Hi, I'm Steve Hollenberg from Hackensack Meridian, and I'm going to talk to you about inotropes and vasoactive agents in cardiogenic shock. I have no disclosures with respect to this talk. Let's start with a case presentation. A 64-year-old man with a known idiopathic dilated cardiomyopathy presents with lethargy insomnolence. His blood pressure is 70 over 50, as seen with a heart rate of 125. An IV is started in the ambulance, and he is into his second liter of crystalloid resuscitation, but his systolic pressure remains 70 millimeters of mercury. So, he probably needs a vasopressor agent. Does it matter what you do? One school of thought says no. If you believe that, well, you've got the 45 minutes that you could have spent listening to this talk. You could do something else. There are 45 things you could do in under 45 minutes that can change your life. You can even boost your metabolism in 45 minutes and maybe become a good volleyball player. However, maybe there is something you can do. Let's start with a definition of shock. Shock is inadequate perfusion and oxidation of cells, and it leads to cellular and then organ dysfunction and damage. Panic shock occurs when this perfusion defect results from cardiac dysfunction, and it has a clinical and a hemodynamic definition. The clinical definition is decreased cardiac output and clinical evidence of tissue hypoxia in the presence of what you think at least is adequate intravascular volume. The hemodynamic definition is a sustained systolic blood pressure less than 90 minutes to distinguish it from a transient drop, probably more than half an hour, with a low cardiac index and an elevated wedge pressure. So regardless of which definition you use, cardiogenic shock is a hemodynamic disease, hemo, blood, dynamic, force. So it has to do with the force of blood. And pathophysiology usually follows a downward spiral. Myocardial dysfunction, often but not always caused by ischemia, leads to systolic and diastolic dysfunction. This leads to decreased cardiac output, decreased systemic perfusion, decreased coronary perfusion, predisposes to ischemia, but also decreased systemic perfusion, causes compensatory vasoconstriction and fluid retention that also predisposes to progressive myocardial dysfunction. On the diastolic side, your elevated left ventricular and diastolic pressure leads to pulmonary congestion and hypoxia and also facilitates ischemia. And if you don't break this cycle, dysfunction, ischemia, ischemia, dysfunction, you can wind up with mortality. Cardiogenic shock can be a challenge because you pretty much have to go down the diagnostic and therapeutic pathways at the same time. You don't want to spend all your time doing diagnostic things without at least treating the low blood pressure, but on the other hand, you'd like to have at least some sense of what might be causing the low blood pressure so you can figure out how best to treat it. So there are initial diagnostic and management steps, which we'll talk about. Then you assess perfusion. If perfusion is adequate with pulmonary congestion, then maybe diuretics or vasodilators are appropriate. If it's inadequate, then you need to support perfusion with vasoactive agents and or mechanical support. And finally, at least in cardiogenic shock caused in the setting of an acute coronary syndrome, you need to think about prompt coronary reperfusion. The diagnostic approach consists of a directed history and physical examination, an EKG. An echocardiogram is very useful in the initial evaluation. You do labs to look for the usual suspects, blood gas, arterial pleas, electrolytes, cardiac enzymes, and CBC. An SX-ray is useful, and we'll talk a little bit about hemodynamic assessment with a pulmonary artery catheterization or something else. Echocardiography is a really good tool, and I would argue that at least at some point, a full, complete echocardiogram is useful. You want to look not only at whether there's a big pericardial effusion and whether LV function is decreased or normal, but you want to see, you want to look at overall and regional systolic function. You want to evaluate for mechanical causes of shock. We talked about in the ACS lecture, papillary muscle rupture, acute VSD, and free wall rupture. You'd like to see if there's mitral regurgitation. If there is, how much of it there is. Right ventricular infarction, preserved left ventricular performance in the setting of right ventricular dysfunction can be diagnosed. And if you actually don't have cardiogenic shock, you might have other causes of shock, such as an odd pulmonary embolism or unsuspected valvular disease. We're going to talk about initial management steps in a little bit, but for the moment, I want to focus on coronary reperfusion. The landmark study in this field is the SHOCK trial, which compared early revascularization to initial medical stabilization in cardiogenic shock. Here are the results of that trial, a 13% absolute reduction in mortality with early revascularization. So that is the standard of care. Now, not all presentations in cardiogenic shock are acute in the setting of an acute coronary syndrome. You might have acute on chronic presentations, and that might actually result from decompensated chronic heart failure. In fact, data from the Critical Trials Network suggests that in 2021, decompensated heart failure may actually be more frequent than acute coronary syndromes. But it's also important to realize that shock is not always