Planning a Multicenter Cooling Trial for Hyperammonemic Metabolic Crises

描述(由申请人提供)：这份R34提案的目标是制定一项程序方案和程序手册，用于对尿素循环障碍(UCDs)或有机酸血症(OAS)引起的高氨血症相关性脑病的幼儿进行治疗性低温作为辅助治疗的随机临床试验。对于试验中这些罕见和非常复杂的患者的统一治疗，跨地点的共识将是至关重要的。在这一年的资助期间，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，这些方案将包括核心辅助降温、代谢和肾脏替代疗法。然后我们将最后确定协议并编写程序手册(MOP)。我们还将标准化收集跨地点的高级神经成像数据，以便在试验期间测试它们作为结果生物标记物的效用。患有高氨血症(HA)相关性脑病和UCDS或OAS的新生儿有很大的神经损伤、发育障碍和死亡的风险。在20世纪80年代，尽管积极地进行血液透析治疗，但因尿素循环完全阻断而出现HA和昏迷的新生儿的死亡率接近50%。在接受治疗的幸存儿童中，79%有一种或多种发育障碍。残疾程度与新生儿昏迷时间显著相关。同样，新生儿OAS合并HA相关性脑病的死亡率为33%或更高。1987年引入氨清除剂疗法用于UCDS的慢性治疗，改善了尿素循环障碍患者的长期治疗结果。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，患有严重UCDS或OAS的儿童在1991年至2000年期间在一家主要的三级保健医疗中心发生的最初高氨危象中的死亡率仍超过50%，超过40%的幸存者表现出相当大的智力残疾。因此，对于患有最严重形式的UCDS和OAS的新生儿或婴儿来说，要真正受益于长期治疗和肝移植的进步，并获得更好的生活质量，需要一种新颖的神经保护干预措施，以改善最初危机的结果。根据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。在它成为非循证的普遍做法之前，研究它对HA相关性脑病的疗效是很重要的。在一组定义明确的患者中进行测试，应该可以为其他HA相关性脑病患者得出结论。未来随机对照试验的目的将是评估全身TH作为辅助神经保护治疗对新生儿和婴幼儿HA相关性脑病的标准护理治疗的有效性和安全性。

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.