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Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti‐inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti‐inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation and oxidative stress remain the main causes of complications in patients with heart failure receiving a left ventricular assist device (LVAD). Selenoproteins are a cornerstone of antioxidant defense mechanisms for improving inflammatory conditions. Methods: In a monocentric, double‐blinded pilot trial patients scheduled for LVAD implantation were randomized to receive 300 mcg of selenium orally the evening before surgery, followed by a high‐dose of intravenous selenium supplementation (3000 mcg after anesthesia induction, 1000 mcg upon intensive care unit [ICU] admission, and 1000 mcg daily in the ICU for a maximum of 14 days) or placebo. The main outcomes were feasibility and effectiveness in restoring serum selenium concentrations. Results: Twenty patients were included in the analysis. The average duration of study intervention was 12.6 days (7–14), with 97.7% dose compliance. No patient received open‐label selenium. The supplementation strategy was effective in compensating low serum selenium concentrations (before surgery: control, 63.5 ± 11.9 mcg/L vs intervention, 65.8 ± 16.5 mcg/L; ICU admission: control, 49.0 ± 9.8 mcg/L vs intervention, 144.2 ± 45.4 mcg/L). Serum selenium concentrations in the intervention group were significantly higher during the observation period (baseline: mean of placebo (MoP), 63.1 vs mean of selenium (MoS), 64.0; ICU admission: MoP, 49.0 vs MoS, 144.6; day 1‐13: MoP, 43.6‐48.5 vs MoS, 100.4‐131.0). Conclusion: Selenium supplementation in patients receiving LVAD implantation is feasible and effective to compensate a selenium deficiency. [ABSTRACT FROM AUTHOR]

In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients. [ABSTRACT FROM AUTHOR]

D-dopachrome tautomerase (D- DT/ MIF-2) is a member of the macrophage migration inhibitory factor ( MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D- DT have been reported to be involved in obesity, but there is little known about the regulation of D- DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D- DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D- DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D- DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF- CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D- DT to MIF in inflamed adipose tissue, and indicate that D- DT may be beneficial in wound repair by improving fibroblast survival and proliferation. [ABSTRACT FROM AUTHOR]

The chemokine CXCL16 and its receptor CXCR6 have been linked to the pathogenesis of acute and chronic cardiovascular disease. However, data on the clinical significance of CXCL16 in patients undergoing cardiac surgery with acute myocardial ischemia/reperfusion (I/R) are still lacking. Therefore, we determined CXCL16 in the serum of cardiac surgery patients and investigated its kinetics and association with the extent of organ dysfunction. 48 patients underwent conventional cardiac surgery with myocardial I/R and the use of cardiopulmonary bypass (CPB) were consecutively enrolled in the present study. We investigated the peri- and post-operative profile of CXCL16. Clinical relevant data were assessed and documented throughout the entire observation period. To identify the influence of myocardial I/R and CPB on CXCL16 release data were compared to those received from patients that underwent off-pump procedure. Pre-operative serum CXCL16 levels were comparable to those obtained from healthy volunteers (1174± 55.64 pg/ml versus 1225 ± 70.94). However, CXCL16 levels significantly increased during surgery (1174 ± 55.64 versus 1442 ± 75.42 pg/ml; P = 0.0057) and reached maximum levels 6 hrs after termination of surgery (1174 ± 55.64 versus 1648 ± 74.71 pg/ml; P < 0.001). We revealed a positive correlation between the intraoperative serum levels of CXCL16 and the extent of organ dysfunction (r² = 0.356; P = 0.031). Patients with high CXCL16 release showed an increased extent of organ dysfunction compared to patients with low CXCL16 release. Our study shows that CXCL16 is released into the circulation as a result of cardiac surgery and that high post-operative CXCL16 levels are associated with an increased severity of post-operative organ dysfunctions. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac surgery is accompanied by an increase of oxidative stress, a significantly reduced antioxidant (AOX) capacity, postoperative inflammation, all of which may promote the development of organ dysfunction and an increase in mortality. Selenium is an essential co-factor of various antioxidant enzymes. We hypothesized a less pronounced decrease of circulating selenium levels in patients undergoing off-pump coronary artery bypass (OPCAB) surgery due to less intraoperative oxidative stress. Methods: In this prospective randomised, interventional trial, 40 patients scheduled for elective coronary artery bypass grafting were randomly assigned to undergo either on-pump or OPCAB-surgery, if both techniques were feasible for the single patient. Clinical data, myocardial damage assessed by myocard specific creatine kinase isoenzyme (CK-MB), circulating whole blood levels of selenium, oxidative stress assessed by asymmetric dimethylarginine (ADMA) levels, antioxidant capacity determined by glutathionperoxidase (GPx) levels and perioperative inflammation represented by interleukin-6 (IL-6) levels were measured at predefined perioperative time points. Results: At end of surgery, both groups showed a comparable decrease of circulating selenium concentrations. Likewise, levels of oxidative stress and IL-6 were comparable in both groups. Selenium levels correlated with antioxidant capacity (GPx: r = 0.720; p<0.001) and showed a negative correlation to myocardial damage (CK-MB: r = −0.571, p<0.001). Low postoperative selenium levels had a high predictive value for the occurrence of any postoperative complication. Conclusions: OPCAB surgery is not associated with less oxidative stress and a better preservation of the circulating selenium pool than on-pump surgery. Low postoperative selenium levels are predictive for the development of complications. Trial registration: ClinicalTrials.gov NCT01409057 [ABSTRACT FROM AUTHOR]

