Thaimine as an adjunct metabolic resuscitator in cardiac arrest

摘要 目前还没有药物干预能够持续提高低存活率。 院外心脏骤停后器官损伤发生率高。在那些最初 活下来，与逮捕有关的器官损伤的死亡率仍然高得令人沮丧，以及其他器官损伤 在存活到出院的uchA骤停患者中很常见，通常会使人虚弱。[1]而大脑 损伤是最致命的，也是最常见的器官损伤，急性肾损伤(AKI)也很常见 与死亡率和不良后果有关，如需要透析[3，4]。我们的小组目前 参与了一项随机试验，以测试硫胺素(维生素B1)是否通过以下方式保护心脏骤停后的大脑 改善有氧代谢体现在乳酸酸中毒的减少。然而，正在进行的研究 由我们小组和其他人进行的研究提出了新的同样重要的问题。有了这份K-24计划， 我们计划通过在这项试验中增加新的子研究来解决其中的两个问题。第一个分项研究测试 假设硫胺素在心脏骤停后不仅保护大脑，还保护肾脏，而 第二项子研究测试了心脏骤停患者存在异常低水平的 A-硫辛酸(LA)是有氧代谢的另一种关键介质，它可能会限制 硫胺素治疗的疗效。第一个子研究的理论基础是基于最近的证据联系 危重疾病中肾功能衰竭时肾脏有氧代谢降低[5，6]的刺激作用 硫胺素对有氧代谢的影响，我们在脓毒症中的随机试验显示硫胺素对肾脏有保护作用 功能。[7]第二个子研究基于我们的初步数据，表明硫胺素可能不完全 在心脏骤停后恢复细胞耗氧量。因为有氧葡萄糖新陈代谢需要 硫辛酸和硫胺素作为两种关键酶的辅助因子，甚至亚急性硫辛酸缺乏症也可能发生 硫胺素作为新陈代谢复苏剂的功效上限。已经显示了LA的实验供应 以防止脑和肾脏缺血损伤；这些发现有助于检查 洛杉矶在我们现有审判的背景下。总而言之，这些研究将推动硫胺作为一种潜在的逮捕后 对AKI的干预并加深我们对AKI中其他关键代谢成分之间关系的理解 同时也为指导未来以患者为导向的研究人员提供了一个极好的平台。这 该奖项将提供一个成熟的和高生产力的临床研究人员和导师，与项目和 指导支持并允许继续扩展其出色的翻译研究培训计划 在BIDMC复苏科学中心(CRS)。科学部分实验的广度 建议(临床试验设计/实施和以患者为基础的实验室工作)与研究一起 多项正在进行的CRS研究提供的基础设施将为学员提供以下经验和专业知识 作为复苏医学领域的下一代研究人员，迈向独立的进展。

ABSTRACT There are currently no medicinal interventions demonstrated to consistently improve the low survival rate and high incidence of organ injury after out-of-hospital cardiac arrest (OHCA). Among those who initially survive OHCA, death from arrest-related injury to organs remains frustratingly high, and other-organ injuries are common and often debilitating among OHCA arrest patients who survive to discharge.[1] While cerebral injury is the most lethal[2] and most prevalent organ injury, acute kidney injury (AKI) is also common and is associated with mortality and adverse outcomes such as the need for dialysis[3,4]. Our group is currently engaged in a randomized trial to test if thiamine (vitamin B1) protects the brain after cardiac arrest by improving aerobic metabolism reflected in the reduction of lactic acidosis. However, ongoing research conducted by our group and others has raised new and equally important questions. With this K-24 proposal, we plan to address two of these questions by adding new sub-studies to this trial. The first sub-study tests the hypothesis that thiamine protects not just the brain but also the kidney after cardiac arrest, while the second sub-study tests the hypothesis that cardiac arrest patients have abnormally low pools of a-lipoic acid (LA), another critical mediator of aerobic metabolism, which may place a cap on the efficacy of thiamine therapy. The rationale for the first sub-study is based on recent evidence linking decreased aerobic metabolism in the kidney to renal failure in critical illnesses,[5,6] the stimulatory effect of thiamine on aerobic metabolism, and our randomized trial in sepsis showing that thiamine protected kidney function.[7] The second sub-study is based on our preliminary data suggesting that thiamine may not fully restore cellular oxygen consumption after cardiac arrest. Because aerobic glucose metabolism requires both lipoic acid and thiamine as cofactors for two key enzymes, even subacute lipoic acid deficiencies may place a cap on the efficacy of thiamine as a metabolic resuscitator. Experimental provision of LA has been shown to protect against ischaemic brain and kidney injury; these findings contribute to the rationale for examining LA in the context of our existing trial. Together, these studies will advance thiamine as a potential post-arrest intervention for AKI and deepen our understanding of the relationship of other key metabolic components in critical illness, while also providing an excellent platform to mentor future patient-oriented researchers. This award will provide an established and highly productive clinical researcher and mentor with both project and mentoring support and allow continued expansion of his outstanding translational research training program in the Center for Resuscitation Science (CRS) at BIDMC. The breadth of experiments in the scientific portion of the proposal (clinical trial design/execution and patient-based laboratory work) along with the research infrastructure provided by multiple ongoing CRS studies will give mentees the experience and expertise to progress towards independence as the next generation of researchers in the field of resuscitation medicine.