L-carnitine Treatment for Vasopressor Dependent Septic Shock

左旋肉碱治疗血管加压药依赖性感染性休克

• 批准号: 8669999
• 负责人: ALAN E JONES
• 金额: $ 56.53万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669999
• 关键词: Acute; Adverse effects; Aftercare; Attenuated; Blood Vessels; Blood flow; Carbohydrates; Cardiac; Cardiovascular system; Caring; Cell Hypoxia; Cessation of life; Clinical; Clinical Trials Design; Coupling; Data; Disease; Dose; Double-Blind Method; Elements; Energy Metabolism; Fatty Acids; Functional disorder; Glucose; Glycolysis; Goals; Hour; Human; Image; Intensive Care Units; Intravenous; Knowledge; Levocarnitine; Literature; Measures; Mechanics; Microcirculation; Multiple Organ Failure; Muscle Tonus; Organ; Organ failure; Outcome; Patients; Perfusion; Phase; Phase III Clinical Trials; Physiological; Placebo Control; Placebos; Probability; Public Health; Randomized; Recovery; Sample Size; Sepsis; Septic Shock; Smooth Muscle; Stress; Study Subject; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Vasoconstrictor Agents; Video Microscopy; Work; arm; attenuation; clinical efficacy; fatty acid oxidation; follow-up; hemodynamics; hypoperfusion; improved; indexing; insight; mortality; novel; oxidation; patient oriented; phase 3 study; public health relevance; randomized placebo controlled trial; randomized trial; resilience; response; success

DESCRIPTION (provided by applicant): More humans die in the intensive care unit from sepsis than from any other cause. Death from sepsis is the culmination of widespread hypoperfusion, cellular hypoxia, and multiple organ failure. A growing body of evidence shows that early therapeutic intervention improves outcomes for patients with sepsis. Novel targeted strategies that bolster a strong and durable systemic hemodynamic response have been proven to reduce or even reverse organ dysfunction in patients with sepsis. L-carnitine provides the key elements of a novel therapy to ameliorate the adverse hemodynamic effects of sepsis. Severe physiological stress forces energy metabolism to shift from primary fatty acid oxidation toward glycolysis and lactate oxidation. Prior work has shown that exogenous L-carnitine administration enhances glucose and lactate oxidation, attenuates fatty acid toxicity, and improves endothelial-smooth muscle coupling and cardiac mechanical efficiency. The overall goal of this proposal is to investigate L-carnitine as a novel adjunctive treatment of septic shock. In this study we will test our primary hypothesis: Early adjunctive L-carnitine administration in vasopressor dependent septic shock will significantly reduce cumulative organ failure at 48 hours with an associated decrease in 28-day mortality suggesting the need for further phase III study. To accomplish this we will conduct a phase II, double blinded, placebo controlled, adaptive randomized trial of 250 eligible patients with vasopressor-dependent septic shock. Study subjects will be assigned to one of four arms: low (6g), medium (12g) or high (18g) dose intravenous L-carnitine or placebo for 12 hours as a part of early resuscitative care. Our first ai is to assess whether L-carnitine reduces cumulative organ failure in patients with septic shock. The first efficacy endpoint of the trial is reduction in cumulative organ failure, defined as a decrease in the sequential organ failure assessment (SOFA) score at 48 hours after treatment. The SOFA data will be used to preferentially allocate subsequent patients to the L-carnitine dose that is most effective. As the trial progresses 28-day mortality data will be used to determine the probability that the dose of L-carnitine associated with the largest decrease in SOFA score would demonstrate efficacy in a subsequent phase III trial. By utilizing the strengths of an adaptive trial approach we can overcome several inefficiencies associated with traditional trials while maintaining protection against false positive results, and allow for dose finding, all while maintaining a manageable sample size. Our second aim is to assess if L-carnitine improves blood flow in the sublingual microvasculature during septic shock. We will use sidestream dark-field video-microscopy imaging of the sublingual microcirculation to directly visualize microcirculatory flow and to determine the effect of L-carnitine and placebo treatment on change in flow. Presently there are no treatments that are specific for targeting attenuation or reversal of organ dysfunction in sepsis. If this project shows benefit with L-carnitine, it will provide a useful, inexpensive, and widely applicable agent to the armamentarium of sepsis therapeutics.

描述（由申请人提供）：重症监护病房中死于败血症的人数比死于任何其他原因的人数还要多。脓毒症死亡是广泛的灌注不足、细胞缺氧和多器官衰竭的结果。越来越多的证据表明，早期治疗干预可以改善脓毒症患者的预后。事实证明，支持强大而持久的全身血流动力学反应的新型靶向策略可以减少甚至逆转脓毒症患者的器官功能障碍。左旋肉碱提供了改善脓毒症不良血流动力学影响的新疗法的关键要素。严重的生理应激迫使能量代谢从初级脂肪酸氧化转向糖酵解和乳酸氧化。先前的研究表明，外源性左旋肉碱给药可增强葡萄糖和乳酸氧化，减轻脂肪酸毒性，并改善内皮-平滑肌耦合和心脏机械效率。该提案的总体目标是研究左旋肉碱作为感染性休克的新型辅助治疗方法。在这项研究中，我们将检验我们的主要假设：在血管加压药依赖性感染性休克中早期辅助使用左旋肉碱将显着减少 48 小时内的累积器官衰竭，并相应降低 28 天死亡率，表明需要进一步的 III 期研究。为了实现这一目标，我们将对 250 名符合条件的血管加压药依赖性感染性休克患者进行 II 期、双盲、安慰剂对照、适应性随机试验。研究受试者将被分配到四个组之一：低剂量 (6g)、中剂量 (12g) 或高剂量 (18g) 静脉注射左旋肉碱或安慰剂 12 小时，作为早期复苏护理的一部分。我们的首要目标是评估左旋肉碱是否可以减少感染性休克患者的累积性器官衰竭。该试验的第一个疗效终点是累积器官衰竭的减少，定义为治疗后 48 小时序贯器官衰竭评估 (SOFA) 评分的下降。 SOFA 数据将用于优先将后续患者分配给最有效的左旋肉碱剂量。随着试验的进展，28 天死亡率数据将用于确定与 SOFA 评分最大下降相关的左旋肉碱剂量在随后的 III 期试验中证明疗效的可能性。通过利用适应性试验方法的优势，我们可以克服与传统试验相关的一些低效率问题，同时保持防止假阳性结果的能力，并允许剂量发现，同时保持可管理的样本量。我们的第二个目标是评估左旋肉碱是否可以改善感染性休克期间舌下微血管的血流量。我们将使用舌下微循环的侧流暗场视频显微镜成像来直接观察微循环流量，并确定左旋肉碱和安慰剂治疗对流量变化的影响。目前还没有专门针对靶向衰减或 逆转脓毒症中的器官功能障碍。如果该项目显示出左旋肉碱的益处，它将为败血症治疗提供一种有用、廉价且广泛适用的药物。