(09-06-2017) Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis

Alpha A Fowler III1*, Aamer A Syed1, Shelley Knowlson2, Robin Sculthorpe3, Don Farthing4, Christine DeWilde1, Christine A Farthing4, Terri L Larus4, Erika Martin5, Donald F Brophy5, Seema Gupta6, Medical Respiratory Intensive Care Unit Nursing2, Bernard J Fisher1 and Ramesh Natarajan1

Abstract Background:
Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. Methods: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n=8), or Hi-AscA (200 mg/kg/24 h, n= 8), or Placebo (5% dextrose/water, n= 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. Results: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9±2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. Conclusions: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. Trial registration: ClinicalTrials.gov identifier NCT01434121.

Keywords: Ascorbic acid, Biological markers, Clinical trials phase I as topic, Multiple organ failure, Organ dysfunction scores, Sepsis

Source: Fowler et al. Journal of Translational Medicine 2014, 12:32 http://www.translational-medicine.com/content/12/1/32

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