this increased cytosolic calcium, of course being in vascular smooth muscle cells, is that it causes vasoconstriction. When norepinephrine binds to an alpha-2 receptor, it causes the same sorts of conformational changes in the G protein, again, GTP taking the place of GDP, the alpha, now alpha-I subunit of the G protein dissociating from the other subunits. Because this is an inhibitory protein, it inhibits the action of adenylate cyclase. Adenylate cyclase, when it's activated, is responsible for the conversion of ATP to cyclic AMP. Because that process does not happen when adenylate cyclase is inhibited, we have decreased concentrations of cyclic AMP in the cytosol. For that reason, phosphokinase A remains inactive. The proteins that need to be phosphorylated in order to allow norepinephrine to be released are not phosphorylated, so we have decreased net norepinephrine release from the presynaptic terminal. The clinical effects of this, again, less presynaptic endogenous norepinephrine release means relative sympatholysis in the autonomic nervous system, which amounts to mild vasodilatory effects. Moving from alpha onto beta-adrenergic receptors, we have isoproteranol, dibutamine, dopamine, epinephrine, and norepinephrine act on beta receptors. This general schematic applies to both beta-1 and beta-2 receptors. After going through the initial intracellular cascade, we'll get into the different downstream effects depending on the cell type and the receptor type. So starting off from the same point, ligand binds, alpha subunit, this time it's the alpha-S subunit of the G protein, takes on GTP in exchange for GDP, moves down the cell membrane, this time in a stimulatory fashion, activates adenylate cyclase, which can then convert ATP to cyclic AMP, increased concentrations of cyclic AMP in the cytosol activate phosphokinase A. In the heart, this activated pKa leads to calcium channel phosphorylation, this channel is open, cytosolic calcium increases, this causes enhanced conduction, meaning increased heart rate, as well as increased contractility. To a lesser degree, this increases the capacity of the sarcoplasmic reticulum to hold on to calcium, increasing its capacity for diastolic relaxation and leucotropy. In vascular smooth muscle mediated by beta-2 receptors, activated pKa activates calcium pumps, thereby increasing calcium uptake by the sarcoplasmic reticulum, decreasing the cytosolic concentration of calcium, thereby causing smooth muscle relaxation and vasodilation. So both beta receptors trigger the same cascade, but in different tissues, eventually leading to activation of proteins with opposite effects on cytosolic calcium concentration. Let's take a break from cell biology and get back to our patient. So remember this is our 15-year-old female admitted with toxic shock syndrome. She's received fluid resuscitation, has a central venous line, she has bounding pulses, flash capillary refill, lactate of 3.8, heart rate of 141, blood pressure of 85 over 29. Which of the following vasoactive medications will best address this patient's principal physiologic disturbance? So the answer we're looking for here is D, phenylephrine. You may have been looking for norepinephrine as an answer choice. That's what I would have chose as well if it were there, as it's really one of our go-tos for first line for septic shock and for warm shock in particular, which this patient clearly has. So then we have to look at a little bit more detail in terms of what the question was actually asking to make our next best choice. And what we're asking for is the medication that will best address the patient's principal physiologic disturbance. So we've already said that this patient's principal physiologic disturbance is pathologic vasodilation. So it then boils down to which of these is the most potent vasoconstrictor, and that's phenylephrine. If we were looking for overall the best clinical choice for this patient, it might actually be epinephrine, since phenylephrine is not all that commonly used in the PICU, certainly in the setting of septic shock. We'll use this as our introduction to phenylephrine, and with that, we're gonna quickly run through all of the adrenergic agents, starting with the pure alpha agents and moving on to the pure beta agonists. So as I mentioned, phenylephrine is a pure alpha-1 agonist. It's therefore a potent vasoconstrictor with its principal role being increasing systemic vascular resistance. It does not have any direct cardiac effects, but it can cause reflexive bradycardia due to hypertension. Phenylephrine is used for any kind of vasodilatory state. It's particularly useful in spinal shock. It can be a go-to when there's a desire to avoid any kind of catecholamine that might also cause beta activation. And because it only acts on one type of receptor, it can be somewhat of a clean drug to use when we're trying to drive perfusion pressures like cerebral perfusion pressure in the setting of TBI, or when we're trying to drive up SVR, for example, in the setting of a cyanotic test spell. Like all alpha adrenergic agents, it can cause end-organ ischemia and can cause particularly severe tissue necrosis with extravasation. Like many of the drugs that we're gonna talk about, it has a rapid onset