Special Issue "Vitamin C in the Critically Ill, Effects on Oxidative Stress and the Immune System"

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editors

Prof. Heleen M Oudemans-van Straaten
E-Mail Website
Guest Editor
Department of Intensive Care, VU University Medical Center, Amsterdam, Netherlands
Dr. Angelique M.E. Spoelstra-de Man
E-Mail Website
Guest Editor
Department of Intensive Care, VU University Medical Center, Amsterdam, Netherlands

Special Issue Information

Dear Colleagues,

Vitamin C is crucial for life. Humans have lost the ability to synthesize this simple molecule and depend on nutritional intake to maintain body stores. Deficiency is no more a historical disease, but develops daily in critically-ill patients. Overwhelming oxidative stress and systemic inflammation confer scurvy-like vitamin C concentrations.

Vitamin C has a myriad of functions. As primary circulating antioxidant, cofactor for mono- and dioxygenase enzymes, mitigator of the inflammatory response with immune supporting properties, vitamin C protects vascular and organ cells and may thereby promote patient recovery. Up to now, deficiency goes unnoticed because an assessment of vitamin C status is not available in clinical practice. While older studies show that repletion of vitamin C improves recovery from organ failure, two recent small controlled trials in severe sepsis have additionally shown an impressive reduction in mortality when pharmacological doses of vitamin C were administered alone or in combination with thiamine and hydrocortisone. However, many questions remain.

It is our pleasure to invite researchers to provide contributions reporting clinical or preclinical research or updated reviews for a Special Issue of Nutrients entitled “Vitamin C in the Critically Ill, Effects on Oxidative Stress and the Immune System”. Manuscript elucidating mechanisms of action, metabolism and recycling, assessment of deficiency, dosing, timing and side effects of vitamin C or combination strategies are very welcome.

Prof. Heleen M Oudemans-van Straaten
Dr. Angelique M.E. Spoelstra-de Man
Guest Editors

Manuscript Submission Information

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Keywords

  • Vitamin C
  • Critically ill
  • Intensive care
  • Sepsis
  • Ischemia reperfusion

Published Papers (8 papers)

