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: 8732112
• 负责人: ALAN E JONES
• 金额: $ 9.96万
• 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/8732112
• 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; 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(申请人提供)：重症监护病房中死于败血症的人比死于其他任何原因的人都多。脓毒症死亡是广泛的低灌注率、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。新的靶向策略，支持强大和持久的全身血流动力学反应，已被证明可以减少甚至逆转脓毒症患者的器官功能障碍。L-卡尼汀提供了一种新的治疗方法的关键成分，以改善脓毒症的不良血流动力学影响。严重的生理应激迫使能量代谢从最初的脂肪酸氧化转向糖酵解和乳酸氧化。既往的研究表明，外源性L-卡尼汀可增强葡萄糖和乳酸的氧化，减轻脂肪酸毒性，改善内皮-平滑肌偶联和心脏机械效率。这项建议的总体目标是研究L-卡尼汀作为感染性休克的一种新的辅助治疗。在这项研究中，我们将检验我们的主要假设：早期辅以L-卡尼汀治疗血管加压剂依赖型感染性休克将显着减少48小时内累积的器官衰竭，并相关地降低28天的死亡率，这表明有必要进行进一步的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剂依赖型败血症休克患者进行II期、双盲、安慰剂对照、适应性随机试验。作为早期复苏护理的一部分，研究对象将被分配到四个手臂中的一个：低(6g)、中(12g)或高(18g)静脉注射L-卡尼汀或安慰剂12小时。我们的第一个人工智能是评估L-卡尼汀是否能减少感染性休克患者的累积器官衰竭。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小时连续器官衰竭评估(SOFA)评分的减少。SOFA数据将被用于优先分配后续患者最有效的L-卡尼汀剂量。随着试验的进行，28天的死亡率数据将被用来确定与SOFA评分下降最大相关的L-卡尼汀剂量在随后的III期试验中显示疗效的可能性。通过利用自适应试验方法的优势，我们可以克服与传统试验相关的几个低效问题，同时保持对假阳性结果的保护，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L-卡尼汀是否能改善感染性休克时舌下微血管的血流。我们将使用侧流暗视野视频显微镜对舌下微循环进行成像，以直接显示微循环血流，并确定L-卡尼汀和安慰剂治疗对血流变化的影响。目前还没有针对靶向衰减或 脓毒症时器官功能障碍的逆转。如果本项目与L-卡尼汀联合应用显示出良好的效果，将为脓毒症治疗提供一种实用、廉价、适用范围广的制剂。