Abstract
BackgroundImmunosuppression 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. MethodsHuman 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.). ResultsIn 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). ConclusionsPhenylephrine 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 registrationNCT02675868 (Clinicaltrials.gov).
Highlights
Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the b-adrenergic receptor
Immunosuppression after surgery, which is associated with infection, is promoted by elevated levels of catecholamines acting via the b-adrenergic receptor
Release of the anti-inflammatory cytokine IL-10 was enhanced by phenylephrine in a dose-dependent fashion
Summary
Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and a- and b-adrenergic antagonists. 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 b-antagonists, but not a-antagonists. In vivo human endotoxaemia experiments and blood withdrawal for in vitro studies were carried out in accordance with the declaration of Helsinki after approval of the local ethics committee of the Radboud University Medical Centre (CMO identifiers 2015e2079 and 2010e10, respectively). The murine surgical peritonitis and human endotoxaemia experiments were part of a broader project investigating (immunologic) effects of vasopressors.[11,17,18] data of control groups have been published previously as detailed below
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