Hello, my name is James Fang, here at the University of Utah, to talk about ionotropic therapy as part of the master class in cardiovascular physiology for the annual Society of Critical Care Medicine meeting. This is the disclaimer, I have no relevant disclosures to make. This is a brief outline of what we hope to cover in the next 15 minutes. Some comments about mechanisms and general principles, we'll discuss the specific ionotropic agents and some clinical issues that may arise. Some general comments about ionotropic therapy that I believe most people should take away include these points. Most ionotropes increase contractility through an increase in either calcium transients or increased myofilament sensitivity to calcium. Most ionotropes will increase cardiac output through increases in stroke volume and heart rate. Disadvantages of ionotropic therapy include increased myocardial oxygen consumption, hypotension, arrhythmias, and the intravenous route of administration that's necessary. Ionotropes are generally a bridge to recovery, more durable circulatory support, or as palliation. It's important to note that we are evolving our thinking of how ionotropic therapy should be classified and used. In a recent review of ionotropic therapy, these authors proposed dividing ionotropic agents into their primary mechanism of action. So for example, conventional ionotropic therapy that is used clinically would be known as calcitropes because they all fundamentally increase calcium transients and myofilament sensitivity to calcium, which thereby increases contractility. However, there are evolving agents that target different approaches. So for example, there are now agents that directly influence the circular protein. So a drug like omacamptomacarbol, which was recently studied in the GALACTIC-HF trial as an oral agent, is a myosin activator. In contrast, there are new drugs now that can improve the energetics of the cardiomyocytes and provide more ATP to generate actin and myosin cross-bridge. These drugs are not yet available clinically, but include drugs like trametazidine and paroxetone. Regardless of the mechanism of their action, all ionotropic agents increase contractility for any given intracellular calcium concentration. This can be represented on a PV loop as an increase in the slope in the end-diastolic pressure-volume relationship, or end-systolic elastance, EES. As seen in the PV loop on the left, you can see that an increase in the end-diastolic pressure-volume relationship, or EES, going from curve 2 to 1, increases the stroke volume or the width of the PV loop for any given end-diastolic volume. There are now a number of agents on the market, and this summary slide describes the ones that are used in clinical practice, as well as those that are being investigated. Dubutamine, dopamine, and epinephrine all work through stimulating the beta-adrenergic receptor, increasing cyclic AMP, and therefore it interests cytosolic calcium concentrations. Milrinone, in contrast, is a phosphodiesterase 3 inhibitor, and therefore prevents the breakdown of cyclic AMP, thereby generating increases in cytosolic calcium. More about this issue later. Levosimendan, which is only available in Europe, is a calcium sensitizer, as well as a PDE3 inhibitor, also increases cytosolic calcium. Digoxin, which we're not going to talk about much, since it is a very weak inotrope, also increases cytosolic calcium, but does so by inhibiting the sodium-potassium ATPase. Distyroxamine is under clinical investigation currently, and has a novel approach to increasing intracytosolic calcium through its activation of Serka2a and its inhibition of the sodium-potassium ATPase. I briefly mentioned Omacamtiv, which is a drug myosin activator currently being reviewed at the FDA, and is only available orally. The mitotropes, perhexylene, trimetazidine, and alepratide are currently undergoing investigation. There are some differences that are worth highlighting in regards to the agents that are used clinically, dubinamine, milrinone, epinephrine, dopamine, and levosimendan. They all result in improvement in contractility, which results in an increase in stroke volume, and because of the increase in heart rate, all reliably increase the cardiac output. However, their impact on systemic vascular resistance is variable. Some of these drugs, such as milrinone, is known as an inodilator, and can reduce systemic vascular resistance through direct effects on the peripheral circulation. Dubinamine, because it's also, in addition to being a beta-1 agonist, a beta-2 agonist, can vasodilate the periphery. In contrast, epinephrine is a vasopressor, as well as an inotrope, and will produce an increase in the SVR. Dopamine, depending upon dose, may systemically vasodilate or vasoconstrict. Levosimendan, again, not used in this country, often will also have a vasoplegic effect. These effects also have a variable impact on pulmonary vascular resistance. Milrinone, in particular, may lower PVR due to some selective pulmonary vasodilation, and is often used, therefore, for right heart failure. The effects on blood pressure are noted in this table. Of note, they're all prorythmic, primarily due to their mechanism of action, which is to increase intracellular calcium and myocardial oxygen demand. There are some specific issues that should be reviewed by providers when using these agents. For example, dubinamine can be complicated by eosinophilic myocarditis. It's unclear why this occurs, but it may be due to some inherent carrier within the dubinamine solution. Milrinone is really excreted and needs to be adjusted for EGFR. Epinephrine has direct effects on the splint and neck bed, and may produce more gastrointestinal ischemia than the other agents. Dopamine, as alluded to, does have differential effects depending upon the dose. One to five mikes per kilo per minute is often considered renal dose dopamine. Five to 10 and higher are often regarded as either inotropic or vasopressor doses. And levosiminin, as mentioned before, is not available in the United States. It's important to recognize that inotropic agents have been associated with poor survival for decades. This is one recent report from a group at UAB in which they reviewed their experience with 200 patients who are on chronic inotropic therapy. As you can see here, the survival was only 50% at nine months and was independent, whether it was dubinamine or milrinone. You can see these patients are quite sick, all class four, low EGFR, low indices, and elevated feeling pressures. Ironically, however, these agents do make people feel better, as noted in this meta-analysis from the Mayo Clinic. When you analyze the randomized studies, the impact in New York Heart Association class is relatively uniform. The concerns about mortality, however, have been a little bit more difficult to tease out, although currently, by guideline, chronic