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Reanalysis of the Effect of Vitamin C on Mortality in the CITRIS-ALI Trial: Important Findings Dismissed in the Trial Report.
Hemilä, H, Chalker, E
Frontiers in medicine. 2020;7:590853
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This article is a re-analysis of data from a clinical trial into the effects of intravenous vitamin C on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure. The authors of this critique argue that the way the results were presented in the original paper is misleading. In particular, they criticise the focus on biomarkers, rather than important clinical outcomes. Apparently, whilst many of the biomarkers showed no significant improvements, vitamin C significantly improved three out of four clinically important outcomes: ICU-free days, hospital-free days, and mortality, but not ventilator-free days. The authors also point out a number of flaws in study design, for example, mortality follow-up was 28 days although vitamin C was only given for four days, and apparently data showed significantly better outcomes whilst patients received vitamin C. Overall, the authors of this critique conclude that the effect of vitamin C on mortality in this study is not equal to placebo as suggested by the authors of the original paper, but that vitamin C causes an 81% reduction in mortality which is similar to that shown in other clinical studies.
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Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis.
Hemilä, H, Chalker, E
Journal of intensive care. 2020;8:15
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Whilst 100mg vitamin C per day may be sufficient to maintain normal plasma vitamin C levels in healthy people, critically ill patients appear to have a much greater need for vitamin C. A previous meta-analysis showed that vitamin C supplementation shortened the stay in intensive care units (ICU) by 7.8% and duration of mechanical ventilation by 18%. The extent to which vitamin C shortened need for ventilation varied greatly between studies and appeared to depend on duration of ventilation in the control group which reflects the severity of illness in the study population. The aim of this study was to confirm this theory by analysing the relationship between the effect of vitamin C in the treatment group and the duration of mechanical ventilation in the control group, as a proxy for the severity of the disease. Nine trials with 975 patients overall were included in the analysis. Vitamin C was administered either orally or intravenously and dosages ranged between 1-6g per day for all but one trial which used 90g per day. Severity of illness at baseline varied greatly between studies, with a 250-fold variation of length of mechanical ventilation. The analysis confirmed that when duration of ventilation was less than 10 hours there was no meaningful benefit from vitamin C whilst there was a 31% decrease in duration of mechanical ventilation when durations were longer than 100 hours, reflecting the severity of the illnesses included in the studies. The study with the highest dose of vitamin C saw the largest effects but the authors attributed this to the fact that this study had the sickest patient population rather than to the high dose of vitamin C.
Abstract
BACKGROUND Our recent meta-analysis indicated that vitamin C may shorten the length of ICU stay and the duration of mechanical ventilation. Here we analyze modification of the vitamin C effect on ventilation time, by the control group ventilation time (which we used as a proxy for severity of disease in the patients of each trial). METHODS We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials and reference lists of relevant publications. We included controlled trials in which the administration of vitamin C was the only difference between the study groups. We did not limit our search to randomized trials and did not require placebo control. We included all doses and all durations of vitamin C administration. One author extracted study characteristics and outcomes from the trial reports and entered the data in a spreadsheet. Both authors checked the data entered against the original reports. We used meta-regression to examine whether the vitamin C effect on ventilation time depends on the duration of ventilation in the control group. RESULTS We identified nine potentially eligible trials, eight of which were included in the meta-analysis. We pooled the results of the eight trials, including 685 patients in total, and found that vitamin C shortened the length of mechanical ventilation on average by 14% (P = 0.00001). However, there was significant heterogeneity in the effect of vitamin C between the trials. Heterogeneity was fully explained by the ventilation time in the untreated control group. Vitamin C was most beneficial for patients with the longest ventilation, corresponding to the most severely ill patients. In five trials including 471 patients requiring ventilation for over 10 h, a dosage of 1-6 g/day of vitamin C shortened ventilation time on average by 25% (P < 0.0001). CONCLUSIONS We found strong evidence that vitamin C shortens the duration of mechanical ventilation, but the magnitude of the effect seems to depend on the duration of ventilation in the untreated control group. The level of baseline illness severity should be considered in further research. Different doses should be compared directly in future trials.
