@article{BleilevensSoppertHoffmannetal.2021, author = {Bleilevens, Christian and Soppert, Josefin and Hoffmann, Adrian and Breuer, Thomas and Bernhagen, J{\"u}rgen and Martin, Lukas and Stiehler, Lara and Marx, Gernot and Dreher, Michael and Stoppe, Christian and Simon, Tim-Philipp}, title = {Macrophage migration inhibitory factor (MIF) plasma concentration in critically ill COVID-19 patients: a prospective observational study}, series = {Diagnostics}, volume = {11}, journal = {Diagnostics}, number = {2}, issn = {2075-4418}, doi = {10.3390/diagnostics11020332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228967}, year = {2021}, abstract = {Mortality in critically ill coronavirus disease 2019 (COVID-19) patients is high and pharmacological treatment strategies remain limited. Early-stage predictive biomarkers are needed to identify patients with a high risk of severe clinical courses and to stratify treatment strategies. Macrophage migration inhibitory factor (MIF) was previously described as a potential predictor for the outcome of critically ill patients and for acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19 disease. This prospective observational study evaluates the predictive potential of MIF for the clinical outcome after severe COVID-19 infection. Plasma MIF concentrations were measured in 36 mechanically ventilated COVID-19 patients over three days after intensive care unit (ICU) admission. Increased compared to decreased MIF was significantly associated with aggravated organ function and a significantly lower 28-day survival (sequential organ failure assessment (SOFA) score; 8.2 ± 4.5 to 14.3 ± 3, p = 0.009 vs. 8.9 ± 1.9 to 12 ± 2, p = 0.296; survival: 56\% vs. 93\%; p = 0.003). Arterial hypertension was the predominant comorbidity in 85\% of patients with increasing MIF concentrations (vs. decreasing MIF: 39\%; p = 0.015). Without reaching significance, more patients with decreasing MIF were able to improve their ARDS status (p = 0.142). The identified association between an early MIF response, aggravation of organ function and 28-day survival may open future perspectives for biomarker-based diagnostic approaches for ICU management of COVID-19 patients.}, language = {en} } @article{MegasSimonsKimetal.2021, author = {Megas, Ioannis-Fivos and Simons, David and Kim, Bong-Sung and Stoppe, Christian and Piatkowski, Andrzej and Fikatas, Panagiotis and Fuchs, Paul Christian and Bastiaanse, Jacqueline and Pallua, Norbert and Bernhagen, J{\"u}rgen and Grieb, Gerrit}, title = {Macrophage migration inhibitory factor — an innovative indicator for free flap ischemia after microsurgical reconstruction}, series = {Healthcare}, volume = {9}, journal = {Healthcare}, number = {6}, issn = {2227-9032}, doi = {10.3390/healthcare9060616}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239632}, year = {2021}, abstract = {(1) Background: Nowadays, the use of microsurgical free flaps is a standard operative procedure in reconstructive surgery. Still, thrombosis of the microanastomosis is one of the most fatal postoperative complications. Clinical evaluation, different technical devices and laboratory markers are used to monitor critical flap perfusion. Macrophage migration inhibitory factor (MIF), a structurally unique cytokine with chemokine-like characteristics, could play a role in predicting vascular problems and the failure of flap perfusion. (2) Methods: In this prospective observational study, 26 subjects that underwent microsurgical reconstruction were observed. Besides clinical data, the number of blood leukocytes, CRP and MIF were monitored. (3) Results: Blood levels of MIF, C-reactive protein (CRP) and leukocytes increased directly after surgery. Subjects that needed surgical revision due to thrombosis of the microanastomosis showed significantly higher blood levels of MIF than subjects without revision. (4) Conclusion: We conclude that MIF is a potential and innovative indicator for thrombosis of the microanastomosis after free flap surgery. Since it is easy to obtain diagnostically, MIF could be an additional tool to monitor flap perfusion besides clinical and technical assessments.}, language = {en} } @article{DresenLeeHilletal.2023, author = {Dresen, Ellen and Lee, Zheng-Yii and Hill, Aileen and Notz, Quirin and Patel, Jayshil J. and Stoppe, Christian}, title = {History of scurvy and use of vitamin C in critical illness: A narrative review}, series = {Nutrition in Clinical Practice}, volume = {38}, journal = {Nutrition in Clinical Practice}, number = {1}, doi = {10.1002/ncp.10914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318176}, pages = {46 -- 54}, year = {2023}, abstract = {In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness—a condition also resulting in death of thousands in the 21st century—has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019.}, language = {en} } @article{HillHeylandRossaintetal.2020, author = {Hill, Aileen and Heyland, Daren K. and Rossaint, Rolf and Arora, Rakesh C. and Engelman, Daniel T. and Day, Andrew G. and Stoppe, Christian}, title = {Longitudinal outcomes in octogenarian critically ill patients with a focus on frailty and cardiac surgery}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {1}, issn = {2077-0383}, doi = {10.3390/jcm10010012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220064}, year = {2020}, abstract = {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.}, language = {en} } @article{DresenPimientoPateletal.2023, author = {Dresen, Ellen and Pimiento, Jose M. and Patel, Jayshil J. and Heyland, Daren K. and Rice, Todd W. and Stoppe, Christian}, title = {Overview of oxidative stress and the role of micronutrients in critical illness}, series = {Journal of Parenteral and Enteral Nutrition}, volume = {47}, journal = {Journal of Parenteral and Enteral Nutrition}, doi = {10.1002/jpen.2421}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318186}, pages = {S38 -- S49}, year = {2023}, abstract = {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.