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Over the past decade, the use of supraphysiologic doses of micronutrients (also called metabolic resuscitation) in critically ill patients has gained significant attention. Building upon preclinical and observational human data, numerous randomized controlled trials have tested the impact of multiple micronutrients on various outcomes in critically ill patients. At the 2022 American Society for Parenteral and Enteral Nutrition Preconference Course, three world‐renowned speakers delivered talks on the (1) overall role of micronutrients and, specifically, (2) selenium and vitamin C and (3) vitamin D and zinc in critically ill patients. Here, the case presentation and discussion from the postsession question and answer period are presented. The moderator for this session was Jose Pimiento, MD, and the speakers and panelists were Christian Stoppe, MD, Todd Rice, MD, and Daren Heyland, MD. Key points: 1.Micronutrient deficiencies are common in intensive care unit patients and may impact outcomes.2.To date, data from randomized controlled trials do not support the use of supraphysiologic doses of micronutrients (vitamin C, vitamin D, selenium, or zinc) in critically ill patients.3.Because of an increased risk of bias, single‐center trials are less reliable than multicenter trials; however, single‐center trials are necessary for the evidence development pathway.4.Given the heterogeneity across micronutrient trials, studies are underway to test micronutrients in burn and cardiac surgery patients, which may identify subpopulations of critically ill patients that may benefit from supraphysiologic micronutrient (therapy). [ABSTRACT FROM AUTHOR]

Elevated hydrogen sulfide (H 2 S) contributes to vasodilatation and hypotension in septic shock, and traditional therapies do not target this pathophysiologic mechanism. High-dose IV hydroxocobalamin scavenges and prevents H 2 S formation, which may restore vascular tone and may accentuate recovery. No experimental human studies have tested high-dose IV hydroxocobalamin in adults with septic shock. In adults with septic shock, is comparing high-dose IV hydroxocobalamin with placebo feasible? We conducted a phase 2 single-center, double-blind, allocation-concealed, placebo-controlled, parallel-group pilot randomized controlled trial comparing high-dose IV hydroxocobalamin with placebo in critically ill adults with septic shock. Patients meeting Sepsis 3 criteria were randomized 1:1 to receive a single 5-g dose of high-dose IV hydroxocobalamin or equivalent volume 0.9% saline solution as placebo. The primary outcome was study feasibility (enrollment rate, clinical and laboratory compliance rate, and contamination rate). Secondary outcomes included between-group differences in plasma H 2 S concentrations and vasopressor dose before and after infusion. Twenty patients were enrolled over 19 months, establishing an enrollment rate of 1.05 patients per month. Protocol adherence rates were 100% with zero contamination. In the high-dose IV hydroxocobalamin group, compared to placebo, there was a greater reduction in vasopressor dose between randomization and postinfusion (-36% vs 4%, P <.001) and randomization and 3-h postinfusion (-28% vs 10%, P =.019). In the high-dose IV hydroxocobalamin group, the plasma H 2 S level was reduced over 45 mins by –0.80 ± 1.73 μM, as compared with –0.21 ± 0.64 μM in the placebo group (P =.3). This pilot trial established favorable feasibility metrics. Consistent with the proposed mechanism of benefit, high-dose IV hydroxocobalamin compared with placebo was associated with reduced vasopressor dose and H 2 S levels at all time points and without serious adverse events. These data provide the first proof of concept for feasibility of delivering high-dose IV hydroxocobalamin in septic shock. ClinicalTrials.gov; No.: NCT03783091; URL: www.clinicaltrials.gov [Display omitted] [ABSTRACT FROM AUTHOR]

Vitamin D's pleiotropic effects include immune modulation, and its supplementation has been shown to prevent respiratory tract infections. The effectivity of vitamin D as a therapeutic intervention in critical illness remains less defined. The current study analyzed clinical and immunologic effects of vitamin D levels in patients suffering from coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). This was a single-center retrospective study in patients receiving intensive care with a confirmed SARS-CoV-2 infection and COVID-19 ARDS. 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum levels, pro- and anti-inflammatory cytokines and immune cell subsets were measured on admission as well as after 10–15 days. Clinical parameters were extracted from the patient data management system. Standard operating procedures included the daily administration of vitamin D 3 via enteral feeding. A total of 39 patients with COVID-19 ARDS were eligible, of which 26 were included in this study as data on vitamin D status was available. 96% suffered from severe COVID-19 ARDS. All patients without prior vitamin D supplementation (n = 22) had deficient serum levels of 25-hydroxyvitamin D. Vitamin D supplementation resulted in higher serum levels of 25-hydroxyvitamin D but not did not increase 1,25-dihydroxyvitamin D levels after 10–15 days. Clinical parameters did not differ between patients with sufficient or deficient levels of 25-hydroxyvitamin D. Only circulating plasmablasts were higher in patients with 25-hydroxyvitamin D levels ≥30 ng/ml (p = 0.029). Patients with 1,25-dihydroxyvitamin D levels below 20 pg/ml required longer mechanical ventilation (p = 0.045) and had a worse acute physiology and chronic health evaluation (APACHE) II score (p = 0.048). The vast majority of COVID-19 ARDS patients had vitamin D deficiency. 25-hydroxyvitamin D status was not related to changes in clinical course, whereas low levels of 1,25-dihydroxyvitamin D were associated with prolonged mechanical ventilation and a worse APACHE II score. [ABSTRACT FROM AUTHOR]

