Thiamine as a Renal Protective Agent in Septic Shock

硫胺素作为感染性休克的肾脏保护剂

• 批准号: 10158498
• 负责人: Ari Moskowitz
• 金额: $ 19.14万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158498
• 关键词: Acute Kidney Tubular Necrosis; Aerobic; Affect; Anaerobic Bacteria; Attenuated; Award; Biological Markers; Blood Pressure; Cardiac Surgery procedures; Cell Respiration; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Complication; Consumption; Creatinine; Critical Illness; Data; Depressed mood; Devices; Dialysis procedure; Education; Frequencies; Future; Genus Hippocampus; Hospital Mortality; Hour; Hypoxia; Injury to Kidney; Intervention; Intravenous; Kidney; Kidney Failure; LCN2 gene; Laboratories; Link; Measures; Mediating; Mentorship; Metabolic; Mitochondria; Outcome; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Oxygen Consumption; Patients; Pentosephosphate Pathway; Perfusion; Peripheral Blood Mononuclear Cell; Physicians; Physiological; Placebos; Play; Positioning Attribute; Production; Protective Agents; Randomized; Randomized Controlled Clinical Trials; Reactive Oxygen Species; Renal Replacement Therapy; Renal function; Research; Research Personnel; Respiration; Resuscitation; Role; Sepsis; Septic Shock; Serum; Specimen; Stress; Syndrome; Testing; Therapeutic; Thiamine; Thiamine Deficiency; Translational Research; United States; Vasodilation; Vitamin B Complex; Work; cofactor; cytokine; density; design; double-blind placebo controlled trial; experience; extracellular; hypoperfusion; improved; insight; mitochondrial dysfunction; mitochondrial metabolism; organ injury; phase III trial; placebo group; post gamma-globulins; prevent; primary outcome; pyruvate dehydrogenase; randomized trial; rat KIM-1 protein; septic patients; skills; thiamine supplementation

Project Summary/Abstract: Septic shock is a common and highly morbid clinical syndrome that affects over 200,000 patients in the United States annually and results in over 40,000 deaths. Kidney failure is a frequent complication of sepsis and septic shock that is associated with worse outcomes. To date, the understanding of kidney injury in sepsis and septic shock has traditionally focused on decreased blood pressure leading to kidney hypoperfusion. Recent studies have challenged this paradigm, however, illustrating that sepsis associated kidney injury often occurs even when perfusion is adequate. These findings suggest that alternative pathophysiologic mechanisms may have a role in sepsis related kidney injury. The mechanisms remain poorly understood and as yet there are no proven interventions aimed at mitigating sepsis-induced kidney injury. Thiamine (vitamin B1), a key cofactor of pyruvate dehydrogenase, is a critical component of oxidative phosphorylation (i.e. aerobic mitochondrial respiration). In the absence of thiamine, mitochondrial metabolism shifts towards anaerobic energy production, which is inefficient and results in lactate production. Thiamine deficiency has also been linked to increased levels of reactive oxygen species. Our research group has previously demonstrated that thiamine deficiency is common in critical illness and inversely associated with lactate levels. We hypothesize that thiamine deficiency during critical illness may occur due to increased metabolic demand which rapidly consumes available thiamine stores. In a randomized trial, our research group has found that the administration of thiamine to thiamine deficient patients with septic shock leads to reduced lactate at 24-hours. In a post-hoc analysis of that study, my work has shown that patients (including both thiamine replete and thiamine deficient patients) who received thiamine had lower creatinine values at 24-hours and were less likely to require kidney replacement therapy (e.g. dialysis). Our research group has also shown improved cellular oxygen consumption in septic patients and cardiac surgery patients who receive thiamine. Given the above, we hypothesize that thiamine attenuates kidney injury during septic shock by supporting aerobic mitochondrial metabolism. To test this hypothesis, we have planned a randomized, double-blind placebo-controlled trial of thiamine to improve in kidney function in patients with septic shock. This award will allow me to further develop as a physician-investigator and to test important hypotheses with potentially significant therapeutic benefits for patients with sepsis and septic shock.

