Central sympatholytics prolong survival in experimental sepsis

Stefan Hofer, Jochen Steppan, Tanja Wagner, Benjamin Funke, Christoph Lichtenstern, Eike Martin, Bernhard M. Graf, Angelika Bierhaus, Markus A. Weigand

Research output: Contribution to journalArticle

Abstract

Introduction: One of the main causes of death in European and US intensive care units is sepsis. It involves a network of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Furthermore, there is an up regulation of transcription factors such as nuclear factor (NF) κB. It has previously been shown that clonidine is able to significantly reduce pro-inflammatory cytokines in surgical patients. We therefore hypothesise that the clinically used central alpha-2 agonist clonidine has the ability to improve survival in experimental sepsis by inhibiting the sympathetic tone and consequently inhibiting the pro-inflammatory cytokine release. Methods: To investigate this therapeutic potential of clonidine in a prospective randomised laboratory investigation we used a murine model of caecal ligation and puncture (CLP) induced sepsis. Animals receiving pre-emptive injections were treated with either clonidine (5 μg/kg) or dexmedetomidine (40 μg/kg) 12 and 1 hours before the operation, as well as 1, 6 and 12 hours afterwards. Another group of animals only received clonidine (5 μg/kg) 1, 6 and 12 hours after the operation, while the pre-emptive injections were normal saline. The control groups received solvent injections at the respective time points. Results: Pre-emptive administration of a central sympatholytic significantly reduced mortality (clonidine: p = 0.015; dexmedetomidine: p = 0.029), although postoperative administration of clonidine failed to significantly prolong survival. Furthermore pre-emptive administration of clonidine significantly attenuated the cytokine response after CLP-induced sepsis (mIL-1beta: p = 0.017; mIL-6: p < 0.0001; mTNF-α: p < 0.0001), preserved blood pressure control (p = 0.024) and down-regulated the binding activity of NF-κB. There were no changes in the pro-inflammatory cytokine response when peripheral blood was incubated with lipopolysaccharide alone compared with incubation with clonidine (10-4M) plus LPS (p > 0.05). Conclusions: Our results demonstrate that the pre-emptive administration of either clonidine or dexmedetomidine have the ability to successfully improve survival in experimental sepsis. Furthermore, there seems to be a connection between the central muscarinic network and the vagal cholinergic response. By down-regulating pro-inflammatory mediators sympatholytics may be a useful adjunct sedative in patients with a high risk for developing sepsis.

Original languageEnglish (US)
Article numberR11
JournalCritical Care
Volume13
Issue number1
DOIs
StatePublished - Feb 6 2009

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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    Hofer, S., Steppan, J., Wagner, T., Funke, B., Lichtenstern, C., Martin, E., Graf, B. M., Bierhaus, A., & Weigand, M. A. (2009). Central sympatholytics prolong survival in experimental sepsis. Critical Care, 13(1), [R11]. https://doi.org/10.1186/cc7709