Liam Byrne1,2,3, Nchafatso G Obonyo1, Sara Diab1, Kimble Dunster1,4, Margaret Passmore1,5, Ai Ching Boon1,5, Louise See Hoe1,5, Karen Hay6, Frank Van Haren2,3, John-Paul Tung1,7, Louise Cullen4,8, Kiran Shekar1,9, Kathryn Maitland10, John F Fraser1,5,9. 1. The Critical Care Research Group, Chermside, Brisbane, Australia. 2. Australian National University, Canberra, ACT, Australia. 3. The Canberra Hospital Yamba Dr, Garran, ACT, Australia. 4. Queensland University of Technology, Brisbane City, Australia. 5. University of Queensland, St Lucia, Australia. 6. QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia. 7. Australian Red Cross Blood Service, Kelvin Grove, Brisbane, Australia. 8. The Emergency Department Royal Brisbane Women and Children's Hospital, Brisbane, Australia. 9. The Adult Intensive Care, The Prince Charles Hospital, Chermside, Brisbane, Australia. 10. Department of Paediatrics, Faculty of Medicine, Imperial College London, UK.
Abstract
BACKGROUND: Animal models of endotoxemia are frequently used to understand the pathophysiology of sepsis and test new therapies. However, important differences exist between commonly used experimental models of endotoxemia and clinical sepsis. Animal models of endotoxemia frequently produce hypodynamic shock in contrast to clinical hyperdynamic shock. This difference may exaggerate the importance of hypoperfusion as a causative factor in organ dysfunction. This study sought to develop an ovine model of hyperdynamic endotoxemia and assess if there is evidence of impaired oxidative metabolism in the vital organs. METHODS: Eight sheep had microdialysis catheters implanted into the brain, heart, liver, kidney, and arterial circulation. Shock was induced with a 4 h escalating dose infusion of endotoxin. After 3 h vasopressor support was initiated with noradrenaline and vasopressin. Animals were monitored for 12 h after endotoxemia. Blood samples were recovered for hemoglobin, white blood cell count, creatinine, and proinflammatory cytokines (IL-1Beta, IL-6, and IL-8). RESULTS: The endotoxin infusion was successful in producing distributive shock with the mean arterial pressure decreasing from 84.5 ± 12.8 mm Hg to 49 ± 8.03 mm Hg (P < 0.001). Cardiac index remained within the normal range decreasing from 3.33 ± 0.56 L/min/m to 2.89l ± 0.36 L/min/m (P = 0.0845). Lactate/pyruvate ratios were not significantly abnormal in the heart, brain, kidney, or arterial circulation. Liver microdialysis samples demonstrated persistently high lactate/pyruvate ratios (mean 37.9 ± 3.3). CONCLUSIONS: An escalating dose endotoxin infusion was successful in producing hyperdynamic shock. There was evidence of impaired oxidative metabolism in the liver suggesting impaired splanchnic perfusion. This may be a modifiable factor in the progression to multiple organ dysfunction and death.
BACKGROUND: Animal models of endotoxemia are frequently used to understand the pathophysiology of sepsis and test new therapies. However, important differences exist between commonly used experimental models of endotoxemia and clinical sepsis. Animal models of endotoxemia frequently produce hypodynamic shock in contrast to clinical hyperdynamic shock. This difference may exaggerate the importance of hypoperfusion as a causative factor in organ dysfunction. This study sought to develop an ovine model of hyperdynamic endotoxemia and assess if there is evidence of impaired oxidative metabolism in the vital organs. METHODS: Eight sheep had microdialysis catheters implanted into the brain, heart, liver, kidney, and arterial circulation. Shock was induced with a 4 h escalating dose infusion of endotoxin. After 3 h vasopressor support was initiated with noradrenaline and vasopressin. Animals were monitored for 12 h after endotoxemia. Blood samples were recovered for hemoglobin, white blood cell count, creatinine, and proinflammatory cytokines (IL-1Beta, IL-6, and IL-8). RESULTS: The endotoxin infusion was successful in producing distributive shock with the mean arterial pressure decreasing from 84.5 ± 12.8 mm Hg to 49 ± 8.03 mm Hg (P < 0.001). Cardiac index remained within the normal range decreasing from 3.33 ± 0.56 L/min/m to 2.89l ± 0.36 L/min/m (P = 0.0845). Lactate/pyruvate ratios were not significantly abnormal in the heart, brain, kidney, or arterial circulation. Liver microdialysis samples demonstrated persistently high lactate/pyruvate ratios (mean 37.9 ± 3.3). CONCLUSIONS: An escalating dose endotoxin infusion was successful in producing hyperdynamic shock. There was evidence of impaired oxidative metabolism in the liver suggesting impaired splanchnic perfusion. This may be a modifiable factor in the progression to multiple organ dysfunction and death.
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Authors: Margaret R Passmore; Liam Byrne; Nchafatso G Obonyo; Louise E See Hoe; Ai-Ching Boon; Sara D Diab; Kimble R Dunster; Kavita Bisht; John-Paul Tung; Mohd H Fauzi; Monica Narula; Sanne E Pedersen; Arlanna Esguerra-Lallen; Gabriela Simonova; Annette Sultana; Chris M Anstey; Kiran Shekar; Kathryn Maitland; Jacky Y Suen; John F Fraser Journal: Respir Res Date: 2018-11-22
Authors: Nchafatso G Obonyo; Liam Byrne; John-Paul Tung; Gabriela Simonova; Sara D Diab; Kimble R Dunster; Margaret R Passmore; Ai-Ching Boon; Louise See Hoe; Sanne Engkilde-Pedersen; Arlanna Esguerra-Lallen; Mohd H Fauzi; Leticia P Pimenta; Jonathan E Millar; Jonathon P Fanning; Frank Van Haren; Chris M Anstey; Louise Cullen; Jacky Suen; Kiran Shekar; Kathryn Maitland; John F Fraser Journal: MethodsX Date: 2019-05-09
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