Septic shock carries high mortality, with one-third of patients exhibiting depletion of the circulating corticosteroid carrier, corticosteroid-binding globulin (CBG) – an independent predictor of a threefold increase in mortality (1). While we established the efficacy of CBG replacement therapy in a precision model of polymicrobial sepsis, sex-specific physiological and survival responses have not yet been evaluated in female cohorts. Addressing this gap is a critical step toward advancing this novel ICU intervention.
Female C57BL/6 mice (N=120, 10-12 weeks old) were pre-fitted with arterial telemetry. Four days later, septic shock was modelled via caecal ligation and puncture (CLP) with dual 21g puncture and 16mm caecal ligation. Postoperatively. mice received fluid and analgesic support and were randomised to intravenous CBG replacement therapy (5 mg/kg at 6 hr, 3.5 mg/kg at 30 hr) or a volume-matched vehicle. Mice were monitored every 8 hr, with terminal bloods collected at 4 days or upon reaching earlier humane endpoints.
CLP induced circulatory shock in all mice, progressing to septic shock by 39 hr culminating in 44% mortality at 4 days. Marked increases in immune and organ damage markers confirmed the onset of multiple organ failure. Intravenous CBG therapy mitigated these outcomes, shortening circulatory shock duration by 75%, and improving survival threefold, reducing mortality to 8.3%. CBG replacement also suppressed the pro-inflammatory cytokine peak, attenuated systemic and organ damage markers, and augmented the anti-inflammatory IL-10 and IFN-β1 responses through to day 4.
By mapping the progression of septic shock in a precise murine model incorporating both male and female mice, we demonstrate profound benefits of CBG replacement therapy on disease, morbidity, and mortality. These strong preclinical findings advocate for a Phase 1 clinical trial of CBG therapy in patients with septic shock.
(1) Meyer EJ, et al. J Clin Endocrinol Metab. 2022;107(6):1636-1646