Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis
Roeland F. Stolk, Eva van der Pasch, Flavia Naumann, Joost Schouwstra, Steffi Bressers, Antonius E. van Herwaarden, Jelle Gerretsen, Roel Schambergen, Mike Marvin Ruth, Johannes G. van der Hoeven, Henk van Leeuwen, Peter Pickkers, Matthijs Kox
Abstract
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.