title: Sedation improves early outcome in severely septic Sprague Dawley rats.
abstract: BACKGROUND
  Sepsis, a systemic inflammatory response to infective etiologies, has a high mortality rate that is linked both to excess cytokine activity and apoptosis of critical immune cells. Dexmedetomidine has recently been shown to improve outcome in a septic cohort of patients when compared to patients randomized to a benzodiazepine-based sedative regimen. We sought to compare the effects of dexmedetomidine and midazolam, at equi-sedative doses, on inflammation and apoptosis in an animal model of severe sepsis.
  
  
  METHODS
  After central venous access, Sprague Dawley rats underwent cecal ligation and intestinal puncture (CLIP) with an 18 G needle without antibiotic cover and received either saline, or an infusion of comparable volume of saline containing midazolam (0.6 mg.kg-1.h-1) or dexmedetomidine (5 ug.kg-1.h-1) for 8 hours. Following baseline measurements and CLIP, blood was sampled for cytokine measurement (tumour necrosis factor (TNF)-alpha and interleukin (IL)-6; n = 4-6 per group) at 2, 4 and 5 hours, and animal mortality rate (MR) was monitored (n = 10 per group) every 2 hours until 2 hours had elapsed. In addition, spleens were harvested and apoptosis was assessed by immunoblotting (n = 4 per group).
  
  
  RESULTS
  The 24 hour MR in CLIP animals (90%) was significantly reduced by sedative doses of either dexmedetomidine (MR = 20%) or midazolam (MR = 30%). While both sedatives reduced systemic levels of the inflammatory cytokine TNF-alpha (P < 0.05); only dexmedetomidine reduced the IL-6 response to CLIP, though this narrowly missed achieving significance (P = 0.05). Dexmedetomidine reduced splenic caspase-3 expression (P < 0.05), a marker of apoptosis, when compared to either midazolam or saline.
  
