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Standard protocols for sepsis treatment, relying on broad-spectrum antibiotics, fluid resuscitation, and ventilation, have remained essentially unchanged for the last three decades. Although decreased mortality has been observed with early goal-directed therapy and activated protein C (1), aggressive anti-inflammatory trials, either in the form of corticosteroid-based therapy (2–5) or more recent specific anti-cytokine approaches (6), not only failed to improve survival but some were even associated with increased mortality (7). Corticosteroids have a long history in the therapy of sepsis, beginning with the landmark study by Schumer (8), which showed a 30% improvement in survival after early dexamethasone (DEX) and prednisolone treatment in patients with septic shock. However, subsequent clinical trials contradicted the original findings by showing that high-dose glucocorticoids did not improve outcome in septic patients (3, 4, 9, 10). It should be noted that low-dose steroids were reintroduced as an adjunctive therapy in patients with adrenal insufficiency (11). There is a growing consensus that appropriate therapy for sepsis cannot rely on the “magic bullet” paradigm where specific, targeted therapy directed against a single mediator will be successful. Two major immune conditions proposed to coexist during the course of sepsis, the systemic inflammatory response syndrome and the compensatory anti-inflammatory response syndrome, emphasize that sepsis constantly fluctuates (12). Thus, successful treatment needs to be frequently adjusted based on the patient’s current immunoinflammatory status. Statistical analysis suggested that the failure of the anticytokine trials may have been related to heterogeneous patient populations, because cohorts with the highest mortality risk were more likely to benefit from anti-inflammatory interventions (13). Using inflammatory cytokines as biomarkers, we developed an approach that allows accurate mortality prediction in the cecal ligation and puncture (CLP) model of murine sepsis (14, 15). To verify this approach in a scenario of targeted treatment, we hypothesized that nonspecific corticosteroid (DEX) suppression of inflammation in subjects predicted to die (P-DIE) would improve survival, whereas the identical treatment applied to animals predicted to live (P-LIVE) will produce little benefit.

Although sepsis causes significant morbidity and mortality, its basic pathology is still not well understood. We investigated the inflammatory and physiologic alterations of non-lethal sepsis using cecal ligation and puncture (CLP), a model that induces peritonitis due to mixed intestinal flora, reproducing the complex immunology of sepsis. Groups of mice were subjected to CLP (25G needle) or sham surgery, had minimitters implanted to continuously monitor temperature and activity, and were sacrificed daily for 6 days. There was significant hypothermia (6-13 hrs post-surgery), and decreases in activity (to day 4) and weight (to day 3) but no mortality in the CLP group. Blood analyses of the CLP-treated mice showed reduced hemoglobin, platelets, lymphocytes, monocytes, and neutrophils, compared to sham animals. Both groups had nearly equivalent neutrophil influx into the peritoneum. Plasma and peritoneal G-CSF, IL-6, as well as the murine chemokines KC and MIP2-alpha were significantly higher in the CLP-treated mice at day 1. Plasma and peritoneal TNF were low (