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（由申请人提供）：为了开始回答儿科重症监护医学中许多最紧迫的问题，多中心合作是必要的。儿科重症监护协作研究网络 (CPCCRN) 已成为解决多中心研究人员面临的障碍的有效模型。我们全国儿童医院 (NCH) 处于非常有利的位置，可以成为 CPCCRN 网络的一部分。我们共有 60 张重症监护病床（40 张儿科病床，20 张心胸病床），每年入院人数超过 2,500 人，是美国最大的重症监护项目之一。我们的 19 名全职教师 享有大量研究资源，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，我们还拥有基于 PICU 和研究所的实验室资源，可以全天候进行样本采集和处理，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 Mark Hall 博士的领导下，我们提出以下目标： 全球具体目标：最大限度地参与 CPCCRN 网络研究，目标是为新知识的产生做出有意义的贡献，以改善危重儿童的状况。 作为本提交文件的一部分，我们提出了题为“GM-CSF 用于神经创伤后免疫刺激 (GIANT)”研究的概念提案。本研究的总体目标是证明粒细胞巨噬细胞集落刺激因子（GM-CSF）药物治疗可以通过恢复免疫功能来降低高危严重创伤性脑损伤（TBI）儿童继发感染的发生率。继发感染和先天免疫功能受损的发生率在严重损伤（尤其是神经外伤）后都很常见。我们已经具备了进行高度标准化、通用化的功能性免疫监测的能力，我们的初步数据表明，免疫功能严重下降的危重患者发生继发感染的风险很高。我们对 FDA 批准的药物 GM-CSF 的经验是，它可以逆转危重疾病/损伤引起的免疫抑制。我们目前正在进行一项由 NIH 资助的针对受伤儿童的 GM-CSF 临床剂量探索试验，但其对感染风险的影响仍然存在 在患有严重 TBI 的儿童中尚不清楚。因此，我们建议对患有严重先天免疫抑制的严重 TBI 儿童进行一项前瞻性、多中心、随机、双盲、安慰剂对照的 GM-CSF 临床试验。我们的中心假设是，GM-CSF 免疫调节将通过安全、快速和持续地改善先天免疫功能，从而降低高危患者危重 TBI 后继发感染的风险。我们将使用免疫表型驱动的方法来筛查受伤后几天内是否存在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以盲法接受 GM-CSF 或安慰剂。将连续监测免疫功能，并根据特定的临床触发因素调查继发感染。随着时间的推移，将比较研究组之间新的院内获得性感染的发生率。此外，我们将连续评估血浆细胞因子水平，以及当存在心室外引流（EVD）时，脑脊液（CSF）细胞因子水平，以将针对 GM-CSF 的功能性免疫反应与血液和大脑中促炎细胞因子的水平相关联。最后，我们将模仿 PECARN/CPCCRN THAPCA 试验中成功使用的方法进行连续的纵向神经发育测试，以测试 GM-CSF 治疗受试者和安慰剂治疗受试者之间的神经发育状态没有差异的零假设。我们预计 GIANT 研究将代表儿科神经创伤治疗的范式转变，因为它将证明免疫刺激在安全降低严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，并将产生迄今为止研究的任何创伤人群中最大、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儿科重症监护协作研究网络的杰出成员。这一观点源于我们庞大且多样化的患者群体、我们的单中心和多中心研究记录、我们独特的重症监护特定和一般研究资源组合以及我们的研究团队的经验。