hypotensive. These are data from the SHOCK trial registry, and they looked at three groups of patients. They looked at classic cardiogenic shock with hypotension and hypoperfusion, and then they looked at nonhypotensive cardiogenic shock with a perfusion defect and hypotension without evidence for hypoperfusion. The groups look pretty much the same at baseline except for age. However, the outcomes were much worse with classic cardiogenic shock than with just a low blood pressure without evidence of hypoperfusion. And in fact, if you look, hypoperfusion without hypotension was worse than hypotension without hypoperfusion. Hypoperfusion is usually manifest as organ dysfunction. In the CNS system, you can have altered consciousness and confusion. In the cardiovascular system, tachycardia, hypotension, elevated filling pressures. In the respiratory system, tachypnea and hypoxia. In the renal system, oliguria, anuria, and elevated creatinine. In the hepatic system, jaundice, elevated liver enzymes, and maybe even decreased synthetic function. And then there are metabolic consequences and hematologic consequences as well. There are a number of ways to assess perfusion clinically, as I just outlined. Biochemically, by elevation of lactate, creatinine, and liver function tests. Hemodynamically, the mixed venous saturation is an index of the adequacy of cardiac output. And it would be nice to assess microcirculatory and cellular perfusion. We don't really have time to talk about this, but that's really where the action is. Cardiogenic shock, however, is really a hemodynamic disease. And as a hemodynamic disease, it makes a certain degree of sense to measure hemodynamics. And that is classically done via pulmonary artery catheterization at the bedside. And you can exclude volume depletion, right ventricular infarction, and mechanical complications. You can assess fluid responsiveness. You can look at filling pressure responses to fluid bolus. But what you'd really like to do is to see whether fluid increases stroke volume. And so you want to measure stroke volume responses to fluids. And as important as anything else is the use to optimize therapy. Cardiac output to guide the use of inotropic agents. Filling pressures to guide the use of vasoactive agents. And when you are using vasoactive agents, titration to the minimal dosage required to achieve your therapeutic goals. And thus minimize increases in oxygen demand and the potential for arrhythmias. Now in the critical care world, there are a lot of people who argue that there aren't any data for pulmonary artery catheterization. And they usually cite this trial, which is the ESCAPE trial. It's an acronym for the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness. And they show these data that show no difference between a PA catheter group and a clinical assessment group. But I would argue it's worthwhile to take at least a little bit closer look at who was in the ESCAPE trial. There were 433 patients. They were sufficiently ill with advanced heart failure to make use of the pulmonary catheter reasonable. But also sufficiently stable to make crossover to PAC for urgent management unlikely. And patients with a creatinine of greater than 3.5, prior use of dopamine, dobutamine, or milrinone were excluded. So it might not be unreasonable to say that if your doctor didn't think you needed a PA catheter, they were probably right. But it's not clear how well the ESCAPE trial applies to patients with cardiogenic shock. And in fact, there are some new retrospective data suggesting that use of a PA catheter in cardiogenic shock, particularly in a landscape in which mechanical circulatory support is contemplated, leads to improved outcome. So let's look at a clinical example. Let's say you have a 53-year-old who presents with an ST elevation MI. He has a focused echo, shows that his ejection fraction is 35%, and he doesn't have a pericardial effusion. He goes to the cath lab. He has a 90% mid-LAD lesion and 80% proximal right. And the LAD is stented because he has an anterior infarction. He comes back to your unit with a blood pressure over 90, over 65, and his heart rate is 100, right? You know, he has an MI. He's revascularized. You don't need a PA catheter. But suppose you actually did it. Let's look at three potential hemodynamic profiles that could result. So patient one has an RA pressure of 14, an elevated PA pressure, an elevated wedge pressure, and a reasonable cardiac output with a decent pulmonary artery saturation. Patient two has a low right atrial pressure, a low PA pressure, a low wedge pressure, and a good cardiac output. Patient three has a high right atrial pressure, a somewhat high pulmonary artery pressure, a high wedge pressure, and a low pulmonary artery saturation with a low cardiac output. So this patient looks the same on clinical assessment. Patient one has high pressures and good cardiac output. He needs diuresis. Patient two has normal pressures and good cardiac output and needs nothing except for supportive care. Patient three has cardiogenic shock with elevated filling pressures and low cardiac output. It's not always so easy to tell on a clinical basis. And your echocardiogram doesn't really help. It shows you an ejection fraction of 35%. So now let's look at the initial approach to management. You want to assure oxygenation. And intubation and ventilation should be instituted if needed, particularly if you're going to the cath lab. You're about to lay