and a short duration. It can be given as both a bolus and an infusion. With infusion dosing relatively similar to norepinephrine and epinephrine. Like phenylephrine, norepinephrine is predominantly an alpha-1 agonist. It does also have some beta-1 effect and very minimal beta-2 effect. But with that alpha-1 predominance, its principal role is vasoconstriction and increasing SVR. The direct beta-1 effect can cause some chironotropy, but usually the increase in SVR and the reflexive bradycardia that occurs due to that is more substantial than the direct beta-1 effect. So on average, heart rates will be the same or slightly lower. The indications for norepinephrine are pretty broad. We're talking about shock states with low or relatively low vascular tone. There's a risk of particularly mesenteric or renal ischemia. This risk is relatively lower than previously thought in some of the older literature and probably on the same scale as other mixed alpha-beta agents. In mixed shock states where perhaps the myocardial dysfunction is a little underestimated, the increase in SVR with norepinephrine can potentially cause decreased cardiac output. This is something to think about in pediatrics since many of our patients do have myocardial dysfunction, even in the setting of predominantly distributive shock. Half-life again is on the order of a couple of minutes. Starting dosing is here, typically not given as a bolus dose. Epinephrine, as you know, is a mixed beta-alpha agonist. It does this in a dose-dependent fashion whereby at relatively low doses, the beta effects predominate, whereas at higher doses, the alpha effects predominate. There's likely a good deal of variability between individuals in terms of the dosing at which we start to see that shift from beta to alpha. This is due to differences in receptor concentration on the target tissues, due to some polymorphisms that actually affect the affinity of the receptors for epinephrine, and due to changes in the rate of drug clearance in the setting of comorbidities or just patient characteristics. Regardless, the main vascular effect is vasoconstriction, which increases SVR. However, at low doses where the beta effects really predominate, we can see mildly decreased SVR. Cardio effects are chronotropy, inotropy, with increased myocardial oxygen consumption. The indications for epinephrine are pretty wide-spanning. Any kind of low cardiac output state, and it's given algorithmically as a component of cardiac arrest and anaphylaxis. Like the other alpha agents, it can cause splenic vasoconstriction. It can be proarrhythmogenic. And beta activation can drive potassium into cells, thereby causing hypokalemia, and can cause hyperglycemia through glycogenolysis. It is important to note that like norepinephrine and dopamine, it is an endogenous catecholamine, and it's very similar in chemical structure to both of those, formed by the addition of just one methyl group to norepinephrine. Its half-life is on the order of a couple minutes. The infusion dosing is seen there. The code dosing is also viewed there. I won't go into it in detail here, but with all the different concentrations of epinephrine, the fact that it's sometimes referred to, especially in code situations, and it's milligram per kilogram dose rather than the micrograms per kilogram dosing, and the fact that there's orders of magnitude of difference between dosing for shock versus cardiac arrest in other states, makes it a really easy area to get confused on, so it's worth kind of just sitting down and reviewing that information. Dopamine has a wide range of effects on various different receptor types, affecting predominantly dopamine receptors at low doses, beta receptors at medium doses, and alpha receptors at high doses. There's classic teaching about what these dose ranges are, with low dosing typically being zero to three or zero to five, moderate dosing being in the three to eight or five to 10 range, and high dosing usually being around 10 or higher than 10, up to usually a maximum dose of 20. However, like epinephrine, this is likely an oversimplification, and what's a moderate dose for one individual may be low or high for another individual. This really just highlights that after we choose a dose, we really have to be mindful of the physiology in front of us as we titrate it. The vascular effects of dopamine depend on which receptor sets we're activating, so the D1 receptors are in the splenic circulation, especially in the renal arteries, where activation causes vasodilation, beta two activation at moderate dosing causes a decrease in systemic vascular resistance through vasodilation, and alpha one activation causes vasoconstriction and increased SVR. In the heart, dopamine increases heart rate and increases contractility, especially at those moderate doses. It does cause an increase in myocardial oxygen consumption. The relatively mixed alpha beta effects of dopamine, like that of epinephrine, really allows it to kind of be a catch-all for general low cardiac output states. However, as we've learned more about its side effect profile, it's started to fall out of favor in some centers in recent years. So dopamine is prorythmogenic. In an adult study, it was actually shown to be twice as