Is ischaemic post-conditoning neuroprotective following perinatal asphyxia?

研究背景在英国，每1000名足月新生儿中就有1-2人在分娩期间出现导致缺氧(出生窒息)和随后的脑损伤(新生儿脑病)的问题。尽管治疗性低温最近在发达国家在这一领域取得了重大进展，但它只为那些降温的婴儿提供了大约50%的脑保护。因此，开发新的、非侵入性的方法是一个重要的未得到满足的需求，这种方法可以单独使用或与低温联合使用，以增强对新生儿脑病的神经保护。目前还没有其他技术或其他治疗方法来满足这一未得到满足的需求。我们建议远程缺血后处理(IPostC)可以满足这一需要。IPostC诞生于1986年首次描述的预适应的概念，其优势在于不需要事先了解缺血损伤，因此临床翻译更远。缺血-再灌注损伤是一种广泛发生在临床场景中的现象，即组织的血液供应中断，然后恢复。矛盾的是，对组织造成重大损害的是再灌注，而不是缺血。然而，在所有哺乳动物物种中都进化出了一种针对缺血再灌注损伤的强大的先天保护机制。短暂、短暂的缺血发作可以保护长时间的致死性缺血，这些发作可以在再灌流期间或指标缺血后的最初几个小时进行。短暂的短暂发作如果在非重要器官上进行也是有效的，例如远离受影响器官的肢体，这构成了远程IPostC的基础。我们将使用磁共振波谱(脑乳酸/N乙酰天冬氨酸水平)作为IPostC益处的替代指标，无论是否有低温-这与新生儿用于预测结果的替代措施相同。我们将使用近红外光谱来检测IPostC期间的脑氧合作用。这种多模式成像使该模型独一无二，是了解IPostC疗效以及机制和生理效应的重要资源。目的和目的建议在大型动物模型中测试远程IPostC。主要目的是确定：1.复苏时远程IPostC是否保护大脑2。如果复苏后延迟3小时的远程IPostC保护大脑3。如果远程IPostC(即时和延迟)增强了低温神经保护4。IPostC的信号通路、低温以及IPostC和低温之间的相互作用5.IPostC的血流动力学和代谢效应潜在的应用和益处成功完成这个项目将使我们能够直接进行人体概念验证研究，因为不需要毒理学研究。在临床环境中，远程IPostC将包括在婴儿出生后短暂地将袖带膨胀到收缩压以上的婴儿双腿周围。这类似于在几个场合测量血压，并将充气的袖口保持几分钟。通过这样做，这种非致命性的缺血被认为可以激活内源性神经保护通路，如抗凋亡蛋白，减少自由基的产生，减弱充血反应和改善脑血流。将这项技术引入NHS将解决NHS四大优先事项中的两个(心脏病、癌症、儿童和产妇)。IPostC可能成为一种简单的复苏治疗方法，可以减少出生窒息后的不良后果。IPostC还可以增强低温神经保护，这已被引入为出生时出现脑病的婴儿的当前护理标准。此外，在体温过低或不安全的地方或情况下也可以使用这项技术。

Context of the researchProblems during birth leading to a lack of oxygen (birth asphyxia) and subsequent brain injury (neonatal encephalopathy) occur in 1-2 per 1000 full term births in the UK. Although therapeutic hypothermia has recently been a significant advance in this field in the developed world, it provides brain protection only to ~50% of those infants cooled. There is therefore a significant unmet need to develop novel, non-invasive approaches, which can be used alone or in combination with hypothermia to augment neuroprotection for neonatal encephalopathy. Currently there are no other technologies or other therapeutic approaches to address this unmet need. We propose that remote ischemic post-conditioning (IPostC) would meet this need. Born from the concept of pre-conditioning first described in 1986, IPostC is advantageous in that prior knowledge of the ischemic insult is not required and thus clinical translation is more far reaching.Ischaemia-reperfusion injury is a widespread phenomenon that occurs in clinical scenarios where blood supply to tissue is interrupted and then restored. Paradoxically, it is reperfusion rather than ischaemia that causes major damage to tissue. There is, however, a powerful innate protective mechanism against ischemia-reperfusion injury that has evolved in all mammalian species. Brief, transient episodes of ischemia protect against a prolonged period of lethal ischaemia and these episodes can be performed during reperfusion or the first few hours after the index ischaemia. The brief transient episodes are also effective if performed on a non-vital organ such as a limb remote to the affected organ, which forms the basis for remote IPostC.We will use magnetic resonance spectroscopy (brain lactate /N acetyl aspartate levels) as a surrogate marker of the benefit of IPostC with and without hypothermia - the same surrogate measure used in newborn infants to predict outcome. We will use near infrared spectroscopy to examine brain oxygenation during IPostC. Such multi-modal imaging makes the model unique and a significant resource for understanding efficacy as well and mechanistic and physiological effects of IPostC.Aims and ObjectivesThe proposal is to test remote IPostC in a large animal model. The main aims are to determine:1. if remote IPostC at resuscitation protects the brain2. if remote IPostC with a delay of 3h after resuscitation protects the brain3. if remote IPostC (both immediate and delayed) augments hypothermic neuroprotection4. signalling pathways of IPostC, hypothermia and the interaction between IPostC and hypothermia 5. haemodynamic and metabolic effects of IPostCIts potential applications and benefitsSuccessful completion of this project will enable us to proceed directly to a human proof of concept study since there are no toxicology studies needed. In the clinical setting, remote IPostC would involve inflating a cuff to supra-systolic pressure briefly around both lower limbs of the infant after birth. This is analogous to taking the blood pressure on several occasions and holding the cuff inflated for minutes. By doing so, this non-fatal ischaemia has been suggested to activate endogenous neuroprotective pathways, such as anti-apoptotic proteins, reduction in free radical production, attenuation of the hyperaemic response and improvement in cerebral blood flow. The introduction of this technology to NHS will address two of the top four priorities of NHS (heart disease, cancer, children and maternity). IPostC may become a simple treatment at resuscitation that reduces adverse outcome following birth asphyxia. IPostC may also augment hypothermic neuroprotection, which has been introduced as the current standard of care for infants presenting with encephalopathy at birth. Moreover, it would also be possible to use this technology in places or situations where hypothermia is not available or safe.