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Background: The EFFORT Protein trial assessed the effect of high vs usual dosing of protein in adult ICU patients with organ failure. This study provides a probabilistic interpretation and evaluates heterogeneity in treatment effects (HTE)., Methods: We analysed 60-day all-cause mortality and time to discharge alive from hospital using Bayesian models with weakly informative priors. HTE on mortality was assessed according to disease severity (Sequential Organ Failure Assessment [SOFA] score), acute kidney injury, and serum creatinine values at baseline., Results: The absolute difference in mortality was 2.5% points (95% credible interval -6.9 to 12.4), with a 72% posterior probability of harm associated with high protein treatment. For time to discharge alive from hospital, the hazard ratio was 0.91 (95% credible interval 0.80 to 1.04) with a 92% probability of harm for the high-dose protein group compared with the usual-dose protein group. There were 97% and 95% probabilities of positive interactions between the high protein intervention and serum creatinine and SOFA score at randomisation, respectively. Specifically, there was a potentially relatively higher mortality of high protein doses with higher baseline serum creatinine or SOFA scores., Conclusions: We found moderate to high probabilities of harm with high protein doses compared with usual protein in ICU patients for the primary and secondary outcomes. We found suggestions of heterogeneity in treatment effects with worse outcomes in participants randomised to high protein doses with renal dysfunction or acute kidney injury and greater illness severity at baseline., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Micronutrient (MN) status alterations (both depletion and deficiency) are associated with several complications and worse outcomes in critically ill patients. On the other side of the spectrum, improving MN status has been shown to be a potential co-adjuvant therapy. This review aims to collect existing data to better guide research in the critical care setting. This narrative review was conducted by the European Society of Intensive Care Medicine Feeding, Rehabilitation, Endocrinology, and Metabolism MN group. The primary objective was to identify studies focusing on individual MNs in critically ill patients, selecting the MNs that appear to be most relevant and most frequently investigated in the last decade: A, B 1 , B 2 , B 3 , B 6 , folate, C, D, E, copper, iron, selenium, zinc, and carnitine. Given the limited number of interventional studies for most MNs, observational studies were included. For each selected MN, the review summarizes the main form and functions, special needs and risk factors, optimal treatment strategies, pharmacological dosing, and clinical implications all specific to critically ill patients. A rigorous rebalancing of research strategies and priorities is needed to improve clinical practice. An important finding is that high-dose monotherapy of MNs is not recommended. Basal daily needs must be provided, with higher doses in diseases with known higher needs, and identified deficiencies treated. Finally, the review provides a list of ongoing trials on MNs in critically ill patients and identifies a priority list of future research topics., (© 2024 The Author(s). Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Purpose of Review: Critical care nutrition guidelines recommend provision of higher protein doses than recommended in health. These recommendations have been predominately based on lower quality evidence and physiological rationale that greater protein doses may attenuate the significant muscle loss observed in critically ill patients. This review discusses the mechanistic action of protein in the critically ill, details results from recent trials on health outcomes, discusses considerations for interpretation of trial results, and provides an overview of future directions., Recent Findings: Two recent large clinical trials have investigated different protein doses and the effect on clinical outcome. Important findings revealed potential harm in certain sub-groups of patients. This harm must be balanced with the potential for beneficial effects on muscle mass and physical function given that two recent systematic reviews with meta-analyses demonstrated attenuation of muscle loss with higher protein doses. Utilizing biological markers such as urea: creatinine ratio or urea levels may prove useful in monitoring harm from higher protein doses., Summary: Future research should focus on prospectively investigating biological signatures of harm as well as taking into the consideration elements that will likely enhance the effectiveness of protein dose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess racial and sex variances in second primary thyroid malignancy (SPTM) cumulative incidence and temporal trends and the radiation exposure effect in pediatric SPTM., Materials and Methods: A retrospective cohort study, a non-experimental epidemiologic design, was used to assess the cumulative incidence (CmI) and temporal trends as well as the exposure effect of radiation in SPTM among children, 0-19 years, in the Surveillance, Epidemiology, and End Results (SEER) registry, National Cancer Institute (NCI), USA. Percent change (PC) and annual percent change (APC) were used to examine CmI rates and temporal trends, while chi-square statistics and binomial regression models were used to examine variable distribution by race and to determine the exposure effect of radiation on SPTM as well as mortality, respectively., Results: The frequency of pediatric thyroid cancer was ( n = 3457) between 1973 and 2013/14, while the PC was 151.2 for all races but 99.8 among whites. Of all pediatric thyroid cancers diagnosed during this period, SPTM accounted for 3% ( n = 99). Compared to whites, blacks/AA were 60% less likely to present with SPTM, adjusted risk ratio, aRR = 0.40, 99% CI 0.06-2.47, while other races were 18% more likely to develop SPTM, aRR = 1.18, 99% CI 0.48-2.87. Additionally, females relative to males were 63% less likely to be diagnosed with SPTM, aRR = 0.37, 99% CI 0.22-0.61. With respect to urbanicity, compared to children in rural areas, those in urban areas were 21% less likely to develop SPTM, aRR = 0.79, 99% CI, 0.12-5.35, while children in metropolitan areas were 40% less likely to develop SPTM, aRR = 0.60, 99% CI, 0.10-3.59. Although imprecise, there was a 5% increased risk of SPTM, with radiation as an exposure effect, aRR = 1.05, 99% CI 1.01-1.75., Conclusions: There are increasing temporal trends in pediatric SPTM with blacks relative to whites having observed lower incidence, despite an increasing percent change among blacks/AA, indicative of the disproportionate burden of this malignant neoplasm. SPTM risk was higher among males and in rural areas, while radiation as a risk for SPTM was clinically and biologically meaningful, albeit an observed statistically insignificant inference due to sampling variability, requiring intervention mapping in radiation exposure margination among children.

Purpose/Objective: Frequent consumption of fermented carbohydrates and bottle feeding contribute to the development of early childhood caries (ECC). There are no substantial findings on the effects of breastfeeding patterns on oral health conditions in children in the United States. We aimed to assess the nexus between exclusive breastfeeding during the first 6 months and oral health disorders, namely toothache, decayed teeth, or unfilled cavities in early childhood. Materials and Methods: Design: Cross-sectional epidemiologic design of nationally representative data collected via telephone surveys in the United States was utilized. Setting: National Survey of Children's Health, 2012 Participants: Population-based random sample of parents/guardians of 24,655 children aged 6 months to 5 years. Main Outcome and Measure: The primary outcome was the presence of oral health disorders (OHD) in children, defined as the parent-reported occurrence of one or more of the following conditions in the past 12 months: toothache, decayed teeth, or an unfilled cavity. This was assessed through a single composite question in the survey, asking parents/guardians if their child had experienced any of these specific oral health issues within the previous year with a binary (yes/no) response option. Results: Among 24,655 children aged 6 months to 5 years, 2392 (9.7%) had experienced an oral health disorder (OHD) in the previous 12 months. In unadjusted analysis, children exclusively breastfed for 6 months were 28% less likely to present with OHD compared to never-breastfed children (OR = 0.72, 95% CI, 0.52-0.98). However, after adjusting for key factors, including maternal health and race/ethnicity, this association was no longer statistically significant (aOR = 1.11, 95% CI 0.79-1.57). Significant predictors of OHD included maternal health (aOR for fair/poor vs. excellent/very good maternal health = 1.79, 95% CI 1.08-2.69) and race/ethnicity, with a higher prevalence among non-Hispanic Black (12.9%) and multi-racial children (12.6%) compared to non-Hispanic White children (7.7%). Conclusions and Relevance: While exclusive breastfeeding for the first six months of life was not found to be a significant predictor of pediatric oral health outcomes after adjustment, maternal health and race/ethnicity were significant determinants of oral health disorders. These findings underscore the importance of comprehensive healthcare approaches that consider maternal well-being and socio-demographic factors. Future research should explore interventions targeting these factors to improve pediatric oral health outcomes.

