Development and Testing of LUCID: A Therapeutic Device for Brain Injury Following Infant Cardiac Arrest

婴儿心脏骤停是一种医疗紧急情况，需要快速复苏以恢复循环。然而， 复苏往往会导致严重的脑损伤，由缺血/再灌注损伤引起。只有36%的婴儿 (1岁)因院外心脏骤停接受治疗，69%的院内心脏骤停婴儿 已成功复苏。这些婴儿目前没有限制脑损伤的治疗选择。海流 心脏骤停后脑损伤的标准治疗方法是治疗性低温。不幸的是，最近的研究 证明在儿童心脏骤停患者中使用治疗性低温并不能提供 显著的益处超过了控制常温所能达到的效果。一种安全有效的神经保护 专门针对再灌注损伤的干预将填补这些疾病治疗中尚未满足的关键需求 易受伤害的病人。 我们对线粒体的分子研究揭示了一种非侵入性调节线粒体的新方法 在再灌流期间发挥作用，减少心脏骤停复苏后的脑损伤。的确，我们的 研究首次：(I)确定了两个波长的近红外光(NIR)，具体和 通过作用于细胞色素c氧化酶(COX)可逆地减少线粒体的呼吸；(Ii)证明 NIR在复氧时应用，对婴幼儿啮齿动物和猪模型具有神经保护作用 心脏骤停/复苏；以及(3)开发了一种能够提供治疗剂量的近红外传输系统 适用于1岁以下的儿童。基于这些数据，我们建议利用COX- 抑制装置(LUID)，一种将安全地向婴儿大脑提供治疗性近红外的医疗装置。至 为了实现这一目标，第一阶段将在3个实验目标中重点开发和验证Lucid： ·开发临床使用的Lucid工程(目标1)。 ·评价LULID的安全性和有效性(目标2)。 ·LUID临床试验开发以及HUD和IDE批准(目标3)。 二期将利用LICID临床设备，实施“婴儿心脏骤停的LUID治疗” (LUTICA)临床试验(目标4)。 该提案结合了多学科的专业知识、令人信服的初步数据和最先进的资源 提供给我们的团队，以解决高度脆弱的患者群体中的重大健康问题。

Cardiac arrest in infants is a medical emergency requiring rapid resuscitation to restore circulation. However, resuscitation often results in significant brain injury, caused by ischemia/reperfusion injury. Only 36% of infants (<1yr old) treated for out-of-hospital cardiac arrest and 69% of infants that suffer in-hospital cardiac arrest are successfully resuscitated. These infants currently have no therapeutic options to limit brain injury. The current standard treatment for post-cardiac arrest brain injury is therapeutic hypothermia. Unfortunately, recent studies demonstrated that use of therapeutic hypothermia in pediatric cardiac arrest patients does not provide significant benefit beyond what is achieved with controlled normothermia. A safe and effective neuroprotective intervention that specifically targets reperfusion injury would fill a critical unmet need in the treatment of these vulnerable patients. Our molecular studies on mitochondria uncovered a novel method to non-invasively modulate mitochondrial function during reperfusion and reduce brain injury following resuscitation from cardiac arrest. Indeed, our studies have, for the first time: (i) identified two wavelengths of near infrared light (NIR) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase (COX); (ii) documented that NIR, applied at the time of reoxygenation, is neuroprotective in rodent and swine models of infant and pediatric cardiac arrest/resuscitation; and (iii) developed a NIR-delivery system capable of providing therapeutic doses to patients up to 1 year old. Based on these data, we propose to produce the clinical Light Utilizing COX- Inhibitory Device (LUCID), a medical device that will safely deliver therapeutic NIR to the infant brain. To achieve this goal, Phase I will focus on device development and validation of LUCID in 3 experimental aims: • Develop LUCID engineered for clinical use (Aim 1). • Evaluate safety and efficacy of LUCID (Aim 2). • LUCID clinical trial development and HUD and IDE approval (Aim 3). Phase II will utilize the LUCID clinical device and execute the “LUCID Therapy for Infant Cardiac Arrest” (LUTICA) clinical trial (Aim 4). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our team to address a significant health problem in a highly vulnerable patient population.