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Jun.06.2020

Inotropes

Summary

  • Inotropes are vasoactive medications that increase cardiac output.
  • Inotropes are used to support cardiac function in low cardiac output states caused by decompensated heart failure, shock, surgery, or cardiac arrest.
  • Many vasoactive agents have both vasopressor and inotropic actions; choice of agent primarily depends on the etiology of hemodynamic instability and goals of treatment.

Pharmacology/Mechanism of Action

Systemic blood pressure is determined by systemic vascular resistance (SVR) and cardiac output. Inotropes increase cardiac contractility and cardiac output via stimulation of beta1-receptors in the heart.[65552] [65553]

Catecholamines mediate their cardiovascular actions predominately through 3 types of receptors: 1) alpha-adrenergic, 2) beta-adrenergic, and 3) dopaminergic. Dopamine displays dose-related receptor activity, targeting dopaminergic receptors at low doses, dopaminergic and beta-receptors at mid-range doses, and shifting to beta- and (preferentially) alpha-receptor stimulation at high doses. Dobutamine is a synthetic catecholamine with a strong affinity for both beta1- and beta2-receptors. Epinephrine is a potent nonselective alpha- and beta-agonist. Its beta effects predominate at lower doses, while alpha1-mediated vasoconstriction predominates at high doses. Isoproterenol is a potent nonselective beta-agonist with a very low affinity for alpha-receptors.[54335] [65549] [65550]

Milrinone is a phosphodiesterase inhibitor (PDI) distinct from other inotropes. PDIs increase cyclic adenosine monophosphate (cAMP) by inhibiting breakdown within cardiac and vascular muscle cells, which leads to an increase in myocardial contractility.[30865] [54335]

Receptor Pharmacology of Catecholamines [54335] [65550] [65549] [65564]

Drug

Dose*

(mcg/kg/minute)

Receptors

Alpha1

Beta1

Beta2

Dopamine

Dobutamine

 

+

++++

+++

-

Dopamine

0.5 to 5

-

+

-

++++

5 to 10

+

++

-

+++

10 to 20

+++

++

-

+

Epinephrine

0.01 to 0.1

+

+++

++

-

0.1 to 0.2

+++

++

++

-

Isoproterenol

 

-

++++

++++

-

*Dose listed for dose-related receptor activity only

Locations and Responses of Select Receptors [54335] [65549] [65550]

Receptor

Primary Location

Stimulation Response

Alpha1

vascular smooth muscle

vasoconstriction

Beta1

heart

positive inotropy and chronotropy

Beta2

vascular and bronchial smooth muscle

vasodilation, bronchodilation

Dopamine1

renovascular smooth muscle

renal vasodilation

Therapeutic Use

  • Agents with both alpha- and beta- effects (e.g., dopamine, epinephrine) are used in cardiogenic shock to increase both mean arterial pressure (MAP) and cardiac output (CO).[65299] [65553] [65554] Mixed agents generally increase CO at lower doses, but may decrease CO at higher doses.[65553]
  • Pure inotropes (e.g., dobutamine, milrinone) are used for treating heart failure or for postoperative CO support when MAP is adequate.[65299] [65553]
  • Inotropes are also used in distributive/vasodilatory shock once adequate perfusion pressure is established, to increase oxygen delivery.[65553]
  • Dobutamine is recommended in hemodynamically stable patients with cardiogenic shock and low-output syndrome.[31689] [65298] [65299] [65564] It is also recommended in patients with septic shock and persistent hypoperfusion despite adequate fluid resuscitation and the use of vasopressors.[61770]
  • Dobutamine is preferred over milrinone in patients who are acutely unstable, hypotensive, or those with renal insufficiency.[65564] [65578] [65583]
  • Milrinone is preferred for patients with chronic heart failure, especially in the presence of significant right ventricular dysfunction, pulmonary hypertension, or concomitant beta-blocker therapy.[65564] [65578] [65583]
  • Isoproterenol use is limited to patients refractory to other inotropic agents.[65552]

Comparative Efficacy

  • Few clinical outcome data are available to guide initial selection of vasoactive agents in patients with cardiogenic shock.[65299]
  • There was no significant difference in mortality when comparing dopamine and norepinephrine as first-line vasoactive agents in the treatment of shock (n = 1,679); however, dopamine was associated with a higher rate of arrhythmias, including arrhythmias severe enough to require discontinuation of the study drug. Among patients with cardiogenic shock (n = 280), mortality was significantly higher in the dopamine group.[43703]
  • Both epinephrine and norepinephrine-dobutamine improved cardiac index, arterial pressure, and oxygen delivery in patients with cardiogenic shock (without acute coronary syndrome) after failure of dopamine (n = 30); however, epinephrine was associated with transient lactic acidosis, inadequate gastric mucosa perfusion, increased heart rate, and arrhythmia.[65585]
  • Dobutamine and milrinone have similar clinical effects in patients with severe heart failure.
  • Both dobutamine and milrinone were used successfully as a pharmacologic bridge to heart transplantation (n = 36) with no significant differences in right heart hemodynamics, need for additional vasodilator/inotropic therapy, need for mechanical cardiac support, or death.[65584]
  • There was no difference in mortality between chronic dobutamine or milrinone in patients with stage D heart failure being discharged from the hospital (n = 112).[65583]

