Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis

脓毒症合并急性器官功能障碍是一种常见的疾病，发病率和死亡率都很高，没有特异的 除抗菌药物外的其他疗法。NHLBI Petal Network 2B期扑热息痛和抗坏血酸 脓毒症：靶向治疗促进康复(ASTER试验)是一项随机双盲平台试验， 将测试两种潜在疗法的效果，对乙酰氨基酚或维生素C与普通安慰剂相比，以改善 900例脓毒症合并肺、心血管疾病患者的肺、心、肾功能障碍 功能障碍包括新冠肺炎引起的脓毒症患者。这项临床试验的部分理由是 我们小组和其他人的新发现：(1)患者循环中的无细胞血红蛋白(CFH)水平升高 脓毒症患者，包括新冠肺炎患者；(2)脓毒症患者血浆CFH升高与死亡和 器官功能障碍，包括ARDS和急性肾损伤；(3)对乙酰氨基酚和维生素C都是 降低CFH导致脂质过氧化和其他氧化性损伤的能力的血红蛋白还原剂 对乙酰氨基酚和维生素C可减轻CFH对微血管的损伤作用 体外培养的人肺血管内皮细胞和离体肺的内皮细胞。尽管ASTER设计得很好，可以测试 对乙酰氨基酚和维生素C的临床疗效，需要关键信息才能了解试验结果 并为潜在的第三阶段研究制定计划。本R01中拟议的研究将确定通过哪些机制 对乙酰氨基酚和维生素C影响败血症的器官功能障碍(目标1)，并确定是否有 可在试验中确定存在差别治疗效果的亚组(目标2)。特定的 目标1将确定扑热息痛和维生素C改善肺和肾脏的机制 通过检验对乙酰氨基酚和维生素C降低氧化水平的假说，脓毒症中的功能障碍 铁基(4+)血红蛋白可减少氧化损伤、炎症和内皮损伤 通过血浆、远端空泡液和尿中血红蛋白氧化(铁基血红蛋白)脂质的生物标志物 过氧化(F2-异前列腺素、异呋喃)、炎症和内皮损伤。远端空域液体将是 通过收集热湿冷凝的流体在十个参与的花瓣网点进行采样 在机械呼吸机回路中放置交换过滤器，这是一种已经开发和验证的方法 威尔博士的研究小组。具体目标2将确定之前描述和验证的 脓毒症患者的高炎症或低炎症亚组患者从以下治疗中受益更多 对乙酰氨基酚或维生素C在AIM 2中发现治疗效果的异质性将对 在未来的3期临床试验中进行预测性浓缩。总括而言，拟议的研究将大大提高 ASTER临床试验的价值在于确定其治疗作用的生物学机制 对乙酰氨基酚和维生素C在NHLBI资助阶段的治疗效果异质性评估 2B个临床试验。

Sepsis with acute organ dysfunction is a common condition with high morbidity and mortality and no specific therapies other than antimicrobials. The NHLBI PETAL Network Phase 2B Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (ASTER trial) is a randomized double blind platform trial that will test the effect of two potential therapies, acetaminophen or vitamin C versus a common placebo to improve lung, cardiovascular and kidney dysfunction in 900 patients with sepsis and pulmonary or cardiovascular dysfunction including patients with sepsis due to COVID-19. The rationale for this clinical trial rests, in part, on novel findings from our group and others that (1) circulating cell-free hemoglobin (CFH) is elevated in patients with sepsis, including those with COVID-19; (2) higher plasma CFH in sepsis is associated with death and organ dysfunction including ARDS and acute kidney injury; (3) both acetaminophen and vitamin C are hemoprotein reductants that reduce the capacity of CFH to cause lipid peroxidation and other oxidant injury and (4) acetaminophen and vitamin C can reduce the injurious effects of CFH on the microvascular endothelium both in vitro and in the isolated perfused human lung. Although ASTER is well designed to test the clinical efficacy of acetaminophen and vitamin C, key information will be needed to understand trial results and plan for potential phase 3 studies. The proposed studies in this R01 will define the mechanisms by which acetaminophen and vitamin C affect organ dysfunction in sepsis (Aim 1) and determine whether there are subgroups that can be identified within the trial for whom a differential treatment effect exists (Aim 2). Specific Aim 1 will determine the mechanisms by which acetaminophen and vitamin C improve lung and kidney dysfunction in sepsis by testing the hypothesis that acetaminophen and vitamin C reduce levels of oxidized ferryl (4+) hemoglobin resulting in decreased oxidative injury, inflammation, and endothelial injury as measured by plasma, distal airspace fluid, and urinary biomarkers of hemoglobin oxidation (ferryl hemoglobin) lipid peroxidation (F2-Isoprostanes, Isofurans), inflammation and endothelial injury. Distal airspace fluid will be sampled at ten participating PETAL Network sites by collecting fluid that condenses on heat moisture exchanger filters placed in the mechanical ventilator circuit, a method that has been developed and validated by Dr. Ware's research group. Specific Aim 2 will identify whether previously described and validated hyperinflammatory or hypoinflammatory subgroups of sepsis patients benefit more from treatment with acetaminophen or vitamin C. A finding of heterogeneity of treatment effect in Aim 2 would be of great value for predictive enrichment in a future phase 3 clinical trial. In summary, the proposed studies will greatly enhance the value of the ASTER clinical trial by determining the biologic mechanisms of the therapeutic effects of acetaminophen and Vitamin C and assessing for heterogeneity of treatment effect in this NHLBI-funded Phase 2B clinical trial.