Neonatal Hypoxic Ischemic Encephalopathy: Potential of Innovative NIRS to Optimize Hypothermia

项目概要/摘要 新生儿缺氧缺血性脑病（HIE）是围产期死亡和长期发病的主要原因，影响1- 5/1000活产。缺氧缺血性损伤（HII）通过一系列持续的神经元损伤导致HIE 几小时到几天治疗性低温（TH）证明，HII引起的脑损伤是可以避免的， 治疗HIE。尽管TH取得了成功，但仍迫切需要进一步的改进，因为高达63%的婴儿仍然 死亡或有长期认知缺陷。此外，治疗指南是高度主观的，没有共识 什么时候治疗轻度HIE我们的第一个前提是，不良后果是由于持续的神经元损伤后， HII.由于神经元是氧的主要消耗者，因此脑氧代谢（CMRO 2）的测量将 提供了一种监测神经元健康和损伤演变的潜在手段。我们的第二个前提是， 血液动力学不稳定通过继发性神经元损伤导致不良结果。继发性损伤 可以通过床边脑血流量（CBF）测量来预防，以确保大脑的代谢需求 得到满足。事实上，直接CBF测量能够评估脑自动调节（CA）和神经血管 耦合（NVC），反映血流动力学的稳定性。床旁测量CMRO 2和CBF可以使 治疗优化，以防止继发性损伤，并告知治疗决定。在R 01 HD 076258中，我们的 主要成就是执行>500频域近红外光谱和扩散相关光谱（FDNIRS- DCS）测量，表明常规床旁直接测量CBF CMRO 2是可能的。我们的主要发现是，TH后几天的CMRO 2是唯一的早期预测因子。 结果，CMRO 2越高（r=0.62，P=0.002）， 贝利婴儿发育量表第三版（BSID-3）。我们的续约目标是尽早、持续地 床旁监测CMRO 2和CBF，证明其作为生命体征的潜力，目的有三：目的1： 扩展当前基础设施，实现新生儿CBF和CMRO的连续、实时床旁监测2 在100 Hz时，与其他临床监护仪的数据集成。目的2：在新生儿缺氧缺血性脑病中， TH期间的CMRO 2、CA和NVC及其与TH后CMRO 2的相关性;验证TH后CMRO 2 预测2年的结果。目的3：在对照组和有HIE风险但不符合TH标准的新生儿中， 在最初24小时内确定CMRO 2、CA和NVC;确定第1天CMRO 2是否预测2年结局。在 在第一笔赠款中，我们证明了CBF和CMRO 2的床边测量是可行的，并发现， TH后CMRO 2预测结果。在这次更新中，我们建议将CMRO 2和CBF变成早期的，连续的， 实时的床旁生命体征我们的目标是确定是否有神经元损伤的证据（CMRO 2降低） 由脑血流动力学不稳定（受损的CA和NVC）介导。如果成功，CMRO 2和CBF 监测可以通过在治疗期间实现血液动力学稳定性的医学优化来改善新生儿结局。 TH以及筛查可能受益于TH的新生儿HIE风险。

PROJECT SUMMARY/ABSTRACT Hypoxic ischemic encephalopathy (HIE), a major cause of perinatal mortality and long-term morbidity, affects 1- 5/1000 live births. Hypoxic ischemic insults (HII) lead to HIE through a cascade of neuronal injury that continues for hours to days. Therapeutic hypothermia (TH) proved that brain injury from HII can be avoided, revolutionizing treatment of HIE. Despite TH success, additional improvements are urgently needed as up to 63% of infants still die or have long term cognitive deficits. Also, guidelines for treatment are highly subjective, with no consensus on when to treat mild HIE. Our first premise is that adverse outcomes are due to ongoing neuronal injury after HII. As neurons are the primary consumer of oxygen, measures of cerebral oxygen metabolism (CMRO2) would provide a potential means to monitor neuronal health and the evolution of injury. Our second premise is that hemodynamic instability contributes to adverse outcomes through secondary neuronal injury. Secondary injury may be preventable with bedside measures of cerebral blood flow (CBF) to ensure the brain’s metabolic needs are met. In fact, direct CBF measures enable assessment of cerebral autoregulation (CA) and neurovascular coupling (NVC), which reflect hemodynamic stability. Bedside measures of CMRO2 and CBF could enable treatment optimization to prevent secondary injury and inform decisions on who to treat. In R01HD076258, our major achievement was performing >500 Frequency-Domain NIRS and Diffuse Correlation Spectroscopy (FDNIRS- DCS) measurements in >100 neonates with HIE, demonstrating that routine direct bedside measurement of CBF and CMRO2 are possible. Our major finding is that CMRO2 in the days after TH was the only early predictor of outcome, with higher CMRO2 strongly associated (r=0.62, P=0.002) with better 18-month cognitive scores of Bayley Scales of Infant Development 3rd edition (BSID-3). Our renewal goal is to perform early, continuous bedside monitoring of CMRO2 and CBF, demonstrating their potential as vital signs with three aims: Aim 1: Extend current infrastructure to enable continuous, real-time bedside monitoring of neonatal CBF and CMRO2 at 100Hz, integrated with data from other clinical monitors. Aim 2: In neonates with HIE, determine evolution of CMRO2, CA and NVC during TH and their association with post-TH CMRO2; validate that post-TH CMRO2 predicts 2-year outcome. Aim 3: In controls and neonates at risk for HIE but not meeting criteria for TH, determine CMRO2, CA and NVC during the first 24 hours; determine if day 1 CMRO2 predicts 2-year outcome. In the first grant, we demonstrated that bedside measures of CBF and CMRO2 are feasible and discovered that CMRO2 after TH predicts of outcome. In this renewal, we propose to turn CMRO2 and CBF into early, continuous, real-time, bedside vital signs. Our goal is to determine if there is evidence of neuronal injury (decreased CMRO2) mediated by cerebral hemodynamic instability (impaired CA and NVC). If successful, CMRO2 and CBF monitoring may improve neonatal outcomes by enabling medical optimization of hemodynamic stability during TH as well as to screen for neonates at risk for HIE who may benefit from TH.