Central sympatholytics prolong survival in experimental sepsis.
BACKGROUND
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-alpha, IL-1beta and IL-6. Furthermore, there is an up regulation of transcription factors such as nuclear factor (NF) kappaB. 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 microg/kg) or dexmedetomidine (40 microg/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 microg/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-alpha: p < 0.0001), preserved blood pressure control (p = 0.024) and down-regulated the binding activity of NF-kappaB. There were no changes in the pro-inflammatory cytokine response when peripheral blood was incubated with lipopolysaccharide alone compared with incubation with clonidine (10-4 M) 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.
Hofer
Stefan
S
Department of Anaesthesiology, University Hospital Heidelberg, Heidelberg, Germany. Stefan.Hofer@med.uni-heidelberg.de
Steppan
Jochen
J
Wagner
Tanja
T
Funke
Benjamin
B
Lichtenstern
Christoph
C
Martin
Eike
E
Graf
Bernhard M
BM
Bierhaus
Angelika
A
Weigand
Markus A
MA
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011950:Receptors, Cholinergic / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D015996:Survival Rate / Q000639:trends; D013565:Sympatholytics / Q000008:administration & dosage*
D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D013565:Sympatholytics