Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C

OBJECTIVES: Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis. DESIGN: Interventional study. SETTING: Research Institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (similar to 80 mm Hg). MEASUREMENTS AND MAIN RESULTS: Sepsis-induced fever (41.4 +/- 0.2 degrees C; mean +/- SE), tachycardia (141 +/- 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 +/- 1 to 67 +/- 2 mm Hg), arterial Po-2 (102.1 +/- 3.3 to 80.5 +/- 3.4 mm Hg), and renal medullary tissue Po-2 (41 +/- 5 to 24 +/- 2 mm Hg) decreased, and plasma creatinine doubled (71 +/- 2 to 144 +/- 15 mu mol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 +/- 0.3 degrees C), heart rate (99.7 +/- 3 beats/min), and plasma creatinine (32.6 +/- 5.8 mu mol/L) all decreased. Arterial (96.5 +/- 2.5 mm Hg) and renal medullary Po-2 (48 +/- 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 +/- 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours. CONCLUSIONS: IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Automated summary

The study showed that high-dose sodium ascorbate had a positive impact on improving clinical status and physiological parameters in sepsis, without adverse side effects. This research provides a basis for further clinical studies to investigate the application of this therapy in septic patients.