Adverse Reactions/Toxicities

Cardiovascular effects

Inotropes may decrease blood pressure and induce hypotension; vasodilatory effects are most common with milrinone and less likely with dobutamine and low-dose dopamine.[65553] [65564] Similar to vasoconstrictors, inotropic agents can induce arrhythmias and myocardial ischemia by increasing myocardial oxygen consumption. Beta-agonists and phosphodiesterase inhibitors (PDIs) increase myocardial oxygen consumption by increasing heart rate and contractility.[65553] Risk of tachycardia and tachyarrhythmias is generally highest with dopamine and lowest with milrinone, although milrinone can cause reflex tachycardia.[65553] [65564]

Endocrine effects

Catecholamines may have potentially harmful effects on pituitary hormone secretion and immune function; these effects appear to be greatest with dopamine.[61770] [65553] [65554] [65557] [65563] [65564]

Metabolic effects

Epinephrine can increase blood glucose and lactate concentrations via stimulation of beta-receptors.[61770] [65550] Beta2-agonists such as isoproterenol and dobutamine can decrease serum potassium concentrations.[65553]

Drug Interactions

Antihypertensives

In general, antihypertensives decrease the response to sympathomimetics.[60589] The cardiac effects of dopamine are antagonized by beta-blockers. However, beta-blockers may potentiate the pressor and arrhythmogenic effects of epinephrine.[32400] [60589]

Halogenated anesthetics

Halogenated anesthetics increase cardiac autonomic irritability and may sensitize the myocardium to the action of intravenous catecholamines resulting in ventricular arrhythmias.[28004] [32400] [60589] [65553]

Monoamine oxidase inhibitors

Use sympathomimetic amines with caution in patients taking monoamine oxidase inhibitors (MAOIs), including linezolid, due to the risk of severe, prolonged hypertension; reduce the initial inotropic dose and carefully titrate. In general, do not use sympathomimetic agents concurrently or within 14 days of an MAOI due to an increased risk of hypertensive crisis.[27957] [28599] [32400] [60589] [65553]

Tricyclic antidepressants

Use sympathomimetic amines with caution in patients taking tricyclic antidepressants due to the risk of severe, prolonged hypertension.[32400]

Safety Issues

Hypovolemia

Correct hypovolemia by restoring blood volume with a suitable plasma expander or whole blood before inotrope administration; inotropes will worsen tachyarrhythmias and induce ischemia if preload is inadequate.[32400] [65553]

Hypotension

Milrinone has the potential to cause hypotension based on its mechanism of action; avoid loading doses, and decrease the initial maintenance dose in patients with hypotension, if necessary.[65552] Vasodilatory effects are most common with milrinone and less likely with dobutamine and low-dose dopamine and more likely in patients with hypovolemia or low systemic vascular resistance (SVR).[65564]

Renal impairment

Milrinone is primarily eliminated by the kidneys and requires dosage adjustment in those with renal insufficiency.[30865] [65552]

Aortic stenosis

Use phosphodiesterase inhibitors and sympathomimetic amines with beta effects with caution in patients with severe aortic or pulmonary valve stenosis; severe myocardial ischemia may occur.[65553]

Pheochromocytoma

Patients with a pheochromocytoma may experience a greater sensitivity to the adverse effects of catecholamines.[32400][60589]

[27957]Nardil (phenelzine) tablet package insert. New York, NY: Pfizer; 2009 Feb.

[28004]Isuprel (isoproterenol) package insert. Lake Forest, IL: Hospira, Inc.; 2013 Mar.

[28599]Zyvox (linezolid) package insert. New York, NY: Pharmacia and Upjohn Company; 2021 Sep.

[30865]Milrinone injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2018 May.

[31689]Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004;110:e82-e293.

[32400]Dopamine hydrochloride and 5% dextrose injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2017 Jul.

[43703]De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89.

[54335]Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation 2008;118:1047-1056.

[60589]Epinephrine 1 mg/mL injection package insert. Largo, FL: Belcher Pharmaceuticals, LLC; 2017 Feb.

[61770]Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017;45:486-552.

[65298]Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011;183:847-855.

[65299]van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation 2017;136:e232-e268.

[65549]Bockenstedt TL, Baker SN, Weant KA, et al. Review of vasopressor therapy in the setting of vasodilatory shock. Adv Emerg Nurs J 2012;34:16-23.

[65550]Stratton L, Berlin DA, Arbo JE. Vasopressors and inotropes in sepsis. Emerg Med Clin N Am 2017;35:75-91.

[65552]Allen JM. Understanding vasoactive medications: focus on pharmacology and effective titration. J Infus Nurs 2014;37:82-86.

[65553]Cooper BE. Review and update on inotropes and vasopressors. AACN Adv Crit Care 2008;19:5-13.

[65554]Hollenberg SM. Inotrope and vasopressor therapy of septic shock. Crit Care Clin 2009;25:781-802.

[65557]Myburgh JA, Higgins A, Jovanovska A. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34:2226-2234.

[65563]Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically ill patients. Br J Pharmacol 2012;165:2015-2033.

[65564]Jentzer JC, Coons JC, Link CB, et al. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther 2015;20:249-260.

[65578]Peterson JW, Felker M. Inotropes in the management of acute heart failure. Crit Care Med 2008;36:S106-S111

[65583]Gorodeski EZ, Chu EC, Reese JR, et al. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Hear Fail 2009;2:320-324.

[65584]Aranda JM, Schofield R, Pauly DF, et al. Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial. Am Heart J 2003;145:324-329.

[65585]Levy B, Perez P, Perny J, et al. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock: a prospective, randomized pilot study. Crit Care Med 2011;39:450-455.

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