Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia.

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson's correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50-100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.

Vitamin C may reduce troponin and CKMB levels after PCI and CABG: a meta-analysis.

BACKGROUND: Ischemia/reperfusion injury contributes to periprocedural myocardial injury (PMI) in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). PMI can be estimated by the elevation of troponin (Tn) and creatine kinase-MB (CKMB) plasma levels, and it is associated with increased risk of cardiovascular events and mortality. Vitamin C might have a beneficial effect on PMI by improving endothelial function, improving myocardial perfusion, and by reducing oxidative stress generated during/after reperfusion. In several small animal models of cardiac stress, vitamin C reduced the increase in Tn and CKMB levels. The aim of this meta-analysis was to investigate whether vitamin C administration may have an effect on Tn and CKMB levels in patients undergoing PCI or CABG. METHODS: We searched PubMed, Cochrane, Embase and Scopus databases for controlled clinical trials reporting on Tn and CKMB levels in adult patients who underwent PCI or CABG and received vitamin C. As secondary outcomes we collected data on biomarkers of oxidative stress in the included trials. In our meta-analysis, we used the relative scale and estimated the effect as the ratio of means. RESULTS: We found seven controlled trials which included 872 patients. All included trials administered vitamin C intravenously, with a range from 1 to 16 g/day, and all initiated vitamin administration prior to the procedure. Vitamin C decreased peak Tn plasma levels in four trials on average by 43% (95% CI: 13 to 63%, p = 0.01) and peak CKMB plasma levels in five trials by 14% (95% CI: 8 to 21%, p < 0.001). Vitamin C also significantly decreased the biomarkers of oxidative stress. CONCLUSIONS: Vitamin C may decrease cardiac enzyme levels in patients undergoing elective PCI or CABG. This may be explained partially by its antioxidant effects. Our findings encourage further research on vitamin C administration during cardiac procedures and in other clinical contexts that increase the level of cardiac enzymes. Future studies should search for an optimal dosing regimen, taking baseline and follow-up plasma vitamin C levels into account.

Rapid screening of critically ill patients for low plasma vitamin C concentrations using a point-of-care oxidation-reduction potential measurement.

BACKGROUND: Hypovitaminosis C and vitamin C deficiency are common in critically ill patients and associated with organ dysfunction. Low vitamin C status often goes unnoticed because determination is challenging. The static oxidation reduction potential (sORP) reflects the amount of oxidative stress in the blood and is a potential suitable surrogate marker for vitamin C. sORP can be measured rapidly using the RedoxSYS system, a point-of-care device. This study aims to validate a model that estimates plasma vitamin C concentration and to determine the diagnostic accuracy of sORP to discriminate between decreased and higher plasma vitamin C concentrations. METHODS: Plasma vitamin C concentrations and sORP were measured in a mixed intensive care (IC) population. Our model estimating vitamin C from sORP was validated by assessing its accuracy in two datasets. Receiver operating characteristic (ROC) curves with areas under the curve (AUC) were constructed to show the diagnostic accuracy of sORP to identify and rule out hypovitaminosis C and vitamin C deficiency. Different cut-off values are provided. RESULTS: Plasma vitamin C concentration and sORP were measured in 117 samples in dataset 1 and 43 samples in dataset 2. Bias and precision (SD) were 1.3 ± 10.0 µmol/L and 3.9 ± 10.1 µmol/L in dataset 1 and 2, respectively. In patients with low plasma vitamin C concentrations, bias and precision were - 2.6 ± 5.1 µmol/L and - 1.1 ± 5.4 µmol in dataset 1 (n = 40) and 2 (n = 20), respectively. Optimal sORP cut-off values to differentiate hypovitaminosis C and vitamin C deficiency from higher plasma concentrations were found at 114.6 mV (AUC 0.91) and 124.7 mV (AUC 0.93), respectively. CONCLUSION: sORP accurately estimates low plasma vitamin C concentrations and can be used to screen for hypovitaminosis C and vitamin C deficiency in critically ill patients. A validated model and multiple sORP cut-off values are presented for subgroup analysis in clinical trials or usage in clinical practice.

Early high-dose vitamin C in post-cardiac arrest syndrome (VITaCCA): study protocol for a randomized, double-blind, multi-center, placebo-controlled trial.

BACKGROUND: High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients. METHODS: This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations. DISCUSSION: Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662 European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL.

