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

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.

Figures

Figure 1

Plasma ascorbic acid levels following intravenous infusion of ascorbic acid. Plasma ascorbic acid levels were subnormal at entry (<50 μM, dotted line). Ascorbic acid levels rose rapidly in the two treatment groups and were significantly higher than placebo within twelve hours (Lo-AscA vs. placebo p < 0.005, Hi-AscA vs. placebo p < 0.0005) remaining consistently elevated for 96 hours. Ascorbic acid levels in the Hi-AscA group were significantly higher than the Lo-AscA group from the 12 hour point forward. These data show that an intermittent ascorbic acid infusion protocol (every 6 hours) produces sustained steady state levels in patients with severe sepsis. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Figure 2

Effect of ascorbic acid infusion on Sequential Organ Failure Assessment (SOFA) score (days 0–4). Daily mean SOFA scores decreased over time with both doses of ascorbic acid infusion (p < 0.05 significantly non-zero) with the higher dose significantly less than placebo (Hi-AscA vs. placebo p < 0.01). Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Figure 3

Serum C-reactive protein (CRP) and procalcitonin levels in septic placebo controls and ascorbic acid infused patients. (A) Both the Lo-AscA and the Hi-AscA dosages produced rapid reductions in serum CRP levels, becoming significantly lower than placebo (*p < 0.05 vs placebo) as early as 24 hours. Ascorbic acid infusion reduced CRP levels in both groups throughout the 4 study days (#p < 0.05 vs 0 hr). CRP levels in placebo patients slowly fell over the course of the 4 day study period. (B) Patients in the Lo-AscA and Hi-AscA groups exhibited reduced serum PCT levels beginning at 12 hours. Patients in the Hi-VitC group exhibited further significant reduction in serum PCT between 36 to 48 hours (#p < 0.05 vs 0 hr). Placebo patients exhibited a trend towards increased PCT levels which declined starting at 72 hours post onset of sepsis. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).

Figure 4

Plasma thrombomodulin (TM) levels measured in septic placebo controls and ascorbic acid infused patients. Plasma TM levels measured in the ascorbic acid infused patients exhibited no rise throughout the 4 days of study. Patients in the placebo group showed a trend towards increased plasma TM levels beginning at 36 hours, though it did not achieve statistical significance. Placebo (О), Lo-AscA (▼), Hi-AscA (▲).