Background:Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders.Methods:Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n=56) and control group (n=44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log odds for mortality rate in time-to-event was analyzed.Results:Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P<0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR)=1.90, 95% confidence interval (CI) 1.39–2.79; OR=1.53, 95% CI 1.17–2.12; and OR=2.92, 95% CI 1.40–6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR=0.31, 95% CI 0.11–0.90, P=0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR=0.32, 95% CI 0.14–0.73, P=0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided.Conclusions:Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required.

Critical care;Melanocortin;cytokine;Mortality;Survival;Bleeding;Transfusion