L-carnitine Treatment for Vasopressor Dependent Septic Shock

描述（由申请人提供）：在重症监护病房死于败血症的人比死于其他任何原因的人都多。脓毒症的死亡是广泛的灌注不足、细胞缺氧和多器官衰竭的高潮。越来越多的证据表明，早期治疗干预可以改善败血症患者的预后。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败血症患者的器官功能障碍。左旋肉碱为改善脓毒症的血流动力学不良反应提供了一种新的治疗方法。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-平滑肌偶联和心脏机械效率。本提案的总体目标是研究左旋肉碱作为感染性休克的一种新的辅助治疗方法。在这项研究中，我们将验证我们的主要假设：血管升压依赖性脓毒性休克患者早期辅助左旋肉碱治疗将显著减少48小时累积器官衰竭，并降低28天死亡率，这表明需要进一步的III期研究。为了实现这一目标，我们将开展一项II期、双盲、安慰剂对照、适应性随机试验，纳入250例血管加压剂依赖性脓毒性休克患者。研究对象将被分配到四组中的一组：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。我们的第一个人工智能是评估左旋肉碱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小时顺序器官衰竭评估（SOFA）评分的降低。SOFA数据将用于优先分配后续患者使用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期试验中证明有效的可能性。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几个低效率问题，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。我们的第二个目的是评估左旋肉碱是否能改善脓毒性休克期间舌下微血管的血流。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。目前还没有针对衰减或

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.