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. 2021 Feb 1;49(2):e179-e190.
doi: 10.1097/CCM.0000000000004770.

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

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

Yugeesh R Lankadeva et al. Crit Care Med. .

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.

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Figures

Figure 1.
Figure 1.
Changes in systemic hemodynamics in response to sodium ascorbate (Na Asc) (closed squares, n = 5) or vehicle (open circles, n = 5) treatment during ovine sepsis and during recovery from Gram-negative infection. Mean arterial pressure (A), norepinephrine dose (B), cardiac output (C), heart rate (D), total peripheral conductance, and core temperature (F) during infusion of Escherichia coli from 0 to 31 hr of sepsis and then recovery over 48 hr following antibiotic therapy. All animals were initially resuscitated with fluid bolus therapy (fluid BT, 30-mL/kg balanced crystalloid over 30 min) from 23.5 to 24 hr of sepsis. Animals were randomized to receive Na Asc (0.5 g/kg) or vehicle, crystalloid BT, from 24 to 24.5 hr of sepsis followed by an infusion of sodium ascorbate (0.5 g/kg/hr) or vehicle crystalloid from 24.5 to 31 hr of sepsis. Norepinephrine doses were titrated to maintain mean arterial pressure at baseline levels (75–80 mm Hg) from 25 to 31 hr of sepsis. All animals received IV antibiotics at 31 hr of sepsis (1-g ceftriaxone), with a repeated dose at 24 hr, and their recovery from infection was monitored over 48 hr. Time 0 is the mean of the 24th hr of baseline and times 23–31 hr of sepsis and 48 hr of recovery are means of 0.5-hr periods. Data are presented as treatment group-specific mean ± sd. p values represent treatment-time interactions from a two-way repeated measures analysis of variance from 23 to 31 hr of Gram-negative sepsis. Following antibiotic therapy and cessation of Escherichia coli infusion, significant differences between the baseline (time 0) time point and the 16-, 24-, 40-, and 48-hr time points are indicated by *p < 0.05 in the vehicle treatment group. p values represent the results of a Dunnett test using absolute values.
Figure 2.
Figure 2.
Changes in renal hemodynamics, intrarenal tissue perfusion, and oxygenation in response to sodium ascorbate (Na Asc) (closed squares, n = 5) or vehicle (open circles, n = 5) treatment during ovine sepsis and during recovery from Gram-negative infection. Renal blood flow (A), renal vascular conductance (B), medullary perfusion (C), cortical perfusion (D), medullary oxygen tension (Po2) (E), and cortical Po2 (F) during infusion of Escherichia coli from 0 to 31 hr of sepsis and then recovery over 48 hr following antibiotic therapy. Fluid and drug infusions and statistical analyses are as detailed in Figure 1. BT = bolus therapy.
Figure 3.
Figure 3.
Changes in renal functional and plasma osmolar gap in response to sodium ascorbate (Na Asc) (closed squares, n = 5) or vehicle (open circles, n = 5) treatment during ovine sepsis and during recovery from Gram-negative infection. Urine output (A), plasma creatinine (B), creatinine clearance (C), fractional sodium excretion (D), plasma osmolar gap (E), and fractional potassium excretion (F) during infusion of Escherichia coli from 0 to 31 hr of sepsis and then recovery over 48 hr following antibiotic therapy. Significant differences between the baseline (time 0) time point and the 16-, 24-, 40-, and 48-hr time points are indicated by *p < 0.05 in the vehicle-treatment group and #p < 0.05 in the Na Asc–treatment group. Fluid and drug infusions and statistical analyses are as detailed in Figure 1. BT = bolus therapy.
Figure 4.
Figure 4.
Changes in arterial blood biochemistry in response to sodium ascorbate (Na Asc) (closed squares, n = 5) or vehicle (open circles, n = 5) treatment during ovine sepsis and during recovery from Gram-negative infection. Arterial blood lactate (A), arterial blood pH (B), oxygen tension (Po2) (C), arterial blood sodium (D), partial pressure of carbon dioxide (Pco2) (E), and arterial blood potassium (F) during infusion of Escherichia coli from 0 to 31 hr of sepsis and then recovery over 48 hr following antibiotic therapy. Significant differences between the baseline (time 0) time point and the 16-, 24-, 40-, and 48-hr time points are indicated by #p < 0.05 in the Na Asc–treatment group. Fluid and drug infusions and statistical analyses are as detailed in Figure 1. BT = bolus therapy.
Figure 5.
Figure 5.
Changes in systemic hemodynamics and renal function in response to megadose sodium ascorbate (Na Asc) treatment in one septic patient with a severe case of coronavirus disease 2019 (n = 1). Norepinephrine dose (A), oxygen tension (Po2) (filled squares) and inspired oxygen fraction (open circles) (B), mean arterial pressure (C), serum creatinine (D), heart rate (E), and urine output (F) are presented at pretreatment (time 0), after a 30-min infusion of Na Asc bolus therapy (BT, 30 g), and then at hourly intervals during an infusion of Na Asc for 6.5 hr (4.6 g/hr).

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