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Background: Evidence on the benefits of fiber-supplemented enteral nutrition (EN) in critically ill patients is inconsistent, and critical care nutrition guidelines lack recommendations based on high-quality evidence. This systematic review and meta-analysis (SRMA) aims to provide a current synthesis of the literature on this topic., Methods: For this SRMA of randomized controlled trials (RCT), electronic databases (MEDLINE, EMBASE, CENTRAL) were searched systematically from inception to January 2024 and updated in June 2024. Trials investigating clinical effects of fiber-supplemented EN versus placebo or usual care in adult critically ill patients were selected. Two independent reviewers extracted data and assessed the risk of bias of the included studies. Random-effect meta-analysis and trial sequential analysis (TSA) were conducted. The primary outcome was overall mortality, and one of the secondary outcomes was diarrhea incidence. Subgroup analyses were also performed for both outcomes., Results: Twenty studies with 1405 critically ill patients were included. In conventional meta-analysis, fiber-supplemented EN was associated with a significant reduction of overall mortality (RR 0.66, 95% CI 0.47, 0.92, p = 0.01, I 2  = 0%; 12 studies) and diarrhea incidence (RR 0.70, 95% CI 0.51, 0.96, p = 0.03, I 2  = 51%; 11 studies). However, both outcomes were assessed to have very serious risk of bias, and, according to TSA, a type-1 error cannot be ruled out. No subgroup differences were found for the primary outcome., Conclusion: Very low-certainty evidence suggests that fiber-supplemented EN has clinical benefits. High-quality multicenter RCTs with large sample sizes are needed to substantiate any firm recommendation for its routine use in this group of patients. PROSPERO registration number: CRD42023492829., (© 2024. The Author(s).)

Competing Interests: CS has received consulting fees; travel compensation; and honoraria for lectures, presentations, or educational events from Fresenius Kabi, Baxter, Abiomed, and B Braun. CS has also received financial support for an investigator-initiated study from Fresenius Kabi. WHH has received support for attending meetings and travel from Fresenius Kabi and their institution has received a grant from Fresenius Kabi.

