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Jun.06.2020

Vasopressors

Summary

  • Vasopressors are used for the treatment of hypotension and hemodynamic instability associated with shock.
  • Vasopressor selection primarily depends on the etiology of hemodynamic instability.
  • Norepinephrine is considered the initial vasopressor of choice for most adult patients in distributive/vasodilatory shock; epinephrine is considered first-line for anaphylactic shock.

Pharmacology/Mechanism of Action

Adrenergic vasopressors activate 3 types of receptors: 1) alpha-adrenergic, 2) beta-adrenergic, and 3) dopaminergic. Dopamine is the metabolic precursor of norepinephrine and displays dose-related receptor activity. At infusion rates of less than 5 mcg/kg/minute, dopamine targets dopaminergic receptors. At infusion rates of 5 to 10 mcg/kg/minute, it continues to stimulate dopaminergic receptors but also activates beta-receptors. At high doses, dopamine maintains beta activity while preferentially targeting alpha-receptors. Norepinephrine, the precursor of epinephrine, is much more selective in its targeting of alpha- and beta-receptors than dopamine and has no activity at dopaminergic 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. Phenylephrine is a pure alpha1-agonist, which increases blood pressure via peripheral vasoconstriction.[54335][65549][65550]

Non-adrenergic vasopressors include vasopressin and angiotensin II. Vasopressin causes potent peripheral vasoconstriction via vasopressin receptors located on vascular smooth muscle cells.[65549][65550] Angiotensin II causes vasoconstriction and increases the release of aldosterone.[62722]

Receptor Pharmacology of Vasopressors [62722][65549][65550]

Drug

Dose*

(mcg/kg/minute)

Receptors

Alpha1

Beta1

Beta2

Dopamine

Vasopressin

Angiotensin II

Angiotensin II

 

-

-

-

-

-

+++

Dopamine

0.5 to 5

-

+

-

++++

-

-

5 to 10

+

++

-

+++

-

-

10 to 20

+++

++

-

+

-

-

Epinephrine

0.01 to 0.1

+

+++

++

-

-

-

0.1 to 0.2

+++

++

++

-

-

-

Norepinephrine

 

++++

++

-

-

-

-

Phenylephrine

 

+++

-

-

-

-

-

Vasopressin

 

-

-

-

-

+++

-

*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

Vasopressin1

vascular smooth muscle

vasoconstriction

Angiotensin II

vascular smooth muscle

vasoconstriction

Therapeutic Use

  • Norepinephrine is the initial vasopressor of choice for most adult patients in distributive/vasodilatory shock and is an attractive option when attempting to increase systemic vascular resistance (SVR) and mean arterial pressure (MAP) with little change in heart rate.[61770] [65552] It is recommended as the initial vasopressor of choice in septic shock.[61770]
  • Dopamine is considered an alternative to norepinephrine in select patients at low risk for tachyarrhythmias or with bradycardia; it increases MAP and cardiac output, primarily due to an increase in stroke volume and heart rate.[61770] [65552]
  • Phenylephrine is a reasonable option in tachycardic patients in distributive/vasodilatory shock due to its lack of beta activity.[65552]
  • Epinephrine is the vasopressor of choice in anaphylactic shock, as it provides beta2 stimulation; it may also be added in cases of refractory hypotension.[61770] [65552] [65559] Epinephrine is the standard vasoactive drug used during cardiopulmonary resuscitation (CPR) for cardiac arrest.[60266]
  • Vasopressin use is typically limited to adjunctive therapy in refractory shock.[61770] [65552] Vasopressin offers no advantage as a substitute for epinephrine during cardiac arrest, and it is no longer recommended as a sole vasoactive drug during CPR.[60266]
  • The mechanism of angiotensin II makes it a plausible treatment option to increase blood pressure and decrease catecholamine requirements in patients with refractory shock; however, comparative data is lacking.[62724]

Comparative Efficacy

  • Data support the use of norepinephrine as a first-line vasopressor in the treatment of shock.
  • There was no significant difference in mortality when comparing norepinephrine and dopamine as first-line vasopressors 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, mortality was significantly higher in the dopamine group.[43703]
  • Comparison of norepinephrine to epinephrine in critically ill patients (n = 280) showed no significant difference in hemodynamic response or mortality but an increase in adverse effects (e.g., tachycardia, transient metabolic effects) associated with epinephrine.[65557]
  • Large studies comparing vasopressin to other vasopressors in septic shock are lacking; data support a sparing effect on norepinephrine dose, but vasopressin use has not been shown to influence mortality.
  • Low-dose vasopressin did not significantly reduce mortality in patients with septic shock (n = 778) when used in conjunction with norepinephrine compared with norepinephrine alone.[65555]
  • Early use of vasopressin with hydrocortisone or placebo did not improve the number of kidney-failure free days or mortality rate when compared to norepinephrine (n = 409); however, there was less use of renal replacement therapy in the vasopressin group.[65556]
  • Data do not support the use of vasopressin as a substitute for epinephrine in cardiac arrest.
  • Repeated injections of standard-dose vasopressin or epinephrine during prolonged advanced cardiac life support resulted in comparable survival (n = 336).[65581]

