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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-I (F1))
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Liang, Isabella Y
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University of Louisville
Schools of Medicine
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Hurt, Ryan T; Matheson, Paul J; Smith, Jason W et al. (2012) Preservation of hepatic blood flow by direct peritoneal resuscitation improves survival and prevents hepatic inflammation following hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 303:G1144-52
Matheson, Paul J; Li, Na; Harris, Patrick D et al. (2011) Glucose-induced intestinal vasodilation via adenosine A1 receptors requires nitric oxide but not K(+)(ATP) channels. J Surg Res 168:179-87
Hurt, Ryan T; Zakaria, El Rasheid; Matheson, Paul J et al. (2009) Hemorrhage-induced hepatic injury and hypoperfusion can be prevented by direct peritoneal resuscitation. J Gastrointest Surg 13:587-94
Matheson, Paul J; Mays, Chester J; Hurt, Ryan T et al. (2009) Modulation of mesenteric lymph flow and composition by direct peritoneal resuscitation from hemorrhagic shock. Arch Surg 144:625-34
Matheson, Paul J; Hurt, Ryan T; Franklin, Glen A et al. (2009) Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock. Surgery 146:739-47; discussion 747-8
Zakaria, El Rasheid; Matheson, Paul J; Flessner, Michael F et al. (2008) Hemorrhagic shock and resuscitation-mediated tissue water distribution is normalized by adjunctive peritoneal resuscitation. J Am Coll Surg 206:970-80;discussion 980-3
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Zakaria, El Rasheid; Mays, Chester J; Matheson, Paul J et al. (2008) Plasma appearance rate of intraperitoneal macromolecular tracer underestimates peritoneal lymph flow. Adv Perit Dial 24:16-21
Zakaria, El Rasheid; Matheson, Paul J; Hurt, Ryan T et al. (2008) Chronic infusion of sterile peritoneal dialysis solution abrogates enhanced peritoneal gene expression responses to chronic peritoneal catheter presence. Adv Perit Dial 24:7-15
Zakaria, El Rasheid; Li, Na; Matheson, Paul J et al. (2007) Cellular edema regulates tissue capillary perfusion after hemorrhage resuscitation. Surgery 142:487-96;discussion 496.e1-2

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