Vitamin C, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, oxidative stress, and microvascular dysfunction. While observational studies have demonstrated that critical illness is associated with low levels of vitamin C, randomized controlled trials (RCTs) of vitamin C, alone or in combination with other antioxidants, have yielded contradicting results. We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials (inception to December 2017) for RCTs comparing vitamin C, by enteral or parenteral routes, with placebo or none, in intensive care unit (ICU) patients. Two independent reviewers assessed study eligibility without language restrictions and abstracted data. Overall mortality was the primary outcome; secondary outcomes were incident infections, ICU length of stay (LOS), hospital LOS, and duration of mechanical ventilation (MV). We prespecified 5 subgroups hypothesized to benefit more from vitamin C. Eleven randomized trials were included. When 9 RCTs (n = 1322) reporting mortality were pooled, vitamin C was not associated with reduced risk of mortality (risk ratio [RR] 0.72, 95% confidence interval [CI]: 0.43-1.20, P = .21). No effect was found on infections, ICU or hospital LOS, or duration of MV. In multiple subgroup comparison, no statistically significant subgroup effects were observed. However, we did observe a tendency towards a mortality reduction (RR 0.21; 95% CI: 0.04-1.05; P = .06) when intravenous high-dose vitamin C monotherapy was administered. Current evidence does not support supplementing critically ill patients with vitamin C. A moderately large treatment effect may exist, but further studies, particularly of monotherapy administration, are warranted. [ABSTRACT FROM AUTHOR]

Background. The aim of study was to test the hypothesis that early enteral nutrition (EN) with calorie-dense and protein rich enteral formula improves enteral energy and protein delivery in critically ill cardiac patients. Methods. Prospective randomized pilot study of 40 ventilated adult patients undergoing elective cardiac surgery with use of cardiopulmonary bypass receiving inotropic support postoperatively. Patients were to receive either standard isocaloric (1000 Kcal/L and 38 g/L protein) early EN (n = 20) or calorie-dense and protein-rich (1300 Kcal/L and 66.7 g/L protein) early EN (n = 20). Results. The mean time to EN initiation was 27 ± 11 h. Early EN with the calorie-dense formula provided significantly more energy and protein enteral delivery on the 2nd, (p < 0.0001), 5th (p = 0.036), and 7th days (p = 0.024), and was associated with higher levels of prealbumin concentration on the 14th day (0.13 ± 0.01 g/L and 0.21 ± 0.1 g/L; p = 0.04) and significantly increased levels of transferrin on the 3rd, 5th, and 7th day (p < 0.05) after surgery. Conclusion. Present findings support hypothesis that early EN using a calorie-dense and protein rich formula leads to better enteral energy and protein delivery and higher levels of short-lived serum proteins. [ABSTRACT FROM AUTHOR]

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 disease. 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 to 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. [ABSTRACT FROM AUTHOR]

Cardiac surgery (CSX) can be lifesaving in elderly patients (age ≥ 80 years) but may still be associated with complications and functional decline. Frailty represents a determinant to outcomes in critically ill patients, but little is known about its influence on elderly CSX-patients. This is a secondary exploratory analysis of a multi-center, prospective observational cohort study of 610 elderly patients admitted to the ICU and followed for one year to document long-term outcomes. CSX-ICU-patients (n = 49) were compared to surgical ICU patients (n = 184) with regard to demographics, frailty, and outcomes. Of all surgical patients, 102 (43%) were considered vulnerable or frail. The subdistribution hazard ratio (SHR) of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.54 (95% confidence interval (CI), 0.34, 0.86, p = 0.007). The p-value for effect modification between surgery group (CSX vs. surgical ICU patients) and Clinical Frailty Scale (CFS) group was not significant (p = 0.37) suggesting that the observed difference in the CFS effect between the CSX and surgical ICU patients is consistent with random error. A further subgroup analysis shows that among surgical ICU patients, the SHR of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.49 (95% CI, 0.29, 0.83) while the corresponding SHR for CSX patients was 0.77 (0.32–1.88). In conclusion, preoperative frailty reduced the rate of discharge to home in both surgical and CSX patients, but a larger sample of CSX patients is needed to adequately address this question in this patient group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]