Hypertonic Modulation of Inflammation following Injury

描述（由申请方提供）：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建议。损伤后晚期死亡的主要原因是多器官功能障碍综合征，其由损伤后早期患者的功能障碍性炎症反应引起。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。这些效应在实验室中已经得到了很好的描述，但尚未在人类中得到证实，特别是在严重受伤的情况下。这项提案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得血液样本，并分析他们在受伤后早期的炎症反应。拟议的试验将由复苏结局联盟（ROC）进行，该联盟通常由美国和加拿大的临床中心组成。本研究是一项三组、盲法、随机试验，比较了7.5%盐水、7.5%盐水/6%右旋糖酐-70和0.9%生理盐水作为低血容量性休克或有严重创伤性脑损伤体征患者的初始复苏液。三个ROC临床研究中心将合作研究在这些研究中心入组的患者的炎症反应。具体目标包括：目标1：描述和表征先天性和细胞免疫系统对损伤后高渗复苏的反应表型。目的2：在人类中确定负责炎症反应高渗调节的细胞机制。目标3：确定高渗复苏后观察到的免疫学变化是否与器官功能障碍和医院感染的临床结局差异相关。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.