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Research

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Open AccessArticle
Perioperative Vitamin C and E levels in Cardiac Surgery Patients and Their Clinical Significance
Nutrients 2019, 11(9), 2157; https://doi.org/10.3390/nu11092157 - 09 Sep 2019
Abstract
Background: Oxidative stress contributes to organ dysfunction after cardiac surgery and still represents a major problem. Antioxidants, such as vitamins C and E might be organ protective. Methods: The primary objective of this prospective observational study was the description to evaluate the perioperative [...] Read more.
Background: Oxidative stress contributes to organ dysfunction after cardiac surgery and still represents a major problem. Antioxidants, such as vitamins C and E might be organ protective. Methods: The primary objective of this prospective observational study was the description to evaluate the perioperative vitamin C and E levels in 56 patients undergoing cardiac surgery with the use of cardiopulmonary bypass. The association of vitamin C with inflammatory reaction, oxidative stress, organ dysfunctions, and clinical outcomes were evaluated in an explorative approach. Results: Vitamin C levels decreased significantly from 6.5 (3.5–11.5) mg/L before surgery to 2.8 (2.0–3.9) mg/L 48 h after surgery (p < 0.0001). Fifty-six percent of patients had a suboptimal vitamin C status even before surgery. In protein-denaturized probes, significantly higher vitamin C concentrations were detected (p = 0.0008). Vitamin E levels decreased significantly from preoperative level 11.6 (9.5–13.2) mg/L to 7.1 (5.5–7.4) mg/L, (p = 0.0002) at the end of cardiopulmonary bypass, remained low during the first day on ICU and recovered to 8.2 (7.1–9.3) mg/L 48 h after surgery. No patient was vitamin E deficient before surgery. Analysis showed no statistically significant association of vitamin C with inflammation, oxidative stress or organ dysfunction levels in patients with previously suboptimal vitamin C status or patients with a perioperative decrease of ≥50% vitamin C after surgery. Patients with higher vitamin C levels had a shorter ICU stay than those who were vitamin C depleted, which was not statistically significant (72 versus 135 h, p = 0.1990). Conclusion: Vitamin C and E levels significantly declined intraoperatively and remained significantly reduced low for 2 days after cardiac surgery. The influence of reduced serum levels on the inflammatory reaction and clinical outcome of the patients remain unclear in this small observational study and need to be investigated further. Given vitamin C´s pleiotropic role in the human defense mechanisms, further trials are encouraged to evaluate the clinical significance of Vitamin C in cardiac surgery patients. Full article
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Open AccessArticle
Effects of Vitamin C on Organ Function in Cardiac Surgery Patients: A Systematic Review and Meta-Analysis
Nutrients 2019, 11(9), 2103; https://doi.org/10.3390/nu11092103 - 04 Sep 2019
Cited by 1
Abstract
Background: Cardiac surgery is associated with oxidative stress and systemic inflammation, which both contribute to postoperative organ dysfunction. Vitamin C is a pleiotropic, antioxidant, and potentially organ-protective micronutrient. Past clinical trials and meta-analyses have focused predominantly on occurrence of postoperative atrial fibrillation. Therefore, [...] Read more.
Background: Cardiac surgery is associated with oxidative stress and systemic inflammation, which both contribute to postoperative organ dysfunction. Vitamin C is a pleiotropic, antioxidant, and potentially organ-protective micronutrient. Past clinical trials and meta-analyses have focused predominantly on occurrence of postoperative atrial fibrillation. Therefore, we investigated the influence of perioperative vitamin C administration on clinically relevant parameters closer related to the patient’s recovery, especially organ function, and overall outcomes after cardiac surgery. Methods: Randomized controlled trials (RCTs) comparing perioperative vitamin C administration versus placebo or standard of care in adult patients undergoing cardiac surgery were identified through systematic searches in Pubmed, EMBASE, and CENTRAL on 23 November 2018. Published and unpublished data were included. Assessed outcomes include organ function after cardiac surgery, adverse events, in-hospital mortality, intensive care unit, and hospital length-of-stay. Data was pooled only when appropriate. Results: A total of 19 RCTs with 2008 patients were included in this meta-analysis. Vitamin C significantly decreased the incidence of atrial fibrillation (p = 0.008), ventilation time (p < 0.00001), ICU length-of-stay (p = 0.004), and hospital length-of-stay (p < 0.0001). However, on average, vitamin C had no significant effects on in-hospital mortality (p = 0.76), or on the incidence of stroke (p = 0.82). High statistical heterogeneity was observed in most analyses. Conclusions: Vitamin C impacts clinically and economically important outcomes, such as ICU and hospital length-of-stay, duration of mechanical ventilation and lowers the incidence of atrial fibrillation. Due to missing reports on organ dysfunction, this meta-analysis cannot answer the question, if vitamin C can improve single- or multiorgan function after cardiac surgery. Full article
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Open AccessArticle
Administration of Intravenous Ascorbic Acid—Practical Considerations for Clinicians
Nutrients 2019, 11(9), 1994; https://doi.org/10.3390/nu11091994 - 23 Aug 2019
Abstract
Emerging data suggest that intravenous ascorbic acid (AA) may be beneficial in patients with sepsis. Clinicians require data on stability of diluted AA for safe administration. We evaluated the stability of AA diluted in normal saline (NS) or 5% dextrose in water (D5W) [...] Read more.
Emerging data suggest that intravenous ascorbic acid (AA) may be beneficial in patients with sepsis. Clinicians require data on stability of diluted AA for safe administration. We evaluated the stability of AA diluted in normal saline (NS) or 5% dextrose in water (D5W) solutions over 14 days at 25 °C and at 4 °C, protected from light, using concentrations of 37 mg/mL and 77 mg/mL (Sandoz) and 40 mg/mL and 92 mg/mL (Mylan). We also assessed stability of a 40 mg/mL solution (Mylan) at 25 °C exposed to light for 75 h. Concentrations were measured using liquid chromatographic separation with ultraviolet light detection on days 0, 0.33, 1, 1.33, 2, 3, 4, 7, 10 and 14. By day 14, solutions at 4 °C retained >97.72% of the initial concentration; at 25 °C, solutions retained >88.02% of the initial concentration, but visual changes were evident after day 2. Multiple linear regression demonstrated that study day and temperature (p < 0.001) but not solution type (p = 0.519), concentration (p = 0.677) or manufacturer (p = 0.808) were associated with the percentage remaining. At 75 h, degradation rates were similar in solutions protected from vs. exposed to light. In conclusion, AA solutions are stable for at least 14 days at 4 °C, with protection from light. Full article
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Open AccessArticle
Influence of Vitamin C on Antioxidant Capacity of In Vitro Perfused Porcine Kidneys
