MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

尽管事故现场的复苏工作取得了进展，但一大批 创伤患者随后死于脓毒症和多器官功能障碍的人数 失败了。我们的假设是，各种微循环的改变， 产生有毒物质，以及之后产生的代谢障碍 严重失血不能通过复苏得到充分纠正 仅限于常规流体，这种改变最终会导致 多器官衰竭。我们最近开发了：1)一种独特的非 肝素化自由创伤失血大鼠模型 休克/复苏与多器官功能障碍和 晚期死亡率；2)重复测量器官功能的技术。 这样一种模式。我们的结果表明，微血管的通畅率 出血后显著减少，但不能恢复 进行充分的复苏。非抗凝剂肝素(NACH)的应用 在出血前或复苏期间，维持微血管 通畅性(初步研究)。即使是之前给过的普通肝素 出血(与大多数模型一样)，或在复苏期间，维持 微血管通畅。血浆肿瘤坏死因子和白介素6(炎性)的升高 细胞因子)，这在出血后更加明显 复苏，表明肝素化或复苏不会 消除细胞因子释放的刺激。建议进行研究以 确定：1)术后器官功能障碍的发生机制 出血/复苏，2)NACH或类肝素作为佐剂 在复苏过程中恢复微循环和器官功能，3) NACH联合应用能否阻断炎性细胞因子的释放 使用氯喹(一种阻止这种细胞因子释放的试剂)，如果这 改善细胞/器官功能。失血后复苏将包括 林格氏乳酸盐和NACH或类肝素(以恢复微血管) 使用/不使用氯喹和，以进一步改善血液流动和提供 额外的代谢支持、多巴胺和/或地尔硫卓或三磷酸腺苷-氯化镁， 将会被实施。我们将评估每一位特工的行动， 个体及其在细胞和器官上的相互作用 (心、肾、肝和肠道(吸收)) 复苏。这样的方法应该为以下各项产生最佳组合： 1)恢复微血管通畅，从而改善传输 底物；2)减少有毒物质(肿瘤坏死因子、白介素6、钾 内毒素)；3)对细胞/器官产生协同有益作用 损伤后的功能；以及4)增加对 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.