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


Anesth Analg. 2019;130(1):15-30. 

In This Article

Vasopressin as a Second-line Agent

Unlike NE, which achieves vasoconstriction through agonism of α1 receptors, vasopressin increases vascular tone through agonism of V1a receptors (Figure 2). Thus, during states of rapidly escalating NE doses and refractory shock, vasopressin is able to provide a distinct mechanism of vasoconstriction.


Arginine vasopressin is an endogenous peptide hormone synthesized in the hypothalamus and released from the posterior pituitary. Initially used in the management of diabetes insipidus and variceal hemorrhage, vasopressin was approved as a vasoconstrictor for vasodilatory shock almost half a century ago.[15] Vasopressin receptors belong to the GPCR superfamily, and V1a receptor agonism leads to increased vascular tone, which is especially pronounced in physiologic states of hypovolemia and low autonomic tone.[16–18] Agonism of V1 receptors causes vascular and mesenteric vasoconstriction, while agonism of V2 receptors in the kidney leads to retention of free water and release of von Willebrand factor, factor VIII, and tissue plasminogen activator from endothelial cells.[9,19,20] Selective agonism of V2 receptors by desmopressin causes vasodilation via cAMP-mediated endothelial NOS activation.[20]

Stimulation of V3 receptors located in the pituitary causes increased adrenocorticotropic hormone production.[17,21] Vasopressin can have vasodilatory effects in certain vascular beds, including the pulmonary arterial system, possibly through activation of oxytocin receptors.[22]

Synthetic Vasopressin Analogues

Terlipressin and selepressin are synthetic analogues of lysine vasopressin with a chemical structure preferentially selective for the V1 receptor.[23] In contrast to vasopressin, which has a V1 to V2 binding ratio of 1, terlipressin has a ratio of 2.2, indicating that its action is more selective for vascular and mesenteric vasoconstriction than for retention of free water.[23] Selepressin has been shown to have 100% sensitivity for V1 receptor agonism and does not exhibit any V2 activity.[24] While the prodrug terlipressin is a partial V1 agonist, its active metabolite lysine vasopressin is a full V1 agonist, which explains its relatively longer half-life of 4–6 hours when compared to arginine vasopressin.[25] Therefore, in contrast to vasopressin, it can be given either as an intermittent bolus of 0.25–1 mg every 6–8 hours or as a continuous infusion.[23]

Clinical Studies

Vasopressin has been studied extensively in septic shock, and, in 2008, the Vasopressin Versus NE Infusion in Patients with Septic Shock (VASST) trial found no significant mortality difference between vasopressin and NE at 28 days (35.4% vasopressin versus 30.3% NE, P = .26) or 90 days (43.9% vasopressin versus 49.6% NE, P = .11).[9] There were also no significant differences in the rate of serious adverse events (10.3% vasopressin versus 10.5% NE, P = 1.00). These data suggest that vasopressin can be a potentially safe and noninferior alternative to NE in the treatment of septic shock.[9]

The Effect of Early Vasopressin versus Norepinephrine on Kidney Failure in Patients with Septic Shock (VANISH) trial examined the rate of renal failure in septic shock and found no significant difference in the number of kidney failure–free days (57.0% vasopressin versus 59.2% NE; 95% CI, −13.0% to 8.5%). Although the vasopressin group was found to have improved creatinine, enhanced urine output, and decreased rate of renal replacement therapy (RRT), there was no difference in 28-day mortality (30.9% vasopressin versus 27.5% NE; absolute difference, 3.4%; 95% CI, −5.4% to 12.3%).[26]

In contrast, there has been a scarce number of RCTs investigating the use of terlipressin in septic shock. Terlipressin has been shown to be superior to vasopressin in reducing catecholamine requirements at 48 hours and was associated with less rebound hypotension when discontinued.[27] However, bolus administration of terlipressin was associated with decreased oxygen delivery, coronary vasoconstriction, excessive splanchnic vasoconstriction, and portal hypertension, which may limit its ability to be given as a bolus medication during vasodilatory shock.[28]

Thresholds for Initiation of Vasopressin

When vasopressin is administered for vasodilatory shock, it is recommended to be infused at a rate of 0.03 units·min−1.[29] Doses higher than 0.03–0.04 units·min−1 have been associated with cardiac and mesenteric ischemia.[30] There have not been adequate studies examining modification of this dosage in the elderly population, and precise NE thresholds for the initiation of vasopressin have not yet been established.[31] NE doses higher than 0.5 μg·kg−1·min−1 have been associated with adverse events, and 1 study demonstrated that NE ≥0.5 μg·kg−1·min−1 was independently associated with a 5-fold increase in mortality (OR = 5.1; 95% CI, 2.0–12.9; P = .001).[32] In an a priori defined subgroup analysis of the VASST trial, patients randomly assigned to vasopressin when the NE dose was <15 μg·min−1 had improved 28- and 90-day survival compared with those randomly assigned to vasopressin when NE dose exceeded 15 μg·min−1.[9]

For these reasons, to take advantage of vasopressin's catecholamine-sparing properties while avoiding the adverse effects of toxic NE doses, we recommend starting vasopressin early in the course of shock, when NE dose exceeds 0.15 μg·kg−1·min−1. However, there is a paucity of high-quality evidence for this threshold, which is why such wide variability exists among institutions.