Modified Clinical Monitoring Assessment Criteria for Multi-Organ Failure during Bacteremia and Sepsis Progression in a Pig Model

Objective: Sepsis animal models commonly fail to predict clinical efficacy of novel therapeutics in humans because most animals are more resistant to pathogens and sepsis is not measured or evaluated in the same manner. We modified the third international consensus clinical criteria for sepsis and septic shock (Sepsis-3) to evaluate and diagnose two swine models of sepsis, as pigs are similar to humans in their immunology and susceptibility to pathogens. Materials and Methods: Eighteen female Yorkshire Swine, anesthetized or conscious, received intravenous E. coli (clinical isolate) infusions of 3 x107 CFU/kg over 4 hours or 2 x108 CFU/kg over 9.5 hours, respectively. Symptoms, vitals and blood were monitored throughout for disease progression. Results: We established a swine-specific Sepsis-3 (ss-Sepsis-3) system, including clinically relevant Sequential (sepsis-related) Organ Failure Assessment (SOFA) scoring criteria for pigs, by adapting human clinical protocols. Both models resulted in acute symptoms of sepsis (SOFA ≥ 2); however, septic shock developed in only 3 of 6 anesthetized animals (SOFA ≥ 2, high lactate levels and requirement for vasopressors). Additionally, acute kidney injury was observed in 2 of 6 conscious animals, defined using a modified clinical Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) system. Anesthetized infected animals also displayed decreased mean arterial pressures and lower temperatures compared to conscious animals, likely caused by anesthesia. Cytokine profiles were complex and varied in both models. Conclusions: The ss-Sepsis-3 scoring system described here quantifies the effects of pathogen infusion and disease severity in Copyright © 2018 The Authors. Published by Scientific Open Access Journals LLC. real-time. Using the same clinical pathogen isolate, the severity of disease progression in the anesthetized model was increased due to the confounding effects of anesthesia. This scoring system provides a framework for adaptation to other large animal models of sepsis to evaluate disease progression, mechanism and effectiveness of therapeutic drugs or devices.