arrhythmogenic as norepinephrine in patients with septic shock. At high doses at which the alpha effects predominate, it can cause the splenic vasoconstriction and potentially ischemia. It also crosses the blood-brain barrier and can decrease prolactin through its D2 effects, as well as decreasing other pituitary hormones. And in recent years, we've really learned a lot more about its immunomodulatory effects, where it causes really a harmful suppression of T lymphocyte proliferation and function. Its chemical structure is also very similar to norepinephrine and epinephrine. It's the precursor to norepinephrine in the synthesis pathway that you can see there. And when given exogenously, a proportion of exogenous dopamine is actually converted by the body to norepinephrine. While its half-life is still measured in the order of minutes, there is a bit of a wider range depending on age and depending on comorbidities. And again, you can see the dosing there. Next up is dibutamine. So dibutamine is generally thought of as a beta agonist. However, its pharmacology is a little bit more complicated than that, and it's important to consider. So the formulation of dibutamine that we use is actually a racemic combination of two dibutamine isomers. One of these is a strong beta agonist and an alpha antagonist. The other is an alpha agonist and a weak beta agonist. The net effect is typically for those alpha effects to cancel out, and we're left with a beta agonist effect where generally the beta one effects predominate over the beta two, but both are certainly present. Therefore, we tend to see that the net vascular effect is vasodilation with decreased SVR. The cardiac effects, of course, are chronotropy and inotropy. And so the indications for this really tend to be for non-vasodilatory shock. And we frequently reach for this in the setting of myocardial dysfunction in particular. Adverse effects, like a lot of these beta agents, as we'll talk through them, is increased myocardial oxygen consumption, tachycardia, arrhythmias, and particularly an increased outflow gradient and LVOT obstruction. The pharmacology, again, is on the order of a half-life on the order of two to three minutes. And you can see here that the dosing is very similar to that of dopamine. Isoproteranol is a pure beta agonist that causes vasodilation and decreased SVR, as well as chronotropy and inotropy. It can also be used for myocardial dysfunction without concomitant vasodilation, but has become less commonly used, especially with the increasing use of the phosphodiesterase inhibitors. It can, however, be used for refractory bradycardia due to its direct beta one effects on chronotropy. Adverse effects include increased myocardial oxygen consumption, arrhythmias, and again, increased outflow gradient and LVOT obstruction, where it's more strictly contraindicated. Similar half-life to most of our other agents, and infusion dosing that is similar in order of magnitude to epinephrine and norepinephrine. Let's change gears and tackle another patient case. A two-year-old male with multiple chronic medical conditions is in the PICU recovering from orthopedic surgery. He has a central venous catheter in place for TPN. Overnight, he develops a fever. His heart rate is 158, and blood pressure is 68 over 40. After administering 40 per kilo of crystalloid, you perform a bedside cardiac ultrasound that demonstrates mildly diminished myocardial function. On exam, the patient is warm with one second capillary refill. You decide to initiate a vasoactive infusion. You decide to initiate a vasoactive infusion. Which of the following is the best option for this patient? The best answer choice is C, epinephrine. This patient has risk factors, signs, and symptoms consistent with septic shock. His shock seems to have both cardiogenic and distributive components. So as we look through these answer choices, agents with a mixed alpha and beta effect are probably going to be the ones that we want to reach for. Dibutamine and isoproteranol, and the patient with sepsis and one second capillary refill may cause additional vasodilation and potential harmful drops in SVR. Milrinone, as we'll learn soon, will also likely decrease SVR more than we want in this patient. So it comes down to dopamine and epinephrine. Both will likely have similar hemodynamic profiles for this patient. However, this is a patient with sepsis, and we actually have pediatric surviving sepsis guidelines that now tell us that epinephrine is a first-line medication to choose for the patient with sepsis, with dopamine really having been relegated to second line after either epinephrine or norepinephrine. Which of the following exerts its primary vasoactive effects through GQ protein activation to increase the release of 1,2-diacylglycerol and inositol triphosphate? A, dibutamine, B, milrinone, C, isoproteranol, D, vasopressin, or E, nitroprusside. The correct answer here is D, vasopressin. So you'll remember from a few moments ago that dibutamine and isoproteranol are primarily beta agonists and therefore act through GS proteins. Milrinone is a phosphodiesterase inhibitor and does not directly interact with G proteins, nor does nitroprusside. So let's talk about vasopressin. So vasopressin mediates its