The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock:: Association with serum lactate and inflammatory cytokine levels

Background. This study was designed to examine the relationship between the timing of antibiotic treatment and both survival rates and hemodynamic/inflammatory correlates of survival in a murine model of Escherichia coli septic shock. Methods. Surgical implantation of an E. coli (O18:K1:H7)-laced, gelatin capsule-encased fibrinogen clot was used to generate a bacteremic model of murine septic shock. Survival duration, hemodynamic responses, and circulating serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and lactate levels were assessed in relation to increasing delays in or absence of antibiotic treatment. Results. A critical inflection point with respect to survival occurred between 12 and 15 h after implantation. When initiated at or before 12 h, antibiotic treatment resulted in <= 20% mortality, but, when initiated at or after 15 h, it resulted in 185% mortality. Physiologically relevant hypotension developed in untreated septic mice by 12 h after implantation. Values for heart rate differed between untreated septic mice and sham-infected control mice by 6 h after implantation, whereas values for cardiac output and stroke volume did not differ until at least 18-24 h after implantation. Antibiotic treatment initiated >= 12 h after implantation was associated with persistence of increased circulating serum lactate, TNF-alpha, and IL-6 levels. Conclusions. The timing of antibiotic treatment relative to hypotension is closely associated with survival in this murine model of septic shock. Delay in antibiotic treatment results in the persistence of inflammatory/ stress markers even after antibiotic treatment is initiated.