Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.
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.


BACKGROUND
ClinicalTrials.gov identifier NCT01434121.
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, PO Box 980050, Richmond, VA 23298-0050, USA. afowler@mcvh-vcu.edu.
Alpha A
AA
Fowler
Aamer A
AA
Syed
Shelley
S
Knowlson
Robin
R
Sculthorpe
Don
D
Farthing
Christine
C
DeWilde
Christine A
CA
Farthing
Terri L
TL
Larus
Erika
E
Martin
Donald F
DF
Brophy
Seema
S
Gupta
Bernard J
BJ
Fisher
Ramesh
R
Natarajan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002116:Calcitonin / Q000097:blood; D015740:Calcitonin Gene-Related Peptide; D003710:Demography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000188:drug therapy; D010919:Placebos; D011498:Protein Precursors / Q000097:blood; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D018180:Thrombomodulin / Q000097:blood
D015415:Biomarkers; C000606589:CALCA protein, human; D010919:Placebos; D011498:Protein Precursors; D018180:Thrombomodulin; D002116:Calcitonin; D002097:C-Reactive Protein; D015740:Calcitonin Gene-Related Peptide; D001205:Ascorbic Acid