Objectives: Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein., Design: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial., Setting: Eighty-five adult ICUs across 16 countries., Patients: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425)., Interventions: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d)., Measurements and Main Results: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups., Conclusions: In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk., Competing Interests: Dr. Bear received funding from Baxter Healthcare (advisory board and speaker fees), Avanos (advisor board fees), and Cardinal Health (speaker fees). Dr. León received funding from B Braun Sharing Expertise. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose: Racial disparities in infant mortality in the United States persist after adjustment for known confounders of race and mortality association, as well as heterogeneity assessment. Epidemiologic and clinical data continue to show the survival disadvantages of Black/AA children: when Black/AAs are compared to whites, they are three times as likely to die from all-cause mortality. The persistent inability to remove the variance in race-mortality association is partly due to unobserved, unmeasured, and residual confounding, as well as implicit biases in public health and clinical medicine in health equity transformation. This current epidemiologic-perspective explanatory model study aimed to examine the possible explanation of racial differences in U.S. infant mortality using medical misadventures as errors and mistakes, and infants' involvement in motor vehicular traffic accidents., Materials and Method: Using CDC WONDER ecologic data from 1968 to 2015, we assessed the infant mortality-rate ratio and percent change associated with medical misadventures as well as motor vehicular accidents or trauma. The rate ratio and percent change were estimated using stratification analysis and trend homogeneity, respectively., Results: There was a Black-white racial difference in medical misadventures during the study period. Relative to the years 1968-1978 (rate ratio [RR], 1.43), there was a steady increase in the mortality-rate ratio in 1979-1998 (52%, RR = 1.52), and mortality was more than two times as likely in 1999-2015 (RR = 2.37). However, with respect to motor vehicular accident/trauma mortality, the mortality ratio, although lower among Blacks in 1968-1978 (RR, 0.92), increased in 1979-1998 by 27% (RR = 1.27) but decreased in 1999-2015 (RR, 1.17), though there was still an excess of 17% mortality among Black/AAs. The percent change for medical misadventures indicated an increasing trend from 9.3% in 1998 to 52% in 2015. However, motor vehicular-related mortality indicated a positive trend in 1998 (38.5%) but a negative trend in 2015 (-8.4%)., Conclusions: There were substantial race differentials or variances in infant mortality associated with medical misadventures compared to traffic accidents, and Black/AA children relative to whites experienced a survival disadvantage. These comparative findings are suggestive of medical misadventures and motor vehicular trauma as potential explanations for some of the persistent Black-white disparities in overall infant mortality in the U.S. From these findings, we recommend a national effort to address these issues, thus narrowing the observed disparities in the U.S. infant mortality burden among Black/AAs.

Background: Delivering higher doses of protein to mechanically ventilated critically ill patients did not improve patient outcomes and may have caused harm. Longitudinal urea measurements could provide additional information about the treatment effect of higher protein doses. We hypothesised that higher urea values over time could explain the potential harmful treatment effects of higher doses of protein., Methods: We conducted a reanalysis of a randomised controlled trial of higher protein doses in critical illness (EFFORT Protein). We applied Bayesian joint models to estimate the strength of association of urea with 30-day survival and understand the treatment effect of higher protein doses., Results: Of the 1301 patients included in EFFORT Protein, 1277 were included in this analysis. There were 344 deaths at 30 days post-randomisation. By day 6, median urea was 2.1 mmol/L higher in the high protein group (95% CI 1.1-3.2), increasing to 3.0 mmol/L (95% CI 1.3-4.7) by day 12. A twofold rise in urea was associated with an increased risk of death at 30 days (hazard ratio 1.34, 95% credible interval 1.21-1.48), following adjustment of baseline characteristics including age, illness severity, renal replacement therapy, and presence of AKI. This association persisted over the duration of 30-day follow-up and in models adjusting for evolution of organ failure over time., Conclusions: The increased risk of death in patients randomised to a higher protein dose in the EFFORT Protein trial was estimated to be mediated by increased urea cycle activity, of which serum urea is a biological signature. Serum urea should be taken into consideration when initiating and continuing protein delivery in critically ill patients., Clinicaltrials: gov Identifier: NCT03160547 (2017-05-17)., (© 2024. The Author(s).)

