Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study

Abstract

Background: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the β-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through β-adrenergic affinity.

Methods: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and β-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 μg kg^-1 min^-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg_-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 μg kg^-1 min^-1) or saline before receiving LPS (2 ng kg^-1 i.v.).

Results: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with β-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03).

Conclusions: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the β-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection.

Clinical trial registration: NCT02675868 (Clinicaltrials.gov).

Keywords: LPS; endotoxaemia; host defense; immunosuppression; phenylephrine; surgical peritonitis, cytokines; β-adrenergic receptor.