THAPCA Trials - Scientific Application

描述(由申请人提供)： 心肺骤停(CA)是一种悲剧性事件，在所有年龄段中通常与高死亡率和低生活质量结局相关。在CA中幸存下来的儿童通常会遭受神经损伤，这可能会导致对所有方面的护理依赖多年。儿童CA的病理生理学和预后在发生在医院外(OH)和院内(IH)之间有很大的不同，通常发生在健康儿童中，而发生在医院内(IH)通常发生在有复杂潜在疾病的儿童中。对于维持儿童CA的两组患者来说，都非常需要神经保护性治疗。最近，具有里程碑意义的RCT在患有OH室颤或心动过速相关CA的成人和出生相关的缺氧缺血性脑病的新生儿中被证明，如果在恢复自主循环或出生的六小时内开始治疗，那么经过治疗的低温(TH)可以改善存活率和良好的神经预后。然而，CA的病因和病理生理学在不同年龄组之间存在重大差异，新生儿和成人的结果不能推断为儿童。尚未在儿童(非新生儿)CA人群中进行TH随机对照试验。现在迫切需要随机对照试验来指导儿科实践。我们的研究团队自2002年以来一直合作，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，进行儿童心脏骤停后治疗性低温(THAPCA)试验。THAPCA试验的主要目标将是确定TH是否改善了在OH(THAPCA-OH试验)和IH(THAPCA-IH试验)环境下CA术后复苏的儿童的存活率和良好的神经行为结果。Vineland适应行为量表将被用作评估幸存者神经行为结果的主要指标。次要终点包括CA后12个月的存活率、神经行为功能从停搏前基线到12个月测量的变化，以及CA后12个月的神经心理和神经异常评分。我们还将通过评估CA后7天内全因28天死亡率、感染发生率、心律失常和血液制品给药来确定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烯醇化酶(NSE)、磁共振成像(MRI)和脑电(EEG)，并将收集参与试验的受试者的DNA。DNA将被储存在一个储存库中，用于未来的研究，以确定可能与缺氧缺血性损伤的敏感性和/或对治疗低温的反应性改变相关的基因多态性。THAPCA试验将是对儿童具有重要公共卫生适用性的开创性研究。THAPCA将确定THAPCA是否能改善在OH或IH环境中持续CA的儿童的存活率和良好的功能结果。THAPCA与NHLBI的使命高度相关，是对NHLBI复苏结果联盟(ROC)的补充。THAPCA将通过开展与儿童CA有关的第一次重大随机对照试验来解决知识方面的严重差距。儿童心脏骤停是一种悲惨的事件，通常会导致死亡或严重的脑损伤。THAPCA试验将确定心脏骤停儿童的全身降温是否会导致更好的生存和更少的脑损伤。

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.