ambulatory inotropic therapy is not recommended for the chronic management of heart failure. I should note that this does not speak to use in the critical care setting, which we'll get to in just a moment. There are differences, as alluded to before, about the mechanism of action between dubinamine and milrinone. You'll recall dubinamine acts by directly binding to the beta-adrenergic receptor and through a G-protein linking to adenocyclase generates cyclic AMP. It's the generation of cyclic AMP that leads to phosphorylation of a number of calcium regulatory proteins and an increase in calcium transients. This of course is going to be blocked by drugs that block the beta-adrenergic receptor, such as a beta-blocker. In contrast, milrinone works intracytosolically by preventing the breakdown of cyclic AMP that's already been generated. In this manner, its effects are arguably independent of the binding of beta-blockers to the beta-adrenergic receptor, and therefore may have preferable use in patients who are on beta-blocker therapy when they present to a critical care setting. However, these are somewhat theoretical differences. The DORAME trial just published last year by a group in Canada directly compared in a double-blinded randomized fashion the differences between milrinone and dubinamine for the treatment of cardiogenic shock. They had to screen 319 patients to randomize 192. The primary endpoint of this critical care study was in-hospital mortality, sudden cardiac death, MI, stroke, the need for renal replacement therapy, or even VAD transplant. You can see that these patients were typical of an ICU in that the average age was 70, 80% were sky-sea stage, the ejection fractions were uniformly low at 25%, and 65% had ischemic cardiogenic shock. Of particular note, the lactate was 3, indicating hypoperfusion. The blood pressure had to be less than 90 to get into the trial. Interesting enough, only 23 of the 192 patients had a PA line in place, so although there were hemodynamic inclusion criteria, very few of these were used to get into the trial. The outcome of the trial at 28 days using this composite primary endpoint was neutral in that there was no particular benefit of milrinone over dubinamine at 30 days. There were also no differences in the component endpoints of the primary endpoint, and there were no differences in tolerability. In fact, when you looked at in-hospital death and a number of subgroups, no particular heterogeneity was noted. Importantly, there were no differences in the immune arterial blood pressure, heart rate, the lactate, renal function, or the use of other vasopressors between the two groups. I should note that the drug was started at 2.5 mpq per minute for dubinamine and 0.125 mpq per minute for milrinone and titrated to doses of either 10 mpq per minute in the case of dubinamine or 0.5 mpq per minute in the case of milrinone. How about the issue of epinephrine versus norepinephrine? Epinephrine, being a beta agonist, does have some inotropic impact. In this very small study of patients presented with cardiogenic shock, you can see that there were no real differences with respect to the immune arterial blood pressure, cardiac index, or stroke volume index, although early during therapy, epinephrine was associated with a higher heart rate. Interesting enough, there was increased lactic acidosis as well as an increase in the cardiac double product with epinephrine, but unfortunately, this is associated with approximately a third of the patients in the group having refractory shock requiring escalation of therapy in contrast to those patients with norepinephrine. There were not enough deaths in this very small study to make a comment on mortality. One question that often comes up is how about the combination of dubinamine and norepinephrine as an inotropic vasopressor combination in contrast to epinephrine. This was studied a number of years ago in a very small randomized study of some 30 patients randomized who had failed dopamine and dubinamine. It took 26 months to complete this study, and the patients had to have a MAP of less than 60 and a cardiac index of less than 2.2 to get into the trial. These drugs were titrated to a MAP of 65 to 70 and to provide an adequate cardiac index. As you can see from the graphs on the right, there were really no differences between these groups with respect to minotaural blood pressure or cardiac index. Interesting, however, though, was epinephrine was associated with a lower heart rate, a lower lactate, but greater intestinal ischemia as measured by the PCO2 gap, and greater diuresis. It's difficult to know how to completely interpret this trial, but I think we have seen this clinically, particularly when we see gastrointestinal complications in the ICU in patients in shock. A meta-analysis in 2015 collating the randomized data of the use of inotropic therapy in randomized trials in critical care settings did not find any increase in mortality with inotropes, although the association has been noted in a number of observational studies, almost certainly confounded by level of illness. A couple of final comments and common clinical dilemmas. When patients are on beta-blockers, again, we often think about milrinone rather than using dabutamine. I should note that in the DORAMI trial, half the patients in both groups were on beta-blockers, suggesting that there perhaps is really no significant difference in the choice. IM management is always complicated in the ICU. There is some heart failure data that might suggest that milrinone is less arrhythmogenic, but this is not a tried and true observation. Of course, all inotropes may be complicated by hypotension, either due to the drug or other issues. This is particularly true of milrinone. In the case of a normal ejection fraction, RV support often becomes an issue, and it must be kept in mind that these agents not only provide inotropic support, but chronotropic support. Renal failure and hepatic failure generally do not play into the choice of inotropic agents, with the exception of milrinone, which is really excreted. Pulmonary hypertension, complicated right heart failure, we often would favor milrinone over some of the other drugs. In summary, as I reviewed early on, most inotropes increase contractility through increases in either calcium transits or increased myofilament sensitivity to calcium. Most will increase cardiac output through increases in stroke volume and heart rate. Disadvantages include hypotension, arrhythmias, and intravenous right of administration. And then finally, use of inotropes is generally a bridge to recovery, more durable circulatory support, or palliation, and this is always something to address in the ICU in any patient in shock. Thank you very much.

ionotropic therapy

cardiovascular physiology

mechanisms of ionotropic therapy

ionotropic agents

clinical issues in ionotropic therapy