Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock

Jonathan H. Chow, MD; Ezeldeen Abuelkasem, MBBCh, MSc; Susan Sankova, MD; Reney A. Henderson, MD; Michael A. Mazzeffi, MD, MPH; Kenichi A. Tanaka, MD, MSc

Disclosures

Anesth Analg. 2019;130(1):15-30. 

In This Article

Epi as a Third-line Agent

Frequently, NE and vasopressin may not be adequate in managing the hemodynamics of vasodilatory shock. Epi, as a potent α1 agonist, can be used as an additional adjunct to maintain acceptable blood pressures. It is a derivative of tyrosine and an endogenous sympathomimetic catecholamine produced in the adrenal gland (Figure 1).[33] Its vasoconstrictor effect is mediated through stimulation of α1 receptors on vascular smooth muscle cells, which are also coupled to the Gq protein (Figure 2).[5,6]

Dose-dependent Effects of Epi

Vascular smooth muscle possesses a high density of α1 receptors relative to β2 receptors, but Epi has a higher affinity for β2 receptors than α1 receptors. Consequently, Epi effect on systemic vascular resistance (SVR) is dose dependent. At low-to-moderate doses (2–10 μg·min−1), Epi predominately stimulates β2 receptors, resulting in an increase in inotropy and a decrease in SVR (Figure 3). Conversely, at higher doses (>10 μg·min−1), Epi predominately stimulates α1 receptors (Figure 2). Because of a higher density of α1 receptors in the systemic vasculature, SVR and MAP increase.[34,35]

Clinical Studies

The 2018 guidelines of the Surviving Sepsis Campaign recommend adding Epi as a secondary or tertiary vasopressor when escalating doses of NE and vasopressin are unable to achieve normotension.[3] Although a trial between NE and Epi found no difference in mortality or time to resolution of hypotension, there was a significantly higher incidence of tachycardia, lactate acidosis, and hyperglycemia in patients receiving Epi, which is why it is only recommended as a third-line agent.[10] However, Epi is still favored over dopamine in septic shock because of previous trials that have attributed dopamine with in-hospital mortality and 28-day mortality.[11,36]

Epi mechanism of vasoconstriction targets the same α1 receptors as NE. When NE is already at a high dose, as would be the case when utilizing a third-line agent, there may be limited utility in administering a drug that targets receptors that are likely already saturated, downregulated, and tachyphylactic.[14] For this reason, unless myocardial dysfunction is present, Epi may not be an optimal drug for the treatment of septic shock.

In other subsets of vasodilatory shock such as anaphylactic shock, Epi is the medication of choice because it reverses the pathophysiologic derangements of anaphylaxis. Its vasoconstrictor effect not only restores SVR and MAP but also improves airway edema from the massive vasodilation of capillary beds.[37] Through its effect on β2 receptors in pulmonary endothelium, it is a potent bronchodilator that improves bronchospasm (Figure 2A).[37] On β2 receptors of mast cells, Epi prevents mast cell degranulation, which suppresses the release of histamine and prostaglandins. This may also explain the efficacy of Epi in treating hypotension associated with systemic mastocytosis.[38]

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