Measuring vitamin C in critically ill patients: clinical importance and practical difficulties-Is it time for a surrogate marker?

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at  https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from  https://link.springer.com/bookseries/8901 .

Estimating Vitamin C Status in Critically Ill Patients with a Novel Point-of-Care Oxidation-Reduction Potential Measurement.

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.

Renal Resistive Index: Response to Shock and its Determinants in Critically Ill Patients.

INTRODUCTION: Shock is characterized by micro- and macrovascular flow impairment contributing to acute kidney injury (AKI). Routine monitoring of the circulation regards the macrocirculation but not the renal circulation which can be assessed with Doppler ultrasound as renal resistive index (RRI). RRI reflects resistance to flow. High RRI predicts persistent AKI. Study aims were to determine whether RRI is elevated in shock and to identify determinants of RRI. MATERIALS AND METHODS: This prospective observational cohort study included two cohorts of patients, with and without shock less than 24-h after intensive care admission. Apart from routine monitoring, three study measurements were performed simultaneously: RRI, sublingual microcirculation, and bioelectral impedance analysis. RESULTS: A total of 92 patients were included (40 shock, 52 nonshock), median age was 69 [60-76] vs. 67 [59-76], P = 0.541; APACHE III was 87 [65-119] vs. 57 [45-69], P < 0.001. Shock patients had higher RRI than patients without shock (0.751 [0.692-0.788] vs. 0.654 [0.610-0.686], P < 0.001). Overall, high age, APACHE III score, lactate, vasopressor support, pulse pressure index (PPI), central venous pressure (CVP), fluid balance, and low preadmission estimated glomerular filtration rate, mean arterial pressure (MAP), creatinine clearance, and reactance/m were associated with high RRI at univariable regression (P < 0.01). Microcirculatory markers were not. At multivariable regression, vasopressor support, CVP, PPI and MAP, reactance/m, and preadmission eGFR were independent determinants of RRI (n = 92, adj. R = 0.587). CONCLUSIONS: Patients with shock have a higher RRI than patients without shock. Independent determinants of high RRI were pressure indices of the systemic circulation, low membrane capacitance, and preadmission renal dysfunction. Markers of the sublingual microcirculation were not.

Renal resistive index as an early predictor and discriminator of acute kidney injury in critically ill patients; A prospective observational cohort study.

BACKGROUND: Acute kidney injury (AKI) complicates shock. Diagnosis is based on rising creatinine, a late phenomenon. Intrarenal vasoconstriction occurs earlier. Measuring flow resistance in the renal circulation, Renal Resistive Index (RRI), could become part of vital organ function assessment using Doppler ultrasound. Our aim was to determine whether RRI on ICU admission is an early predictor and discriminator of AKI developed within the first week. METHODS: In this prospective cohort of mixed ICU patients with and without shock, RRI was measured <24-h of admission. Besides routine variables, sublingual microcirculation and bioelectrical impedance were measured. AKI was defined by the Kidney Disease Improving Global Outcomes criteria. Uni- and multivariate regression and Receiver Operating Characteristics curve analyses were performed. RESULTS: Ninety-nine patients were included, median age 67 years (IQR 59-75), APACHE III score 67 (IQR 53-89). Forty-nine patients (49%) developed AKI within the first week. AKI patients had a higher RRI on admission than those without: 0.71 (0.69-0.73) vs. 0.65 (0.63-0.68), p = 0.001. The difference was significant for AKI stage 2: RRI = 0.72 (0.65-0.80) and 3: RRI = 0.74 (0.67-0.81), but not for AKI stage 1: RRI = 0.67 (0.61-0.74). On univariate analysis, RRI significantly predicted AKI 2-3: OR 1.012 (1.006-1.019); Area Under the Curve (AUC) of RRI for AKI 2-3 was 0.72 (0.61-0.83), optimal cut-off 0.74, sensitivity 53% and specificity 87%. On multivariate analysis, RRI remained significant, independent of APACHE III and fluid balance; adjusted OR: 1.008 (1.000-1.016). CONCLUSIONS: High RRI on ICU admission was a significant predictor for development of AKI stage 2-3 during the first week. High RRI can be used as an early warning signal RRI, because of its high specificity. A combined score including RRI, APACHE III and fluid balance improved AKI prediction, suggesting that vasoconstriction or poor vascular compliance, severity of disease and positive fluid balance independently contribute to AKI development. TRIAL REGISTRATION: ClinicalTrials.gov NCT02558166.