#36 Inotropes
Get excited for a jam-packed episode full of Critical Care goodness! Nick & Cyrus deconstruct, demystify and unpack Inotropes. These medications are essential in the world of critical care when we have to manage cardiogenic shock. What are the different inotropes? How can you decide which one is right for your patient? And... what's the difference between an Inotropic and an Ionotropic agent? You'll learn all this and so much more on this week's episode of Critical Care Time: The Podcast for Everyone Who Cares for the Critically Ill!
Definitions
Inotropes are medications that alter the force of cardiac contractions (cardiac output; CO).
We can divide the hemdynamic effects of inotropes into two categories:
Chronotropic effect - affects the rate of cardiac contraction (heart rate; HR)
Inotropic effect - affects the force of cardiac contraction (stroke volume; SV)
Additionally many inotropes also affect systemic arteriolar vascular tone or afterload. We can describe inotropes in terms of their effects on systemic vascular resistance (SVR) as either:
Inodilators - inotropes that also decrease SVR
Inoconstrictors - inotropes that also increase SVR
In order to understand how these effects interact, recall two important physiology concepts:
CO = HR x SV
MAP = CO x SVR
The combination of increased CO and decreased SVR can either increase or decrease mean arterial pressure (MAP); for this reason the effects of inodilators on blood pressure can be complex.
Inodilators don’t necessarily decrease blood pressure!
Overview of inotropic medication pharmacology
Categories of inotropic medications
Catecholamines (e.g., Dobutamine, Epinephrine, Dopamine, Isoproterenol)
Phosphodiesterase Inhibitors (e.g., Milrinone)
Other meds with ionotropic effects (e.g. Angiotensin II, Levosimendan, and calcium)
Inotropes signal by several overlapping but distinct second messenger pathways.
Overview of the signaling pathways responsible for the effects of inotropes. See Overguard et al for more.
Beta agonists activate beta1 and beta2 adrenergic receptors (g-protein coupled receptors) in the heart and vasculature which mediate several effects:
Directly increase HR (positive chronotropic effect)
Activate adenylate cyclase leading to increased cyclic AMP (cAMP).
cAMP leads to increased calcium channel activity, which potentiates actin-myosin binding and increases the force of contraction. (positive inotropic effect)
cAMP also activate cAMP dependent kinases, increase phospholamban phosphorylation, and lead to vasodilation.
Milrinone acts downstream in this pathway by increasing levels of cAMP. Thus Milrinone has a positive inotropic effect and vasodilatory effect, but minimal effect on heart rate.
Alpha agonists bind to alpha1 adrenergic receptors and cause vasoconstriction in vascular smooth muscle.
Some beta-agonists are also alpha agonists (e.g. epinephrine, high-dose dopamine) which is why they have predominantly inopressor effects.
Other catecholamine inotropes (e.g. dobutamine, low-dose dopamine) do not bind to alpha adrenergic receptors, and have no vasopressor activity.
Calcium is an essential cofactor for all of the these signaling pathways.
Other receptors converge on these pathways and can augment these effects:
Cardiac dopamine receptors cause chronotropic effects. This is likely why dopamine causes stronger chronotropic effects than other catecholamines.
Vasopressin receptors activate Gq and mediate vasoconstriction by the vasopressin receptor.
Angiotensin II has positive inotropic and positive chronotropic effects via the ATII receptor and also increases endogenous catecholamine secretion, causing additional inotropic & chronotropic effects.
The differences between signaling pathways account for the variation in effect, as illustrated below.
Comparison of the hemodynamic effects of different inotrope medications. Created by Nick Mark. See here for source code.
Interactive visualization of the hemodynamic effects of different inotropes. Created by Nick Mark. See here for source code.
Specific Inotropes
Dobutamine
Mechanism of Action:
Synthetic catecholamine. Primarily β1-adrenergic agonist, moderate β2 activity (vasodilation).
Increases contractility with mild vasodilatory effects.
Hemodynamic Effects:
Increases cardiac output.
Decreases systemic vascular resistance (afterload reduction).
Increased HR but not as much as some other catecholamines (epi, dopamine, isoproterenol)
Clinical Uses:
Acute decompensated heart failure (ADHF) with low cardiac output.
Cardiogenic shock where afterload reduction is beneficial.
Can also be used for ambulatory inotropic therapy as a bridge to definitive management or for palliation
Side effects:
Can cause arrythmias & tachycardia.
