Interventional Pharmacology: Inotropes and Vasopressors

General (including evidence of efficacy)

Inotropes and vasopressors

Inotropes and/or vasopressors are essential in the management of cardiogenic shock complicating myocardial infarction/ischemia and in the treatment of hemodynamic instability occurring during coronary interventions. They help stabilize patients at risk for progressive hemodynamic collapse or serve as a life-sustaining bridge to a more definitive therapy.

Differences between drugs within the class

Inotropes

Inotropes augment cardiac contractility and shift the Frank-Starling curve in an upward and leftward direction, so that stroke work and cardiac output at any given filling pressure are increased. Although this occurs at the expense of increased myocardial oxygen consumption, severe hypotension compromises myocardial perfusion markedly. Thus the hemodynamic benefits of inotropes and vasoconstrictors usually outweigh this risk when used as a bridge to more definitive therapies.

Commonly used inotropes include catecholaminergic agents, such as dopamine, dobutamine, and the phosphodiesterase inhibitors (e.g., milrinone). Norepinephrine and epinephrine are catecholamines with inotropic properties, but are generally classified as vasopressors due to their potent vasoconstrictive effects.

The selection of agents in the catheterization laboratory is largely driven by expert opinion, the pattern of hemodynamic compromise, and physician preference. In cardiogenic shock, complicating acute myocardial infarction, dopamine or dobutamine may be used as first-line agents in patients with moderate hypotension (systolic blood pressure (SBP) 70 to 100 mm Hg), while norepinephrine is usually the preferred therapy for patients with severe hypotension (SBP <70 mm Hg)

Using combinations of agents in moderate doses may be potentially more effective than maximal doses of an individual medication.

Catecholamines increase myocardial inotropy and chronotropy by binding to beta-1-adrenergic receptors and increasing adenylate cyclase activity in myocytes. Increased cAMP formation promotes intracellular calciuminflux through voltage-dependent calcium channels.

This triggers further release of calcium from the sarcoplasmic reticulum and increases cytosolic calcium availability to the actin-myosin-troponin system, which results in increased cardiac contractility. Phosphodiesterase inhibitors also increase cAMP, but they do so more distally in the pathway by inhibiting its degradation.

Vasopressors

The acute goal in cardiogenic shock is to ensure adequate coronary and central nervous system perfusion pressure. Vasopressors can provide initial hemodynamic support and temporarily maintain perfusion to these vital organs until more definitive therapies, such as revascularization or mechanical support can be instituted.

Administration

Inotropes

Dopamine

Dopamine is administered by IV infusion. The dose should be tailored to achieve the desired hemodynamic effect. Intermediate doses are usually used for the treatment of heart failure, while high doses are required for hypotension. Doses should not exceed 20 to 30 µg/kg/min.

Continuous infusions should be administered by central venous access to reduce the risk of extravasation. In the event of extravasation of dopamine, subcutaneous phentolamine should be infiltrated throughout the ischemic area.

Dobutamine

• Dobutamine is generally initiated at 2 µg/kg/min and titrated to optimize cardiac output (maximal dose: 40 µg/kg/min)

• The half-life is approximately 2 minutes, and steady state levels are usually attained within 10 minutes.

Phosphodiesterase inhibitors

Intravenous milrinone is commonly initiated with a bolus of 50 µg/kg, followed by a continuous infusion at a rate of 0.375 to 0.75 µg/kg/min. Severe renal impairment necessitates a dose reduction.

Isoproterenol

The usual starting dose is 2 µg/min IV infusion, and can be increased to 5 to 10 µg/min depending on the heart rate response.

Vasopressors

Norepinephrine

• Typical doses of IV norepinephrine are 5 to 20 µg/min (range 0.5 to 30 µg/min).

• Continuous infusions should be administered by central venous access to reduce the risk of extravasation.

Epinephrine

For the treatment of shock, 2 to 10 µg/min IV infusion may be given. Continuous infusions should be administered by central venous access to reduce the risk of extravasation.

Phenylephrine

Phenylephrine can be given as an 100 µg IV bolus dose. If a continuous infusion is required it is generally started at 100 to 180 µg/min and titrated based on clinical response. As the blood pressure stabilizes, the rate can be decreased to 40 to 60 µg/min.

