THAPCA Trials - Scientific Application

描述（由申请人提供）： 心脏骤停（CA）是一种悲剧性事件，在所有年龄组中通常与高死亡率和低生活质量结局相关。CA幸存的儿童通常会遭受神经损伤，这可能导致多年的所有方面的护理依赖。儿科CA的病理生理学和结局在院外（OH）（通常发生在健康儿童中）和院内（IH）（通常发生在患有复杂基础疾病的儿童中）之间存在很大差异。对于患有小儿CA的两组患者，都非常需要神经保护治疗。最近，在OH室颤或心动过速相关CA的成人和出生相关缺氧缺血性脑病的新生儿中进行的具有里程碑意义的RCT表明，在自主循环恢复或出生后6小时内开始治疗性低温（TH）后，生存率提高，神经功能结局良好。然而，不同年龄组CA的病因学和病理生理学存在重大差异，新生儿和成人的结果不能外推至儿童。尚未在儿童（非新生儿）CA人群中进行TH的RCT。现在迫切需要RCT来指导儿科实践。自2002年以来，我们的研究团队一直在一起工作，并将两个联邦资助的儿科临床研究网络（PECARN和CPCCRN）聚集在一起，进行儿科心脏骤停后的治疗性低温（THAPCA）试验。THAPCA试验的主要目的是确定TH是否改善了OH（THAPCA-OH试验）和IH（THAPCA-IH试验）环境中CA后复苏的儿童的生存率和良好的神经行为结局。Vineland适应行为量表将用作评估幸存者神经行为结局的主要指标。次要终点包括CA后12个月的生存率、从停搏前基线到12个月测量的神经行为功能变化以及CA后12个月的神经心理学和神经学异常评分。我们还将通过评估CA后7天内全因28天死亡率、感染、心律失常和血液制品给药的发生率来确定TH的安全性。最后，我们将分析脑损伤的替代指标，包括血清神经元特异性烯醇化酶（NSE）、磁共振成像（MRI）和脑电图（EEG），并将收集试验受试者的DNA。DNA将储存在储存库中，用于未来的研究，以确定可能与缺氧缺血性损伤易感性和/或治疗性低温反应性改变相关的遗传多态性。THAPCA试验将是具有重要公共卫生适用性的开创性研究。THAPCA将确定TH是否能改善OH或IH环境下持续CA的儿童的生存率和良好的功能结局。THAPCA与NHLBI的使命高度相关，并补充了NHLBI复苏结果联盟（ROC）。THAPCA将通过开展第一个与儿童CA相关的主要RCT来解决知识方面的关键差距。儿童心脏骤停是一种悲剧性事件，通常会导致死亡或严重脑损伤。THAPCA试验是一项研究，将确定心脏骤停儿童的全身冷却是否会导致更好的生存率和更少的脑损伤。

DESCRIPTION (provided by applicant): Cardiopulmonary arrest (CA) is a tragic event that is often associated with high mortality and poor quality of life outcome in all age groups. Children who survive CA commonly sustain neurological injury that potentially results in many years of dependency for all aspects of care. The pathophysiology and outcome of pediatric CA differs greatly between those that occur out-of-hospital (OH), commonly in healthy children, and those that occur in-hospital (IH), typically in children with complex underlying disorders. There is a great need for neuroprotec- tive therapies for both groups sustaining pediatric CA. Recently, landmark RCTs in adults with OH ventricular fibrillation or tachycardia associated CA and in newborns with birth associated hypoxic ischemic encephalopathy have demonstrated improved survival with good neurological outcome after therapeutic hypothermia (TH) when initiated within six hours of return of return of spontaneous circulation or birth. There are, however, major differ- ences in the etiology and pathophysiology of CA across age groups, and results in neonates and adults cannot be extrapolated to children. No RCT of TH has been performed in the pediatric (non-newborn) CA population. RCTs are now urgently needed to guide pediatric practice. Our investigative team has worked together since 2002 and has brought together two federally funded pediatric clinical research networks (PECARN and CPCCRN) to conduct the Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Trials. The primary objective of the THAPCA Trials will be to determine if TH improves survival with good neurobehavioral outcome in children who have been resuscitated after CA in the OH (THAPCA-OH Trial) and IH (THAPCA-IH Trial) settings. The Vineland Adaptive Behavior Scales will be used as the primary measure to assess neurobehavioral outcome in survivors. Secondary endpoints include survival at 12 months post CA, change in neurobehavioral function from pre-arrest baseline to the 12-month measurement, and neuropsychological and neurological abnormality scores at 12 months post CA. We will also determine the safety of TH by assessing all-cause 28-day mortality, incidence of infections, arrhythmias, and blood product administration within 7 days of CA. Finally, we will analyze surrogate indicators of brain injury including serum neuron specific enolase (NSE), magnetic resonance imaging (MRI), and electroencephalograms (EEG), and will collect DNA from subjects enrolled in the trials. DNA will be stored in a repository for future studies to identify genetic polymorphisms that may be associated with altered suscep- tibility to hypoxic-ischemic injury and/or responsiveness to therapeutic hypothermia. The THAPCA Trials will be seminal studies with important public health applicability in children. THAPCA will establish whether TH results in improved survival with good functional outcome in children who have sustained CA in the OH or IH setting. THAPCA is highly relevant to the mission of the NHLBI, and complements the NHLBI Resuscitation Outcomes Consortium (ROC). THAPCA will address critical gaps in knowledge by conducting the first major RCT related to CA in childhood. Cardiac arrest in children is a tragic event that often results in death or severe brain injury. The THAPCA Trials are studies that will determine whether whole body cooling of children who have had cardiac arrest will result in better survival and less brain injury.