Epinephrine
Mechanism of Action:
Potent catecholamine, non-selective agonist for α1, β1, and β2 receptors. Strong inotropic and vasoconstrictive effects.
Because of B2 effects epinephrine increases lactate production.
Hemodynamic Effects:
Increases heart rate, contractility, and systemic vascular resistance.
Clinical Uses:
Advanced cardiac life support (ACLS) as a first-line agent in cardiac arrest.
3rd line vasopressor in sepsis
Cardiogenic shock, especially post-cardiac surgery, such as when there is concomitant vasoplegia or bradycardia.
Also a great choice in anaphylaxis
Side Effects/Limitations:
Tachycardia, arrhythmias, risk of myocardial ischemia.
Lactic acidosis
Milrinone
Mechanism of Action:
Phosphodiesterase-3 (PDE3) inhibitor. Increases intracellular cyclic AMP, leading to calcium influx and stronger myocardial contractions. Because it works downstream of the beta-adrenergic receptor it does not cause as much tachycardia.
It also has Strong Vasodilatory effects (inodilator), decreasing both SVR and PVR
Hemodynamic Effects:
Increases cardiac output and decreases afterload (vasodilation).
Does NOT increase heart rate to the same extent as beta-agonist, is associated with increased SVTs and increased incidence of atrial fibrillation... so keep an eye out for that.
Clinical Uses:
Acute decompensated heart failure (especially in patients on β-blockers). Especially if normotensive or hypertensive
Cardiogenic shock with elevated pulmonary vascular resistance
RV failure
Patients with significant tachycardias on other inotropes
Like dobutamine - can be a bridge to heart transplant or mechanical circulatory support, as well as palliation.
Side Effects/Limitations:
Hypotension, especially in volume-depleted patients.
Less likely to cause tachycardia but it still has proarrhythmic effects
Milrinone is Renally cleared, so dosage adjustment needed in renal dysfunction.
Dopamine
Mechanism of Action:
Catecholamine with dose-dependent receptor selectivity:
Allegedly has different dose ranges/effects.
Low/Moderate doses (5-10 mcg/kg/min): β1-adrenergic agonism → Increased cardiac contractility and heart rate.
High doses (>10 mcg/kg/min): α1-adrenergic agonism → Peripheral vasoconstriction, increased systemic vascular resistance.
Hemodynamic Effects:
Low doses: Increases heart rate and cardiac output.
High doses: Strong vasoconstriction, increased systemic vascular resistance, increased blood pressure.
Clinical Uses:
Historically used in cardiogenic shock and heart failure, but limited in favor of more specific agents.
Preferred in patients with bradycardia who require both inotropic support and vasopressor effects.
Room temp stable, found on crash carts
Side Effects/Limitations:
Risk of tachyarrhythmias (especially at moderate to high doses).
Controversy regarding renal perfusion benefits at low doses.
Limited use in modern practice due to better alternatives for specific hemodynamic profiles.
Mechanism:
Synthetic catecholamine
Pure beta effects; its a particularly strong positive chronotrope.
Hemodynamics
Inotrope, chronotrope, and weak vasodilator
Uses:
Used to simulate an exercise stress-test in the cath lab given B1 and B2 activity
Otherwise, it can be used for
Severe Bradycardia such as heart block
Bridge to transvenous pacemaker placement
code
Calcium
Mechanism:
Calcium is required for all the effects of inotropes
Calcium is often low in people with critical illness → always worth checking, especially if you can do so using point of care tests.
Check ionized calcium not total!
Conisder hypocalcemia particularly in people receiving massive transfusions, on renal replacement therapy, on high dose loop diuretics, or those with alkalosis.
There’s a wooden pearl that calcium chloride works faster, based on a theoretical idea that gluconate requires hepatic metabolism. This probably isn’t true. The bigger issue is that calcium chloride has 3x more calcium per gram, so people just end up giving a bigger dose!
Angiotensin II
Mechanism of Action: Peptide hormone, typically used as a vasopressor.
See our discussion in the Vasopressors: Beyond the basics episode for more about ATII.
However in addition to being a potent vasopressor, ATII also has positive inotropic and positive chronotropic effects and increases endogenous catecholamine secretion. For this reason it’s also used in cardiogenic shock.
Levosimendan
Mechanism of Action: Calcium sensitizier, similar in effect to milrinone. Levosimendan binds to troponin C in a calcium-depednent manner which subsequently increases contractility.
Not FDA approved in the United States, though widely used in Europe for >20 years