Collaborative Pediatric Critical Care Research Network (UG1)

 描述(由申请人提供)：多中心合作是必要的，以开始回答我们在儿科重症监护医学中许多最紧迫的问题。协作性儿科重症监护研究网络(CPCCRN)已成为解决多中心研究人员面临的障碍的有效模式。我们在全国儿童医院(NCH)处于非常有利的地位，可以成为CPCCRN网络的一部分。我们每年总共有60张重症监护床位(40张儿科床位，20张心胸病床)和2500人次入院，是全国最大的重症监护项目之一。我们的19名全职教职员工 享受卓越的研究资源，包括重症监护特定研究协调员、数据收集者和生物统计支持。此外，我们拥有PICU和研究所的实验室资源，可以全天候收集和处理样本，并为CPCCRN网络提供尖端生物标记物和免疫功能量化服务。在马克·霍尔博士的领导下，我们提供了以下全球具体目标：最大限度地参与CPCCRN网络研究，目标是为产生新的知识，改善危重儿童的状况做出有意义的贡献。 作为这份报告的一部分，我们提出了题为“GM-CSF用于神经创伤后的免疫刺激(GIGNAL)”研究的概念提案。这项研究的总体目标是证明使用药物粒细胞-巨噬细胞集落刺激因子(GM-CSF)治疗可以通过恢复免疫功能来降低严重颅脑损伤(TBI)高危儿童的继发感染发生率。继发感染和先天免疫功能受损是危重损伤尤其是神经损伤后的常见并发症。我们已经开发了进行高度标准化、通用化、功能性免疫监测的能力，我们的初步数据显示，免疫功能严重下降的重伤患者发生继发感染的风险很高。我们使用FDA批准的药物GM-CSF的经验是，它可以逆转危重疾病/伤害诱导的免疫抑制。我们目前正在进行一项由美国国立卫生研究院资助的GM-CSF在受伤儿童中的临床剂量发现试验，但它对感染风险的影响仍然存在 在患有严重脑外伤的儿童中未知。因此，我们提出了一项前瞻性、多中心、随机、双盲、安慰剂对照的临床试验，用于严重脑外伤儿童的GM-CSF，这些儿童被发现有严重的先天免疫抑制。我们的中心假设是，GM-CSF的免疫调节将通过安全、快速和持续的改善先天性免疫功能来降低高危患者严重脑外伤后继发感染的风险。我们将使用免疫表型驱动的方法来筛选在损伤后的几天内是否存在严重的先天免疫抑制。有严重免疫抑制的受试者将被随机分配到盲法接受GM-CSF或安慰剂治疗。将对免疫功能进行连续监测，并将根据特定的临床触发因素调查继发感染。新的医院获得性感染的发生率将随着时间的推移在不同研究组之间进行比较。此外，我们将连续评估血浆细胞因子水平，以及当存在脑室外引流(EVD)时，脑脊液(CSF)细胞因子水平，以将对GM-CSF的功能性免疫反应与血液和脑内促炎细胞因子水平相关联。最后，我们将仿照PECARN/CPCCRN THAPCA试验中成功使用的方法进行一系列纵向神经发育测试，以检验GM-CSF和安慰剂治疗对象之间神经发育状况没有差异的零假设。我们预计，这项庞大的研究将代表着儿科神经创伤治疗的范式转变，因为它将展示免疫刺激在安全降低危重损伤后感染风险方面的作用，将展示实时免疫功能监测的可行性，并将产生迄今所研究的所有创伤人群中最大和最全面的免疫功能数据集。我们也坚信，全国儿童医院将成为协作性儿科重症监护研究网络的杰出成员。这一观点是由我们庞大而多样化的患者群体、我们的单中心和多中心研究的跟踪记录、我们独特的危重护理专用和一般研究资源组合以及我们调查团队的经验提供的。

 DESCRIPTION (provided by applicant): Multi-center collaboration is necessary to begin to answer many of our most pressing questions in pediatric critical care medicine. The Collaborative Pediatric Critical Care Research Network (CPCCRN) has emerged as an effective model for addressing the hurdles facing multi-center investigators. We at Nationwide Children's Hospital (NCH) are exceptionally well positioned to become a part of the CPCCRN network. With a total of 60 critical care beds (40 pediatric, 20 cardiothoracic) and > 2,500 admissions annually, we are one of the largest critical care programs in the country. Our 19 full-time faculty enjoy remarkable access to research resources including critical care-specific research coordinators, data collectors, and biostatistical support. In addition we have in-PICU and Research Institute-based laboratory resources that permit around-the-clock sample collection and processing as well as provide cutting-edge biomarker and immune function quantitation services for the CPCCRN network. Under the leadership of Dr. Mark Hall, we offer the following: Global Specific Aim: To maximally participate in CPCCRN network studies with a goal of contributing meaningfully to the generation of new knowledge for the betterment of critically ill children. As part of this submission we present the concept proposal entitled, "GM-CSF for Immunostimulation After NeuroTrauma (GIANT)" study. The overall objective of this study is to demonstrate that treatment with the drug granulocyte-macrophage colony-stimulating factor (GM-CSF) can reduce the incidence of secondary infection in high-risk, children with severe traumatic brain injury (TBI) through restoration of immune function. The incidence of secondary infection and impairment of innate immune function are both common following critical injury, particularly neurotrauma. We have developed the capacity to perform highly standardized, generalizable, functional immune monitoring and our preliminary data show that critically injured patients with severe reduction immune function are at high risk for the development of secondary infection. Our experience with the FDA-approved drug GM-CSF is that it can reverse critical illness/injury-induced immune suppression. We are currently conducting an NIH-funded clinical dose-finding trial of GM-CSF in injured children, but its effect on infection risk remains unknown in children with severe TBI. We therefore propose a prospective, multi-center, randomized, double-blind, placebo controlled clinical trial of GM-CSF in children with severe TBI who are found to have severe innate immune suppression. Our central hypothesis that immunomodulation with GM-CSF will result in reduction in the risk of secondary infection after critical TBI in high-risk patients through safe, rapid, and sustained improvement in innate immune function. We will use an immunophenotype-driven approach to screen for the presence of severe innate immune suppression in the days immediately following injury. Subjects with severe immune suppression will be randomly assigned to receive GM-CSF or placebo in a blinded fashion. Immune function will be monitored serially and secondary infection will be investigated in response to specific clinical triggers. The incidence of new, nosocomially acquired infection will be compared between study groups over time. In addition, we will serially evaluate plasma cytokine levels and, when an external ventricular drain (EVD) is present, cerebrospinal fluid (CSF) cytokine levels to correlate the functional immune response to GM-CSF with levels of pro-inflammatory cytokines in the blood and the brain. Lastly, we will carry out serial, longitudinal neurodevelopmental testing modeled after the approach used successfully in the PECARN/CPCCRN THAPCA trials to test the null hypothesis that neurodevelopmental status will be no different between GM-CSF- and placebo-treated subjects. We anticipate that the GIANT study will represent a paradigm shift in the management of pediatric neurotrauma in that it will demonstrate the role of immune stimulation in safely reducing infection risk after critical injury, will show the feasibility of real-time immune functin monitoring, and will yield the largest and most comprehensive set of immune function data of any trauma population yet studied. We also firmly believe that Nationwide Children's Hospital will serve as an outstanding member of the Collaborative Pediatric Critical Care Research Network. This view is informed by our large and diverse patient population, our track record of single- and multi-center research, our unique portfolio of critical care-specific and general research resources, and the experience of our investigative team.