Introduction
Review
Pathophysiology
Role of vitamin C: in vitrostudies
Endothelial dysfunction
Endothelial permeability
Impairment of microcirculatory flow
Myocardial effects of vitamin C in ischemia/reperfusion
Immune effects of vitamin C in sepsis
Role of vitamin C: animal studies
Ischemia/reperfusion
Model; dose and timing of ascorbate [study] | Pathophysiological effect | Mechanisms |
---|---|---|
Ischemia reperfusion
| ||
Cardiac arrest (VF-ES) in rats; 50 and 100 mg/kg i.v. at start of CPR [33] | Increases successful resuscitation after cardiac arrest rates and 72-hour survival (100 mg/kg better than 50 mg/kg) | Preservation of histology |
Reduced mitochondrial swelling | ||
Preserves mitochondrial respiration (complex I and IV) | ||
Inhibits MDA ↑ | ||
LAD coronary artery ischemia ± ischemic preconditioning in pigs; 2 g i.v. + 25 mg/minute before IPC or before ischemia [42] | Does not affect infarct size | |
Attenuates the beneficial effect of ischemic preconditioning indicating free oxygen radicals are involved in ischemic preconditioning | ||
Middle cerebral artery clamping in mice; DHA 40, 250 and 500 mg/kg, AA 250 and 500 mg/kg, before, 15 minutes and 3 hours after [81] | DHA gives dose-dependent: | DHA passes blood–brain barrier, ascorbate does not |
● Reperfusion blood flow ↑ | No beneficial effect of ascorbate | |
● Infarct size ↓ | ||
● Neurological deficit ↓ | ||
● Mortality ↓ (if given before ischemia) | ||
Abdominal aortic clamping in rats; 100 mg/kg i.v. before [37] | Attenuates lung injury | MDA in blood and lung ↓ |
Renal ischemia in rabbits; 15 mg/kg 24 hours and 1 hour before and 0.83 mg/minute during [34] | Ameliorates renal structure and function | PAF and PAF-like lipids ↓ |
Myeloperoxidase activity ↓ | ||
Hepatic ischemia (clamping HA–PV) rats; 30, 100, 300, and 1,000 mg/kg 5 minutes before [38] | Bile flow and cholate secretion ↑ | 30 and 100 mg/kg: |
Extremely high dose is prooxidant | ● AST and lipid peroxidation ↓ | |
● Prevents ↓ of cytochrome P450 1,000 mg/kg | ||
● Injury and loss of function ↑ | ||
IPC + hepatic ischemia (clamping left HA and PV) in rats; 100 mg/kg i.v. after IPC before clamping [41] | Ascorbate or IPC plus ascorbate after IPC reduce mitochondrial damage and dysfunction | Prevents mitochondrial: |
● Swelling | ||
● Peroxide ↑, MDA ↑ | ||
● GSH and GSH/GSSG ↓ | ||
● Glutamate dehydrogenase ↓ | ||
● ATP ↓ (ascorbate plus IPC) | ||
Liver ischemia in rats; 100 mg/kg i.v. 1 hour before [40] | Attenuates reperfusion liver injury | Attenuation of O2
– and NO release |
Liver ischemia (clamping HA and PV) in rats; oral vitamin C for 5 days [39] | Attenuates myocardial injury and protects cardiac function after liver ischemia | Systemic hydroxyl radical ↓ |
Myocardial MDA | ||
Skeletal muscle ischemia in rats; oral vitamin C for 5 days [35] | Preserves muscle function | Muscle myeloperoxidase ↓ |
Reduces edema | Neutrophil infiltration ↓ | |
Respiratory burst ↓ | ||
Skeletal muscle tourniquet in rats; 50 mg/kg i.v. before ischemia, before reperfusion, or both [36] | Preserves muscle function | Blood malondialdehyde↓ |
Reduces edema | Muscle malondialdehyde = | |
Neutrophil influx | ||
Sepsis
| ||
Systemic and microcirculation
| ||
CLP in rats; 76 mg/kg i.v. directly after [32] | Restores blood pressure and density of perfused capillaries | |
