Thaimine as an adjunct metabolic resuscitator in cardiac arrest

摘要 目前还没有药物干预措施证明可以持续改善低生存率 以及院外心脏骤停（OHCA）后器官损伤的高发生率。在那些最初 在OHCA幸存者中，与逮捕有关的器官损伤的死亡率仍然高得令人沮丧， 是常见的，往往使人衰弱的OHCA逮捕病人谁生存出院。[1]虽然大脑 损伤是最致命的[2]和最普遍的器官损伤，急性肾损伤（阿基）也很常见， 与死亡率和不良结局（如需要透析）相关[3，4]。我们的团队目前 参与了一项随机试验，以测试硫胺素（维生素B1）是否能在心脏骤停后保护大脑， 改善有氧代谢，反映在乳酸酸中毒的减少。然而，正在进行的研究 我们小组和其他人进行的研究提出了新的和同样重要的问题。有了这个K-24提案， 我们计划通过在本试验中增加新的子研究来解决其中两个问题。第一个子研究测试 假设硫胺素在心脏骤停后不仅保护大脑，还保护肾脏， 第二个子研究检验了心脏骤停患者具有异常低的 α-硫辛酸（LA）是有氧代谢的另一个关键介质，它可能会限制 硫胺素治疗的疗效。第一个子研究的基本原理是基于最近的证据， 肾脏有氧代谢减少，导致危重病中的肾衰竭，[5，6] 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保护肾脏 功能[7]第二个子研究是基于我们的初步数据表明，硫胺素可能不完全 恢复心脏骤停后的细胞耗氧量。因为有氧葡萄糖代谢需要 硫辛酸和硫胺素作为两种关键酶的辅因子，即使亚急性硫辛酸缺乏也可能使 硫胺素作为代谢复苏剂的功效上限实验性提供LA已被证明 以防止缺血性脑和肾损伤;这些发现有助于检查 在我们现有的审判中。总之，这些研究将推动硫胺素作为一种潜在的逮捕后， 阿基的干预，并加深我们对其他关键代谢成分之间关系的理解， 危重病，同时也提供了一个很好的平台，以指导未来的病人为导向的研究人员。这 该奖项将提供一个既定的和高生产力的临床研究人员和导师与项目和 指导支持，并允许继续扩大他杰出的翻译研究培训计划 在BIDMC的复苏科学中心（CRS）。科学部分实验的广度 提案（临床试验设计/执行和基于患者的实验室工作）沿着研究 多个正在进行的CRS研究提供的基础设施将为学员提供经验和专业知识， 作为复苏医学领域的下一代研究人员，朝着独立的方向前进。

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.