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

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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.