Collaborative Pediatric Critical Care Research Network (UG1)

儿科重症监护协作研究网络 (UG1)

• 批准号: 8991005
• 负责人: MARK W HALL
• 金额: $ 25.28万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-24 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991005
• 关键词: Address; Admission activity; Adult; Beds; Biological Markers; Blinded; Blood; Brain; Cerebrospinal Fluid; Child; Childhood; Childhood Injury; Clinical; Collaborations; Colony-Stimulating Factor Therapy; Controlled Clinical Trials; Country; Critical Care; Critical Illness; Critically ill children; Data; Development; Dose; Double-Blind Method; FDA approved; Faculty; Funding; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Health Care Costs; Immune; Immune response; Immunization; Immunologic Monitoring; Immunophenotyping; Immunosuppression; Impairment; Incidence; Infection; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Leadership; Medicine; Modeling; Monitor; Morbidity - disease rate; Nervous System Trauma; Nosocomial Infections; Outcome; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Placebo Control; Placebos; Plasma; Population; Positioning Attribute; Process; Public Health; Randomized; Research; Research Institute; Research Personnel; Resources; Risk; Role; Services; Source; Testing; Time; Toxic effect; Trauma; Traumatic Brain Injury; Traumatic injury; United States National Institutes of Health; Ventricular; base; cytokine; experience; high risk; immune function; immunoregulation; improved; injured; innate immune function; member; patient population; prevent; programs; prospective; response; restoration; sample collection; secondary infection

 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.

 描述（由应用程序提供）：多中心协作对于开始回答我们许多小儿重症监护医学中最紧迫的问题是必要的。协作小儿重症监护研究网络（CPCCRN）已成为解决多中心研究人员面临的障碍的有效模型。我们在全国儿童医院（NCH）的位置非常好，可以成为CPCCRN网络的一部分。每年有60个重症监护床（40个儿科，20个心胸）和> 2,500次入院，我们是该国最大的重症监护计划之一。我们的19个专职教师 享受可观的访问研究资源，包括特定于特定的研究协调员，数据收集者和生物统计学支持。此外，我们还拥有基于PICU和研究所的实验室资源，可允许全天候的样本收集和处理，并为CPCCRN网络提供尖端的生物标志物和免疫功能定量服务。在马克·霍尔（Mark Hall）博士的领导下，我们提供以下内容：全球特定目的：最大程度地参与CPCCRN网络研究，其目标是有意义地促进新知识的产生，以改善重症儿童。 作为本提交的一部分，我们介绍了题为“神经抑制后的免疫刺激的GM-CSF（巨人）”研究。这项研究的总体目的是证明，用药物粒细胞巨噬细胞刺激因子（GM-CSF）治疗可以通过恢复免疫功能来降低高危脑损伤（TBI）严重创伤性脑损伤（TBI）儿童的发生率。严重损伤，尤其是神经疾病后，继发感染和先天免疫学功能的损害的发生率都是常见的。我们已经开发了执行高度标准化，可概括，功能免疫学监测的能力，我们的初步数据表明，严重降低免疫学功能的严重伤害患者对继发感染的发展有很高的风险。我们在FDA批准的药物GM-CSF方面的经验是，它可以逆转严重疾病/受伤引起的免疫抑制。我们目前正在对受伤儿童的GM-CSF进行NIH资助的临床剂量发现试验，但其对感染风险的影响仍然存在 严重TBI的儿童未知。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GM-CSF对严重TBI儿童的临床试验，他们被发现具有严重的先天免疫抑制。我们的中心假设是，通过安全，快速，快速，持续的先天免疫抑制功能改善，高危患者的临界TBI后，对GM-CSF进行免疫调节将降低继发性感染的风险。我们将使用免疫表型驱动的方法来筛查受伤后紧接的几天中严重的先天免疫抑制。患有严重免疫抑制的受试者将被随机分配为以盲目的方式接受GM-CSF或安慰剂。免疫功能将被串行监测，并针对特定的临床触发因素进行研究。随着时间的推移，将在研究组之间比较新的，医院获得的感染事件。此外，我们将序列地评估血浆细胞因子水平，并且当存在外部心室漏（EVD）时，脑脊液（CSF）细胞因子水平将对GM-CSF的功能免疫反应与血液和大脑中脑炎的促炎细胞因子的水平相关联。最后，我们将进行以在Pecarn/CPCCRN THAPCA试验中成功使用的方法来测试无效假设，即神经发育状态在GM-CSF和安慰剂训练的受试者之间将没有什么不同。我们预计，这项巨型研究将代表小儿神经瘤管理的范式转变，因为它将证明免疫刺激在严重受伤后安全降低感染风险中的作用，将显示实时免疫抑制的可行性，并且将产生最大，最全面的Immuno功能数据，并研究了任何技术人群的研究。我们还坚信，全国儿童医院将成为协作小儿重症监护研究网络的杰出成员。我们的大量患者群体，单一和多中心研究的记录，我们的独特的特定护理和一般研究资源的组合以及我们的调查团队的经验来了解这种观点。