Thiamine v placebo to improve oxygen consumption after in-hospital cardiac arrest

硫胺素与安慰剂对比改善院内心脏骤停后的耗氧量

• 批准号: 9336332
• 负责人: Katherine M Berg
• 金额: $ 19.09万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336332
• 关键词: Acidosis; Anaerobic Bacteria; Antihypertensive Agents; Award; Back; Blinded; Blood Circulation; Cardiac; Cardiac Surgery procedures; Cause of Death; Cell Respiration; Cells; Cessation of life; Characteristics; Citric Acid Cycle; Critical Illness; Data; Death Rate; Defect; Development Plans; Disease; Dose; Employee Strikes; Enrollment; Enzymes; Event; Failure; Fever; Functional disorder; Heart Arrest; Hospitals; Hour; Hypoxemia; Impairment; Intervention; Lactate Dehydrogenase; Lactic Acidosis; Lead; Literature; Measurement; Measures; Mentorship; Metabolic; Metabolism; Mitochondria; Monitor; Morbidity - disease rate; Nervous System Trauma; Neurological outcome; Outcome; Oxygen; Oxygen Consumption; Patients; Phase; Physiologic pulse; Physiological; Placebos; Process; Production; Pyruvate; Randomized; Randomized Controlled Trials; Refractory; Research; Research Personnel; Respiratory Failure; Resuscitation; Sepsis; Septic Shock; Severity of illness; Shock; Stress; Syndrome; Tachycardia; Temperature; Testing; Thiamine; Thiamine Deficiency; Time; Tissues; Translational Research; United States; Vasoconstrictor Agents; career development; experience; improved; improved outcome; indexing; metabolic rate; mitochondrial dysfunction; mortality; mouse model; placebo controlled study; primary outcome; public health relevance; pyruvate dehydrogenase; secondary outcome; sedative; skills; survival outcome

 DESCRIPTION (provided by applicant): Over 200,000 people suffer an in-hospital cardiac arrest (IHCA) each year in the United States, and over 80% of those will die. In spite of this extremely high mortality, relatively few trials have been done to investigate treatments to improve outcomes after IHCA. In patients who achieve return of spontaneous circulation (ROSC), the most common cause of death is shock and multi- organ failure. The post-arrest syndrome has been likened to sepsis/septic shock, and both conditions appear to be characterized by impaired oxygen extraction in many patients. This may contribute to increased lactate, failure to clear lactate, and decreased oxygen consumption (VO2), all of which are associated with higher mortality in both sepsis and post-cardiac arrest. We have also found that pyruvate dehydrogenase (PDH), an enzyme required for the Krebs Cycle, is low in sepsis and after cardiac arrest, and that lower levels are associated with higher mortality in sepsis. All of these indicators suggest a dysfunction in aerobic metabolism, and an intervention that could rectify this defect could lead to lower lactate values, increased VO2 and potentially better outcomes. Thiamine, a co-factor of PDH, is also required for aerobic metabolism. We have found that thiamine deficiency is common in septic shock and after cardiac arrest, and that thiamine levels are inversely associated with lactate levels in septic shock and other forms of critical illness. We have also found that thiamine administration lowers lactate and improves survival in thiamine deficient septic shock patients, is associated with a rise in VO2 in criticall ill patients with preserved cardiac index (regardless of thiamine level), and appears to increase PDH activity after major cardiac surgery. We therefore hypothesize that thiamine will increase VO2, increase PDH activity and decrease lactate after IHCA. We propose a phase II randomized, blinded, placebo-controlled trial in 60 patients who obtain sustained ROSC after in-hospital cardiac arrest and have preserved cardiac index to test this hypothesis. All enrolled patients will be randomized to either thiamine 200mg or placebo every 12 hours for 24 hours. We will record VO2 and cardiac index data continuously for 24 hours, and will check PDH quantity and activity and lactate at 0, 12 and 24 hours. The primary outcome will be the change in VO2, and the secondary outcomes will be change in PDH activity and lactate. We anticipate that VO2 and PDH activity will rise while lactate will decrease in patients who receive thiamine as compared to placebo. Prior research on VO2 after cardiac arrest is extremely limited, and as such we believe our data will be a significant contribution to the literature on cardiac arrest and the post-arrest syndrome, even if our study results are not positive.

 描述（由申请人提供）：美国每年有超过 200,000 人发生院内心脏骤停 (IHCA)，其中 80% 以上会死亡。尽管死亡率极高，但研究改善 IHCA 后结局的治疗方法的试验相对较少。在恢复自主循环（ROSC）的患者中，最常见的死亡原因是休克和多器官衰竭。逮捕后综合征被比作败血症/败血性休克，这两种情况的特点似乎都是许多患者的吸氧受损。这可能导致乳酸增加、乳酸清除失败和耗氧量 (VO2) 减少，所有这些都与脓毒症和心脏骤停后的较高死亡率相关。我们还发现，丙酮酸脱氢酶（PDH）（一种克雷布斯循环所需的酶）在脓毒症和心脏骤停后水平较低，并且较低水平与脓毒症较高的死亡率相关。所有这些指标都表明有氧代谢存在功能障碍，而纠正这一缺陷的干预措施可能会导致乳酸值降低、摄氧量增加，并可能带来更好的结果。硫胺素是 PDH 的辅助因子，也是有氧代谢所必需的。我们发现，硫胺素缺乏在感染性休克和心脏骤停后很常见，并且在感染性休克和其他形式的危重疾病中，硫胺素水平与乳酸水平呈负相关。我们还发现，硫胺素给药可降低硫胺素缺乏的败血性休克患者的乳酸并提高生存率，与心脏指数保持不变的危重患者的摄氧量升高相关（无论硫胺素水平如何），并且似乎会增加大型心脏手术后的 PDH 活性。因此，我们假设硫胺素会在 IHCA 后增加 VO2、增加 PDH 活性并减少乳酸。我们建议对 60 名在院内心脏骤停后获得持续 ROSC 并保留心脏指数的患者进行一项 II 期随机、盲法、安慰剂对照试验来检验这一假设。所有入组患者将被随机分配接受硫胺素 200 毫克或安慰剂，每 12 小时一次，持续 24 小时。我们将连续24小时记录VO2和心脏指数数据，并在0、12和24小时检查PDH数量和活性以及乳酸。主要结果是摄氧量的变化，次要结果是 PDH 活性和乳酸的变化。我们预计，与安慰剂相比，接受硫胺素治疗的患者的 VO2 和 PDH 活性会升高，而乳酸会降低。先前对心脏骤停后摄氧量的研究极其有限，因此我们相信我们的数据将对心脏骤停和心脏骤停相关文献做出重大贡献。 逮捕后综合症，即使我们的研究结果并不积极。