Purpose of Review: Vitamin C can be a potential adjunctive treatment option for critically ill individuals due to its pleiotropic effects as electron donor in many enzymatic reactions throughout the body. Recently, several important randomized controlled trials (RCTs) investigating vitamin C in critically ill patients have been published., Recent Findings: Two recent large RCTs administering high-dose vitamin C to patients with sepsis and COVID-19 showed signs of harm. Though performed at high standard, these trials had several limitations. Recent studies in cardiac surgery and burns showed decreased cardiac enzymes and improved clinical outcomes after cardiac surgery, and decreased fluid requirements, reduced wound healing time and in-hospital mortality after burns. Vitamin C may hold benefit in the management of other ischemia/reperfusion injury populations, including postcardiac arrest patients and after solid organ transplantation. Currently, covering basal vitamin C requirements during critical illness is recommended, though the exact dose remains to be determined., Summary: Future work should address optimal vitamin C timing, since early versus late drug administration are likely distinct, and duration of therapy, where withdrawal-induced injury is possible. Additionally accurate assessment of body stores with determination of individual vitamin requirements is crucial to ascertain patient and subgroups most likely to benefit from vitamin C., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with hematological malignancies (HMs) are more frequently admitted now than in the past to the intensive care unit (ICU) due to more aggressive approaches in primary therapy of HMs and the need for critical care support. Pathophysiological alterations derived from HMs and the different hematological therapies, such as chemotherapy, negatively affect gastrointestinal (GI) function, metabolism, and nutrition status. Further, malnutrition strongly influences outcomes and tolerance of the different hematological therapies. In consequence, these critically ill patients frequently present with malnutrition and pathophysiological alterations that create challenges for the delivery of medical nutrition therapy (MNT) in the ICU. Frequent screening, gauging tolerance, and monitoring nutrition status are mandatory to provide individualized MNT and achieve nutrition objectives. The present review discusses how HM impact GI function and nutrition status, the importance of MNT in patients with HM, and specific considerations for guidance in providing adequate MNT to these patients when admitted to the ICU., (© 2024 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: The PRECISe trial is a pragmatic, multicenter randomized controlled trial that evaluates the effect of high versus standard enteral protein provision on functional recovery in adult, mechanically ventilated critically ill patients. The current protocol presents the rationale and analysis plan for an evaluation of the primary and secondary outcomes under the Bayesian framework, with an emphasis on clinically important effect sizes., Methods: This protocol was drafted in agreement with the ROBUST-statement, and is submitted for publication before database lock and primary data analysis. The primary outcome is health-related quality of life as measured by the EQ-5D-5L health utility score and is longitudinally assessed. Secondary outcomes comprise the 6-min walking test and handgrip strength over the entire follow-up period (longitudinal analyses), and 60-day mortality, duration of mechanical ventilation, and EQ-5D-5L health utility scores at 30, 90 and 180 days (cross-sectional). All analyses will primarily be performed under weakly informative priors. When available, informative priors elicited from contemporary literature will also be incorporated under alternative scenarios. In all other cases, objectively formulated skeptical and enthusiastic priors will be defined to assess the robustness of our results. Relevant identified subgroups were: patients with acute kidney injury, severe multi-organ failure and patients with or without sepsis. Results will be presented as absolute risk differences, mean differences, and odds ratios, with accompanying 95% credible intervals. Posterior probabilities will be estimated for clinically important benefit and harm., Discussion: The proposed secondary, pre-planned Bayesian analysis of the PRECISe trial will provide additional information on the effects of high protein on functional and clinical outcomes in critically ill patients, such as probabilistic interpretation, probabilities of clinically important effect sizes, and the integration of prior evidence. As such, it will complement the interpretation of the primary outcome as well as several secondary and subgroup analyses., Competing Interests: Declaration of competing interest MvdP received travel and speaker fees from Nutricia and research funding from Nestle Health Science and Fresenius-Kabi, not related to this research. EDW received research grants, travel and speakers fees from the Belgian Government Health, KCE (Belgian Health Care), Baxter Healthcare, Fresenius, Nestlé and Art Medical., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN., Methods: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion., Results: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L., Conclusions: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L., Trial Registration: ISRCTN12233792, registered on November 24, 2017., (© 2024. The Author(s).)

Background: A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice., Methods: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted., Results: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I 2  = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I 2  = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I 2  = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I 2  = 0%; 7 studies)., Conclusion: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted., Prospero Id: CRD42023441059., (© 2024. The Author(s).)

Background: Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI., Methods: In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated., Results: Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4-0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1-1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT., Conclusions: In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT., Trial Registration: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The landmark NUTRIREA-2 and NUTRIREA-3 trials compared the route and dose of nutrition, respectively, in critically ill patients with circulatory shock. The results of both trials support a "less-is-more" paradigm shift in the early acute phase of critical illness. In this review, the authors outline and appraise the results of the NUTRIREA-2 and NUTRIREA-3 trials, introduce the concept of identifying the "sweet spot" for nutrition dose based on severity of illness/nutrition risk and nutrition dose, and identify the unintended consequences of delivering full-dose nutrition in sicker critically ill patients during the early acute phase of critical illness., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Background: Cardiac surgery patients with a prolonged stay in the intensive care unit (ICU) are at high risk for acquired malnutrition. Medical nutrition therapy practices for cardiac surgery patients are unknown. The objective of this study is to describe the current nutrition practices in critically ill cardiac surgery patients worldwide., Methods: We conducted a prospective observational study in 13 international ICUs involving mechanically ventilated cardiac surgery patients with an ICU stay of at least 72 h. Collected data included the energy and protein prescription, type of and time to the initiation of nutrition, and actual quantity of energy and protein delivered (maximum: 12 days)., Results: Among 237 enrolled patients, enteral nutrition (EN) was started, on average, 45 h after ICU admission (range, 0-277 h; site average, 53 [range, 10-79 h]). EN was prescribed for 187 (79%) patients and combined EN and parenteral nutrition in 33 (14%). Overall, patients received 44.2% (0.0%-117.2%) of the prescribed energy and 39.7% (0.0%-122.8%) of the prescribed protein. At a site level, the average nutrition adequacy was 47.5% (30.5%-78.6%) for energy and 43.6% (21.7%-76.6%) for protein received from all nutrition sources., Conclusion: Critically ill cardiac surgery patients with prolonged ICU stay experience significant delays in starting EN and receive low levels of energy and protein. There exists tremendous variability in site performance, whereas achieving optimal nutrition performance is doable., (© 2023 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

