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1 Surgery, Washington University School of Medicine, St. Louis, MO, USA
2 Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
3 Surgery, Washington University School of Medicine, St. Louis, MO, USA; Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; Medicine, Washington University School of Medicine, St. Louis, MO, USA
4 Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; Surgery, Washington University School of Medicine, St. Louis, MO, USA; Medicine, Washington University School of Medicine, St. Louis, MO, USA
5 Surgery, Washington University School of Medicine, St. Louis, MO, USA; Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: coopersmithc{at}wustl.edu.
Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 hours following cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 hours after the septic insult. The first aim of this study was to see if earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die based upon high IL-6 levels. Mice (n=184) were subjected to CLP, had IL-6 levels drawn six hours later and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning six or twelve hours post-operatively. Overall one-week survival improved from 25.5% to 35.9% with earlier administration of antibiotics (p<0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 hours, while none survived if antibiotics were started later (p<0.05). Based upon these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n=54) had their blood drawn six hours after CLP and then were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6.
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