3.
Vitamin C: an essential "stress hormone" during sepsis.
Marik, PE
Journal of thoracic disease. 2020;12(Suppl 1):S84-S88
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Most mammals can synthesise vitamin C, except humans, other primates and guinea pigs, who lost this ability through a mutation. It is estimated that goats produce 2-4g of vitamin C per day, but significantly more when stressed. Vitamin C is thought to play an important role in our stress response. This short review articles discusses the importance of vitamin C during stress, in particular the stress of sepsis. The adrenal glands, our “stress organs”, contain very high levels of vitamin C which is released when the hypothalamus-pituitary-adrenal (HPA) axis (which deals with our response to stressors) is stimulated. In animals, there is an inverse relationship between vitamin C internal manufacture and cortisol release under stress: the less vitamin C an animal can produce, the more cortisol they release. A number of vitamin C’s biological actions including antioxidant, anti-inflammatory, immune function, synthesis of the stress hormones adrenaline and noradrenaline and wound healing, may play an important role during a stress response. During sepsis vitamin C gets used up at alarming rate. Sepsis is a complex disease and vitamin C’s biological actions can affect many of the underlying pathophysiological processes. Preclinical and clinical studies have shown a beneficial effect of vitamin C in patients with sepsis and synergistic effects are seen with thiamine (vitamin B1), corticosteroids and antibiotics.
Abstract
The stress response is a preserved evolutionary response that functions to enhance the survival of the species. In mammals, the stress response is characterized by activation of the HPA axis and sympathoadrenal system (SAS) as well as the increased synthesis and secretion of vitamin C. Cortisol, catecholamines, and vitamin C act synergistically to increase hemodynamic reserve, maintain immune function and protect the host against excessive oxidant injury. Humans (and anthropoid apes) have lost the ability to synthesize vitamin C and therefore have an impaired stress response. The inability to produce vitamin C has serious implications in septic humans. Treatment with vitamin C appears to restore the stress response and improve the survival of stressed humans.
4.
Vitamin C: should we supplement?
Spoelstra-de Man, AME, Elbers, PWG, Oudemans-Van Straaten, HM
Current opinion in critical care. 2018;24(4):248-255
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Vitamin C deficiency is frequently encountered in critically ill patients due to their increased needs and diminished intake. The aim of this review was to summarise the current role of Vitamin C in critically ill patients. The review discussed clinical and preclinical studies published in the past 5 years investigating repletion and pharmacological dosing of intravenous vitamin C as adjuvant therapy in trauma, ischemia/reperfusion injury (tissue damage caused when blood supply returns to tissue) and sepsis (the body's response to an infection). Results indicate that during critical illness, vitamin C has antioxidant, anti-inflammatory and immune-supporting effects. It also acts as a cofactor for certain enzymes. Authors conclude that vitamin C supplementation (repletion and/or pharmacological dose) is a promising potential adjuvant therapy for critical illnesses with increased oxidative stress.
Abstract
PURPOSE OF REVIEW Hypovitaminosis C and vitamin C deficiency are very common in critically ill patients due to increased needs and decreased intake. Because vitamin C has pleiotropic functions, deficiency can aggravate the severity of illness and hamper recovery. RECENT FINDINGS Vitamin C is a key circulating antioxidant with anti-inflammatory and immune-supporting effects, and a cofactor for important mono and dioxygenase enzymes. An increasing number of preclinical studies in trauma, ischemia/reperfusion, and sepsis models show that vitamin C administered at pharmacological doses attenuates oxidative stress and inflammation, and restores endothelial and organ function. Older studies showed less organ dysfunction when vitamin C was administered in repletion dose (2-3 g intravenous vitamin C/day). Recent small controlled studies using pharmacological doses (6-16 g/day) suggest that vitamin C reduces vasopressor support and organ dysfunction, and may even decrease mortality. SUMMARY A short course of intravenous vitamin C in pharmacological dose seems a promising, well tolerated, and cheap adjuvant therapy to modulate the overwhelming oxidative stress in severe sepsis, trauma, and reperfusion after ischemia. Large randomized controlled trials are necessary to provide more evidence before wide-scale implementation can be recommended.
