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However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Aim<\/jats:title>\n                <jats:p>To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic <jats:italic>E. coli<\/jats:italic> sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2\u2009\u00d7\u200910<jats:sup>5<\/jats:sup>\u20132\u2009\u00d7\u200910<jats:sup>9<\/jats:sup>\u00a0cfu\/mL was used for the dose optimisation phase (<jats:italic>n<\/jats:italic>\u2009=\u20094) and upon dose confirmation the model was developed (<jats:italic>n<\/jats:italic>\u2009=\u20095). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48\u00a0h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The 2\u2009\u00d7\u200910<jats:sup>7<\/jats:sup>\u00a0cfu\/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91\u00a0mmHg (71, 102) to 50\u00a0mmHg (48, 57) (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and lactate levels increased from a median of 0.5\u00a0mM (0.3, 0.8) to 2.1\u00a0mM (2.0, 2.3) (<jats:italic>p<\/jats:italic>\u2009=\u20090.02) post-shock. The baseline median hyaluronan levels increased significantly from 25\u00a0ng\/mL (18, 86) to 168\u00a0ng\/mL (86, 569), <jats:italic>p<\/jats:italic>\u2009=\u20090.05 but not the median vasopressor dependency index which increased within 1\u00a0h of resuscitation from zero to 0.39\u00a0mmHg<jats:sup>\u22121<\/jats:sup> (0.06, 5.13), <jats:italic>p<\/jats:italic>\u2009=\u20090.065, and. Over the 48\u00a0h, there was a significant decrease in the systemic vascular resistance index (<jats:italic>F<\/jats:italic>\u2009=\u20097.46, <jats:italic>p<\/jats:italic>\u2009=\u20090.01) and increase in the pro-inflammatory cytokines [IL-6 (<jats:italic>F<\/jats:italic>\u2009=\u20098.90, <jats:italic>p<\/jats:italic>\u2009=\u20090.02), IL-8 (<jats:italic>F<\/jats:italic>\u2009=\u20095.28, <jats:italic>p<\/jats:italic>\u2009=\u20090.03), and VEGFA (<jats:italic>F<\/jats:italic>\u2009=\u20096.47, <jats:italic>p<\/jats:italic>\u2009=\u20090.02)].<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.<\/jats:p>\n              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