Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the most common sequelae of severe sepsis leading to greater than 40% mortality. In the 200,000 people fortunate enough to survive ALI annually, many years of persisting pulmonary disability, cognitive abnormalities, and post-traumatic stress disorder result. Proinflammatory and procoagulant processes uniformly follow the onset of sepsis. They damage lung vasculature and alveolar epithelium and lead to ALI/ARDS. Three decades of efforts to attenuate septic responses that induce lung injury using targeted single mediator antagonism have failed to reduce mortality. Only low tidal volume """"""""lung-protective"""""""" ventilation and conservative fluid management strategies show a mortality benefit. An intervention that attenuates multiple, dysregulated pathways seems most likely to improve outcomes. This application presents new data showing that parenterally infused high dose ascorbic acid (vitamin C) disrupts multiple proinflammatory/procoagulant cascades that lead to lung injury in septic humans and mice. Subnormal plasma vitamin C levels are a consistent feature in septic patients, varying inversely with the incidence of multiple organ failure and directly with survival No multicenter trials have examined parenteral vitamin C infusion as an intervention to attenuate sepsis-induced lung injury. We propose to conduct a randomized, double-blind, placebo-controlled, multi-center phase II proof of concept trial examining high dose intravenous vitamin C (ascorbic acid) infusion in human sepsis induced acute lung injury. Our central hypothesis is that: Parenteral augmentation of vitamin C (ascorbic acid) by intravenous infusion will attenuate lung injury that follows onset of severe sepsis. We further hypothesize that: Attenuated lung injury in patients receiving vitamin C will be associated with reduced plasma levels of injury biomarkers and improved measurements of lung function. The proposal contains a tightly linked basic science lung injury study in a murine model of septic lung injury employing mice in whom enzyme that synthesizes vitamin C has been knocked out, thus simulating human sepsis. The phase 11 trial will be conducted by 4 highly experienced physician- investigators with a history of lung injury research.

Public Health Relevance

Acute lung injury resulting from severe sepsis is a leading cause of death and disability worldwide. Thus far no safe, readily available, cost effective therapy has been discovered. This application contains studies that propose to use high dose intravenous vitamin C as a drug intervention in patients who have developed lung injury from severe sepsis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZHL1-CSR-F (O2))
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Harabin, Andrea L
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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Holder, Andre L; Overton, Elizabeth; Lyu, Peter et al. (2017) Serial Daily Organ Failure Assessment Beyond ICU Day 5 Does Not Independently Add Precision to ICU Risk-of-Death Prediction. Crit Care Med 45:2014-2022
Bharara, Amit; Grossman, Catherine; Grinnan, Daniel et al. (2016) Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome. Case Rep Crit Care 2016:8560871
Carr, Anitra C; Shaw, Geoffrey M; Fowler, Alpha A et al. (2015) Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care 19:418
Fowler 3rd, Alpha A; Syed, Aamer A; Knowlson, Shelley et al. (2014) Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 12:32