Hypertonic Modulation of Inflammation following Injury

描述（由申请人提供）：这是一项旨在确定院前高渗复苏与常规晶体复苏对损伤后早期炎症反应的影响的提案。损伤后晚期死亡的主要原因是多器官功能障碍综合征，这是由于患者在损伤后早期炎症反应不正常造成的。先前的研究表明，高渗盐水可能有利于调节这种初始反应，从而减少随后的器官损伤。这些影响已经在实验室中得到了很好的描述，但尚未在人体中得到证实，特别是在严重损伤的情况下。该建议利用了一个独特的机会，从参加NIH支持的高渗复苏多中心试验的患者中获取血液样本，并在损伤后早期分析他们的炎症反应。拟议的试验将由复苏结果联盟（ROC）进行，该联盟通常由美国和加拿大的临床中心组成。本研究是一项三臂、盲法、随机试验，比较7.5%生理盐水、7.5%生理盐水/6%葡聚糖-70和生理盐水（0.9%）作为低血凝性休克或有严重创伤性脑损伤迹象的患者的初始复苏液。三个ROC临床站点将合作研究在这些站点入组的患者的炎症反应。具体目的包括：目的1：描述和表征损伤后高渗复苏反应的先天和细胞免疫系统的表型。目的2：定义，在人类，负责炎症反应的高渗调节的细胞机制。目的3：确定高渗复苏后观察到的免疫变化是否与器官功能障碍的发展和医院感染所表现的临床结果差异相关。这些研究的结果将为确定复苏策略的最终治疗用途提供有价值的信息。

DESCRIPTION (provided by applicant): This is a proposal to determine the effect of prehospital hypertonic resuscitation vs. conventional resuscitation with crystalloid on the inflammatory response early after injury. The leading cause of late mortality following injury is multiple organ dysfunction syndrome, which results from dysfunctional inflammatory response of the patient early after injury. Previous studies, suggest that hypertonic saline may be beneficial in modulating this initial response and thus decrease the subsequent organ injury. These effects, which have been well described in the laboratory, have yet to be proven in humans, particularly in the setting of severe injury. This proposal takes advantage of a unique opportunity to obtain blood samples from patients enrolled in a NIH supported multi-center trial of hypertonic resuscitation and analyze their inflammatory responses early after injury. The proposed trial is to be conducted by the Resuscitation Outcomes Consortium (ROC), which consists often clinical centers in the US and Canada. This study is a three arm, blinded, randomized trial comparing 7.5% saline, 7.5% saline/6% dextran-70 and normal saline (0.9%) as the initial resuscitation fluid administered to patients in hypovelemic shock or with signs of sever traumatic brain injury. Three of the ROC clinical sites will collaborate to study then inflammation response of patients enrolled at theses sites. The specific aims include: Aim 1: To profile and characterize the phenotype of the innate and cellular immune systems in response to hypertonic resuscitation following injury. Aim 2: To define, in humans, the cellular mechanisms responsible for hypertonic modulation of the inflammatory response. Aim 3: To determine whether immunologic changes observed following hypertonic resuscitation associated with differences in clinical outcome as manifested by the development of organ dysfunction, and nosocomial infection. The results of these studies will provide valuable information to determine the ultimate therapeutic use of the resuscitation strategy.