}, language = {en} } @article{HillDossowHeylandetal.2022, author = {Hill, Aileen and Dossow, Vera von and Heyland, Daren K. and Rossaint, Rolf and Meybohm, Patrick and Fox, Henrik and Morshuis, Michiel and Elke, Gunnar and Panholzer, Bernd and Haneya, Assad and B{\"o}ning, Andreas and Niemann, Bernd and Zayat, Rashad and Moza, Ajay and Stoppe, Christian}, title = {Preoperative nutritional optimization and physical exercise for patients scheduled for elective implantation for a left-ventricular assist device — The PROPER-LVAD study}, series = {Surgeries}, volume = {3}, journal = {Surgeries}, number = {4}, issn = {2673-4095}, doi = {10.3390/surgeries3040031}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288317}, pages = {284 -- 296}, year = {2022}, abstract = {Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted.}, language = {en} } @article{AverdunkBernhagenFehnleetal.2020, author = {Averdunk, Luisa and Bernhagen, J{\"u}rgen and Fehnle, Karl and Surowy, Harald and L{\"u}decke, Hermann-Josef and Mucha, S{\"o}ren and Meybohm, Patrick and Wieczorek, Dagmar and Leng, Lin and Marx, Gernot and Leaf, David E. and Zarbock, Alexander and Zacharowski, Kai and Bucala, Richard and Stoppe, Christian}, title = {The Macrophage Migration Inhibitory Factor (MIF) promoter polymorphisms (rs3063368, rs755622) predict acute kidney injury and death after cardiac surgery}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {9}, issn = {2077-0383}, doi = {10.3390/jcm9092936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213126}, year = {2020}, abstract = {Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT\(_{5-7}\) (rs5844572/rs3063368,"-794") and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT\(_7\)) had a significantly higher risk of acute kidney injury (AKI) compared to others (23\% vs. 13\%; OR 2.01 (1.40-2.88), p = 0.0001). Carriers of CATT\(_7\) were also at higher risk of death (1.8\% vs. 0.4\%; OR 5.12 (0.99-33.14), p = 0.026). The GC genotype was associated with AKI (20\% vs. GG/CC:13\%, OR 1.71 (1.20-2.43), p = 0.003). Multivariate analyses identified CATT\(_7\) predictive for AKI (OR 2.13 (1.46-3.09), p < 0.001) and death (OR 5.58 (1.29-24.04), p = 0.021). CATT\(_7\) was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT\(_7\) allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.}, language = {en} } @article{MengerLeeNotzetal.2022, author = {Menger, Johannes and Lee, Zheng-Yii and Notz, Quirin and Wallqvist, Julia and Hasan, M. Shahnaz and Elke, Gunnar and Dworschak, Martin and Meybohm, Patrick and Heyland, Daren K. and Stoppe, Christian}, title = {Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials}, series = {Critical Care}, volume = {26}, journal = {Critical Care}, number = {1}, doi = {10.1186/s13054-022-04139-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299700}, year = {2022}, abstract = {Background The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration. Methods Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials. Results Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95\% confidence interval 0.62-0.97, p = 0.03; I2 = 30\%), reduced intensive care unit length of stay (12 studies: mean difference - 3.13 days, 95\% CI - 5.36 to - 0.89, n = 1250, p = 0.006; I2 = 70\%), and shorter duration of mechanical ventilation (9 studies: mean difference - 5.07 days, 95\% CI - 7.42 to - 2.73, n = 572, p < 0.0001; I2 = 54\%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels. Conclusions Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results.}, language = {en} } @article{NotzHerrmannSchlesingeretal.2021, author = {Notz, Quirin and Herrmann, Johannes and Schlesinger, Tobias and Helmer, Philipp and Sudowe, Stephan and Sun, Qian and Hackler, Julian and Roeder, Daniel and Lotz, Christopher and Meybohm, Patrick and Kranke, Peter and Schomburg, Lutz and Stoppe, Christian}, title = {Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS}, series = {Nutrients}, volume = {13}, journal = {Nutrients}, number = {6}, issn = {2072-6643}, doi = {10.3390/nu13062113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241112}, year = {2021}, abstract = {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 (r\(_s\) = -0.495), PCT (r\(_s\) = -0.413), IL-6 (r\(_s\) = -0.429), IL-1β (r\(_s\) = -0.440) and IL-10 (r\(_s\) = -0.461). Positive associations were found for CD8\(^+\) T cells (r(_s\) = 0.636), NK cells (r\(_s\) = 0.772), total IgG (r\(_s\) = 0.493) and PaO\(_2\)/FiO\(_2\) ratios (r\(_s\) = 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.}, language = {en} } @article{NotzLeeMengeretal.2022, author = {Notz, Quirin and Lee, Zheng-Yii and Menger, Johannes and Elke, Gunnar and Hill, Aileen and Kranke, Peter and Roeder, Daniel and Lotz, Christopher and Meybohm, Patrick and Heyland, Daren K. and Stoppe, Christian}, title = {Omega-6 sparing effects of parenteral lipid emulsions-an updated systematic review and meta-analysis on clinical outcomes in critically ill patients}, series = {Critical Care}, volume = {26}, journal = {Critical Care}, number = {1}, doi = {10.1186/s13054-022-03896-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299710}, year = {2022}, abstract = {Background Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients. Methods A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed. Results 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95\% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95\% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] - 6.88; 95\% CI - 11.27, - 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD - 3.53; 95\% CI - 6.16, - 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95\% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care. Conclusion Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact.}, language = {en} }