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
Externally publishedYes

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Sympatholytics
Clonidine
Sepsis
Survival
Dexmedetomidine
Cytokines
Punctures
Cholinergic Agents
Injections
Ligation
Hypnotics and Sedatives
Interleukin-1
Intensive Care Units
Cause of Death
Interleukin-6
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

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

Central sympatholytics prolong survival in experimental sepsis. / Hofer, Stefan; Steppan, Jochen; Wagner, Tanja; Funke, Benjamin; Lichtenstern, Christoph; Martin, Eike; Graf, Bernhard M.; Bierhaus, Angelika; Weigand, Markus A.

In: Critical Care, Vol. 13, No. 1, R11, 06.02.2009.

Research output: Contribution to journalArticle

Hofer, S, Steppan, J, Wagner, T, Funke, B, Lichtenstern, C, Martin, E, Graf, BM, Bierhaus, A & Weigand, MA 2009, 'Central sympatholytics prolong survival in experimental sepsis', Critical Care, vol. 13, no. 1, R11. https://doi.org/10.1186/cc7709
Hofer S, Steppan J, Wagner T, Funke B, Lichtenstern C, Martin E et al. Central sympatholytics prolong survival in experimental sepsis. Critical Care. 2009 Feb 6;13(1). R11. https://doi.org/10.1186/cc7709
Hofer, Stefan ; Steppan, Jochen ; Wagner, Tanja ; Funke, Benjamin ; Lichtenstern, Christoph ; Martin, Eike ; Graf, Bernhard M. ; Bierhaus, Angelika ; Weigand, Markus A. / Central sympatholytics prolong survival in experimental sepsis. In: Critical Care. 2009 ; Vol. 13, No. 1.
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AU - Wagner, Tanja

AU - Funke, Benjamin

AU - Lichtenstern, Christoph

AU - Martin, Eike

AU - Graf, Bernhard M.

AU - Bierhaus, Angelika

AU - Weigand, Markus A.

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N2 - 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.

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