CLP in mice; 200 mg/kg 30 minutes before [6] | Improves microvascular constriction and arterial pressure responses to norepinephrine | iNOS expression ↓ |
iNOS mRNA ↓ | ||
ROS production ↓ | ||
CLP in mice; baseline and 23 hours after 200 mg/kg [48] | Restores arteriolar conducted vasoconstriction | Reduces increased: |
● nNOS activity | ||
● Nitrite/nitrate | ||
CLP in rats; 76 mg/kg after 1 hour, 6 hours and 2 hours [44] | Prevents maldistributed blood flow and low arterial blood pressure | Blood flow impairment: |
● Requires NADPH oxidase | ||
● Reversal by ascorbate or BH4
| ||
● eNOS dependent | ||
FIP in mice; 10 or 200 mg/kg i.v. 6 hours after [47] | Prevents/reverses septic impairment of capillary blood flow for 18 hours and improves survival | Blood flow impairment depends on the NADPH oxidase subunit gp91phox |
Ascorbate effects are eNOS dependent | ||
Ascorbate suppresses iNOS ↑ activity | ||
FIP in mice; 10 mg/kg i.v. prophylactic or delayed [46] | Prevention or reversal of septic platelet adhesion and/or flow stoppage | Capillary flow stoppage |
● eNOS dependent | ||
● Platelet adhesion predicts 90 % | ||
CLP in mice; 200 mg/kg i.v. at baseline and 3 hours after [50] | Prevents vascular leakage | Inhibits production of: |
● O2
– and NO by NADPH oxidase, iNOS and nNOS | ||
● Peroxynitrite | ||
● 3-Nitrotyrosine-positive proteins ↓ | ||
● Inhibits PP2A activation | ||
Preserves endothelial occludin phosphorylation | ||
Organ injury and function
| ||
Intraperitoneal LPS in guinea pigs; low vs. high vitamin C diet [51] | Dietary vitamin C | Hepatic lipid peroxidation ↓ |
Increases hepatic vitamin C and vitamin E content | Hepatic protein carbonyls ↓ | |
Reduces oxidative damage to lipids and proteins | Hepatic GSH and GSH/GSSG ↑ (vitamin C + vitamin E) | |
CLP in rats; 100 mg/kg directly after [53] | Decreases hepatic injury | Suppresses AST and ALT ↑ |
Improves drug-metabolizing function | Prevents GSH and GSH/GSSG ↓ | |
Prevents CYP1A1 and CYP2E1 mRNA, and CYP1A2 activity | ||
FIP or LPS in mice; 200 mg/kg i.p. after LPS [54] | Attenuates sepsis-induced acute lung injury and improves 72-h survival | Preserves lung architecture and barrier |
Proinflammatory chemokine expression ↓ microvascular thrombosis ↓ | ||
Nuclear factor-kappaB activation ↓ | ||
Normalizes coagulation | ||
Immune defense against infection
| ||
Klebsiella pneumonia in mice; ascorbate deficient vs. ascorbate supplemented for 25 days [56] | Ascorbate deficiency increases death from infection | No effect on: |
● Cellular response | ||
● Amino acid and lipid peroxidation | ||
Higher concentration of bacteria in ascorbate deficiency |
Sepsis
Ascorbate depletion
Systemic circulation, microcirculation and permeability
Effects on organ injury and function
Role of vitamin C in ischemia/reperfusion and sepsis: human volunteers
Plasma concentrations, dose and pharmacokinetics of vitamin C: patients
Plasma concentrations
Dosing
Role of vitamin C in ischemia/reperfusion: clinical studies
Percutaneous coronary intervention
Cardiac surgery
Study | Design | Intervention | Number of patients | Incidence of new POAF (%) |
Pvalue | Other clinical benefits |
---|---|---|---|---|---|---|
Dingchao and colleagues [101] | Controlled; patients undergoing cardiopulmonary bypass | i.v. vitamin C; 250 mg/kg i.v. before | 45 | MDA ↓; CK, CK-MB ↓; postbypass defibrillation 0 vs. 12.5 %; CI ↑, LOS ICU ↓, LOS hospital ↓ | ||
