Intensive Care Medicine Experimental (Oct 2024)

An ovine septic shock model of live bacterial infusion

  • Nchafatso G. Obonyo,
  • Sainath Raman,
  • Jacky Y. Suen,
  • Kate M. Peters,
  • Minh-Duy Phan,
  • Margaret R. Passmore,
  • Mahe Bouquet,
  • Emily S. Wilson,
  • Kieran Hyslop,
  • Chiara Palmieri,
  • Nicole White,
  • Kei Sato,
  • Samia M. Farah,
  • Lucia Gandini,
  • Keibun Liu,
  • Gabriele Fior,
  • Silver Heinsar,
  • Shinichi Ijuin,
  • Sun Kyun Ro,
  • Gabriella Abbate,
  • Carmen Ainola,
  • Noriko Sato,
  • Brooke Lundon,
  • Sofia Portatadino,
  • Reema H. Rachakonda,
  • Bailey Schneider,
  • Amanda Harley,
  • Louise E. See Hoe,
  • Mark A. Schembri,
  • Gianluigi Li Bassi,
  • John F. Fraser

DOI
https://doi.org/10.1186/s40635-024-00684-x
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 20

Abstract

Read online

Abstract Background Escherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. 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. Aim To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock. Methods Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 105–2 × 109 cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. 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. Results The 2 × 107 cfu/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 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg−1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)]. Conclusions This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.

Keywords