somebody flat, and the cath lab is not a good place to intubate somebody who is now short of breath because they're in pulmonary edema, and you just lay them flat. You want venous access. You want to achieve pain relief. You want to monitor the EKG continuously for arrhythmias. And if you're hypotensive, you want hemodynamic support. And that's the subject of much of the rest of this talk. Hemodynamic resuscitation has three potential components, fluids, vasopressors, and inotropes. Now I recognize that catecholamines have both vasopressor and inotropic actions. But for the purpose of clarity, I'd like in this talk to refer to vasopressors as therapies whose aim is to increase blood pressure, and to inotropes as therapies whose aim is to increase cardiac output. And remember that the ultimate goal is not really a number of blood pressure or a number for cardiac output, but rather adequate perfusion. Tissue perfusion is a function of both flow and pressure. So remember mean arterial pressure is a function of cardiac output and vascular resistance. Cardiac output is determined by heart rate times stroke volume. Stroke volume depends on the left ventricular size and the degree of shortening. And that shortening in turn depends on preload, afterload, and contractility. However, you also need a reasonable blood pressure. And in the inset is an autoregulation curve that shows that perfusion is maintained through a reasonable range of arterial pressure, ranging from about 60 to 150 millimeters of mercury. Up above, you're in malignant hypertension range. And it's not entirely clear exactly where that cut point is, but somewhere in this range there is a blood pressure after which perfusion is linearly related to mean arterial pressure, the so-called critical blood pressure. So if you want to keep blood pressure above that target, what is the blood pressure target to aim for? There aren't a lot of data to inform this, but there are a little bit of data about what to aim for coming out of the critical care literature. And this is the sepsis spam study published out in the New England Journal, high versus low blood pressure target in patients with septic shock. And what you can see is this was a randomized trial in which they randomized patients to aim for a mean arterial pressure of 65 or 85. You can see that in the low target group they actually achieved around 75, but in the high target group they really did achieve a blood pressure of 85. And cumulative survival, the end point, no difference depending on target. However, there's a little wrinkle in the sepsis spam study. There was a pre-specified analysis of a subgroup of patients with pre-existing hypertension. And they looked at those two groups separately. So you can see for the whole groups there was no difference in renal outcome in terms of doubling of serum creatinine. And if you had no chronic hypertension there was no difference, but if you had chronic hypertension you did better with a higher mean arterial pressure in terms of doubling of serum creatinine and the same answer with need for renal replacement therapy. So a little suggestion in a predetermined subgroup that some patients with pre-existing chronic hypertension might do better with a higher blood pressure. For everybody else, however, a blood pressure target of 65 is probably reasonable. This slide is a reminder of the mechanism of action of various catecholamines. Catecholamines have effects on alpha receptors, beta-1 receptors, and beta-2 receptors. In the vascular smooth muscle, both norepinephrine and epinephrine stimulate alpha receptors and cause contraction. Epinephrine has a little bit of a beta-2 effect that causes vasodilation. And in the cardiac muscle, norepinephrine is predominantly a beta-1 agent that stimulates adenyl cyclase and raises cyclic AMP and leads to contraction. Norepinephrine has both beta-1 and beta-2 effects through the G-stimulatory protein, again, to increase cardiac contractility. Now I'm sure most of you have seen charts like this with vasopressor agents compared with their cardiac effects and peripheral vascular effects and this many pluses and that many pluses and zeroes and such, and I myself have published charts like this. But I would argue that these really aren't very useful. It's more useful to conceive of adrenergic agents in terms of their alpha and beta effects and in terms of their effects on pressure and flow. So as you see in this chart, they're arrayed out from phenylephrine to isoproterenol in terms of relative alpha and beta effects. Phenylephrine is predominantly an alpha agent that increases pressure and really, if anything, decreases flow. Isoproterenol is a beta agent that increases flow and, if anything, decreases pressure, and the rest of the drugs are somewhere in between, with epinephrine increase having more of a beta effect in general than dopamine or norepinephrine. Norepinephrine, also called noradrenaline in some places, stimulates the alpha-adrenergic and beta-1-adrenergic receptors. It's mostly vasoconstricted, but it does have some inotropic effect, and like all potent vasoconstrictors, it has the potential for digital ischemia. Dopamine has a somewhat more complicated pharmacology. It stimulates both adrenergic and dopaminergic receptors, and its hemodynamic effects are dose-dependent. At low doses, 1 to 3 micrograms per kilogram per minute, it has renal effects on flow and urine output. At intermediate doses, it has predominantly inotropic