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071., (© 2023. The Author(s).)

Background: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE., Methods: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted., Results: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high., Conclusions: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness., Trial Registration: PROSPERO (CRD42023438187). Registered 21/06/2023., (© 2023. The Author(s).)

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting., (© 2023. The Author(s).)

Nutritional assessment and provision of nutritional therapy are a core part of intensive care unit (ICU) patient treatment. The ESPEN guideline on clinical nutrition in the ICU was published in 2019. However, uncertainty and difficulties remain regarding its full implementation in daily practice. This position paper is intended to help ICU healthcare professionals facilitate the implementation of ESPEN nutrition guidelines to ensure the best care for their patients. We have aimed to emphasize the guideline recommendations that need to be implemented in the ICU, are advised, or are optional, and to give practical directives to improve the guideline recommendations in daily practice. These statements were written by the members of the ICU nutrition ESPEN special interest group (SIG), based on a survey aimed at identifying current practices relating to key issues in ICU nutrition. The ultimate goal is to improve the ICU patients quality of care., Competing Interests: Declaration of competing interest Ronan Thibault received consulting and conference fees: Aguettant, Baxter, BBraun, Boehringer Ingelheim, Fresenius-Kabi, Nestlé Health Science, Nutricia, Roche, Servier; conference fees: Astra-Zeneca, Homeperf, Lactalis, Le Cancer; research support: Takeda-Shire, Valorex. Danielle E. Bear has received consulting fees from Avanos and Cardinal Health and speaker fees from Cardinal Health and Baxter. Juan Carlos Montejo Gonzalez has received speaker fees from Abbott, Baxter, Fresenius Kabi, and Vegenat. Michael Hiesmayr has received board membership and consulting fees from Fresenius-Kabi, and speaker fees from Baxter and Fresenius Kabi. Mehmet Uyar has received speaker fees from Abbott, Baxter, Fresenius, Nestlé. Elisabeth de Waele has received research grants from Baxter and Danone, and speaker fees from ART Medical, Baxter, and Danone. Steffen Weber-Carstens has received consulting fees from Dräger. Pierre Singer received consulting and conference fees: Baxter, Fresenius Kabi, Cosmed, conference fees: Nestle, Nutricia, consulting fees: ART medical, and grants from Fresenius Kabi, ART medical, and B Braun. Arabella Fischer and Péter Tamási declare no conflict of interest., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Personalization of ICU nutrition is essential to future of critical care. Recommendations from American/European guidelines and practice suggestions incorporating recent literature are presented. Low-dose enteral nutrition (EN) or parenteral nutrition (PN) can be started within 48 h of admission. While EN is preferred route of delivery, new data highlight PN can be given safely without increased risk; thus, when early EN is not feasible, provision of isocaloric PN is effective and results in similar outcomes. Indirect calorimetry (IC) measurement of energy expenditure (EE) is recommended by both European/American guidelines after stabilization post-ICU admission. Below-measured EE (~ 70%) targets should be used during early phase and increased to match EE later in stay. Low-dose protein delivery can be used early (~ D1-2) (< 0.8 g/kg/d) and progressed to ≥ 1.2 g/kg/d as patients stabilize, with consideration of avoiding higher protein in unstable patients and in acute kidney injury not on CRRT. Intermittent-feeding schedules hold promise for further research. Clinicians must be aware of delivered energy/protein and what percentage of targets delivered nutrition represents. Computerized nutrition monitoring systems/platforms have become widely available. In patients at risk of micronutrient/vitamin losses (i.e., CRRT), evaluation of micronutrient levels should be considered post-ICU days 5-7 with repletion of deficiencies where indicated. In future, we hope use of muscle monitors such as ultrasound, CT scan, and/or BIA will be utilized to assess nutrition risk and monitor response to nutrition. Use of specialized anabolic nutrients such as HMB, creatine, and leucine to improve strength/muscle mass is promising in other populations and deserves future study. In post-ICU setting, continued use of IC measurement and other muscle measures should be considered to guide nutrition. Research on using rehabilitation interventions such as cardiopulmonary exercise testing (CPET) to guide post-ICU exercise/rehabilitation prescription and using anabolic agents such as testosterone/oxandrolone to promote post-ICU recovery is needed., (© 2023. The Author(s).)