Nutrients 2019, 11(8), 1774; https://doi.org/10.3390/nu11081774 - 01 Aug 2019
Abstract
Systemic and localized ischemia and reperfusion injury remain clinically relevant issues after organ transplantation and contribute to organ dysfunctions, among which acute kidney injury is one of the most common. An in vitro test-circuit for normothermic perfusion of porcine kidneys after warm ischemia [...] Read more.
Systemic and localized ischemia and reperfusion injury remain clinically relevant issues after organ transplantation and contribute to organ dysfunctions, among which acute kidney injury is one of the most common. An in vitro test-circuit for normothermic perfusion of porcine kidneys after warm ischemia was used to investigate the antioxidant properties of vitamin C during reperfusion. Vitamin C is known to enhance microcirculation, reduce endothelial permeability, prevent apoptosis, and reduce inflammatory reactions. Based on current evidence about the pleiotropic effects of vitamin C, we hypothesize that the antioxidant properties of vitamin C might provide organ-protection and improve the kidney graft function in this model of ischemia and reperfusion. Methods: 10 porcine kidneys from 5 Landrace pigs were perfused in vitro for 6 h. For each experiment, both kidneys of one animal were perfused simultaneously with a 1:1 mixture of autologous blood and modified Ringer’s solution at 38 °C and 75 mmHg continuous perfusion pressure. One kidney was treated with a 500 mg bolus injection of vitamin C into the perfusate, followed by continuous infusion of 60 mg/h vitamin C. In the control test circuit, an equal volume of Ringer’s solution was administered as a placebo. Perfusate samples were withdrawn at distinct points in time during 6 h of perfusion for blood gas analyses as well as measurement of serum chemistry, oxidative stress and antioxidant capacity. Hemodynamic parameters and urine excretion were monitored continuously. Histological samples were analyzed to detect tubular- and glomerular-injury. Results: vitamin C administration to the perfusate significantly reduced oxidative stress (49.8 ± 16.2 vs. 118.6 ± 23.1 mV; p = 0.002) after 6 h perfusion, and increased the antioxidant capacity, leading to red blood cell protection and increased hemoglobin concentrations (5.1 ± 0.2 vs. 3.9 ± 0.6 g/dL; p = 0.02) in contrast to placebo treatment. Kidney function was not different between the groups (creatinine clearance vit C: 2.5 ± 2.1 vs. placebo: 0.5 ± 0.2 mL/min/100 g; p = 0.9). Hypernatremia (187.8 ± 4.7 vs. 176.4 ± 5.7 mmol/L; p = 0.03), and a lower, but not significant decreased fractional sodium excretion (7.9 ± 2 vs. 27.7 ± 15.3%; p = 0.2) were observed in the vitamin C group. Histological analysis did not show differences in tubular- and glomerular injury between the groups. Conclusion: Vitamin C treatment increased the antioxidant capacity of in vitro perfused kidney grafts, reduced oxidative stress, preserved red blood cells as oxygen carrier in the perfusate, but did not improve clinically relevant parameters like kidney function or attenuate kidney damage. Nevertheless, due to its antioxidative properties vitamin C might be a beneficial supplement to clinical kidney graft perfusion protocols. Full article
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Open AccessArticle
Estimating Vitamin C Status in Critically Ill Patients with a Novel Point-of-Care Oxidation-Reduction Potential Measurement
Nutrients 2019, 11(5), 1031; https://doi.org/10.3390/nu11051031 - 08 May 2019
Cited by 1
Abstract
Vitamin C deficiency is common in critically ill patients. Vitamin C, the most important antioxidant, is likely consumed during oxidative stress and deficiency is associated with organ dysfunction and mortality. Assessment of vitamin C status may be important to identify patients who might [...] Read more.
Vitamin C deficiency is common in critically ill patients. Vitamin C, the most important antioxidant, is likely consumed during oxidative stress and deficiency is associated with organ dysfunction and mortality. Assessment of vitamin C status may be important to identify patients who might benefit from vitamin C administration. Up to now, vitamin C concentrations are not available in daily clinical practice. Recently, a point-of-care device has been developed that measures the static oxidation-reduction potential (sORP), reflecting oxidative stress, and antioxidant capacity (AOC). The aim of this study was to determine whether plasma vitamin C concentrations were associated with plasma sORP and AOC. Plasma vitamin C concentration, sORP and AOC were measured in three groups: healthy volunteers, critically ill patients, and critically ill patients receiving 2- or 10-g vitamin C infusion. Its association was analyzed using regression models and by assessment of concordance. We measured 211 samples obtained from 103 subjects. Vitamin C concentrations were negatively associated with sORP (R2 = 0.816) and positively associated with AOC (R2 = 0.842). A high concordance of 94–100% was found between vitamin C concentration and sORP/AOC. Thus, plasma vitamin C concentrations are strongly associated with plasma sORP and AOC, as measured with a novel point-of-care device. Therefore, measuring sORP and AOC at the bedside has the potential to identify and monitor patients with oxidative stress and vitamin C deficiency. Full article
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Open AccessArticle
Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis
Nutrients 2019, 11(4), 708; https://doi.org/10.3390/nu11040708 - 27 Mar 2019
Cited by 2
Abstract
A number of controlled trials have previously found that in some contexts, vitamin C can have beneficial effects on blood pressure, infections, bronchoconstriction, atrial fibrillation, and acute kidney injury. However, the practical significance of these effects is not clear. The purpose of this [...] Read more.
A number of controlled trials have previously found that in some contexts, vitamin C can have beneficial effects on blood pressure, infections, bronchoconstriction, atrial fibrillation, and acute kidney injury. However, the practical significance of these effects is not clear. The purpose of this meta-analysis was to evaluate whether vitamin C has an effect on the practical outcomes: length of stay in the intensive care unit (ICU) and duration of mechanical ventilation. We identified 18 relevant controlled trials with a total of 2004 patients, 13 of which investigated patients undergoing elective cardiac surgery. We carried out the meta-analysis using the inverse variance, fixed effect options, using the ratio of means scale. In 12 trials with 1766 patients, vitamin C reduced the length of ICU stay on average by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003). In six trials, orally administered vitamin C in doses of 1–3 g/day (weighted mean 2.0 g/day) reduced the length of ICU stay by 8.6% (p = 0.003). In three trials in which patients needed mechanical ventilation for over 24 hours, vitamin C shortened the duration of mechanical ventilation by 18.2% (95% CI 7.7% to 27%; p = 0.001). Given the insignificant cost of vitamin C, even an 8% reduction in ICU stay is worth exploring. The effects of vitamin C on ICU patients should be investigated in more detail. Full article
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Review

