MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

尽管在事故现场的复苏方面取得了进展， 许多创伤患者随后死于脓毒症和多器官衰竭， 失败 我们的假设是各种微循环改变， 有毒物质的产生，以及 严重失血不能通过复苏得到充分纠正， 传统的流体，这种改变最终导致 多器官衰竭 我们最近开发了：1）一个独特的非- 肝素化无限制大鼠创伤出血模型 休克/复苏与多器官功能障碍有关， 晚期死亡率; 2）重复测量器官功能的技术， 这样的模型。 我们的研究结果表明，微血管通畅性 出血后急剧下降，尽管 充分复苏。 非抗凝肝素（NACH）给药 在出血前或复苏期间，维持微血管 通畅性（初步研究）。 即使是以前使用的常规肝素 出血（如在大多数模型中），或在复苏过程中， 微血管通畅 血浆TNF和IL-6（炎性细胞因子）的增加 细胞因子），这在出血后甚至更明显， 复苏，表明肝素化或复苏不 消除对细胞因子释放的刺激。 建议开展研究， 确定：1）器官功能障碍的机制， 出血/复苏，2）无论是NACH还是类肝素作为佐剂 在复苏过程中恢复微循环和器官功能，3） 当联合使用时，炎症细胞因子释放是否可以被NACH阻断 用氯喹（一种阻断这种细胞因子释放的药物），如果这 改善细胞/器官功能。 出血后复苏将包括 乳酸林格氏液和NACH或类肝素（用于恢复微血管） 使用/不使用氯喹，并进一步改善血流并提供 额外的代谢支持，多巴胺和/或地尔硫卓，或ATP-MgCl 2， 将被管理。 我们将评估这些代理人的行为， 以及它们之间相互作用对细胞和器官的影响 （心脏、肾脏、肝脏和肠道（吸收））功能 复苏术 这种办法应产生以下方面的最佳组合： 1)恢复微血管通畅，从而改善 2）减少有毒物质（TNF、IL-6、K 内毒素）; 3）对细胞/器官产生协同有益作用 损伤后的功能;和4）提供增加的抵抗力， 随后的败血症。

Despite advances in resuscitation at the scene of the accident, a large number of trauma patients subsequently die of sepsis and multiple organ failure. Our hypothesis is that the various microcirculatory alterations, generation of toxic substances, and metabolic disturbances produced after severe blood loss are not adequately corrected by resuscitation with conventional fluids alone, and that such alterations eventually lead to multiple organ failure. We have recently developed: 1) a unique non- heparinized, unrestrained rat model of trauma-hemorrhagic shock/resuscitation which is associated with multiple organ dysfunction and late mortality; 2) techniques of repeated measurement of organ function in such a model. Our results indicate that microvascular patency is dramatically decreased after hemorrhage and is not restored despite adequate resuscitation. Administration of non-anticoagulant heparin (NACH) before hemorrhage or during resuscitation, maintained the microvascular patency (Preliminary studies). Even regular heparin given before hemorrhage (as in most models), or during resuscitation, maintained the microvascular patency. The increase in plasma TNF and IL-6 (inflammatory cytokines) during hemorrhage, which were even more pronounced after resuscitation, suggests that heparinization or resuscitation does not eliminate the stimulus for cytokine release. Studies are proposed to determine: 1) the mechanism of organ dysfunction after hemorrhage/resuscitation, 2) whether NACH or heparanoids as an adjuvant during resuscitation restores microcirculation and organ function, 3) whether inflammatory cytokine release can be blocked by NACH when combined with chloroquine (an agent which blocks such cytokine release) and if this improves cell/organ function. Post-hemorrhage resuscitation will comprise Ringer's lactate and NACH or heparanoids (to restore microvasculature) with/without chloroquine and, to further improve blood flow and provide additional metabolic support, dopamine, and/or diltiazem, or ATP-MgCl2, will be administered. We will evaluate the action of each these agents, individually and their interaction with each other, on cell and organ (cardiac, renal, hepatic, and gut (absorptive)) function after resuscitation. Such an approach should yield an optimal combination for: 1) restoring microvascular patency, thus improving the delivery of substrates; 2) decreasing the release of toxic substances (TNF, IL-6,K endotoxin); 3) producing synergistic beneficial effects on cell/organ function following injury; and 4) providing increased resistance to subsequent sepsis.