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SunGold Kiwifruit Supplementation of Individuals with Prediabetes Alters Gut Microbiota and Improves Vitamin C Status, Anthropometric and Clinical Markers.
Wilson, R, Willis, J, Gearry, RB, Hughes, A, Lawley, B, Skidmore, P, Frampton, C, Fleming, E, Anderson, A, Jones, L, et al
Nutrients. 2018;10(7)
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Increased plasma glucose levels are linked with increased oxidative stress. An increase in the uptake of antioxidants such as vitamin C through diet has been demonstrated by several studies as contributing to the maintenance of normal glucose levels and reducing the risk factors for Type 2 diabetes. The aim of this study was to investigate the vitamin C status, anthropometric measurements and faecal microbiota of an individual on consumption of high vitamin C kiwi fruit for a period of 12 weeks. Baseline measures were compared at the end of 12 weeks resulting in significant increase in plasma vitamin C status (14 µmol/L, p < 0.001). Significant reduction in blood pressure measurement (4 mmHg, p = 0.029), reduction in waist- to- hip ratio and waist- circumference, decrease in blood glucose marker HbA1c (1 mmol/mol, p = 0.005) and increase in fasting glucose (0.1 mmol/L, p = 0.046) were also observed at the end of twelve weeks. Faecal microbiota composition showed an increase in the abundance of uncharacterised bacterial family. The authors concluded that these result were not sufficiently significant to draw conclusions and further studies with larger sample sizes are required to confirm the outcomes of this study.
Abstract
Kiwifruit are a nutrient dense food and an excellent source of vitamin C. Supplementation of the diet with kiwifruit enhances plasma vitamin C status and epidemiological studies have shown an association between vitamin C status and reduced insulin resistance and improved blood glucose control. In vitro experiments suggest that eating kiwifruit might induce changes to microbiota composition and function; however, human studies to confirm these findings are lacking. The aim of this study was to investigate the effect of consuming two SunGold kiwifruit per day over 12 weeks on vitamin C status, clinical and anthropometric measures and faecal microbiota composition in people with prediabetes. This pilot intervention trial compared baseline measurements with those following the intervention. Participants completed a physical activity questionnaire and a three-day estimated food diary at baseline and on completion of the trial. Venous blood samples were collected at each study visit (baseline, 6, 12 weeks) for determination of glycaemic indices, plasma vitamin C concentrations, hormones, lipid profiles and high-sensitivity C-reactive protein. Participants provided a faecal sample at each study visit. DNA was extracted from the faecal samples and a region of the 16S ribosomal RNA gene was amplified and sequenced to determine faecal microbiota composition. When week 12 measures were compared to baseline, results showed a significant increase in plasma vitamin C (14 µmol/L, p < 0.001). There was a significant reduction in both diastolic (4 mmHg, p = 0.029) and systolic (6 mmHg, p = 0.003) blood pressure and a significant reduction in waist circumference (3.1 cm, p = 0.001) and waist-to-hip ratio (0.01, p = 0.032). Results also showed a decrease in HbA1c (1 mmol/mol, p = 0.005) and an increase in fasting glucose (0.1 mmol/L, p = 0.046), however, these changes were small and were not clinically significant. Analysis of faecal microbiota composition showed an increase in the relative abundance of as yet uncultivated and therefore uncharacterised members of the bacterial family Coriobacteriaceae. Novel bacteriological investigations of Coriobacteriaceae are required to explain their functional relationship to kiwifruit polysaccharides and polyphenols.