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 b-adrenergic receptor. Phenylephrine, generally regarded as a selective a-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through b-adrenergic affinity.Methods: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and aand b-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30e50 mg kg À1 min À1 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 mg kg À1 min À1 ) or saline before receiving LPS (2 ng kg À1 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 b-antagonists, but not a-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 (þ42%, P¼0.0069), spleen (þ59%, P¼0.04), and liver (þ35%, P¼0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (þ76%, P¼0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (e15%, P¼0.03).Conclusions: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the b-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).

Hypotension as a marker or mediator of perioperative organ injury: a narrative review

“…Moreover, attempts to reverse hypotension through vasopressor therapy may unmask adverse unintended consequences in vulnerable Composite outcome patients, including bacterial overgrowth, biofilm formation, 22 and host immunosuppression. 23,24 These studies reinforce the notion that most clinicians are unclear as to when, or how, to treat critical hypotension.…”

“…108 Persistent sympathoexcitation reduces recycling of critical GPCRs required for efficient inotropy, and calcium overload and consequent bioenergetic compromise. Beyond direct cellular injury, phenylephrine 24 and norepinephrine 23 promote infection and bacterial outgrowth by inducing immunosuppression. Conversely, reduced vagal activity augments both the acute 109 and chronic 110 inflammatory response; vagal loss may be an unavoidable or unintended consequence of various perioperative interventions including anaesthetic agents, 111 withdrawal of ACEIs, 112 and upper limb blocks.…”

The Pharmacological Effects of Phenylephrine are Indirect, Mediated by Noradrenaline Release from the Cytoplasm

“…PE has been reported to exhibit unexpected pharmacological effects in preclinical studies [12,[15][16][17] and clinical treatments [18][19][20], which are characteristic of α 2 -and β-adrenoceptor stimulation. These actions are not easily explained by a direct α 1 -adrenoceptor-mediated response to PE, a drug very frequently used in medical practice, which was shown and concluded in the studies published with several recombinant and native assays [2,[38][39][40] as typically representative of α 1 -agonists.…”

“…Similar unexpected observations were also found in human experiments and clinical practice, such as PE production of a β-adrenoceptor-mediated action in the human forearm [ 18 ]. β-receptor-mediated immunosuppression in response to PE infusion was recently shown in humans, specifically, enhanced IL-10 and reduced proinflammatory cytokine production [ 19 ], which compromised host defence and increased susceptibility to infection. Adverse effects, including an increased heart rate, a typical β-adrenoceptor action and decreased blood pressure, have been reported even after eye-drop applications in a meta-analysis [ 20 ].…”

Modulation of Inflammatory Signaling Molecules in Bordetella pertussis Antigen-Challenged Human Monocytes in Presence of Adrenergic Agonists

“…The adrenergic system plays a critical role in stress signaling [60] and the adrenergic modulation of the innate immune response and, therefore, represents novel immunomodulatory and anti-inflammatory targets for the treatment of infectious diseases [61]. Phenylephrine (PE) is a selective α-adrenergic receptor (α-AR) agonist that exerts potent anti-inflammatory effects [62] through the modulation of cytokine production, although the stimulation of α-AR is mainly associated with pro-inflammatory effects [63]. Isoproterenol (ISO) is another adrenergic receptor agonist for the β2-adrenergic receptor (β2-AR) and has been shown to induce an adaptive immune response [64].…”