The optimal feeding strategy in critically ill patients is a matter of debate, with current guidelines recommending different strategies regarding energy and protein targets. Several recent trials have added to the debate and question our previous understanding of the provision of nutrition during critical illness. This narrative review aims to provide a summary of interpretation of recent evidence from the view of basic scientist, critical care dietitian and intensivist, resulting in joined suggestions for both clinical practice and future research. In the most recent randomised controlled trial (RCT), patients receiving 6 versus 25 kcal/kg/day by any route achieved readiness for ICU discharge earlier and had fewer GI complications. A second showed that high protein dosage may be harmful in patients with baseline acute kidney injury and more severe illness. Lastly, a prospective observational study using propensity score matched analysis suggested that early full feeding, especially enteral, compared to delayed feeding is associated with a higher 28-day mortality. Viewpoints from all three professionals point to the agreement that early full feeding is likely harmful, whereas important questions regarding the mechanisms of harm as well as on timing and optimal dose of nutrition for individual patients remain unanswered and warrant future studies. For now, we suggest giving low dose of energy and protein during the first few days in the ICU and apply individualised approach based on assumed metabolic state according to the trajectory of illness thereafter. At the same time, we encourage research to develop better tools to monitor metabolism and the nutritional needs for the individual patient accurately and continuously., (© 2023. The Author(s).)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DEB has received speaker fees from Baxter Healthcare and Cardinal Health and advisory board fees from Avanos. TK declares no conflicts of interest.

Background & Aims: Micronutrients, principally vitamins and minerals, play an important role both in health and in disease. Parenteral micronutrient products are commonly prescribed for critically ill patients both in line with the terms of the product's license, and for other indications where there is an underpinning physiological rationale, or precedent, for their use but little evidence. This survey sought to understand United Kingdom (UK) prescribing practice in this area., Methods: A 12-question survey was circulated to healthcare professionals working in UK critical care units. The survey was designed to explore several aspects of micronutrient prescribing or recommendation practice by the critical care multidisciplinary team, including indications and underpinning clinical rationale for using these products, dosing, and considerations with respect to micronutrients delivered as part of nutrition. Results were analysed, exploring indications, considerations relating to diagnoses, therapies including renal replacement therapies, and method of nutrition., Results: 217 responses were included in the analysis, with 58% from physicians and the remaining 42% from nurses, pharmacists, dietitians and other healthcare disciplines. Vitamins were most commonly prescribed or recommended for Wernicke's encephalopathy (prescribed or recommended by 76% of respondents), treatment of refeeding syndrome (64.5%), and for patients with unknown or uncertain alcohol intake history (63.6%). These clinically suspected or confirmed indications were cited more frequently as a reason to prescribe than laboratory identified deficiency states. 20% of respondents indicated that they would prescribe or recommend parenteral vitamins for patients requiring renal replacement therapy. The practice of vitamin C prescribing was heterogeneous, including dose and indication. Trace elements were prescribed or recommended less often than vitamins, with the most frequently reported indications being for patients requiring parenteral nutrition (42.9%), biochemically confirmed deficiency states (35.9%), and for treatment of refeeding syndrome (26.3%)., Conclusions: Micronutrient prescribing in ICUs in the UK is heterogeneous, with clinical scenarios where there is an evidence base or an established precedent for their use often guiding decisions to use micronutrient products. Further work to examine the potential benefits and harms on patient-oriented outcomes of micronutrient product administration should be undertaken, to facilitate their judicious and cost-effective use, with a focus on areas where they have a theoretical benefit., Competing Interests: Declaration of competing interest MO has received research funding from Fresenius Medical and Baxter. LKC, NL, EC and CMcK