项目概要/摘要： 感染性休克是一种常见的高度病态的临床综合征，在美国有超过20万患者受到感染。 每年有超过4万人死亡。肾衰竭是败血症的常见并发症， 败血性休克与更差的结果相关。到目前为止，对脓毒症肾损伤的认识， 败血性休克传统上集中于导致肾灌注不足的血压降低。最近 然而，研究已经挑战了这种范式，说明败血症相关的肾损伤经常发生， 即使在灌注充分时也是如此。这些发现表明，替代的病理生理机制可能 在脓毒症相关的肾损伤中起作用。对这些机制仍然知之甚少， 旨在减轻脓毒症引起的肾损伤的经证实的干预措施。 硫胺素（维生素B1）是丙酮酸脱氢酶的关键辅因子，是氧化还原酶的关键组分。 磷酸化（即有氧线粒体呼吸）。在缺乏硫胺素的情况下， 转向无氧能量生产，这是低效的，并导致乳酸盐的生产。硫胺素 缺乏症还与活性氧水平的增加有关。我们的研究小组 先前的研究表明，硫胺素缺乏症在危重病中很常见， 乳酸水平。我们推测，重症期间硫胺素缺乏可能是由于增加 快速消耗可利用的硫胺素储存的代谢需求。 在一项随机试验中，我们的研究小组发现， 感染性休克的患者在24小时内导致乳酸减少。在对这项研究的事后分析中，我的工作 已经表明，接受硫胺素的患者（包括硫胺素充足和硫胺素缺乏的患者） 24小时肌酐值较低，不太可能需要肾脏替代治疗（例如， 透析）。我们的研究小组还显示，脓毒症患者的细胞耗氧量有所改善， 接受硫胺素治疗的心脏手术患者。 鉴于上述情况，我们假设硫胺素通过以下方式减轻感染性休克期间的肾损伤： 线粒体有氧代谢为了验证这一假设，我们计划进行一项随机、双盲 硫胺素改善感染性休克患者肾功能的安慰剂对照试验这个奖项将 让我进一步发展为一个医生调查员，并测试潜在的重要假设 对脓毒症和脓毒性休克患者具有显著的治疗益处。

项目成果

Variation in SOFA (Sequential Organ Failure Assessment) Score Performance in Different Infectious States.

• DOI: 10.1177/0885066620944879
• 发表时间: 2021-10
• 期刊: Journal of intensive care medicine
• 影响因子: 3.1
• 作者: Pawar RD;Shih JA;Balaji L;Grossestreuer AV;Patel PV;Hansen CK;Donnino MW;Moskowitz A
• 通讯作者: Moskowitz A

Vitamin C levels amongst initial survivors of out of hospital cardiac arrest.

• DOI: 10.1016/j.resuscitation.2020.09.005
• 发表时间: 2020-11
• 期刊: Resuscitation
• 影响因子: 6.5
• 作者: Gardner R;Liu X;Wang Y;Cole A;Heydrick S;Donnino MW;Moskowitz A
• 通讯作者: Moskowitz A

Hemodynamic decompensation in normotensive patients admitted to the ICU with pulmonary embolism.

• DOI: 10.1016/j.jcrc.2019.07.017
• 发表时间: 2019-07
• 期刊: Journal of critical care
• 影响因子: 3.7
• 作者: Het Patel;J. Shih;Ryan Gardner;P. Patel;Catherine E. Ross;M. Hayes;A. Moskowitz;M. Donnino

Trends in Endotracheal Intubation During In-Hospital Cardiac Arrests: 2001-2018.

院内心脏骤停期间气管插管的趋势：2001- 2018年。

• DOI: 10.1097/ccm.0000000000005120
• 发表时间: 2022-01-01
• 期刊: Critical care medicine
• 影响因子: 8.8

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Health-Related Quality of Life in Sepsis.

• DOI: 10.1097/cce.0000000000000270
• 发表时间: 2020-12
• 期刊: Critical care explorations
• 作者: Grossestreuer AV;Moskowitz A;Andersen LW;Holmberg MJ;Konacki V;Berg KM;Chase M;Cocchi MN;Donnino MW
• 通讯作者: Donnino MW