Sepsis followed by multiple organ failure, MSOF, is the leading cause of mortality and morbidity in the trauma/burn patient. This process is now recognized to be due to "auto-destructive" inflammation, which may begin immediately after the trauma (burn). The initial generalized inflammatory response to local trauma, which appears to be oxidant induced, leads to a marked amplification of a subsequent septic insult. Our hypothesis is that an initial trauma (burn) leads to oxidant induced systemic inflammation and tissue lipid peroxidation. This initial process then causes a marked accentuation of the inflammatory (oxidant) response to a subsequent "septic" insult which is characterized by hemodynamic instability and direct cellular damage due to oxidant induced blood flow maldistribution and further cell membrane lipid peroxidation. If the inflammation persists, a gradual and self-perpetuating multi-system organ failure can result. Our aims are first to determine whether the systemic response to the initial traumatic insult, produced by a skin burn can be attenuated by using parenterally or topically administered antioxidants. Secondly, we want to determine whether the subsequent sepsis induced tissue injury can be decreased by increasing tissue 02 delivery or by decreasing systemic oxidant release with anti-oxidant administration. We also want to determine whether these approaches will decrease the rate of subsequent multiple organ failure. Thirdly, we want to determine whether established multiple organ failure can be corrected once established using these agents. We will use physiologic changes, especially 02 consumption, VO2, oxidant induced biochemical changes and histologic changes to monitor the degree of injury. In addition, we will measure cellular metabolism using nuclear magnetic resonance spectroscopy to determine how this data corresponds with our other markers of injury. We will use as our models, the rat and to a lesser extent, the sheep with a 20% TBS third degree burn challenged at 3 days with endotoxin and the rat zymosan induced peritonitis model, which has both an initial severe sepsis and later MSOF phase. The antioxidants to be studied can be categorized as an 02 radical scavenger, an iron chelator, a xanthine oxidase inhibitor, or a NSAID with non- specific antioxidant properties. All agents are being used in some form in man. Our long term objective is to define prevention and treatment modalities as well as reliable markers of injury, including NMRS, which can be used in injured man.
NIH ExPorter
NIH ExPorter