Perinatal Brain Injury: Potential of Innovative NIRS to Optimize Hypothermia

描述（由申请人提供）：由于缺氧缺血引起的新生儿脑病（NE）是一个主要的公共卫生问题，因为它发生在每1000个足月活产婴儿中，并且具有毁灭性的后果。许多受影响的新生儿患有终身运动障碍和癫痫，但越来越多的认知和行为障碍的高患病率正在得到重视。在缺氧缺血时，血液和氧气输送减少，随后是再灌注，并伴有短暂的能量恢复。接下来是一个“机会之窗”，其中兴奋性毒性和相关的脑代谢增加最终导致二次能量衰竭和不可逆转的细胞死亡。在这个窗口，治疗性低温（TH）是目前唯一有效的治疗方法。TH的作用主要是通过降低脑代谢，从而保持能量储存。尽管目前脑损伤检测的金标准是磁共振成像（MRI），但MRI作为一种筛查工具是不切实际的，也不能提供床边监测来优化个体对治疗的反应。市售的连续波（CW）近红外光谱（NIRS）系统提供了脑氧饱和度（SO2）的床边测量，但SO2不能单独评估氧代谢，因为氧输送没有考虑在内。我们需要的是一种能够监测脑代谢的床边工具，以检测代谢的升高，这表明正在发生的缺氧缺血性损伤，以及代谢的降低，这表明对治疗有反应。脑氧消耗（cro2）是脑代谢的直接指标，因此我们建议使用频域近红外光谱（FDNIRS）和漫射相关光谱（DCS）的创新组合在床边测量cro2指数。我们的初步研究表明，有围产儿脑损伤MRI证据的新生儿cmoro2升高，并证实经甲状肾上腺素治疗的新生儿cmoro2明显低于正常对照组。根据这些令人兴奋的结果，并响应RFA PAR-10-230“新生儿可筛查疾病的创新疗法和工具”，我们现在提出一项可行性研究，以确定FDNIRS-DCS是否可以筛查累及，评估对治疗的反应，并预测需要早期筛查和立即干预的最大新生儿群体之一的结果：新生儿脑病。为了评估早期结果，我们提出了一种创新的方法，结合先进的神经行为测试、区域FDNIRS-DCS测量和使用无镇静情况下获得的MRI定量分析。如果我们的假设被证明是正确的，我们将准备确定FDNIRS-DCS提供的cmor2床边指标是否可以优化新生儿个体的TH，从而改善神经发育结局。在这一阶段的成功也将允许探索FDNIRS-DCS的潜力，以确定新出现的NE新疗法的额外益处，并筛查其他可治疗的新生儿疾病。

DESCRIPTION (provided by applicant): Neonatal encephalopathy (NE) due to hypoxia-ischemia is a major public health concern as it occurs in 6/1000 live term births and has devastating consequences. Many affected neonates suffer lifelong motor disabilities and epilepsy, but increasingly the high prevalence of cognitive and behavioral disabilities is becoming appreciated. In hypoxia-ischemia there is a decrease in blood and oxygen delivery, followed by reperfusion with transient energy recovery. What follows is a "window of opportunity" where excitotoxicity and associated increased cerebral metabolism eventually lead to secondary energy failure and irreversible cell death. In this window, therapeutic hypothermia (TH) is currently the only treatment available with proven efficacy. TH acts primarily by decreasing cerebral metabolism, thus preserving energy stores. Although the current gold standard for brain injury detection is magnetic resonance imaging (MRI), MRI is impractical as a screening tool and cannot provide bedside monitoring to optimize individual responses to therapies. Commercially available continuous wave (CW) near infrared spectroscopy (NIRS) systems provide bedside measures of cerebral oxygen saturation (SO2) but SO2 alone cannot assess oxygen metabolism, as oxygen delivery is not taken into account. What is needed is a bedside tool that can monitor cerebral metabolism to detect elevations in metabolism that suggest evolving hypoxic-ischemic injury, and decreases in metabolism that suggest response to therapy. Cerebral oxygen consumption (CMRO2) is a direct measure of cerebral metabolism and therefore we propose to measure an index of CMRO2 at the bedside using the innovative combination of Frequency Domain Near-Infrared Spectroscopy (FDNIRS) and Diffuse Correlation Spectroscopy (DCS). Our initial studies show that CMRO2 is elevated in neonates with MRI evidence of perinatal brain injury, and confirm that neonates on TH have significantly lower CMRO2 than normal controls. Following these exciting results, and in response to the RFA PAR-10-230 "Innovative Therapies and Tools for Screenable Disorders in Newborns" we now propose a feasibility study to determine if FDNIRS-DCS can screen for involvement, assess response to treatment, and predict outcomes in one of the largest neonatal populations requiring early screening and immediate intervention: neonatal encephalopathy. To assess early outcomes we propose an innovative combination of advanced neurobehavioral testing, regional FDNIRS-DCS measures and quantitative MRI analysis using MRIs obtained without sedation. If our hypotheses prove true, we will be poised to determine if bedside indices of CMRO2 provided by FDNIRS-DCS can optimize TH for individual neonates, thereby improving neurodevelopmental outcomes. Success at this stage will also allow exploration of the potential for FDNIRS-DCS to determine the additional benefits of emerging new treatments for NE and to screen for other treatable neonatal disorders.