MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

使用非肝素化的无限制大鼠创伤出血模型， 我们的研究表明， 有TNF和IL-6的释放， 几个器官（心脏、肝脏、肾脏、肠道和血管）和晚期 mortality. 然而，该模型的局限性在于， 心血管和血液动力学反应以及流体Rs，可以 只表现得很尖锐。 由于创伤患者会被持续监控 医院和重症监护病房（ICU）的液体管理是 根据需要提供，我们假设， 细胞和器官功能障碍的实验模型可以更准确地 通过以下初始创伤出血性损伤进行评估， 通过类似于ICU的密切监测测量液体优化 设置.我们还假设血管内液体的优化 出血后液体优化的慢性模型中的容量可能延迟 细胞和器官功能逐渐恶化， 单靠这一点不足以防止这些问题。因此，委员会认为， 将需要药物作为液体Rs的抑制剂。 研究是 建议确定：（l）建立一个扩大的 监测血压（BP）、中心静脉压（CVP）、 循环血容量（CBV）、尿量、心输出量（CO）， 非肝素化正常大鼠肝细胞功能和血流量 借助计算机数据采集系统， 测量和输注维护液; 2）可行性 创伤出血后长期监测上述参数 3）是否长期优化血管内液体 创伤-出血后容量/液体给药时的Rs 所需的基础延缓心血管，血液动力学，细胞 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的模型与 涉及慢性RS; 5）是否化学修饰的肝素（无 显着的抗凝活性）、ATP-MgCl 2、地尔硫卓或 作为辅助治疗的戊茶碱（下调炎性细胞因子） 恢复和维持血流动力学稳定性，细胞和器官 功能，降低损伤后对脓毒症的易感性， 出血 待测血流动力学参数和器官功能 包括平均BP、CVP、CBV、CO、肝细胞功能、肾、肠 （吸收能力）和器官血流。此外，内皮， 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，沿着与选定的释放 将测量介质（TNF、IL-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， CVP、尿量或CBV。涉及慢性疾病的拟议研究 用液体监测各种血液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 用于治疗和护理大量失血的患者， 降低了对随后败血症的易感性。

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.