Direct Peritoneal Resuscitation from Hypovolemic Shock

描述(由申请人提供)： 失血性休克的病理生理包括细胞代谢功能紊乱、内皮屏障特性、体液和电解质的重新分配、全身炎症反应、有害的肠道血管收缩和不成比例的内脏低灌流，即使在足够的液体补充以恢复和维持血流动力学后，这种情况仍然存在。这些病理生理事件导致局部和远程组织损伤，最终导致多器官衰竭(MOF)，其机制尚不清楚。假设失血性休克常规复苏(CR)时加用平衡生理盐液加葡萄糖(2.5%)直接腹膜内复苏(DPR)可逆转本综合征的病理生理过程，改善复苏结果，潜在地预防MOF和提高存活率：a)抑制失血性休克引起的全身炎症反应，b)通过直接肠道复苏增加内脏血流和心输出量，c)通过改善内皮细胞对血管扩张剂的反应性，以及d)通过防止失血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上进行体内研究，该模型将被CR或CR+DPR复苏，并测定以下内容：1)血清细胞因子谱和前列腺素类代谢物水平；2)内皮细胞对内皮依赖性、受体介导和非受体介导以及内皮非依赖性激动剂的剂量-反应曲线；3)组织水(血管内、间质和细胞内)在QAR作用下在肠道和腹壁的分布模式；4)中性粒细胞在肠微血管内皮细胞紊乱中的作用，通过在抗中性粒细胞血清和特异性抗体存在下测量微血管反应；以及5)DPR逆转休克综合征病理生理学的机制。长期目标是开发一种临床前方案，将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预防失血性休克复苏后的多器官衰竭。

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.