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., (© 2023 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Micronutrient supplementation as part of the medical nutrition therapy for critically ill patients has received much attention in the past few years. Nevertheless, in clinical practice uncertainty remains about the optimal supplementation strategy, including which substance at which dosage should be administered at what time to specific groups of patients. Thus, the aim of this narrative review is to summarize the current evidence and recommendations for the micronutrients vitamin C and vitamin D. The physiological and pathophysiological roles of both vitamins are presented, recently published clinical trials are discussed, and the recommendations of the current guidelines are summarized. In addition, pragmatic tips for use in everyday clinical practice in the intensive care unit are given., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes., Methods: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547., Findings: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline., Interpretation: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores., Funding: None., Competing Interests: Declaration of interests The UK sites received support in the form of protein supplement supply from Nutrinovo (prosource tube feed [TF]) and Stanningly Pharma (Renapro Shot), and CA$20 000 from Nutricia to cover insurance and project management costs locally. Those that provided financial and product support for the trial had no role in designing the protocol, conducting the trial, or analysing the data, and did not have access to the data nor influence the content of the publication. We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A multidisciplinary group of international physicians involved in the medical nutrition therapy (MNT) of adult critically ill patients met to discuss the value, role, and open questions regarding supplemental parenteral nutrition (SPN) along with oral or enteral nutrition (EN), particularly in the intensive care unit (ICU) setting. This manuscript summarizes the discussions and results to highlight the importance of SPN as part of a comprehensive approach to MNT in critically ill adults and for researchers to generate new evidence based on well-powered randomized controlled trials (RCTs). The experts agreed on several key points: SPN has shown clinical benefits, resulting in this strategy being included in American and European guidelines. Nevertheless, its use is heterogeneous across European countries, due to the persistence of uncertainties, such as the optimal timing and the risk of overfeeding in absence of indirect calorimetry (IC), which results in divergent opinions and barriers to SPN implementation. Education is also insufficient. The experts agreed on actions needed to increase evidence quality on SPN use in specific patients at a given time point during acute critical illness or recovery., (© 2022. The Author(s).)

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; I 2  = 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; I 2  = 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; I 2  = 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., Trial Registration: PROSPERO international prospective database of systematic reviews (CRD42021256939-05 July 2021)., (© 2022. The Author(s).)

Objectives: To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients., Data Sources: Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials., Study Selection: Randomized controlled trials testing IV vitamin C in critically ill patients., Data Abstraction: Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes., Data Synthesis: Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75-1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52-0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79-1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49-0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C., Conclusions: IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted., Competing Interests: Dr. Hill disclosed relations with Woerwag Pharma supplying the investigational product for a study regarding vitamin C in cardiac surgery patients. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Uncertainty remains about the best route and timing of medical nutrition therapy in the acute phase of critical illness. Early combined enteral nutrition (EN) and parenteral nutrition (PN) may represent an attractive option to achieve recommended energy and protein goals in select patient groups. This meta-analysis aims to update and summarize the current evidence., Methods: This systematic review and meta-analysis includes randomized controlled trials (RCTs) targeting the effect of EN alone vs a combination of EN with PN in the acute phase of critical illness in adult patients. Assessed outcomes include mortality, intensive care unit (ICU) and hospital length of stay (LOS), ventilation days, infectious complications, physical recovery, and quality-of-life outcomes., Results: Twelve RCTs with 5543 patients were included. Treatment with a combination of EN with PN led to increased delivery of macronutrients. No statistically significant effect of a combination of EN with PN vs EN alone on any of the parameters was observed: mortality (risk ratio = 1.0; 95% CI, 0.79-1.28; P = .99), hospital LOS (mean difference, -1.44; CI, -5.59 to 2.71; P = .50), ICU LOS, and ventilation days. Trends toward improved physical outcomes were observed in two of four trials., Conclusion: A combination of EN with PN improved nutrition intake in the acute phase of critical illness in adults and was not inferior regarding the patients' outcomes. Large, adequately designed trials in select patient groups are needed to answer the question of whether this nutrition strategy has a clinically relevant treatment effect., (© 2021 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

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. Trial registration PROSPERO international prospective database of systematic reviews (CRD42021259238)., (© 2022. The Author(s).)