vasoconstrictor effects through the V1A receptor. The V1A receptor is associated with a G protein and it's a G-alpha-Q subunit. So it has the same intracellular pathways as the alpha-1 receptor pathways. So here with the V1 receptor, towards the left of the screen, you can see that pathway, the activation of phospholipase C leading to the release of IP3 and DAG, eventually causing an increase in cytosolic calcium, which causes vasoconstriction. Now in these cells, vasopressin has multiple other effects that you can see here, including platelet aggregation, ACTH release, the modulation of several other signaling pathways, but we're really gonna focus on the increased SVR from the calcium-mediated vasoconstriction in the cell. Like I mentioned, the V1A receptor is the one that we're concerned with here. It mediates that vasoconstriction in a substantial increase in systemic vascular resistance. There are no direct cardiac effects of vasopressin, though it does potentially increase myocardial oxygen consumption due to that increase in afterload. Of note, many of the catecholamines that we discussed earlier can increase pulmonary activity or earlier can increase pulmonary vascular resistance through alpha-1 activation in the pulmonary vasculature. It seems that vasopressin receptors are expressed to a lesser degree than those alpha-1 receptors in the pulmonary vasculature, so vasopressin can be a good choice to potentially spare increases in PVR that may be harmful in certain disease states. The main indication for vasopressin in shock is vasodilatory shock. It's usually a second line or an addition to alpha-adrenergic agents once those doses start to climb. Adverse effects like the alpha agent are splanchnic ischemia, and we also see limb ischemia with vasopressin. The infusion dosing is seen there. There is a cardiac arrest dosing recommendation here, though it has been removed from the ACLS guidelines. And it's important to note that even though the antidiuretic dosing of vasopressin is less than this hypotensive dosing of vasopressin that we use, the ADH effects of the drug are usually not seen in the setting of hypotension. Let's change gears again for another case. A 12-year-old boy presents with general malaise and abdominal discomfort. In the emergency department, he has the following vital signs, heart rate, 126, respiratory rate, 28, blood pressure, 108 over 70, stating 93%. He is awake and alert, has cool distal extremities, and a possible gallop on exam. Chest X-ray demonstrates a large cardiac silhouette and moderate pulmonary edema. An echocardiogram demonstrates severe LV dysfunction and dilation. Which of the following interventions should you initiate? A, The best answer here is milrinone. So this patient has acute heart failure and cardiogenic shock. A normal saline bolus would be strictly contraindicated. Norepinephrine would likely cause a harmful increase in SVR and cardiac afterload. Low-dose dopamine or epinephrine can sometimes be considered in these clinical situations. However, the fact that the patient does have a normal blood pressure suggests that SVR is quite high and that an inodilator like milrinone would have the best side effect profile and likely the best efficacy. That brings us to the inodilators and specifically the phosphodiesterase 3 inhibitors. So we may all be getting a little burnt out by the cell biology at this point, but thankfully, again, the biology of the phosphodiesterase 3 inhibitors overlaps with that of the drugs that we've already talked about. You'll remember from earlier that the beta agonists mediate their effects both in the heart and in the smooth muscle through the activation of adenylate cyclase. Adenylate cyclase converts ATP to cyclic AMP, and cyclic AMP then has multiple downstream effects. The phosphodiesterases are a family of enzymes that break down cyclic AMP into AMP, thus deactivating cyclic AMP, decreasing its concentration in the cytoplasm, and inhibiting those downstream effects. So by inhibiting phosphodiesterases, the phosphodiesterase inhibitors increase the concentration of cyclic AMP and potentiate those same effects that the beta agonists had, that being contractility and inotropy in the heart and vasodilation with decreased SVR in the vasculature. Again, phosphodiesterase inhibition leads to decreased degradation of cyclic AMP, allowing continued PKA activity, increasing contractility, and vasodilation. Also enhances sarcoplasmic reticular uptake of calcium, which allows for leucotropy. The principal vascular effects are vasodilation with decreased SVR. It's an inotrope. The main indications are cardiogenic shock. You usually want to do this when there's high or normal blood pressure. Adverse effects are hypotension due to low SVR. The average half-life is on the order of a couple hours, but this is highly variable. And in looking through this, I've seen anything from 30 minutes to 17 hours cited, depending on a number of factors. Because of this long half-life, it is recommended that milrinone be administered as a bolus followed by an infusion, though many centers omit this bolus in clinical practice due to the concern for hypotension. The other common phosphodiesterase-3 inhibitor is amrinone. Both of these drugs. Let's tackle a few