have nothing to disclose., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Peripheral nerve stimulation (PNS) is an effective neuromodulation therapy for chronic neuropathic and nociceptive pain. Although the total number of PNS implantations has increased over the last decade, no curriculum exists to guide training and learning of this therapy. The goal of the North American Neuromodulation Society (NANS) education committee is to develop a series of competency-based curriculums for neuromodulation therapies. The PNS curriculum is the latest part of such series, following the curriculums for spinal cord stimulation and intrathecal drug delivery system., Materials and Methods: A multidisciplinary task force (anesthesiology, physical medicine and rehabilitation, neurosurgery, preventive medicine and public health, and neurology) was created by the educational committee of NANS to develop a PNS curriculum in accordance with the Accreditation Council for Graduate Medical Education (ACGME) milestones. The curriculum was created based on the best available evidence and expert knowledge (from our task force members) of available PNS systems. The final PNS curriculum was approved by the NANS board., Results: A PNS curriculum was developed by the task force. Milestones included professionalism, practice-based learning, interpersonal communication, medical knowledge, systems-based practice, procedural skills, and patient care. Each milestone was defined into three categories: early learner, advanced learner, and practitioner., Conclusions: This manuscript provides a PNS training curriculum developed by a multidisciplinary task force of the NANS educational committee in accordance with the milestones described by ACGME for basic learners, advanced learners, and practitioners. This curriculum will help provide a structured training and evaluation process for obtaining proficiency in PNS treatment(s)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Acute kidney injury impacts the micronutrient status by various mechanisms including decreased enteral absorption, changes in redistribution, altered metabolism, and increased consumption. When renal replacement therapy (RRT) is applied, there are additional losses of vitamins, trace elements, and amino acids, and their derivatives due to diffusion or adhesion. Varied data exist regarding the degree of micronutrient losses and plasma concentrations in patients who receive RRT, and these differ by RRT modality, dose, duration, and type of micronutrient. Water-soluble vitamins, selenium, copper, and carnitine are among the most frequently reported depleted nutrients. The role of micronutrient supplementation in critically ill patients undergoing RRT and the optimal dose and mode of administration are yet to be determined., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Critically ill patients with COVID-19 are at high nutrition risk. This study aimed to describe the nutrition support practices in a single centre critical care unit during the initial surge of the COVID-19 pandemic. Practices were explored from ICU admission to post-ICU follow-up clinic and patients who received veno-venous extra-corporeal membrane oxygenation (VV-ECMO) were compared to those who did not., Methods: This retrospective observational study included COVID-19 positive, adult ICU patients who were mechanically ventilated for ≥72 h. Data were collected from ICU admission until the time of post-ICU clinic. For in-ICU data, results are compared between patients who did and did not receive VV-ECMO., Results: 252 patients were included (VV-ECMO n = 58). Adequate energy and protein was delivered in 193 (76.6%) patients during their ICU admission with no differences between those who did and did not receive VV-ECMO (44 (75.9%) vs. 149 (76.8%)). Parenteral nutrition only being required in 12 (4.8%) patients. Following stepdown to the ward 77 (70%) patients required ongoing enteral nutrition support, and 74 (66.7%) required a texture modified diet or were NBM. Following hospital discharge, nearly a third of ICU survivors (28.4%) were referred for dietetic input. The most common referral reason was loss of weight. Breathlessness and fatigue were the most commonly reported nutrition impact symptoms experienced following hospital discharge., Conclusion: Results show it is possible to reach nutritional adequacy for most patients and that neither VV-ECMO nor proning were barriers to nutritional adequacy. Nutritional issues for patients who were critically ill with COVID-19 persist following stepdown to ward level and into the community and strategies to manage this require further investigation., Competing Interests: Conflict of interest GH received conference registration fees