Planning a Multicenter Cooling Trial for Hyperammonemic Metabolic Crises

规划针对高氨代谢危机的多中心冷却试验

• 批准号: 8445667
• 负责人: Uta Lichter-Konecki
• 金额: $ 16.92万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445667
• 关键词: Acute Liver Failure; Acute Lung Injury; Adult; Ammonia; Biological Markers; Cessation of life; Child; Child Mortality; Childhood; Chronic; Clinical Research; Clinical Trials; Clinical Trials Design; Collection; Coma; Complex; Consensus; Critical Care; Data; Development; Developmental Disabilities; Disease; Encephalopathies; Ensure; Environment; Funding; Future; Grant; Heart Arrest; Hemodialysis; Hyperammonemia; Infant; Institutional Review Boards; Intellectual functioning disability; Intensive Care; Intervention; Logistics; Magnetic Resonance Imaging; Manuals; Medical; Medical center; Medicine; Metabolic; Metabolism; Monitor; Multicenter Trials; National Institute of Child Health and Human Development; Neonatal; Neonatology; Nephrology; Nervous System Trauma; Neurologic; Neurology; Newborn Infant; Organ Transplantation; Outcome; Patients; Pilot Projects; Population Study; Procedures; Protocols documentation; Quality of life; Randomized Clinical Trials; Randomized Controlled Trials; Rare Diseases; Renal Replacement Therapy; Reporting; Research; Research Personnel; Retrospective Studies; Risk; Safety; Sepsis; Site; Solid; Specialist; Structure; Survivors; System; Testing; Therapeutic; Therapy Clinical Trials; Treatment Protocols; United States National Institutes of Health; Work; Writing; base; data management; disability; evidence base; improved; interest; liver transplantation; meetings; mortality; natural hypothermia; neonate; neuroimaging; novel; operation; public health relevance; standard of care; tertiary care; urea cycle

DESCRIPTION (provided by applicant): The objective of this R34 proposal is to develop a protocol and manual of procedures for the conduct of a randomized clinical trial of therapeutic hypothermia as adjunct therapy in young children with hyperammonemia associated encephalopathy resulting from urea cycle disorders (UCDs) or organic acidemias (OAs). Consensus across sites will be critical for uniformity of treatment in these rare and very complex patients in the trial. During this one year grant we will work to build consensus across the 19 participating sites regarding the overall treatment protocol for these children that will have at is core adjunct hypothermia, metabolic and renal replacement therapy. We will then finalize the protocol and write the Manual of Procedures (MOP). We will also standardize the collection of advanced neuroimaging data across sites so that their utility as biomarkers for outcome can be tested during the trial. Newborns with hyperammonemia (HA) associated encephalopathy and UCDs or OAs are at great risk for neurological injury, developmental disability, and death. In the 1980s the mortality of neonates that presented with HA and in coma due to complete blocks in the urea cycle approached 50%, despite aggressive treatment with hemodialysis. Of the surviving children on therapy, 79% had one or more developmental disability. The degree of disability was significantly correlated to the duration of neonatal coma. Similarly, the mortality f neonatal OAs with HA associated encephalopathy was 33% and higher. The introduction of ammonia scavenger therapy for the chronic treatment of UCDs in 1987 improved outcome of long-term treatment for patients with urea cycle disorders. However, despite advances in intensive care and hemodialysis, over the subsequent decade mortality of children with severe UCDs or OAs still exceeded 50% for an initial hyperammonemic crisis at a major tertiary care medical center between 1991 and 2000 and more than 40% of survivors showed considerable intellectual disability. Thus, for neonates or young infants with the most severe forms of UCDs and OAs to truly benefit from the advances in long-term treatment and from liver transplant and to have a better quality of life, a novel, neuroprotective intervention is needed to improve the outcome of the initial crisis. Based on the results of small clinical studies, therapeutic hypothermia (TH) may constitute such a neuroprotective therapy. It is important to investigate its efficacy for HA associated encephalopathy definitively before it becomes common practice that is not evidence-based. Testing this in a well defined group of patients should allow to draw conclusions for other patients with HA associated encephalopathy. The purpose of the future randomized controlled trial will be to assess the efficacy and safety of whole body TH as adjunct neuroprotective therapy to standard of care treatment of neonates and young infants with HA associated encephalopathy.

描述（由申请人提供）：本R34提案的目的是制定一项治疗性低温作为尿素循环障碍（UCDs）或有机酸血症（OAs）引起的高氨血症相关脑病的随机临床试验的方案和程序手册。在这些罕见和非常复杂的患者的试验中，跨站点的共识对于治疗的一致性至关重要。在这一年的拨款中，我们将努力在19个参与地点就这些儿童的整体治疗方案达成共识，这些治疗方案将以低温、代谢和肾脏替代治疗为核心。然后我们将最终确定协议并编写程序手册（MOP）。我们还将标准化各站点的高级神经成像数据收集，以便在试验期间测试其作为结果生物标志物的效用。患有高氨血症（HA）相关脑病和ucd或oa的新生儿发生神经损伤、发育残疾和死亡的风险很大。在20世纪80年代，尽管进行了积极的血液透析治疗，但由于尿素循环完全阻断而出现血凝素和昏迷的新生儿死亡率仍接近50%。在接受治疗的幸存儿童中，79%患有一种或多种发育障碍。残疾程度与新生儿昏迷持续时间显著相关。同样，新生儿OAs合并HA相关脑病的死亡率为33%或更高。1987年引入氨清除剂治疗慢性ucd，改善了尿素循环障碍患者长期治疗的结果。然而，尽管在重症监护和血液透析方面取得了进展，在随后的十年中，1991年至2000年期间，在一家主要三级医疗中心，严重ucd或OAs患儿的死亡率仍然超过50%，超过40%的幸存者表现出相当程度的智力残疾。因此，对于最严重形式的ucd和oa的新生儿或年幼婴儿来说，要真正从长期治疗和肝移植的进步中受益，并获得更好的生活质量，需要一种新的神经保护干预措施来改善初始危机的结果。基于小型临床研究的结果，治疗性低温（TH）可能构成这样一种神经保护疗法。重要的是，在其成为无证据的常规做法之前，明确调查其对HA相关脑病的疗效。在一组明确的患者中进行测试，应该可以为其他HA相关脑病患者得出结论。未来的随机对照试验的目的是评估全身TH作为新生儿和年幼婴儿血凝素相关脑病标准护理治疗的辅助神经保护治疗的有效性和安全性。