Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis

Am J Respir Crit Care Med. 2020 Sep 15;202(6):830-842. doi: 10.1164/rccm.202002-0339OC.

Abstract

Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of β-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas β-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects.

Keywords: immunoparalysis; norepinephrine; sepsis; vasopressin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / immunology
  • Anti-Inflammatory Agents / therapeutic use
  • Humans
  • Immunity, Active / drug effects*
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Models, Animal
  • Netherlands
  • Norepinephrine / adverse effects*
  • Norepinephrine / immunology*
  • Norepinephrine / therapeutic use
  • Reagent Kits, Diagnostic
  • Shock, Septic / drug therapy*
  • Shock, Septic / immunology*
  • Vasoconstrictor Agents / adverse effects*
  • Vasoconstrictor Agents / immunology*
  • Vasoconstrictor Agents / therapeutic use

Substances

  • Anti-Inflammatory Agents
  • Reagent Kits, Diagnostic
  • Vasoconstrictor Agents
  • Norepinephrine