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.

Objectives: To determine the incidence of enteral feed intolerance, identify factors associated with enteral feed intolerance, and assess the relationship between enteral feed intolerance and key nutritional and clinical outcomes in critically ill patients., Design: Analysis of International Nutrition Survey database collected prospectively from 2007 to 2014., Setting: Seven-hundred eighty-five ICUs from around the world., Patients: Mechanically ventilated adults with ICU stay greater than or equal to 72 hours and received enteral nutrition during the first 12 ICU days., Interventions: None., Measurement and Main Results: We defined enteral feed intolerance as interrupted feeding due to one of the following reasons: high gastric residual volumes, increased abdominal girth, distension, subjective discomfort, emesis, or diarrhea. The current analysis included 15,918 patients. Of these, 4,036 (24%) had at least one episode of enteral feed intolerance. The enteral feed intolerance rate increased from 1% on day 1 to 6% on days 4 and 5 and declined daily thereafter. After controlling for site and patient covariates, burn (odds ratio 1.46; 95% CIs, 1.07-1.99), gastrointestinal (odds ratio 1.45; 95% CI, 1.27-1.66), and sepsis (odds ratio 1.34; 95% CI, 1.17-1.54) admission diagnoses were more likely to develop enteral feed intolerance, as compared to patients with respiratory-related admission diagnosis. enteral feed intolerance patients received about 10% less enteral nutrition intake, as compared to patients without enteral feed intolerance after controlling for important covariates including severity of illness. Enteral feed intolerance patients had fewer ventilator-free days and longer ICU length of stay time to discharge alive (all p < 0.0001). The daily mortality hazard rate increased by a factor of 1.5 (1.4-1.6; p < 0.0001) once enteral feed intolerance occurred., Conclusions: Enteral feed intolerance occurs frequently during enteral nutrition delivery in the critically ill. Burn and gastrointestinal patients had the highest risk of developing enteral feed intolerance. Enteral feed intolerance is associated with lower enteral nutrition delivery and worse clinical outcomes. Identification, prevention, and optimal management of enteral feed intolerance may improve nutrition delivery and clinical outcomes in important "at risk" populations., Competing Interests: Dr. Heyland received funding from Takeda Pharmaceuticals (consulting). Drs. Dukes, Chen, and Almansa disclosed that they are employees of Takeda Pharmaceuticals, and Dr. Heyland functions as a paid consultant for Takeda. Dr. Day’s institution received funding from Clinical Evaluation Research Unit, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48-96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.

