MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

使用非肝素化、无拘束的创伤-出血大鼠模型 休克和急性晶体复苏(Rs)，我们的研究表明 有肿瘤坏死因子和白介素6的释放，功能的抑制 几个器官(心、肝、肾、肠道和血管)和晚期 死亡率。然而，该模型的局限性在于，对 心血管和血流动力学反应以及液体R，可以是 只表现得很犀利。由于创伤患者受到持续监测 医院和重症监护病房(ICU)的体液管理 在需要的基础上提供的，我们假设 实验模型中的细胞和器官功能障碍可以更准确地 通过最初的创伤-出血性伤害后评估，并有一段时间 通过类似于ICU的严密监控测量到的液体优化 布景。我们还假设血管内液体的最佳化 出血后液体优化的慢性模型中的体积可能延迟 细胞和器官功能的进行性恶化，但液体 仅靠这一点是不足以预防这些问题的。因此， 将需要药理药剂作为液体R的附件。研究是 建议确定：L)设立延期的可行性 血压(BP)、中心静脉压(CVP)、 循环血容量(CBV)、尿量、心输出量(CO)、 非肝素化正常大鼠的肝细胞功能和血流 在计算机数据采集系统的帮助下建立的模型 维护液的测量和输注；2)可行性 创伤出血后上述指标的长期监测 3)血管内液体是否长期优化 创伤后容量-AS上液体注射的出血/RS 所需基础延缓心血管、血流动力学、细胞的恶化 和器官功能：4)细胞和器官功能障碍的机制 涉及急性液体RS的模型中的出血-Rs与 涉及慢性RS；5)是否有化学修饰的肝素(无 显著的抗凝血活性)、ATP-MgCl2、地尔硫卓或 己酮可可碱(下调炎性细胞因子)作为辅助药物 恢复和维持血流动力学、细胞和器官的稳定性 功能，降低创伤后脓毒症的易感性 大出血。待测血液动力学参数和器官功能 包括平均BP、CVP、CBV、CO、肝细胞功能、肾脏、肠道 (吸收能力)和器官血流量。此外，内皮细胞， 肠细胞和肝细胞功能，肝脏α和β肾上腺素能 受体、组织腺嘌呤核苷酸、组织和细胞cAMP和cGMP 水平、电解质和H2O含量，以及选定的 将测定介质(肿瘤坏死因子、白介素6、儿茶酚胺)。我们计划 确定血流动力学和心血管稳定性是否与CO、BP、 中心静脉压、尿量或CBV。建议的研究涉及慢性阻塞性肺疾病 用液体监测各种血流动力学和心血管参数 创伤出血后的优化应提供有用的信息 用于治疗和护理失血过多的病人 降低继发性脓毒症的易感性。

Using a non-heparinized, unrestrained rat model of trauma-hemorrhagic shock and acute crystalloid resuscitation (Rs), our studies have shown that there is release of TNF and IL-6, depression of the function of several organs (heart, liver, kidney, gut and blood vessels) and late mortality. The limitations of the model, however, are that monitoring of cardiovascular and hemodynamic responses as well as fluid Rs, can be performed only acutely. Since trauma patients are continuously monitored and fluid management in hospitals and intensive-care units (ICU) is provided on an as needed basis, we hypothesize that the full extent of cell and organ dysfunction in experimental models can be more accurately assessed by following the initial trauma-hemorrhagic insult, with a period of fluid optimization measured with close monitoring similar to an ICU setting. We also hypothesize that optimization of intravascular fluid volume in a chronic model of fluid optimization after hemorrhage may delay the progressive deterioration of cell and organ function but that fluids alone will not be sufficient to prevent the problems. Consequently, pharmacologic agents as adjuncts to fluid Rs will be needed. Studies are proposed to determine: l) the feasibility of establishing an extended model of monitoring blood pressure (BP), central venous pressure (CVP), circulating blood volume (CBV), urine output, cardiac output (CO), hepatocellular function and blood flow in a non-heparinized normal rat model with the aid of a computer-based data acquisition system for measurements and infusion of maintenance fluids; 2) the feasibility of chronically monitoring the above parameters following trauma-hemorrhage and acute Rs; 3) whether long-term optimization of intravascular fluid volume after trauma-hemorrhage/Rs with fluid administration on an as needed basis delays the deterioration of cardiovascular, hemodynamic, cell and organ function: 4) the mechanisms of cell and organ dysfunction after hemorrhage-Rs in a model involving acute fluid Rs vs the model which involves chronic Rs; 5) whether chemically modified heparin (without significant anticoagulant activity), ATP-MgCl2, diltiazem or pentoxifylline (which downregulate inflammatory cytokines) as an adjunct to Rs restores and maintains hemodynamic stability, cell and organ function and decreases the susceptibility to sepsis after injury and hemorrhage. The hemodynamic parameters and organ functions to be measured include mean BP, CVP, CBV, CO, hepatocellular function, renal, gut (absorptive capacity), and organ blood flow. Moreover, endothelium, enterocyte and hepatocyte function, hepatic alpha- and beta-adrenergic receptors, tissue adenine nucleotides, tissue and cell cAMP and cGMP levels, electrolytes and H2O contents, along with the release of selected mediators (TNF, IL-6, catecholamines) will be measured. We plan to determine if hemodynamic and cardiovascular stability is linked to CO, BP, CVP, urine output or CBV. The proposed studies involving chronic monitoring of various hemodynamic and cardiovascular parameters with fluid optimization following trauma-hemorrhage should provide useful information for the treatment and care of patients with major blood loss and for decreasing the susceptibility to subsequent sepsis.