Intestinal failure in children: A contemporary retrospective review by the Pediat

描述(申请人提供)：婴儿和儿童的肠衰竭(IF)是一种破坏性的疾病，可以广泛地定义为在没有补充的肠外营养(PN)的情况下肠道无法维持生命。在损伤或切除后，肠道必须充分适应，以实现与PN的独立，否则患者有营养不良、终末期肝病、血管血栓形成、败血症和死亡的风险。这些并发症在儿科人群中尤其普遍。目前的医学文献不足以确定预测预后的因素，如果患者在短时间内在任何一个中心就诊的患者太少，以至于医疗、营养、手术和移植方案都是相似的。目前公认的治疗方法是基于轶事经验和关于小型非对照研究的报告，因此在我们对最佳治疗策略的理解中产生了相当大的知识差距。理解结果的一个主要障碍是在儿科IF领域没有全面的、多中心的研究，也没有大型的前瞻性研究。我们建议建立一个由儿科中心组成的财团，这些中心对IF有公认的兴趣。具体目标1是调查可行性并计划一个预期的多中心联合体，该联合体将收集、维护、分析和报告IF儿童的临床、营养、外科、流行病学和结局数据，包括来自血清、尿液、组织和DNA样本的信息。由即将建立的前瞻性注册中心汇编的临床数据将被用来开发一个模型，以预测IF患者的三个关键结果，包括独立于PN、胆汁淤积和死亡。我们将建议收集和存储生物样本，供临床和基础科学家在我们联盟内外使用，以加强我们对IF相关病理生理条件下的生理机制的了解，如肠道适应、PN相关的胆汁淤积、营养不良和粘膜免疫。结合预期登记，我们将建议确定、实施和完成适当有效的随机对照治疗试验，这些试验将构成这些具有复杂临床条件的儿童护理的循证实践模式的基础。为了确保我们能够创造富有成效的协作，我们提出了具体的目标#2，即对当代患有IF的婴儿和儿童队列进行多中心回顾，以确定此类研究将能够确定将能够预测以下关键结果的人口统计学、临床和营养风险因素的可行性：(1)需要长期PN(&gt；360天)，(2)停止PN，(3)发展为胆汁淤积症，(4)需要肠道移植，以及(5)死亡。我们将使用收集的数据和从回溯性研究中获得的经验来确定我们的财团对IF儿童进行多中心前瞻性研究的可行性，并进行随机对照治疗试验。如果成功，这些数据将用于未来的RO1应用。与公共卫生相关婴儿和儿童的肠衰竭(IF)是一种破坏性的疾病，其定义是肠道在没有补充营养的情况下无法维持生命，这些营养必须注入大静脉，通常位于胸部。患有IF的儿童有发展为营养不良、肝硬变、血栓、血液感染和死亡的风险；然而，目前的医学文献不足以确定使医生能够预测儿童是否会康复或需要肠道移植的因素。为了解决与IF儿童相关的重要问题，我们建议(1)与全国各地的许多儿科中心建立有效的合作关系，这些中心有能力照顾这些医学上复杂的儿童，以及(2)回顾过去七年的情况，以确定哪些因素将确定哪些儿童不太可能被排除在补充营养之外，哪些可能需要肠道移植，哪些可能死亡。

DESCRIPTION (provided by applicant): Intestinal failure (IF) in infants and children is a devastating condition that can be broadly defined as the inability of the intestinal tract to sustain life without supplemental parenteral nutrition (PN). Following injury or resection, the intestinal tract must adapt sufficiently to achieve independence from PN, or the patient is at risk for nutritional deficiencies, end-stage liver disease, vascular thrombosis, sepsis, and death. These complications are particularly prevalent in the pediatric population. The current medical literature is insufficient to determine factors that predict outcome in patients with IF as too few patients are seen at any one center in a short enough time that medical, nutritional, surgical, and transplant options are similar. Currently accepted therapies are based on anecdotal experience and reports of small uncontrolled studies, thus creating a sizeable knowledge gap in our understanding of optimal treatment strategies. A major obstacle to understanding outcomes is that there are no comprehensive, multi-center studies, nor large prospective studies in the field of pediatric IF. We propose to establish a consortium comprised of pediatric centers with a recognized interest in IF. Specific Aim #1 is to investigate the feasibility and plan a prospective, multi-center consortium that will collect, maintain, analyze, and report clinical, nutritional, surgical, epidemiological, and outcome data in children with IF, including information derived from serum, urine, tissue, and DNA specimens. The clinical data compiled by the to-be-established prospective registry will be used to develop a model to predict three critical outcomes in IF patients that include independence from PN, development of cholestasis, and death. We will propose to collect and store biological samples to be used by clinical and basic scientists, within and outside our consortium, to enhance our understanding of the physiological mechanisms that underlie pathophysiological conditions associated with IF such as intestinal adaptation, PN related cholestasis, nutritional deficiencies, and mucosal immunity. In conjunction with the prospective registry, we will propose to identify, conduct, and complete appropriately powered randomized, controlled treatment trials that will form the foundation of an evidence-based practice model in the care of these children with complicated clinical conditions. To ensure our ability to create a productive collaboration, we propose Specific Aim #2 which is to perform a multi-center, retrospective review of a contemporary cohort of infants and children with IF to determine the feasibility that such a study will be able to identify demographic, clinical, and nutritional risk factors that will predict the following critical outcomes: (1) need for long-term PN (> 360 days), (2) discontinuation of PN, (3) development of cholestasis, (4) need for intestinal transplant, and (5) death. We will use the data collected and the experiences gained from the retrospective study to determine the feasibility of our consortium to conduct a multi-centered, prospective study of children with IF and to conduct randomized, controlled therapeutic trials. If successful, these data will be utilized for a future RO1 application. PUBLIC HEALTH RELEVANCE Intestinal failure (IF) in infants and children is a devastating condition that is defined as the inability of the intestinal tract to sustain life without supplemental nutrition that must be infused into a large vein, usually one located in the chest. Children with IF are at risk for developing nutritional deficiencies, cirrhosis, blood clots, blood infections, and death; yet the current medical literature is not sufficient to identify factors that that will allow doctors to predict whether the child will recover or need an intestinal transplant. To address the important problems related to children with IF, we propose to (1) establish an effective, collaborative relationship with a number of pediatric centers around the country who are recognized for their ability to care for these medically complicated children and (2) to look back over the last seven years to identify factors that will identify those children who are not likely to be removed from supplemental nutrition, who will likely require an intestinal transplant, or who is likely to die.