Update on vitamin C administration in critical illness.

PURPOSE OF REVIEW: Several studies have recently explored the effects of intravenous vitamin C in sepsis. We aimed to summarize their findings to provide perspectives for future research. RECENT FINDINGS: Sepsis trials examined 6 g/day of intravenous vitamin C with or without the thiamine and/or hydrocortisone compared with placebo or hydrocortisone. Network meta-analysis reported that intravenous vitamin C, thiamine, hydrocortisone, or combinations of these drugs was not proven to reduce long-term mortality. However, the component network meta-analysis suggested an association of high-dose (>6 g/day) and very-high dose vitamin C (>12 g/day) and decreased mortality but with low certainty. The preclinical investigations have, however, advanced to much higher doses of intravenous vitamin C therapy since a scoping review on harm reported that mega-doses of intravenous vitamin C (50-100 g/day) had been administered without any conclusive adverse effects. In a Gram-negative sheep model, renal tissue hypoperfusion was reversed, followed by improvements in kidney function when a mega-dose of vitamin C (150 g/day equivalent) was administered. SUMMARY: The effect of intravenous vitamin C in critically ill patients has yet to be determined and might be dose-dependent. Clinical studies of very high or mega doses of vitamin C are justified by preclinical data.

Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19.

Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID-19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram-negative bacteria-induced sepsis. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID-19.

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 (~80 mm Hg). MEASUREMENTS AND MAIN RESULTS: Sepsis-induced fever (41.4 ± 0.2°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 Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/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°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (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.