more questions in our last minutes here. The green pressure-volume relationship on the right represents that of a healthy child. After an intervention, the child's new LV pressure-volume relationship is in red. What was the intervention? A. Milrinone bolus and infusion B. Normal saline bolus C. Norepinephrine infusion D. Dibutamine infusion E. Furosemide injection The best answer here is C, norepinephrine infusion. This really just serves as a reminder to take a look at these pressure-volume relationships as they will likely appear on the board's exam. In short, the shift from the green to the red dotted line is the classic appearance of the application of increased afterload. The purple line, which is the end-systolic pressure-volume relationship, which represents contractility, has not changed. So anytime you're just changing afterload or preload, you're not changing the slope of that line. When the slope of that line comes down, that indicates enhanced contractility. We would see that with either milrinone or with dibutamine. Volume loading with normal saline, assuming, again, that this is a normal heart, would actually widen the base of the curve, representing a higher stroke volume. But the application of afterload narrows the dimensions of the curve, representing less stroke volume for more cardiac work. Another question. A six-year-old previously healthy girl presents with a purpuric rash, altered mental status, and the following vital signs. Heart rate, 167, respiratory rate, 46, blood pressure, 62 over 33, setting 93%. You administer 60 per kilo of balanced crystalloid solutions. Her heart rate briefly decreased and blood pressure briefly increased with the first two 20-per-kilo boluses, but her vital signs after the third bolus remain the same as above. She has cool distal extremities. Her serum lactate is six. Which of the following is your next step? A, after placing a central venous catheter, start epinephrine. B, start epinephrine peripherally while preparing to place the catheter. C, after placing a central venous catheter, start norepinephrine. D, start norepinephrine peripherally, then place the central line. E, after placing the central venous catheter, start dopamine. F, start dopamine first, then place the central venous catheter. G, after placing a central venous catheter, start phenylephrine. H, start phenylephrine first while preparing to place the central. So the best answer is B, start epinephrine peripherally at 0.1 mics per kilo per minute while preparing to place a central venous catheter. And basically this patient has cold decompensated shock. So first she clearly needs immediate intervention. We should not wait to start an agent until after our central venous catheter is in place. So it is perfectly acceptable and preferred to start our agent of choice peripherally while preparing to place more central access. Since she seems to be in a high SVR state, we're going to preferentially go with something with more beta adrenergic effect. So we're not going to choose norepinephrine, nor are we going to choose phenylephrine. We're going to narrow it down to epinephrine and dopamine. And then we're going to defer to the surviving sepsis campaign and choose epinephrine as our first option. And here is that guidance. So I believe Dr. Weiss will go into more detail on this in his talk in sepsis, but basically these recommendations favor epinephrine over dopamine and norepinephrine over dopamine. So the first line for warm shock should really be norepinephrine and the first line for cold shock should be epinephrine. They do allow for dopamine to be substituted as the first line if epinephrine or norepinephrine is not readily available. And here are some of the data supporting those recommendations. So there have been two relatively small pediatric randomized control trials comparing epinephrine to dopamine in septic shock. There were trends or actual statistically significant differences favoring epinephrine in each of these in terms of risk of mortality, organ failure-free days among survivors and earlier shock resolution. Data comparing norepinephrine to other vasoactive agents is lacking in children. There is limited data to show that it is actually efficacious relative to continued fluid resuscitation, but a lot of what we're going by are adult studies, which I alluded to earlier that have demonstrated that norepinephrine is associated with superior survival outcomes, a lot of which is driven by a lower incidence of arrhythmias relative to dopamine. So in summary, shock and other shock-like states requiring vasoactive medications are complex and require a thorough assessment of patient physiology. Understanding adrenergic receptor interactions and intracellular signaling pathways and effects can guide an appropriate vasoactive medication selection. And finally, there is substantial overlap between vasoactive medications in terms of their physiologic actions, but understanding side effect profiles and current evidence and guidelines can be useful in optimizing medical management. Thank you for your time and attention. Take care.

vasoactive agents

pharmacology

cardiovascular system

adrenergic receptors

mechanisms of action

case scenarios

clinical settings

pediatric intensivist