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Open AccessReview
The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review
Nutrients 2019, 11(5), 977; https://doi.org/10.3390/nu11050977 - 28 Apr 2019
Cited by 1
Abstract
Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients. This review assesses the effectiveness and safety of vitamin C administration [...] Read more.
Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients. This review assesses the effectiveness and safety of vitamin C administration in cancer. The PubMed and EMBASE databases were searched and all study designs except for phase I studies, and case reports were included in this review. A total of 19 trials were included. In only 4 trials randomization was used to determine if patients received vitamin C or a placebo. The result of this review does not prove that there is a clinically relevant positive effect of vitamin C supplementation in cancer patients in general on the overall survival, clinical status, quality of life (QOL) and performance status (PS), since the quality of the studies published is low. Interventions and patient groups are very diverse, hence an effect in some patient groups is possible. There seems to be a better effect with intravenous than oral administration. Nevertheless, treatment with vitamin C is safe with minimal side effects. Thereby, we think it is safe to examine the effects of vitamin C on specific groups of patients in a randomized controlled setting. Full article
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Open AccessReview
Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid
Nutrients 2018, 10(11), 1762; https://doi.org/10.3390/nu10111762 - 14 Nov 2018
Cited by 6
Abstract
Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination [...] Read more.
Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host’s response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C. Full article
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