Septic shock carries high mortality, with one-third of patients exhibiting depletion of the corticosteroid carrier, corticosteroid-binding globulin (CBG), which predicts a threefold increase in mortality. We investigated CBG replacement therapy in a precision murine model of polymicrobial sepsis, addressing the urgent need for novel ICU interventions
Male C57BL/6 mice (N=106, 8-10 weeks old) were pre-fitted with wireless arterial telemetry and then underwent cecal ligation and puncture (CLP) with dual 21g puncture and 18mm cecal ligation. Mice were randomised to postoperative support with or without intravenous CBG therapy (3.5 mg/kg at 6 hrs, 2.5 mg/kg at 30 hrs) and monitored every 8 hrs. Terminal bloods were collected at humane endpoints or 4 days.
CLP induced circulatory shock in all mice, progressing to septic shock by 39 hrs with 58% mortality at 4 days; marked increases in immune and organ damage biomarkers indicated multiple organ failure. Intravenous CBG therapy shortened circulatory shock duration by 75%, improved survival threefold (to 17% mortality), suppressed the pro-inflammatory cytokine peak (45-59%), reduced systemic and organ damage biomarkers, and augmented anti-inflammatory IL-10 and IFN-β1 responses to 4 days.
We have mapped the progression of septic shock in a precise murine model, demonstrating significant benefits of CBG therapy on disease, morbidity, and mortality. Our findings advocate for a Phase I trial of CBG therapy in septic shock patients.