  
  CONCLUSIONS
  Sedation with midazolam and dexmedetomidine both improve outcome in polymicrobial severely septic rats. Possible benefits conveyed by one sedative regimen over another may become evident over a more prolonged time-course as both IL-6 and apoptosis were reduced by dexmedetomidine but not midazolam. Further studies are required to evaluate this hypothesis.
authors.affiliation: Department of Anesthesiology, First Hospital, Peking University, No, 8 Xishiku St, Beijing 100034, PR China. qqhhong@163.com
authors.forename: Hong
authors.initials: H
authors.lastname: Qiao
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
authors.forename: Xinmin
authors.initials: X
authors.lastname: Wu
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D020927:Dexmedetomidine / Q000627:therapeutic use*; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D006993:Hypnotics and Sedatives; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D020927:Dexmedetomidine; D053148:Caspase 3; D008874:Midazolam
references.citation: Nat Rev Drug Discov. 2003 May;2(5):391-405
references.pmid: 12750742
references.citation: Nat Immunol. 2000 Dec;1(6):496-501
references.pmid: 11101871
references.citation: Anesthesiology. 2008 Mar;108(3):457-66
references.pmid: 18292683
references.citation: Br J Anaesth. 2001 May;86(5):650-6
references.pmid: 11575340
references.citation: Life Sci. 1995 Nov 17;57(26):2413-23
references.pmid: 8847962
references.citation: J Clin Invest. 2007 Feb;117(2):289-96
references.pmid: 17273548
references.citation: Eur J Pharmacol. 2008 Jul 7;588(2-3):217-31
references.pmid: 18514187
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R1048-53
references.pmid: 15947070
references.citation: Fam Pract. 2005 Aug;22(4):375-80
references.pmid: 15805127
references.citation: Eur Surg Res. 2001;33(2):77-9
references.pmid: 11399872
references.citation: Crit Care Clin. 2009 Jul;25(3):551-70, ix
references.pmid: 19576530
references.citation: N Engl J Med. 2001 Nov 8;345(19):1368-77
references.pmid: 11794169
references.citation: Curr Opin Anaesthesiol. 2001 Dec;14(6):685-91
references.pmid: 17019166
references.citation: Vet Immunol Immunopathol. 2003 Sep 15;95(1-2):11-9
references.pmid: 12969632
references.citation: Br J Anaesth. 2007 Apr;98(4):550-2
references.pmid: 17363413
references.citation: J Neuroimmunol. 1996 Dec;71(1-2):19-24
references.pmid: 8982098
references.citation: N Engl J Med. 2008 Jan 10;358(2):111-24
references.pmid: 18184957
references.citation: Crit Care Med. 2001 Jul;29(7):1303-10
references.pmid: 11445675
references.citation: Brain Behav Immun. 2007 Aug;21(6):736-45
references.pmid: 17467231
references.citation: Anesth Analg. 2003 Feb;96(2):524-31, table of contents
references.pmid: 12538207
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L998-L1006
references.pmid: 18836031
references.citation: J Neuroimmune Pharmacol. 2008 Dec;3(4):218-29
references.pmid: 18773298
references.citation: N Engl J Med. 2001 Mar 8;344(10):699-709
references.pmid: 11236773
references.citation: Anesthesiology. 2006 Jul;105(1):105-10
references.pmid: 16810001
references.citation: J Parasitol. 2005 Feb;91(1):193-5
references.pmid: 15856901
references.citation: Crit Care. 2009;13(1):R11
references.pmid: 19196475
references.citation: Eur J Pharmacol. 2003 Apr 25;467(1-3):223-31
references.pmid: 12706479
references.citation: N Engl J Med. 2003 Jan 9;348(2):138-50
references.pmid: 12519925
references.citation: Anesthesiology. 2009 May;110(5):1077-85
references.pmid: 19352168
references.citation: Eur J Pharmacol. 2004 Oct 11;502(1-2):87-97
references.pmid: 15464093
references.citation: Am J Clin Nutr. 1977 Aug;30(8):1285-8
references.pmid: 18930
references.citation: Crit Care. 2006;10(2):R42
references.pmid: 16542492
references.citation: Antimicrob Agents Chemother. 1994 Apr;38(4):812-6
references.pmid: 8031051
references.citation: Crit Care Med. 2004 Jun;32(6):1322-6
references.pmid: 15187514
references.citation: Crit Care Med. 2004 Jun;32(6):1272-6
references.pmid: 15187505
references.citation: Infect Immun. 2003 Jan;71(1):22-9
references.pmid: 12496145
references.citation: Intensive Care Med. 2004 Feb;30(2):197-206
references.pmid: 14564378
references.citation: JAMA. 2009 Feb 4;301(5):489-99
references.pmid: 19188334
references.citation: JAMA. 1997 May 21;277(19):1531-8
references.pmid: 9153367
references.citation: J Neuroimmunol. 2008 Dec 15;205(1-2):44-50
references.pmid: 18954912
references.citation: Nature. 1999 Jan 21;397(6716):218
references.pmid: 9930695
references.citation: Lancet. 2005 Jan 1-7;365(9453):63-78
references.pmid: 15639681
references.citation: J Immunol. 2008 Apr 1;180(7):4978-85
references.pmid: 18354223
references.citation: Arch Intern Med. 2007 Aug 13-27;167(15):1655-63
references.pmid: 17698689
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 May;280(5):G968-73
references.pmid: 11292606
references.citation: Crit Care Med. 2008 Dec;36(12):3171-7
references.pmid: 19020432
references.citation: Toxicol Lett. 1983 May;16(3-4):281-4
references.pmid: 6344337
references.citation: Anesthesiology. 2003 Feb;98(2):428-36
references.pmid: 12552203
references.citation: Crit Care. 2010;14(2):R38
references.pmid: 20233428
references.citation: Nat Rev Immunol. 2006 Nov;6(11):813-22
references.pmid: 17039247
references.citation: Crit Care Med. 2004 Nov;32(11):2173-82
references.pmid: 15640628
references.citation: J Immunol. 2003 Jan 1;170(1):503-7
references.pmid: 12496437