Adverse Reactions/Toxicities

Cardiac effects

Vasoconstrictors can increase myocardial oxygen consumption by increasing ventricular wall tension and decrease myocardial oxygen supply via vasoconstriction of coronary vessels; this can induce myocardial ischemia.[65553] Catecholamines can trigger tachyarrhythmias; tachycardia and arrhythmogenesis are more prominent with dopamine than with other vasopressor agents.[65554]

Peripheral ischemia

Splanchnic hypoperfusion and extensive peripheral vasoconstriction may occur with potent vasoconstrictors.[65552]

Endocrine effects

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

Metabolic effects

Epinephrine can increase blood glucose and lactate concentrations via stimulation of beta-receptors.[61770] [65550]

Drug Interactions

Antihypertensives

In general, antihypertensives decrease the response to vasopressors.[57578] [60589] [64705] Due to their mechanism, angiotensin-converting enzyme (ACE) inhibitors may increase the response to angiotensin II while angiotensin II receptor blockers may decrease the response to angiotensin II.[62722] The cardiac effects of dopamine are antagonized by beta-blockers. However, beta-blockers may potentiate the pressor and arrhythmogenic effects of epinephrine.[32400] [60589]

Vasodilators

Vasodilators (e.g., nitrates, phosphodiesterase inhibitors) antagonize the effects of vasopressors.[57578][60589][64705]

Digoxin

Digoxin may potentiate the arrhythmogenic effects of catecholamines.[28272][60589]

Halogenated anesthetics

Halogenated anesthetics increase cardiac autonomic irritability and may sensitize the myocardium to the action of intravenous catecholamines resulting in ventricular arrhythmias.[32400] [43697] [60589]

Monoamine oxidase inhibitors

Use sympathomimetic vasopressors with caution in patients taking monoamine oxidase inhibitors (MAOIs), including linezolid, due to the risk of severe, prolonged hypertension; reduce the initial vasopressor 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] [43697] [57578] [64705] [60589]

Tricyclic antidepressants

Use sympathomimetic vasopressors with caution in patients taking tricyclic antidepressants due to the risk of severe, prolonged hypertension.[32400] [43697] [57578] [64705]

Phenothiazines

Do not use epinephrine to counteract circulatory collapse or hypotension caused by phenothiazines due to a paradoxical further lowering of blood pressure. If a vasoconstrictor is required, norepinephrine and phenylephrine are most suitable.[28997][60589]

Contrast media

Never inject intravascular contrast medium after the administration of vasopressors due to potentiation of severe neurologic effects.[61854]

Safety Issues

Extravasation

Administer vasopressors through a central vein whenever possible; prolonged administration through a peripheral vein may result in extravasation and skin necrosis. If peripheral administration is necessary, use a 20-gauge or larger catheter and assess the site frequently. If extravasation occurs, administer phentolamine 5 to 10 mg directly to the site.[65552] [65553]

Hypovolemia

Correct hypovolemia by restoring blood volume with a suitable plasma expander or whole blood before vasopressor administration. If a vasopressor is continuously administered to maintain blood pressure in the absence of blood volume replacement, severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite normal blood pressure, tissue hypoxia, and lactic acidosis may occur.[32400] [43697] [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.

[28272]Lanoxin (digoxin) tablets package insert. St. Michael, Barbados: Concordia Pharmaceuticals Inc.; 2019 Feb.

[28599]Zyvox (linezolid) package insert. New York, NY: Pharmacia and Upjohn Company; 2020 Aug.

[28997]Thorazine (chlorpromazine) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2017 Mar.

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

[43697]Levophed (norepinephrine bitartrate) injection package insert. Lake Forest, IL: Hospira, Inc.;2020 Jun.

[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.

[57578]Vazculep (phenylephrine) injection package insert. Chesterfield, Mo: Avadel Legacy Pharmaceuticals, LLC; 2019 Oct.

[60266]Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132:S444-64.

[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.

[61854]Conray (iothalamate meglumine) injection package insert. Princeton, NJ: Guerbet; 2017 Mar.

[62722]Giapreza (angiotensin II) injection package insert. San Diego, CA: La Jolla Pharmaceutical Company; 2017 Dec.

[62724]Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-430.

[64705]Biorphen (phenylephrine hydrochloride) injection package insert. Deer Park, IL; Eton Pharmaceuticals, Inc.: 2021 Mar.

[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.

[65555]Russell JA, Walley KR, Singer J, et al. vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-887.

[65556]Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 2016; 316:509-518.

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

[65559]Smith N, Lopez RA, Silberman M. Distributive shock. [Updated 2020 Apr 24]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020 Jan.

[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.

[65581]Mukoyama T, Kinoshita K, Nagao K, et al. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation 2009;80;755-761.