Honors Capstone Project
Date of Submission
Dr. Thomas Fondy
Arts and Science
Capstone Prize Winner
Won Capstone Funding
Sciences and Engineering
Biology | Laboratory and Basic Science Research
Background. While various medical treatments have been proven effective in the treatment of sepsis in animal models, the only current clinically accepted treatment of human sepsis is limited to the use of activated protein C. The complex pathogenesis of human sepsis presents a challenge in precisely duplicating the process of disease development in the particular animal models which are currently employed for preclinical testing. Further research examining the pathogenesis of this deadly condition is essential for the implementation of novel therapies that target distinct disease mechanisms. The objective of this 48-hour study is to utilize a clinical model that accurately replicates severe human sepsis along with gut ischemia/reperfusion (I/R). I/R further leads to the injury of multiple organs within the time period most closely mirroring disease progression in humans.
Methodology. The experimental protocol was approved by the Committee for the Humane Use of Animals at SUNY Upstate Medical University and complied with the National Institutes of Health Guidelines for the Use of Experimental Animals in Research. Five pigs were subjected to a “two-hit” injury involving the clamping of the superior mesenteric artery (SMA) for 30 minutes as well as a laparotomy used for insertion of a fecal clot, following appropriate administration of anesthetics and ventilation. A drain was inserted into this laparatomy wound twelve hours post injury. Monitoring of animals took place under a standard Intensive Care Unit setting over the course of 48 hours, with oxygen desaturation resolved by increasing FiO2. Hemodynamics were stabilized through administration of antibiotics and intravenous fluids as needed, while measurements of arterial and mixed venous blood gases as well as lung, kidney, liver, renal, and hemodynamic function measurements were recorded. Progression of the abdominal compartment syndrome was determined by monitoring bladder pressure changes. Serial measurements of peritoneal and plasma ascites were also taken for evaluation of cytokine concentration. Morphometric analysis was carried out using the organ tissues harvested and fixed at necropsy.
Results. All animals presented with polymicrobial sepsis. Over the course of 48 hours the lung, liver, kidney, and intestine showed ongoing deterioration and histopathological as well as clinical damage. This was found to occur in conjunction with increased levels of cytokines within the peritoneal fluid and serum.
Conclusion. In combining both sepsis and ischemia reperfusion injury, the animal model used in this study is valid for uncovering the intricate pathophysiological progression of septic shock and its transition to multiple organ dysfunction syndrome. This system mirrors the systemic inflammation and major organ systems dysfunction seen in humans. Through demonstrating the success of the current animal model, prospective treatments may be developed through conducting sophisticated preclinical trials.
Polinkovsky, Lyuba, "Pathophysiology and Treatment of Septic and Traumatic Shock" (2011). Syracuse University Honors Program Capstone Projects. 263.
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