Objectives: The aim of this overview of systematic reviews was to synthesize, appraise, and present all systematic review (SR) evidence on the clinical efficacy of glutamine administration to severely ill patients., Methods: Medline, Scopus, the Cochrane Library, and Prospero were searched up to March 2020. Systematic reviews and meta-analyses of randomized controlled trials published in English, comparing immunomodulating diets-containing exclusively glutamine-with standard diets for critically ill adult patients were selected. Data were collected from each selected systematic review and all available primary studies. The primary outcome was overall mortality; secondary outcomes were rate of infectious complications, hospital and intensive care unit (ICU) length of stay (LOS)., Results: Seventeen SRs were eligible for inclusion. Of the SRs, 16 included meta-analyses with moderate degree of overlap (corrected covered area = 10%). These included 117 randomized controlled trials with 9933 patients. Glutamine supplementation was not associated with overall mortality and ICU LOS. However, it may reduce the rate of infectious complications overall (N = 3666, risk ratio, 0.82; 95% confidence interval [CI], 0.73-0.92; I 2  = 33%: low quality of evidence). LOS was limited with the supplementation of glutamine (N = 4353 weighted mean difference, -2.90; 95% CI, -3.66 to -2.15; I 2  = 81%: very low quality of evidence), but this effect was diminished when only studies with low risk for bias were synthesized., Conclusion: Glutamine could demonstrate a beneficial role in critical care patients of diminishing the rate of infectious complications and hospital and ICU LOS. However, future studies with better quality would confirm this finding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies., Methods: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds., Results: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness., Conclusions: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Medical nutrition therapy in daily intensive care often is challenging for the clinician. The severity of disease with possible compromises of conscience, hemodynamics, respiration, renal and gastrointestinal systems requires an individual adaptation of the nutrient-supply adjusted to the disease phase and secondary metabolic tolerance. For these adjustments, clinicians should consider the nature of the acute disease leading to critical illness and also the preceding nutrition state, comorbidities and demographics, as well as the prognosis of the patient. Close monitoring is necessary for a rapid response in case the medical condition changes or new medical or nutritional problems arise.This pragmatic educational article describes recommended nutrition therapies for different patient cohorts in intensive care medicine based on currently valid (inter)national guidelines., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht-Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein. Erklärung zu nichtfinanziellen Interessen Dr. A. Hill wurde 2019 durch das Clinician Scientist Programm der Medizinischen Fakultät der RWTH Aachen gefördert. Aktives Mitglied in den Gesellschaften/Berufsverbänden: DGEM, ESPEN DGAI, WAKWIN, BDA, ERAS Cardiac Surgery. Förderung von Forschungsprojekten durch das START Programm der Medizinischen Fakultät RWTH Aachen, die B. Braun Stiftung und Fresenius Kabi AG., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Enteral and parenteral nutrition of adult critically ill patients varies in terms of the route of nutrient delivery, the amount and composition of macro- and micronutrients, and the choice of specific, immune-modulating substrates. Variations of clinical nutrition may affect clinical outcomes. The present guideline provides clinicians with updated consensus-based recommendations for clinical nutrition in adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function., Methods: The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. According to the S2k-guideline classification, no systematic review of the available evidence was required to make recommendations, which, therefore, do not state evidence- or recommendation grades. Nevertheless, we considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of other societies. The liability of each recommendation was described linguistically. Each recommendation was finally validated and consented through a Delphi process., Results: In the introduction the guideline describes a) the pathophysiological consequences of critical illness possibly affecting metabolism and nutrition of critically ill patients, b) potential definitions for different disease phases during the course of illness, and c) methodological shortcomings of clinical trials on nutrition. Then, we make 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in critically ill patients. Among others, recommendations include the assessment of nutrition status, the indication for clinical nutrition, the timing and route of nutrient delivery, and the amount and composition of substrates (macro- and micronutrients); furthermore, we discuss distinctive aspects of nutrition therapy in obese critically ill patients and those treated with extracorporeal support devices., Conclusion: The current guideline provides clinicians with up-to-date recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. The period of validity of the guideline is approximately fixed at five years (2018-2023)., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Emerging evidence suggests a pivotal role of macrophage migration inhibitory factor (MIF) in the systemic inflammatory immune response. MIF is located in various cell types and rapidly released after different stimuli like inflammation, surgical stress or ischemia and reperfusion. MIF is a known key player in the inflammatory response and contributes to several biological functions including the control of cell cycle (through activation of ERK1/2), sensing of pathogen stimuli (upregulation of TLR4 expression), recruitment of various immune cells (neutrophils, monocytes) and prevention of p53-mediated apoptosis of macrophages. While MIF`s pro-inflammatory effects are crucial for an effective host defense, elevated MIF levels were repeatedly shown to be associated with the development of organ dysfunction and deleterious sequelae. Even more puzzling, increasing evidence indicates a protective role of this pleiotropic cytokine during ischemia and reperfusion injury in the myocardium. This review focuses on new insights regarding the biological significance of MIF release in the context of critical illness and ischemia/ reperfusion.