MICA: Optimising brain protection and reducing birth asphyxia disability: safety and efficacy of early high dose MELATONIN and COOLING with late EPO

出生时的问题导致婴儿缺氧，会导致被称为新生儿脑病（NE）的大脑功能紊乱，这可能导致长期的脑损伤和脑瘫。事实证明，在婴儿出生后尽快将其降温3摄氏度，持续三天是安全的，可以长期保护大脑，甚至可以改善上学年龄的孩子的表现。为了防止死亡或残疾，需要冷却治疗的婴儿数量是6-7。冷却已得到国家临床卓越研究所（NICE）的认可，并在英国各地的新生儿重症监护病房采用，用于中度至重度新生儿NE。然而，尽管冷却是新生儿新生儿症的重要一步，44-53%的婴儿仍然有不良后果。在过去的5年里，研究已经在N Robertson （PI）和S Juul（共同申请人）的实验室进行。褪黑素和2。促红细胞生成素（Epo）；这些研究都表明，在冷却过程中加入其中一种药物是安全的，而且对动物（褪黑激素）和动物和婴儿（促生成素）的效果更好。这些药物作用于缺氧后损伤级联的不同部位：褪黑素是一种自然产生的激素，由松果体产生，在生理水平上控制昼夜循环。在较高的水平（血浆水平比正常夜间水平高10,000倍），褪黑素具有强大的非受体作用，可以清除有害的自由基。我们的研究表明，在受伤后尽快达到褪黑素的治疗范围对于获得最大的益处至关重要。我们与Chiesi制药公司的合作始于2013年，此前我们的初步研究显示，褪黑激素在缺氧后10分钟显著增强脑保护。Chiesi已经开发出一种新的褪黑素配方，对婴儿是安全的；这种新配方最近在我们的实验室进行了评估，并计算了在3小时而不是8小时达到治疗水平的褪黑激素的最佳速率和剂量。2. 促红细胞生成素（Epo）是一种最初因其刺激红细胞生成的作用而被发现的蛋白质。Epo具有脑保护、修复和再生的特性，在动物损伤后1周的亚急性期和在婴儿冷却后16.5小时开始时，Epo已被证明具有保护作用。S Juul一直是Epo脑保护领域的领导者，在剂量反应和安全性方面拥有独特的知识，是美国Epo脑保护的2项临床试验的PI。我们的目的是进行一项研究，以解决以下问题：在损伤后1小时早期给予优化的高剂量褪黑激素，并在恢复体温后24小时以更快的输注速率和晚促红细胞生成素相结合，是否比单独冷却更好地保护大脑？三联疗法（降温、褪黑素和促生成素）是否比双联疗法（降温发挥褪黑素或降温加促生成素）产生更好的保护作用？与我们之前的方案相比，在损伤后3小时达到治疗水平的优化高剂量褪黑素是否能改善保护作用，而我们之前的方案是在损伤后8小时达到治疗水平。我们将使用已建立的NE仔猪重症监护模型来解决这些问题。可以对仔猪进行重症监护和监测，其大小允许使用与婴儿相同的静脉注射线和导管，药物治疗都是基于新生儿重症监护病房的协议，仔猪大脑的成熟阶段与人类大脑相似，大脑生长在出生前后突增。我们使用与新生儿新生儿相同的3特斯拉MRI系统和相同的序列，使数据具有临床相关性和可翻译性。如果这些数据是积极的，将被转化为婴儿的临床试验，并可能导致显著的结果。

Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy (NE), which can result in long term brain damage and cerebral palsy. Cooling a baby by 3 degrees Celsius for three days as soon as possible after birth has been shown to be safe and leads to long term brain protection and improved outcome even to school age. The number of babies that need to be treated with cooling to prevent one from being dead or disabled is 6-7. Cooling has been endorsed by the National Institute for Clinical Excellence (NICE) and adopted in neonatal intensive care units around the UK for babies with moderate to severe NE. However, although cooling is a major step forward for babies with NE, 44-53% of babies still have adverse outcomes. Over the last 5 years, studies have been performed in the laboratory of N Robertson (PI) and S Juul (co-applicant) on 1. melatonin and 2. erythropoietin (Epo) respectively; these studies have both shown that adding one of these agents to cooling is safe and leads to better outcomes in animals (melatonin) and in animals and babies (Epo). These agents act at different parts of the cascade of injury after hypoxia: 1. Melatonin is a naturally occurring hormone produced by the pineal gland which entrains the day/night cycle at physiological levels. At higher levels (plasma levels 10,000 times higher than normal night time levels), melatonin has powerful non-receptor actions to scavenge damaging free radicals. Our studies have shown the critical importance of reaching the therapeutic range of melatonin as quickly as possible after the injury for most benefit. Our collaboration with the pharmaceutical company, Chiesi, started in 2013 following our initial study showing significant augmentation of brain protection with melatonin at 10 mins after hypoxia. Chiesi has developed a novel melatonin formulation which is safe for babies; this new formulation was assessed recently in our laboratory and the optimal rate and dosing of melatonin to achieve therapeutic levels at 3h rather than 8h has been calculated. 2. Epo is a protein originally identified for its role in stimulating red blood cell generation. Epo has brain protection and repair and regeneration properties and have been shown to be protective when starting in the subacute phase up to 1 week after the injury in animals and at 16.5 h in babies with cooling.S Juul has been a leader in the Epo brain protection field and has unique knowledge of dose response and safety and is PI on the 2 clinical trials of Epo brain protection in the USA. Our aim is to perform a study which addresses the following questions:1. Does the combination of an optimised high dose melatonin given early on at 1h after the injury and at a faster infusion rate and late Epo at 24h after rewarming lead to better brain protection than cooling alone (triple versus single therapy)2. Does triple therapy (Cooling, melatonin and Epo) lead to bettie protection than double therapy (Cooling play melatonin or cooling plus Epo)3. Does the optimised high dose melatonin with therapeutic levels achieved in 3h after injury lead to improved protection compared to our previous protocol where therapeutic levels were achieved at 8h after injury. We will use an established piglet intensive care model of NE to address these questions. Intensive care and monitoring can be given to the piglet, the size allows for the same intravenous lines and catheters to be used as in babies, the medications are all based on protocols from the NICU and the maturational stage of the piglet brain is similar to human brain with the brain growth spurt occurring around birth. We use the same 3 Tesla MRI system and same sequences as we do in babies with NE, making the data clinically relevant and translational. These data, if positive, will be translated to clinical trials in babies and could lead to significant benefit to outcomes.