Vitamin C in critical illness: end of the story or still a place?

PURPOSE OF REVIEW: Critical illness is associated with decreased micronutrient levels, including vitamin C, an essential antioxidant for systemic inflammation. This review discusses the most recent evidence of high-dose vitamin C monotherapy in critically ill adults. RECENT FINDINGS: Three randomized-controlled trials (RCTs) were published in 2022. A pilot study including 40 patients with septic shock could not detect significant differences in outcome parameters after administering vitamin C. A multicenter study with 124 septic patients showed no significant difference in 28-day mortality, while vitamin C was associated with an increased risk of acute kidney dysfunction. The LOVIT trial, an international prospective RCT in 872 septic patients, revealed an increased risk of the composite endpoint persistent organ dysfunction plus death at day 28 in the high-dose vitamin C group. Six systematic reviews and meta-analyses (SRMA), including up to 4740 patients published before and 2 SRMA publications including these RCTs showed divergent results on clinical endpoints including mortality. SUMMARY: The use of high-dose intravenous vitamin C cannot be recommended for the septic critically ill in clinical practice since the LOVIT trial. Further research is needed to evaluate its potential role in other critically ill patients.

What the clinician needs to know about medical nutrition therapy in critically ill patients in 2023: A narrative review.

Medical nutrition therapy (MNT) represents an essential element in the medical care of critically ill patients admitted to an intensive care unit (ICU). Increasing awareness exists that energy and nutrients not only preserve body structures such as lean body/muscle mass but also represent promising therapeutic elements to target the profound metabolic, inflammatory, endocrinologic, and immunologic alterations occurring during critical illness. However, despite intense research activities for years, diverse aspects of MNT such as the optimal timing, dosing, and composition of energy and macronutrient supply, as well as the role of micronutrients, are still an issue of debate resulting from strong heterogeneity in methods and findings of respective studies. These discrepancies are also reflected in diverging recommendations of international clinical nutrition guidelines for specific topics. In addition, implementing targeted, personalized MNT strategies in routine clinical practice underlies difficulties and challenges resulting from disease-specific issues and/or organizational, structural, and educational aspects. This narrative review aims to summarize the most recent evidence relevant to clinical practice on selected aspects of MNT in adult patients in the ICU and to provide guidance for implementing evidence-based approaches for adequate energy and nutrient supply in the ICU setting.

[Bacterial gut microbiota-key player in sepsis]. / Das bakterielle intestinale Mikrobiom ­ Key Player in der Sepsis.

The gut microbiota is comprised of over 1200 different bacteria and forms a symbiotic community with the human organism, the holobiont. It plays an important role in the maintenance of homeostasis, e.g., of the immune system and essential metabolic processes. Disturbances in the balance of this reciprocal relationship are called dysbiosis and, in the field of sepsis, are associated with incidence of disease, extent of the systemic inflammatory response, severity of organ dysfunction, and mortality. In addition to providing guiding principles in the fascinating relationship between "human and microbe," this article summarizes recent findings regarding the role of the bacterial gut microbiota in sepsis, which is one a very relevant in intensive care medicine.

Resting Energy Expenditure in the Critically Ill and Healthy Elderly-A Retrospective Matched Cohort Study.

The use of indirect calorimetry to measure resting energy expenditure (mREE) is widely recommended as opposed to calculating REE (cREE) by predictive equations (PE). The aim of this study was to compare mREE with cREE in critically ill, mechanically ventilated patients aged ≥ 75 years and a healthy control group matched by age, gender and body mass index. The primary outcome was the PE accuracy rate of mREE/cREE, derived using Bland Altman plots. Secondary analyses included linear regression analyses for determinants of intraindividual mREE/cREE differences in the critically ill and interindividual mREE differences in the matched healthy cohort. In this retrospective study, 90 critically ill patients (median age 80 years) and 58 matched healthy persons were included. Median mREE was significantly higher in the critically ill (1457 kcal/d) versus the healthy cohort (1351 kcal/d), with low PE accuracy rates (21% to 49%). Independent predictors of mREE/cREE differences in the critically ill were body temperature, heart rate, FiO2, hematocrit, serum sodium and urea. Body temperature, respiratory rate, and FiO2 were independent predictors of interindividual mREE differences (critically ill versus healthy control). In conclusion, the commonly used PE in the elderly critically ill are inaccurate. Respiratory, metabolic and energy homeostasis variables may explain intraindividual mREE/cREE as well as interindividual mREE differences.

Downregulation of TRAIL-Receptor 1 Increases TGFß Type II Receptor Expression and TGFß Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells.

The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor ß (TGFß). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFß-RII. We further show that transient expression of the miR-370 mimic decreased TGFß1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFß1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFß1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFß1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFß and therefore represents a potential tumour suppressor in late-stage PDAC.

Negative control of TRAIL-R1 signaling by transforming growth factor ß1 in pancreatic tumor cells involves Smad-dependent down regulation of TRAIL-R1.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by both, overexpression of transforming growth factor (TGF)ß and resistance of the tumor cells to many apoptosis-inducing stimuli. The latter negatively impacts the outcome of therapeutic efforts and represents one important mechanism which tumor cells utilize to escape the immune surveillance. Since TGFß acts as a tumor promoter in advanced tumor stages and suppression of apoptosis is a known driver of tumor progression, it is possible that TGFß functions as a crucial determinant of tumor cell sensitivity to apoptosis in PDAC. Here, we have studied the impact of TGFß on TNF-related apoptosis inducing ligand (TRAIL)-induced signaling in PDAC cells. In TGFß-responsive Panc1 and Colo357 cells, TGFß1 reduced total and plasma membrane-associated levels of TRAIL-R1 but not those of TRAIL-R2. Consistent with the known predominant role of TRAIL-R1 in TRAIL-mediated signaling in PDAC, TGFß1 inhibited TRAIL-induced DISC formation and apoptosis as well as phosphorylation of MAPKs and IκBα. Similarly, it also reduced signaling of TRAIL-R1 following its specific activation with an agonistic antibody. In contrast, specific TRAIL-R2 signaling remained unchanged. The TGFß1 effect on TRAIL-R1 expression was mimicked by ectopic expression of a kinase-active version of the TGFß type I receptor ALK5 (ALK5-T204D) but not by ALK5 double mutant lacking the ability to phosphorylate Smad proteins (RImL45-T204D). Moreover, TGFß regulation of TRAIL-R1 was absent in two PDAC cell lines lacking the Smad4 gene DPC4 and siRNA-mediated silencing of Smad4 in Smad4-positive Panc1 cells abolished the TGFß-mediated decrease in TRAIL-R1 expression, together showing that ALK5/Smad4 signaling is crucial for TGFß regulation of TRAIL-R1 expression. Our results suggest a novel tumor-promoting function of TGFß1. By downregulating TRAIL-R1, TGFß1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of PDAC.