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

Phenylephrine

Phenylephrine is not recommended for the routine management of septic shock. However, it still plays an important role in the management of other forms of vasodilatory shock, such as anesthetic-induced hypotension from induction agents, volatile anesthetics, and neuraxial medications. Unlike the previously described medications, phenylephrine can be administered peripherally, which makes it a useful medication to rapidly control hypotension when a central venous catheter is not present.

Pharmacology

Structurally, phenylephrine is closely related to Epi and is an exogenous selective α1 agonist. It lacks the hydroxyl group in position 4 (Figure 1) and is also missing the typical catechol (benzene-1,2-diol) structure and is therefore not considered a catecholamine.[39] It is renally excreted with a half-life of 2.1–3.4 hours.

Three different subtypes of α1 receptors exist (α1a, α1b, α1d), and the difference in their distribution accounts for the variable effect phenylephrine has on the vasculature, heart, eyes, and bladder.[40] The smooth muscle cells of the vasculature contain α1 and β2 adrenergic receptors, while myocardial cells predominantly contain β1 and β2 adrenergic receptors. Therefore, phenylephrine increases venous return and can cause reflex bradycardia secondary to systemic vasoconstriction.

Clinical Studies

Phenylephrine has been studied under a wide variety of conditions, including during general anesthesia, but there is limited evidence supporting its use in sepsis.[29] In a small human study of 32 patients with septic shock, patients were randomly assigned to either phenylephrine or NE to maintain MAP >65 mm Hg.[41] There was no difference between the groups with respect to CO, acidemia, gastric tonometry, and creatinine. Another study of only 15 patients examined the short-term effects of an 8-hour temporary switch from NE to phenylephrine during septic shock and found that this switch was associated with a significant increase in lactate and a decrease in renal clearance and hepatosplanchnic blood flow.[42] Large-scale RCT data are lacking, and, for this reason, phenylephrine's effects in septic shock are not known.

Phenylephrine is, however, routinely used in the perioperative setting for the short-term treatment of hypotension associated with administration of anesthesia. Tachyphylaxis has been observed with prolonged infusion due to downregulation of α1 receptors.[43] Dosing ranges from 10 to 200 μg as a bolus, while infusion dosing ranges from 0.05 to 2 μg·kg−1·min−1. There is evidence that age has an effect on the dose response to phenylephrine. In a study evaluating hemodynamic changes during phenylephrine infusion in 27 healthy volunteers, those in the older group (mean, 69 years old) were found to have a higher increase in systolic blood pressure and a smaller heart rate decrease than those in the younger group (mean, 26 years old).[44] Age-related vascular stiffness is thus an important consideration in titrating phenylephrine.

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