Roeland Stolk1,2,3, Eva van der Pasch1,4, Flavia Naumann1,4, Joost Schouwstra1,4, Steffi Bressers1,4, Teun van Herwaarden5, Jelle Gerretsen1,4, Roel Schambergen1,4, Mike Ruth6, Hans van der Hoeven1,4, Henk van Leeuwen7, Peter Pickkers1,4, Matthijs Kox1,8. 1. Radboudumc, 6034, Department of Intensive Care Medicine, Nijmegen, Netherlands. 2. Radboudumc, 6034, Radboud Centre for Infectious Diseases, Nijmegen, Netherlands. 3. Rijnstate, 1322, Intensive Care, Arnhem, Netherlands. 4. Radboudumc, 6034, Radboud Centre for Infectious diseases, Nijmegen, Netherlands. 5. Radboudumc, 6034, Department of Laboratory Medicine, Nijmegen, Netherlands. 6. Radboudumc, 6034, Department of Medical Microbiology, Nijmegen, Netherlands. 7. Rijnstate, 1322, Department of Intensive Care Medicine, Arnhem, Netherlands. 8. Radboudumc, 6034, Radboud Centre for Infectious diseases, Nijmegen, Netherlands; matthijs.kox@radboudumc.nl.
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. MEASUREMENTS AND MAIN RESULTS: Leukocytes from 6-9 donors were stimulated in the presence or absence of norepinephrine and vasopressin. One-hundred-and-ninety C57BL/6J mice received continuous infusion of norepinephrine or vasopressin via micro-osmotic pumps and were challenged with lipopolysaccharide or underwent cecal ligation and puncture (CLP). Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin or saline, and intravenously challenged with lipopolysaccharide. The relationship between norepinephrine infusion rate and the use of β-blockers, and plasma cytokines was assessed in 195 septic shock patients. RESULTS: Norepinephrine attenuated the production of pro-inflammatory mediators and reactive oxygen species, while augmenting anti-inflammatory interleukin-10 production both in vitro and in lipopolysaccharide-challenged mice. Norepinephrine infusion during CLP resulted in increased bacterial dissemination to spleen, liver and blood. In lipopolysaccharide-challenged volunteers, norepinephrine enhanced plasma interleukin-10 concentrations and attenuated release of the pro-inflammatory cytokine interferon gamma-induced protein-10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more anti-inflammatory cytokine balance, whereas β-blocker use was associated with a more pro-inflammatory cytokine balance. CONCLUSION: 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.
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. MEASUREMENTS AND MAIN RESULTS: Leukocytes from 6-9 donors were stimulated in the presence or absence of norepinephrine and vasopressin. One-hundred-and-ninety C57BL/6J mice received continuous infusion of norepinephrine or vasopressin via micro-osmotic pumps and were challenged with lipopolysaccharide or underwent cecal ligation and puncture (CLP). Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin or saline, and intravenously challenged with lipopolysaccharide. The relationship between norepinephrine infusion rate and the use of β-blockers, and plasma cytokines was assessed in 195 septic shockpatients. RESULTS: Norepinephrine attenuated the production of pro-inflammatory mediators and reactive oxygen species, while augmenting anti-inflammatory interleukin-10 production both in vitro and in lipopolysaccharide-challenged mice. Norepinephrine infusion during CLP resulted in increased bacterial dissemination to spleen, liver and blood. In lipopolysaccharide-challenged volunteers, norepinephrine enhanced plasma interleukin-10 concentrations and attenuated release of the pro-inflammatory cytokine interferon gamma-induced protein-10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more anti-inflammatory cytokine balance, whereas β-blocker use was associated with a more pro-inflammatory cytokine balance. CONCLUSION: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.
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Authors: Ranjit Lall; Dipesh Mistry; Emma Skilton; Nafisa Boota; Scott Regan; Julian Bion; Simon Gates; Anthony C Gordon; Janet Lord; Daniel Francis McAuley; Gavin Perkins; Mervyn Singer; Duncan Young; Tony Whitehouse Journal: BMJ Open Date: 2021-02-16 Impact factor: 2.692
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