The dose in cases of cardiac arrest is 1 mg IV bolus (10 ml of 1:10,000 solution) every 3 minutes.

Pharmacologic action

Inotropes

Dopamine

• Dopamine is a naturally occurring neurotransmitter and the precursor of norepinephrine.

• Dopamine acts on several different receptors, each with different affinities for the drug:

  At low doses (2 to 5 µg/kg/min), stimulation of dopaminergic receptors leads to vasodilation in the renal, mesenteric, coronary, and cerebral beds. At this dose, dopamine induces increased natriuresis, although no definitive evidence for improvement in renal function exists.

  At intermediate doses (5 to 10 µg/kg/min), dopamine increases cardiac contractility and chronotropy. This occurs directly by stimulating beta-1 receptors and indirectly by releasing norepinephrine from sympathetic nerves.

  At high doses (10 to 20 µg/kg/min), alpha-receptor mediated peripheral vasoconstriction dominates.

• Dopamine is metabolized in the kidney, liver, and plasma and is excreted in the urine.

Dobutamine

Dobutamine is a synthetic catecholamine that stimulates beta-1 and beta-2 adrenergic receptors, but has little action on alpha-receptors. It has potent inotropic activity with only modest chronotropic effect.

Dobutamine increases stroke volume and cardiac output, and lowers pulmonary capillary wedge pressure and systemic vascular resistance. It is therefore especially useful for patients with decompensated systolic heart failure and low cardiac output but in whom extreme hypotension is not present.

In the presence of severe hypotension, beta-2 induced peripheral vasodilation may be harmful and the addition of vasoconstrictors, such as dopamine or norepinephrine, may be necessary to support the blood pressure.

Phosphodiesterase inhibitors

The hemodynamic actions of milrinone result from a combination of inotropic and vasodilating properties. Milrinone exerts positive inotropic actions by inhibiting PDE-3 in cardiac myocytes. PDE inhibition reduces the breakdown of intracellular cAMP, thereby enhancing calcium delivery and resulting in increased contractility. Milrinone also increases cGMP in vascular smooth muscle resulting in peripheral vasodilation. It tends to increase heart rate slightly.

Isoproterenol

• Isoproterenol is a synthetic sympathomimetic amine. It has nearly exclusive beta-receptor activity (primarily beta 1) with almost no alpha-receptor effect. This results in positive inotropic and chronotropic activity. It has weak vasodilator properties (beta effect), which may lead to a mild drop in blood pressure.

• The plasma half-life is 2 minutes.

Vasopressors

Norepinephrine

Norepinephrine is an endogenous catecholamine released by postganglionic adrenergic nerves. It has potent alpha-receptor activity, which leads to marked peripheral vasoconstriction. It only has modest beta-1 activity and therefore, has less potent direct inotropic properties.

Epinephrine

Epinephrine is an endogenous catecholamine that acts on beta-1, beta-2, and alpha-receptors. Beta-adrenergic activity predominates at low doses (<0.01 µg/kg/min) of epinephrine and results in increased stroke volume, heart rate, and cardiac output. At higher doses (>0.2 µg/kg/min), it is a potent vasoconstrictor due to alpha-mediated peripheral vasoconstriction.

Due to its inotropic, chronotropic, and vasoconstrictive effects, epinephrine is the vasopressor of choice during cardiac resuscitation. It enhances coronary perfusion pressure, which is a major determinant of the return of spontaneous circulation after cardiac arrest.

Phenylephrine

Phenylephrine is a synthetic alpha-adrenergic receptor agonist with virtually no affinity for beta receptors. Therefore, it is a potent vasoconstrictor with essentially no chronotropic or inotropic effects. Phenylephrine is metabolized in the liver and gastrointestinal tract and has duration of action of 20 minutes.

It may be used to manage severe hypotension, but for the failing heart the undesirable increase in afterload and oxygen consumption mitigate any benefits of beta-1 stimulation.

