Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Seve

Updated: Sep 19, 2021

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS


The interplay between inflammation and oxidative stress is a vicious circle, potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe diseases. This single-center retrospective study investigated micronutrient levels under Se and Zn supplementation in critically ill patients with COVID-19 induced acute respiratory distress syndrome (ARDS) and explored potential relationships with immunological and clinical parameters. According to intensive care unit (ICU) standard operating procedures, patients received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets, and clinical data were extracted from the patient data management system on admission and after 10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 patients (64%) survived ICU discharge. On admission, the majority of patients had low Se status biomarkers and Zn levels, along with elevated inflammatory parameters. Se supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p = 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with CRP (rs = −0.495), PCT (rs = −0.413), IL-6 (rs = −0.429), IL-1β (rs = −0.440) and IL-10 (rs = −0.461). Positive associations were found for CD8+ T cells (rs = 0.636), NK cells (rs = 0.772), total IgG (rs = 0.493) and PaO2/FiO2 ratios (rs = 0.504). In addition, survivors tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). Sufficient Se and Zn levels may potentially be of clinical significance for an adequate immune response in critically ill patients with severe COVID-19 ARDS

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS

Materials and Methods

2.1. Study Design and Patients

This is an observational single-center study at the University Hospital Wuerzburg, which adheres to the STROBE-Guidelines [22]. The institutional review board of the University of Wuerzburg waived the need for ethic approval (63/20-KR, 25 March 2020 and 20200528 01, 5 June 2020) due to sole retrospective chart review in conjunction with routine clinical and laboratory diagnostics. Informed consent was not necessary according to local legislation (Bayerisches Krankenhausgesetz, Art. 24, Abs. 4). The study period (20 March to 31 October 2020) was chosen to cover the first wave of COVID-19 in Germany and ICU patients with a confirmed SARS-CoV-2 infection [23] were consecutively screened for eligibility. Patients with moderate to severe ARDS, who were allocated to the ARDS and extracorporeal membrane oxygenation (ECMO) center of the University Hospital Wuerzburg, were further considered for the study. To be finally included, the individual chart review had to provide information about Se and Zn levels on admission and/or after 10 to 14 days of intensive care. Assignment to any other ICU of the University Hospital Wuerzburg and missing nutrient status were the two exclusion criteria. The allocation of patients was performed by an interdisciplinary committee of clinical experts.

2.2. Micronutrient Supplementation and Nutrition

Micronutrient supplementation was based on the local COVID-19 ICU standard operating procedures at the ARDS and ECMO center of the University Hospital Wuerzburg. It was started on the first day of intensive care and continued until discharge or death. Patients received intravenous administration of 1.0 mg Se as selenite (Biosyn Arzneimittel GmbH, Fellbach, Germany) daily and different combinations of artificial nutrition. Fresubin® HP Energy (n = 21), Fresubin® Renal (n = 9), Diben® (n = 12), Survimed® OPD (n = 4; each Fresenius Kabi Austria GmbH, Graz, Austria) and Cernevit® + ADDEL TRACE® (n = 22; Baxter Deutschland GmbH, Unterschleißheim, Germany) provided various amounts of Zn and Se, among other micronutrients. SmofKabiven® (n = 22; Fresenius Kabi Austria GmbH, Graz, Austria) contained Zn. Monitoring of the nutrient status included a full assessment of Se, selenoprotein P (SELENOP), GPx3, and Zn on admission as well as after 10 to 14 days of intensive care. Serum samples were prepared for transport at −80 °C and analyzed in the Institute of Experimental Endocrinology (Charité-Universitätsmedizin Berlin, Berlin, Germany) as described recently [20,21]. Concentrations of Se and Zn were determined using total reflection X-ray fluorescence (S4 T-STAR, Bruker Nano GmbH, Berlin, Germany). SELENOP was quantified with a commercial ELISA-kit (selenates ELISA, seemed GmbH, Berlin, Germany) according to the manufacturer’s instructions. The activity of GPx3 was assessed via consumption of nicotinamide adenine dinucleotide phosphate (NADPH) at 340 nm in a coupled enzymatic assay as initially described by Flohé and Günzler [24]. To this end, samples were incubated with reduced glutathione, NADPH, sodium acid (NaN3), and glutathione reductase. The enzymatic reaction was started with hydrogen peroxide. Reference ranges were adopted from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, where similar methods have been used on a large number of samples in healthy adults [25,26].


3.1. Demographics and Baseline Characteristics

In total, 22 patients were included in this study between March and October 2020 (Figure 1). Overall, 64% were male, 36% were female, and the median age was 60.5 years (50–69). On admission to ICU, a median SOFA score of 15 (13–16) indicated high severity of illness. In addition, 95% of the patients suffered from severe ARDS at any time during intensive care and 64% survived upon discharge from ICU (Table 1).

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS


Taken together, the present findings strengthen the notion of a clinical significance of adequate Se and Zn supply for critically ill patients with severe COVID-19 ARDS. Commonly observed deficiencies can be effectively compensated by applying the outlined supplementation strategy. Se and Zn might be involved in the reduction in inflammation and the restoration of critical lymphocyte counts for the cytotoxic immune response, which may further translate into clinical improvement. However, the results need to be considered within the limits of an observational study, so that adequately designed trials are encouraged to fully elucidate the clinical relevance of micronutrient supplementation in patients with severe COVID-19.

Credited to MDPI


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