Objectives: We recently reported that cardiac surgical patients in our institution exhibited low selenium blood levels preoperatively, which were further aggravated during surgery and independently associated with the development of postoperative multiorgan failure. Low circulating selenium levels result in a decreased antioxidant capacity. Both can be treated effectively by sodium-selenite administration. Little is known about the kinetics of exogenously administered sodium-selenite during acute perioperative oxidative stress. The aim of this study was to assess the effects of perioperative high-dose sodium-selenite administration on selenium blood concentrations in cardiac surgical patients. Methods: One hundred four cardiac surgical patients were enrolled in this prospective observational trial. Patients received an intravenous bolus of 2000 mg selenium after an induction of anesthesia and 1000 mg selenium every day further during their intensive care unit (ICU) stay. Selenium blood levels were measured at regular intervals. Results: Preoperative sodium-selenite administration increased selenium blood concentrations to normal values on ICU admission, but failed to prevent a significant decrease of circulating selenium on the first postoperative day. During the further ICU stay, selenium blood levels were normalized by the administration strategy and did not exceed the German reference range. No acute selenium-specific side effects occurred. When matching the participating patients to a historical control group without sodium-selenite administration, the chosen strategy was associated with a decrease in SAPS II (23 ± 7 versus 29 ± 8, P = 0.005) and SOFA scores (4 3 versus 7 ± 2, P = 0.007) on the first postoperative day, but was unable to improve the postoperative outcome in patients staying >1 d in ICU. Conclusions: Despite preemptive high-dose sodium-selenite administration, cardiac surgical patients experienced a significant decrease in circulating selenium levels on the first postoperative day. [ABSTRACT FROM AUTHOR]

Introduction: An increasing number of patients require implantation of left ventricular assist device (LVAD) for the management of their end-stage heart failure. Organ dysfunctions and infectious complications belong to the most common adverse events, resulting from inflammation and oxidative stress. The essential trace element selenium is considered as cornerstone of the antioxidant defense mechanisms, which may offer therapeutic benefits. Hypothesis: Selenium supplementation provides beneficial effects after LVAD implantation. Methods: Adult patients scheduled to undergo LVAD implantation (destination therapy) were randomized to receive 300μg of sodium-selenite the evening before surgery, followed by high dose IV selenium supplementation (3000μg after induction, 1000μg on ICU admission, and 1000μg daily in ICU) or placebo. Patients with known severe renal dysfunction & chronic liver disease were excluded. The main outcomes of the pilot study were to determine its efficacy, feasibility (recruitment rates) and monitoring of adherence to the protocol. In an explorative approach, we evaluated major clinical endpoints, for the following confirmatory study. Results: In total, 20 patients met the inclusion criteria. The average recruitment rate was 1.5 patients/month (0-3). The average duration of the study intervention was 12.6 days (7-14) and there was a 97.7% compliance with dose administration. During the postoperative course, the inflammatory response, assessed by IL6 was similar between the groups. The number and duration of organ dysfunctions, requiring the need for ICU support was comparable. The placebo group showed a no significant faster recovery in this small cohort 12.5h (0.1-29.4) vs 20.5h (0.2-28.2). The intervention group presented a higher cardiac output, higher systolic and mean blood pressures, as well as lower pulmonary and central venous blood pressures on the 1. day of surgery. Conclusions: Selenium supplementation in patients receiving LVAD implantation was feasible and showed efficacy on patients' outcomes. A larger, more definitive trial is currently being planed. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery.Methods: This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon's perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC).Results: Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients' serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07).Conclusions: Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown.Trial Registration: This clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov ( NCT01285271 ; first received: January 24, 2011). [ABSTRACT FROM AUTHOR]

The cardiac surgery-related ischemia-reperfusion-related oxidative stress triggers the release of cytotoxic reactive oxygen and nitrogen species, contributing to organ failure and ultimately influencing patients' short- and long-term outcomes. Selenium is an essential co-factor for various antioxidant enzymes, thereby contributing to the patients' endogenous antioxidant and anti-inflammatory defense mechanisms. Given these selenium's pleiotropic functions, we investigated the effect of a high-dose selenium-based anti-inflammatory perioperative strategy on functional recovery after cardiac surgery. This prospective study constituted a nested sub-study of the SUSTAIN CSX trial, a double-blinded, randomized, placebo-controlled multicenter trial to investigate the impact of high-dose selenium supplementation on high-risk cardiac surgery patients' postoperative recovery. Functional recovery was assessed by 6-min walk distance, Short Form-36 (SF-36) and Barthel Index questionnaires. 174 patients were included in this sub-study. The mean age (SD) was 67.3 (8.9) years, and 78.7 % of the patients were male. The mean (SD) predicted 30-day mortality by the European System for Cardiac Operative Risk Evaluation II score was 12.6 % (9.4 %). There was no difference at hospital discharge and after three months in the 6-min walk distance between the selenium and placebo groups (131 m [IQR: not performed – 269] vs. 160 m [IQR: not performed – 252], p = 0.80 and 400 m [IQR: 299–461] vs. 375 m [IQR: 65–441], p = 0.48). The SF-36 and Barthel Index assessments also revealed no clinically meaningful differences between the selenium and placebo groups. A perioperative anti-inflammatory strategy with high-dose selenium supplementation did not improve functional recovery in high-risk cardiac surgery patients. [ABSTRACT FROM AUTHOR]