Roeland F Stolk1, Flavia Naumann2, Eva van der Pasch2, Joost Schouwstra2, Steffi Bressers2, Antonius E van Herwaarden3, Jelle Gerretsen2, Roel Schambergen2, Mike Ruth4, Hans G van der Hoeven2, Henk J van Leeuwen5, Peter Pickkers2, Matthijs Kox6. 1. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Intensive Care Medicine, Hospital Rijnstate, Arnhem, The Netherlands. 2. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands. 5. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Intensive Care Medicine, Hospital Rijnstate, Arnhem, The Netherlands. 6. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: matthijs.kox@radboudumc.nl.
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).
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).
Authors: Md Obayed Raihan; Brenna M Espelien; Brett A McGregor; Courtney Hanson; Afrina Brishti; Nathan A Velaris; Travis D Alvine; David S Bradley; Matthew Nilles; Mikhail Y Golovko; Junguk Hur; James E Porter Journal: Vaccines (Basel) Date: 2022-02-17
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