Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C. Issue 2 (February 2021)

• Record Type: Journal Article
• Authors: Lankadeva, Yugeesh R.; Peiris, Rachel M.; Okazaki, Nobuki; Birchall, Ian E.; Trask-Marino, Anton; Dornom, Anthony; Vale, Tom A. M.; Evans, Roger G.; Yanase, Fumitaka; Bellomo, Rinaldo; May, Clive N.
• Is Part Of: Critical care medicine. Volume 49:Issue 2(2021)
• Publication Date: 2021-02
• Subjects: acute kidney injury -- antioxidant -- coronavirus disease 2019 -- hypoxia -- sepsis -- sodium ascorbate; Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000004770
• Languages: English
• ISSNs: 0090-3493

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.