Control | 40 | |||||
Carnes and colleagues [82] | Matched control; CABG | Oral vitamin C; 2 g night before, 500 mg daily for 5 days | 43 | 16.3 | 0.048 | |
Matched control | 43 | 34.9 | ||||
Eslami and colleagues [98] | RCT; CABG | β-Blocker + oral vitamin C; 2 g night before, 1 g twice daily for 5 days | 50 | 4 | 0.002 | |
β-Blocker alone | 50 | 26 | ||||
Bjordahl and colleagues [99] | RCT; CABG | Oral vitamin C; 2 g night before, 1 g twice daily for 5 days | 89 | 30.3 | 0.985 | Shorter time on ventilator, 1.2 vs. 1.4 days, P = 0.032 |
Placebo | 96 | 30.2 | ||||
Papoulidis and colleagues [100] | RCT; CABG | i.v. vitamin C; 2 g 3 hours before CPB | 85 | 44.7 | 0.041 | Time to SR conversion ↓, LOS hospital ↓, LOS ICU ↓ |
i.v. saline | 85 | 61.2 | ||||
Rodrigo and colleagues [95] | RCT | Preoperative PUFA; 2 g/day for 5 days; vitamin C 1 g/day + vitamin E 400 IU/day for 2 days preoperatively and postoperatively until discharge | 103 | 9.7 | <0.001 | Oxidative stress-related biomarkers in atrial tissue ↓ |
Placeboa
| 100 | 32 |
Critically ill patients
Study | Design | Intervention | Number of patients | Outcome |
---|---|---|---|---|
Nathens and colleagues [104] | RCT; trauma and MOF | i.v. vitamin C 1 g three times daily; enteral vitamin E 1,000 IU three times daily | 301 | Pulmonary morbidity ↓, new MOF ↓, LOS ventilation ↓, LOS ICU ↓ |
With TPN, vitamin C 100 mg and vitamin E 10 IU daily; with EN, vitamin C 340 mg/l, vitamin E 60 IU/l | 294 | |||
Crimi and colleagues [107] | RCT; critically ill (mainly trauma, cardiogenic shock) | Vitamin C 500 mg/day and vitamin E (400 IU/day) in EN | 105 | Ventilator-free days ↓, 28-day mortality ↓ |
Saline solution for 10 days | 111 | |||
Collier and colleagues [103] | Prospective vs. retrospective 1-year cohort; trauma | i.v. or oral vitamin C 1 g three times daily + oral vitamin E 1,000 IU three times daily + selenium 200 μg i.v. | 2,272 | LOS ICU ↓, LOS hospital ↓, mortality ↓; OR 0.32, 95 % CI 0.22 to 0.46 |
Standard therapy | 2,022 | |||
Berger and colleagues [105] | RCT; complicated cardiac surgery, trauma, SAB | Selenium 540 i.v. day 1, 270 μg days 2 to 5; zinc 60 mg i.v. day 1, 30 mg days 2 to 5; vitamin B1 305 mg i.v. day 1, 205 mg days 2 to 5; vitamin C 2.7 g i.v. day 1, 1.6 g days 2 to 5; vitamin E 600 mg i.v. day 1, 300 mg days 2 to 5 | 102 | New organ failure ND, new infections ND, LOS shorter in trauma, CRP ↓ in cardiac surgery and trauma, recovery of health after discharge ↑ |
Vitamin B1 100 mg i.v. days 1 to 3 (both groups); vitamin C 500 mg i.v. days 1 to 5 (both groups) | 98 | |||
Heyland and colleagues [106] | RCT, 2 × 2 factorial; critically ill adults with multiple organ failure | Selenium 500 μg i.v., selenium 300 μg or zinc 20 mg or β-carotene 10 mg; vitamin E 500 mg or vitamin C 1,500 mg | 307 | No difference in 28-day mortality or length of stay |
Burn
| Placebo | 300 | ||
Tanaka and colleagues [84] | RCT; severe burn <2 hours | Ringer lactate + 66 mg/kg/hour vitamin C | 19 | Fluid requirements ↓, body weight gain ↓, PF ratio ↑, days on mechanical ventilation ↓ |
Ringer lactate for 24 hours | 18 | |||
Kahn and colleagues [85] | Retrospective; severe burn <10 hours | Ringer lacate + 66 mg/kg/hour vitamin C | 17 | Fluid requirements ↓, urinary output ↑ |
Ringer lactate for 24 hours | 16 |