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

Norepinephrine as an Initial Agent

Pharmacology

NE is recommended as the first-line agent for the treatment of vasodilatory shock.[3] NE is an endogenous sympathetic hormone (Figure 1), and its potent vasoconstrictor effects are mediated by agonism of α1 receptors on vascular smooth muscle cells (Figure 2). By this same mechanism, at high doses, NE can also increase pulmonary vascular resistance, increase myocardial workload, cause cardiac ischemia, and lead to severe hypertension.[7] Systemic vasoconstriction can impair perfusion of the mesentery, resulting in organ dysfunction and metabolic acidosis at high doses.

Clinical Studies

Although no vasopressor has demonstrated a mortality benefit over another in septic shock,[8–10] NE is more likely to improve hypotension with fewer arrhythmias (relative risk [RR] = 0.43; 95% CI, 0.26–0.69; P < .001) when compared to dopamine.[11] The same study found that use of NE over dopamine was associated with a lower rate of in-hospital or 28-day mortality (RR = 0.91; 95% CI, 0.83–0.99; P = .028).[11] In a randomized control trial (RCT) comparing NE against Epi, there was also no difference in 28-day mortality, 90-day mortality, or the time to achieve target MAP.[10] However, those receiving Epi did develop tachycardia, lactic acidosis, and hyperglycemia at a significantly higher rate than patients who were randomly assigned to NE.[10]

NE has not only been used to treat septic shock, but it also has been used extensively to treat vasoplegic syndrome (VS) associated with liver transplantation and cardiopulmonary bypass (CPB). In cardiac surgery, the Vasopressin versus NE in Patients with Vasoplegic Shock after Cardiac Surgery (VANCS) trial found that the rate of mortality and major complications occurred more frequently in the NE arm than in the vasopressin arm (32% vasopressin versus 49% NE, hazard ratio [HR] for vasopressin, 0.55; 95% CI, 0.38–0.80; P = .0014).[12] NE use was also associated with a higher rate of atrial fibrillation (82.1% NE versus 63.8% vasopressin, P = .0014), although there was no difference in the rates of mesenteric ischemia (1.3% NE versus 2.0% vasopressin, P = .68) or myocardial infarction (11.3% NE versus 7.4% vasopressin, P = .25).[12]

Clinical Use

The initial dose of NE ranges from 0.08 to 0.12 μg·kg−1·min−1, and no studies have been adequately powered to detect dosing difference in the elderly population.[13] It is well established that as the dose of NE increases, receptor desensitization and tachyphylaxis occur from phosphorylation and internalization of α1 receptors on vascular smooth muscle cells.[14] When this tachyphylaxis occurs, other vasoconstrictors with mechanisms distinct from NE must be used for maintenance of blood pressure.

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