Direct Peritoneal Resuscitation from Hypovolemic Shock

描述（由申请人提供）： 出血性休克的病理生理学包括细胞代谢功能内皮屏障特性的破坏、体液和电解质的重新分布、全身性炎症反应、有害的肠血管收缩和不成比例的内脏灌注不足，即使在恢复和维持血液动力学的充分补液后，这种情况仍持续存在。这些病理生理事件导致局部和远端组织损伤，最终导致多器官功能衰竭（MOF）的机制，这是知之甚少。假设用补充有葡萄糖的平衡生理盐溶液开始直接腹膜内复苏（DPR）（2.5%），在出血性休克常规复苏（CR）时，可以逆转该综合征的病理生理学，改善复苏结局，潜在地预防（MOF）并提高生存率：a）通过抑制血管扩张诱导的全身炎症反应，B）通过直接肠复苏以增强内脏灌注和心输出量，c）通过改善内皮细胞对血管扩张剂的反应性，和d）通过防止脱水引起的水和电解质失衡。为了解决这一假设，我们将利用活体显微镜和定量放射自显影（QAR）在失血性休克的啮齿动物模型中进行体内研究，该模型将用CR或CR+DPR复苏并确定以下：1）血清细胞因子谱和前列腺素类代谢物水平; 2）内皮细胞功能，具有对内皮依赖性、受体介导的和非受体介导的以及内皮非依赖性激动剂的剂量-反应曲线; 3）组织水的分布模式（4）通过测定抗PMN血清和特异性抗体存在下的微血管反应，探讨中性粒细胞在肠微血管内皮紊乱中的作用;（5）DPR逆转休克综合征病理生理的机制。长期目标是开发一种临床前方案，利用DPR作为将结果转化为创伤患者的前奏，并最终开发一种临床方案，利用DPR预防出血性休克伴复苏的多器官衰竭。

DESCRIPTION (provided by applicant): 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.