Sedation improves early outcome in severely septic Sprague Dawley rats.
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.
Qiao
Hong
H
Department of Anesthesiology, First Hospital, Peking University, No, 8 Xishiku St, Beijing 100034, PR China. qqhhong@163.com
Sanders
Robert D
RD
Ma
Daqing
D
Wu
Xinmin
X
Maze
Mervyn
M
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
D006993:Hypnotics and Sedatives; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D020927:Dexmedetomidine; D053148:Caspase 3; D008874:Midazolam
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