Sepsis is defined as the systemic inflammatory response syndrome and frequently results from severe infection. Sepsis and the resultant multiorgan failure it induces are the number one cause of death in the surgical intensive care unit and a leading cause of morbidity and mortality in the neonatal and medical intensive care unit. The Center for Disease Control has estimated that approximately 500,000 people develop sepsis annually. Despite medical advances, the critically-ill patient who develops sepsis and hypotension has a mortality of 40 to 60 percent, levels that have remained unchanged over the past 15 years. Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen turnover, protein degradation, and vascular smooth muscle tone which are markedly abnormal during sepsis. Increased intracellular free calcium ([Ca2+]i) can be a potent cell toxic. Our hypothesis has been that disturbances in cellular calcium regulation are responsible for many of the metabolic manifestations of sepsis and may be the driving force behind the development of the multiorgan failure. 19F nuclear magnetic resonance spectroscopy and the 19F NMR active calcium indicator 5FBAPTA provide a unique opportunity to determine the key variable, viz. [Ca2+]i, in vivo and in intact perfused organs thereby avoiding changes in cellular calcium which may occur during cell culture or in preparation of isolated cells. The purpose of this investigation is to utilize NMR spectroscopy to determine the nature of the alterations in intracellular calcium under physiologic conditions which exist in vivo during this lethal disorder. The cecal ligation and perforation model of sepsis will be used to induce sepsis in rats. At 24 hours following surgery, 19F NMR spectroscopy and 5FBAPTA will be used to measure [Ca2+]i both in vivo and in perfused organs from septic and sham operated rats. Potential mechanisms responsible for or contributing to increased [Ca2+]i will also be investigated. The results from this investigation will impact upon current controversial clinical issues such as the role of calcium supplementation in the hypocalcemic septic patient, and may provide a rationale for the selection of specific calcium reducing agents which have been demonstrated to increase survival in animal models of sepsis/endotoxemia.
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