An anti-inflammatory melanocortin fusion polypeptide augments whole blood resuscitation of hemorrhagic shock in a rodent polytrauma model

BACKGROUND: Severe trauma induces a cytokine storm that is associated with impaired resuscitation and recovery. We investigated the impact of AQB-565, an anti-inflammatory melanocortin fusion polypeptide, as a novel treatment adjunct for whole blood resuscitation of hemorrhagic shock using a rat polytrauma shock model. METHODS: Hemorrhagic shock with polytrauma was induced in 64 Sprague-Dawley rats. The rats were randomized to receive one of four intravenous treatments at 15 minutes posthemorrhage (T15): saline control, AQB-565, tranexamic acid (TXA), or combined AQB-565+ TXA. The rats were given autologous transfusion of shed whole blood at 60 minutes and as needed thereafter to achieve mean arterial pressure (MAP) of 60 mm Hg for up to 3 hours. Survival, hemodynamics, cytokine profiles, and hemorrhage volumes were compared between groups. RESULTS: There was a significant overall effect of treatment group on MAP (two-way rmANOVA p =0.02) that coincided with blood transfusion. MAP was significantly increased at T105 with AQB-565+TXA versus saline control ( p =0.046). Inflammatory plasma cytokines, including interleukin-6, were significantly decreased with AQB-565 versus control groups (ANOVA p values ≤ 0.01). Seventeen (26.6%) rats died before 3 hours. There was a trend towards increased survival for treatments containing AQB-565 versus controls that was not statistically significant (Kaplan-Meier log rank p =0.06). CONCLUSIONS: A melanocortin pathway-activating polypeptide suppressed inflammation and improved hemodynamic response to whole blood transfusion in this hemorrhagic shock model.