Which second-line agents are available for vasopressor therapy in sepsis/septic shock and when are they indicated?

Updated: Oct 07, 2020
  • Author: Andre Kalil, MD, MPH; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM  more...
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Second-line vasopressors appropriate for patients who have persistent hypotension despite maximal doses of norepinephrine or dopamine include sythenthetic human angiotensin II, epinephrine, phenylephrine, and vasopressin.

In December 2017, synthetic human angiotensin II (Giapreza) was approved by the FDA for adults with septic or other distributive shock. Approval was based on the ATHOS-3 clinical trial (n = 321) in patients with vasodilatory shock and critically low blood pressure. Eligible patients had vasodilatory shock despite intravenous volume resuscitation with at least 25 mL/kg over the previous 24 hours and the administration of high-dose vasopressors. Significantly more patients responded to treatment with the angiotensin II injection added to conventional therapy compared with those on conventional therapy plus placebo. At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (P = .01). [71]

Epinephrine clearly increases MAP in patients unresponsive to other vasopressors, mainly by virtue of its potent inotropic effects on the heart; thus, it should probably be the first alternative agent considered in patients with septic shock who show a poor clinical response to norepinephrine or dopamine. [11, 60] Adverse effects include tachyarrhythmias, myocardial and splanchnic ischemia, and increased systemic lactate concentrations.

Phenylephrine exerts a pure alpha-receptor agonist effect, which results in potent vasoconstriction, albeit at the expense of depressed myocardial contractility and heart rate. Phenylephrine may be considered a first-line agent in patients with extreme tachycardia; its pure alpha-receptor activity will not result in increased chronotropy. [90]

Vasopressin, or antidiuretic hormone (ADH), has been proposed for use in septic shock because it is an endogenous peptide with potent vasoactive effects and its circulating levels are depressed in septic shock. According to the 2012 Surviving Sepsis Campaign guidelines, vasopressin should not be the single initial vasopressor but should be reserved for salvage therapy. [11] After first-line treatment, 0.03 U/min of vasopressin may be added to norepinephrine, with an anticipated effect equivalent to that of norepinephrine alone. [11, 60]

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