Stratification is the key: Inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis*

OBJECTIVE: This study examined the effectiveness of prospective stratification to identify and target high-dose glucocorticoid therapy for subjects developing lethal sepsis. DESIGN: Prospective, randomized, laboratory-controlled experiment. SETTING: University research laboratory. SUBJECTS: Adult female outbred CD-1 mice. INTERVENTIONS: Mice (n = 88) were subjected to sepsis induced by cecal ligation and puncture (CLP). Mice were prospectively divided into two groups, predicted to die (P-DIE) or predicted to live (P-LIVE), based on plasma levels of interleukin (IL)-6 obtained 6 hours after CLP. Following stratification, dexamethasone (DEX, 2.5 mg/kg, two doses) was administered to half the animals in each group whereas the other half received saline. MEASUREMENTS AND MAIN RESULTS: Without stratification, DEX conferred no benefit. In the P-DIE group, none of saline-treated mice lived whereas 40% of the DEX-treated mice survived. Of the nonsurvivors, 67% had death delayed by 24-48 hours compared with saline-treated mice. Twenty-four hours post-CLP, the lymphocyte count was higher in the P-DIE than in the P-LIVE mice regardless of treatment status, whereas the opposite trend was noted for neutrophils. Plasma cytokine and cytokine inhibitor levels in the saline-treated animals showed that levels in the P-DIE group were higher than those in the P-LIVE group (e.g., 60 vs. 10 ng/mL for IL-6 and 453 vs.129 ng/mL for IL-1 receptor antagonist). Interestingly, DEX therapy did not decrease 24 hours post-CLP circulating cytokines in either the P-DIE or the P-LIVE group. CONCLUSIONS: Following CLP-induced sepsis, early and accurate survival prediction allows targeted immunosuppression that improves survival. Better survival occurred without suppression of the typical proinflammatory mediators, suggesting that the deaths were not mediated by excessive cytokine-driven inflammation. Nonspecific anti-inflammatory/immunosuppressive treatment administered to more rigorously defined cohorts may be more successful than mediator-specific drugs used indiscriminately.