Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest

使用深低温（<20°C）进行脑保护开创了安全有效的现代时代 心脏和主动脉的手术在很大程度上，由于先进的循环管理策略， 利用深低温停循环对近端主动脉和主动脉弓的手术已经稳步增加 在过去的十年里。尽管取得了这些进展，但神经系统并发症仍然是一个令人清醒的限制。的确， 7%-13%的患者患有永久性神经功能障碍。此外，术后认知能力下降 （POCD）发生在36%的心脏手术患者术后6周，重要的是，持续42%的 患者术后5年，生活质量下降。尽管深度低温已经成为 几十年来，在需要循环停止的成人患者中，中度低温是护理标准， 通常用于许多中心。然而，这种向中等温度的过渡完全是基于 没有充分评估神经或神经认知结果的观察性研究。 对病人或病人家属来说，没有什么比一次成功的手术更具有毁灭性的了。 生活，但复杂的认知障碍，导致生活质量下降和功能丧失， 依赖我们的多学科神经病学结果研究小组的长期目标是了解 心脏手术后神经和神经认知功能障碍的潜在机制，并减少 这些毁灭性的后果。在拟议的研究中，我们将测试我们的假设，深hypo- 手术循环停止期间的体温（<20°C）限制了POCD，并将大脑连接保持在更高水平。 低温（20.1 °C-24°C）不劣于中度低温（24.1 °C-28 ° C）， 深度低温因此，我们前瞻性随机临床试验的主要目的是：1）确定 深低温、低低温和中度低温对手术后神经认知功能和生活质量的影响 2）确定深低温与低低温与中度低温对脑连接和脑缺血的影响。 外科循环停止后神经元损伤的代谢特征;以及3）确定温度 外科手术中的炎症调节机制--治疗影响白细胞SUMO化模式 使用循环停止。我们提出的研究将是第一个随机试验，以评估的影响， 深、低、中低温停循环对神经认知功能和脑功能的影响 连通性。我们的初步数据强烈支持在循环过程中中度低温的有害影响， 因此，这项研究可能会极大地改变实践并提高患者安全性。本研究将 这也是第一个在人类中评估小泛素样修饰物缀合途径在 在需要停止循环的心脏手术中保护大脑。因此，本研究具有重要意义， 通过彻底改变我们对皮下注射影响的理解，垂直推进心脏外科领域， 通过为最佳低温治疗提供强有力的证据， 在外科循环停止期间，通过确定新的治疗干预目标， 增强器官对血液供应暂时中断的抵抗力。

The use of deep hypothermia (<20°C) for cerebral protection ushered in the modern era of safe and effective operations on the heart and aorta. In large part due to advanced circulatory management strategies, surgical procedures on the proximal aorta and arch utilizing deep hypothermic circulatory arrest have steadily increased over the last decade. Despite these advances, neurologic complications remain a sobering limitation. Indeed, 7%-13% of patients endure permanent neurologic dysfunction. In addition, postoperative cognitive decline (POCD) occurs in 36% of cardiac surgery patients at 6 weeks after surgery, and importantly, persists in 42% of patients up to 5 years after surgery and reduces quality of life. Although deep hypothermia has been the standard of care for decades in adult patients requiring circulatory arrest, moderate hypothermia is now more commonly used in many centers. However, this transition to moderate temperatures has been based entirely on observational studies that have not adequately assessed neurological or neurocognitive outcomes. Little is more devastating to a patient or the patient's family than to have a successful operation that prolongs life, but is complicated by cognitive impairment resulting in a diminished quality of life and loss of functional in- dependence. The long-term goal of our multidisciplinary Neurologic Outcome Research Group is to understand the mechanisms underlying neurologic and neurocognitive dysfunction after cardiac surgery, and to reduce the incidence of these devastating outcomes. In the proposed study, we will test our hypothesis that deep hypo- thermia (<20°C) during surgical circulatory arrest limits POCD and preserves brain connectivity to a greater degree than moderate hypothermia (24.1°C-28°C) and that low hypothermia (20.1°C-24°C) is non-inferior to deep hypothermia. Thus the primary aims of our prospective, randomized clinical trial are to 1) determine the effect of deep vs low vs moderate hypothermia on neurocognitive function and quality of life after surgical cir- culatory arrest; 2) determine the effect of deep vs low vs moderate hypothermia on brain connectivity and met- abolic signatures of neuronal damage following surgical circulatory arrest; and 3) determine how temperature management affects leukocyte SUMOylation patterns as a mechanism of inflammatory modulation in surgeries employing circulatory arrest. Our proposed study will be the first randomized trial to evaluate the effects of deep vs low vs moderate hypothermia during circulatory arrest on neurocognitive function and functional brain connectivity. Our preliminary data strongly supports a detrimental effect of moderate hypothermia during circu- latory arrest and thus this study is likely to dramatically alter practice and improve patient safety. This study will also be the first study in humans to assess the role of the small ubiquitin-like modifier conjugation pathway in protecting the brain during cardiac surgery requiring circulatory arrest. Thus, this study is significant, and will vertically advance the field of cardiac surgery by revolutionizing our understanding of the effects of hypother- mia on neurologic and neurocognitive outcomes, by providing strong evidence for optimal hypothermic tem- peratures during surgical circulatory arrest, and by identifying new targets for therapeutic intervention to in- crease the resistance of organs to a transient interruption in blood supply.