Indications and contraindications

Inotropes

Dopamine

In the cardiac catheterization laboratory, dopamine is indicated in the management of cardiogenic or vasodilatory shock and in patients with symptomatic bradycardia unresponsive to atropine or pacing. Dopamine is contraindicated in patients with atrial fibrillation and other tachyarrhythmias.

Phosphodiesterase inhibitors

Milrinone is indicated in the short-term management of acute systolic heart failure to augment cardiac output and reduce ventricular filling pressure. It may also be helpful in selected cases of hemodynamic compromise related to myocardial infarction.

Isoproterenol

Isoproterenol is indicated for resistant bradycardia that has failed to respond to atropine and dopamine.

Dobutamine

Dobutamine is indicated for patients with low cardiac output and severe heart failure. It has limited utility in the setting of acute ischemia because it significantly increases myocardial oxygen consumption.

Vasopressors

Norepinephrine

Norepinephrine is indicated for the treatment of cardiogenic shock with severe hypotension and shock refractory to other sympathomimetics. However, it is predominantly used in distributive/septic shock.

Epinephrine

It should be avoided in patients with myocardial ischemia in whom the increased heart rate and contractility would further increase myocardial oxygen demand.

It is primarily used in the setting of cardiac emergencies, such as shock, cases requiring cardiac resuscitation, or anaphylactic reactions, because of its powerful inotropic, chronotropic, and vasoconstriction activity.

It is contraindicated in the hypertrophic obstructive cardiomyopathy patient.

Phenylephrine

Phenylephrine is used to treat hypotension in the catheterization laboratory (e.g., transient hypotension from balloon inflation-related ischemia) through its vasoconstrictive effect on the peripheral arterial vasculature.

Undesirable effects

Inotropes

Dopamine

• Major adverse effects include provocation of tachycardia and arrhythmias, and myocardial ischemia.

• Peripheral tissue ischemia and gangrene may develop with very high doses and prolonged infusions.

Dobutamine

The major side effects are an excessive increase in heart rate and ventricular arrhythmias, both which mandate dose reduction or drug discontinuation.

Phosphodiesterase inhibitors

Adverse effects include ventricular arrhythmias, hypotension, and a small incidence of thrombocytopenia (2%)

Isoproterenol

Isoproterenol can induce arrhythmias and markedly increase myocardial oxygen demand and may aggravate or induce ischemia.

Vasopressors

Norepinephrine

• Adverse effects include tachyarrhythmias and precipitation of myocardial ischemia.

• In the event of extravasation of norepinephrine, subcutaneous phentolamine should be infiltrated throughout the ischemic area.

Epinephrine

Adverse effects include tachyarrhythmias, severe hypertension and increased myocardial oxygen demand. High and prolonged doses can cause direct cardiac toxicity through damage to arterial walls and stimulation of myocyte apoptosis.

Phenylephrine

• It may cause reflex bradycardia that can be blocked with atropine.

• It may cause an excessive hypertensive response if not properly dosed.

Alternative approaches

Amrinone is now infrequently used due to dose-related thrombocytopenia.

What's the Evidence?

De Backer, D, Biston, P, Devriendt, J. “Comparison of dopamine and norepinephrine in the treatment of shock”. N Engl J Med.. vol. 362. 2010. pp. 779-89. (A contemporary multicenter RCT examining dopamine vs. norepinephrine as first-line vasopressor therapy in shock patients, and showing no significant difference in death rates but more adverse events with the use of dopamine. Notably, an increased death rate was observed in the subgroup of patients with cardiogenic shock treated with dopamine.)

Havel, C, Arrich, J, Losert, H. “Vasopressors for hypotensive shock”. Cochrane Database Syst Rev. 2011 May 11. pp. CD003709(Meta-analyses of RCTs comparing various vasopressor regimens for hypotensive shock. The authors concluded that there is no sufficient evidence that any one of the six investigated vasopressors is clearly superior over the other.)

Overgaard, CB, Dzavik, V. “Inotropes and vasopressors: Review of physiology and clinical use in cardiovascular disease”. Circulation. vol. 118. 2008. pp. 1047-56. (An authoritative review that examined the mechanisms of action of common inotropes and vasopressors, and the contemporary evidence for their use in important cardiac conditions.)

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