effects, raising heart rate and cardiac output, and at high doses, greater than 10, it's predominantly a vasoconstrictor that raises blood pressure. Its side effects include tachycardia, arrhythmias, and immunosuppression via an effect on prolactin, and some dinosaur clinicians notwithstanding, dopamine is now well-known not to improve renal function. Dopamine and norepinephrine were compared in the SOAP2 trial done by Daniel DeBacker and Jean-Louis Vincent out in Belgium, and what you can see is the primary endpoint, 28 days, actually is not statistically significant, but norepinephrine was slightly better than dopamine. Now, there was a pre-specified subgroup analysis of the SOAP2 trial, and the hypothesis was that if dopamine had an effect on anything, it would have an effect in patients with cardiogenic shock. And actually, the opposite was seen. In patients with cardiogenic shock, norepinephrine was better, and so in the guidelines, norepinephrine is actually preferred for patients with cardiogenic shock. Epinephrine, also known as adrenaline, as mentioned, has both an alpha and a beta adrenergic agonist effect, both of which are very potent. It's a vasoconstrictor and an inotrope, and it also has metabolic effects and can raise lactate independent of a hemodynamic effect. It has, because of the potency of effects, it's probably more arrhythmogenic than either of the other agents. Epinephrine was compared to a combination of norepinephrine versus dobutamine in septic patients in the CATS study published out by Jalali Anand in 2007, and as you can see, there was no difference. In cardiogenic shock, Bruno Levy published a small study looking at epinephrine versus norepinephrine after myocardial infarction. Cardiac index was the primary endpoint, but the trial was stopped early for adverse effects, and you can see the results. There really wasn't much of a difference in hemodynamic effects, although epinephrine over here on the right caused a bigger increase in lactate. The incidence of refractory shock with epinephrine was much higher than with norepinephrine, and so the trial was stopped. Phenylephrine is a pure alpha agonist. With an attack barrel receptor system, it causes reflex bradycardia, although that doesn't happen very much in cardiogenic shock. Phenylephrine isn't nearly as potent as the other agents, however. In the setting of tachyarrhythmias, phenylephrine has an alpha and not a beta effect. So it's a useful alternative, although it usually doesn't work very well when used alone. Vasopressin is a peptide hormone synthesized in the hypothalamus and then transferred down to the pituitary. Its secretion is stimulated by increased osmolarity, but more potently by hypotension and also by pain, hypoxia, and acidosis. You can see on the right that levels are elevated in patients with cardiogenic shock and not so much in patients with septic shock. And vasopressin is an alternative vasoconstrictive agent, particularly in patients with arrhythmias or those who don't respond to other vasopressors. All vasoactive therapies have complications, prominently tachyarrhythmias, the potential for myocardial ischemia through increased myocardial oxygen demand, and also potentially through coronary vasoconstriction. The same vasoconstrictive effects can impair splancting circulation with potential effects on gut mucosal integrity and can potentially cause digital ischemia. There's also the potential for immunosuppression, not only with dopamine through prolactin, but actually some evidence that the other catecholamines also have something of an immunosuppressive effect, at least at high doses. Let's move on to inotropic agents. This slide depicts sites of action of various inotropes. Dobutamine, as mentioned, operates through the beta-adrenergic receptors. Digoxin inhibits the sodium-potassium pump, thus increasing intracellular sodium, which is then exchanged for calcium, increasing intracellular calcium. Levosimendan and omacandib-micarbol, which we're going to talk about later, work directly on the contractile apparatus. Dobutamine is a selective beta-1 adrenergic agonist. It has a rapid onset with a halftime of two to three minutes and potential tolerance after two or three days. There's no demonstrated mortality benefit with dobutamine, as we'll see. Tachyarrhythmias can be a problem, and dobutamine also can stimulate beta-2 receptors and cause vasodilation, thus its term as an inodilator, and it may exacerbate hypotension. Milrinone is a bipyridine phosphodiesterase inhibitor that increases cyclic AMP by decreasing its metabolism. It has both inotropic and vasodilatory actions, and because it doesn't work through the beta-adrenergic receptors, but rather through phosphodiesterases, it may be somewhat more effective when beta-adrenergic receptors are downregulated, as in chronic congestive heart failure. Unfortunately, milrinone has a long half-life, so if you have hypotension, it lasts for a long time. Just last week, the DO-RE-MI trial was published in the New England Journal of Medicine comparing milrinone with dobutamine in the treatment of cardiogenic shock. They looked at 192 patients with cardiogenic shock defined clinically by SCI classes, 80% class C, which is classic cardiogenic shock. The primary endpoint was a compositive death, cardiac arrest, mechanical circulatory support,

inotropes

vasoactive agents

cardiogenic shock

hemodynamic disease

coronary reperfusion

pulmonary artery catheterization

vasopressors