The pathophysiology of Hemorrhagic shock consists of disruption of the cellular metabolic functions endothelial barrier properties, redistribution of body fluids and electrolytes, a systemic inflammatory response, and a deleterious intestinal vasoconstriction and a disproportionate splanchnic hypoperfusion, which persists even after adequate fluid replacement that restores and maintains hemodynamics. These pathophysiologic events cause local and remote tissue injury that culminates in multiple organ failure (MOF) by mechanisms, which are poorly understood. It is hypothesize that initiation of direct intraperitoneal resuscitation (DPR) with a balanced physiologic salt solution supplemented with glucose (2.5%), at the time of conventional resuscitation (CR) from hemorrhagic shock can reverse the pathophysiology of this syndrome, improving resuscitation outcome, potentially preventing (MOF) and improving survival: a) by suppressing the hemorrhage-induced systemic inflammatory response, b) by direct intestinal resuscitation to enhance visceral perfusion and cardiac output, c) by improving endothelial cell responsiveness, to vasodilators, and d) by preventing the hemorrhage-induced water and electrolytes imbalance. To address this hypothesis, we will utilize intravital microscopy, and quantitative autoradiography (QAR) to perform in vivo studies in a rodent model of hemorrhagic shock, which will be resuscitated with either CR or CR+DPR and determine the following: 1) Serum cytokines profile and level of prostanoid metabolites; 2) Endothelial cell function with dose-response curves to endothelial-dependent, receptor-mediated and non-receptor mediated as well as endothelial-independent agonists; 3) The pattern of distribution of tissue water (intravascular thetaiv, interstitial thetaif, intracellular thetaic) in the gut and abdominal wall with QAR; 4) The role of neutrophils in the derangement of intestinal microvascular endothelium by measuring microvascular responses in the presence of anti-PMN serum and specific antibodies; and 5) The mechanisms involved in the ability of DPR to reverse the pathophysiology of the shock syndrome. Long-term objectives are to develop a pre-clinical protocol that utilizes DPR as a prelude to translation of the results to trauma patients and finally a clinical protocol that utilize DPR to prevent multiple organ failure in hemorrhage shock with resuscitation.
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