from Nutricia Ltd. LC has no conflicts of interest to declare. DEB has received speaker fees from Baxter Healthcare., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Background: Optimising outcomes for critically ill patients with COVID-19 patients requires early interdisciplinary rehabilitation. As admission numbers soared through the pandemic, the redeployed workforce needed rapid, effective training to deliver these rehabilitation interventions., Methods: The COVID-19 ICU Remote-Learning Rehab Course (CIRLC-rehab) is a one-day interdisciplinary course developed after the success of CIRLC-acute. The aim of CIRLC-rehab was to rapidly train healthcare professionals to deliver physical, nutritional and psychological rehabilitation strategies in the ICU/acute setting. The course used blended learning with interactive tutorials delivered by shielding critical care professionals. CIRLC-rehab was evaluated through a mixed-methods approach, including questionnaires, and follow-up semi-structured interviews to evaluate perceived impact on clinical practice. Quantitative data are reported as n (%) and means (SD). Inductive descriptive thematic analysis with methodological triangulation was used to analyse the qualitative data from the questionnaires and interviews., Results: 805 candidates completed CIRLC-rehab . 627 (78.8%) completed the post-course questionnaire. 95% ( n = 596) found CIRLC-rehab extremely or very useful and 96.0% ( n = 602) said they were very likely to recommend the course to colleagues. Overall confidence rose from 2.78/5 to 4.14/5. The course promoted holistic and humanised care, facilitated informal networks, promoted interdisciplinary working and equipped the candidates with practical rehabilitation strategies that they implemented into clinical practice., Conclusion: This pragmatic solution to educating redeployed staff during a pandemic increased candidates' confidence in the rehabilitation of critically ill patients. There was also evidence of modifications to clinical care utilising learning from the course that subjectively facilitated holistic and humanised rehabilitation, combined with the importance of recognising the humanity, of those working in ICU settings themselves. Whilst these data are self-reported, we believe that this work demonstrates the real-term benefits of remote, scalable and rapid educational delivery., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: 33N Lrd. is a private limited company specialising in healthcare data analytics and training. It is run by working NHS clinicians and provides the Clinically Led Workforce and Activity Redesign Programme. 33N provided resources for CIRLC for no monetary gains. Blackboard International B.V: Blackboard provides educational services to support teaching and learning solutions. Blackboard’s EdTech platform ‘Learn Ultra’ was provided for CIRLC for free in the first wave of the pandemic., (© The Intensive Care Society 2021.)

Background: Clinical research on nutritional and metabolic interventions in critically ill patients is heterogenous regarding time points, outcomes and measurement instruments used, impeding intervention development and data syntheses, and ultimately worsening clinical outcomes. We aimed to identify and develop a set of core outcome domains and associated measurement instruments to include in all research in critically ill patients., Methods: An updated systematic review informed a two-stage modified Delphi consensus process (domains followed by instruments). Measurement instruments for domains considered 'essential' were taken through the second stage of the Delphi and a subsequent consensus meeting., Results: In total, 213 participants (41 patients/caregivers, 50 clinical researchers and 122 healthcare professionals) from 24 countries contributed. Consensus was reached on time points (30 and 90 days post-randomisation). Three domains were considered 'essential' at 30 days (survival, physical function and Infection) and five at 90 days (survival, physical function, activities of daily living, nutritional status and muscle/nerve function). Core 'essential' measurement instruments reached consensus for survival and activities of daily living, and 'recommended' measurement instruments for physical function, nutritional status and muscle/nerve function. No consensus was reached for a measurement instrument for Infection. Four further domains met criteria for 'recommended,' but not 'essential,' to measure at 30 days post-randomisation (organ dysfunction, muscle/nerve function, nutritional status and wound healing) and three at 90 days (frailty, body composition and organ dysfunction)., Conclusion: The CONCISE core outcome set is an internationally agreed minimum set of outcomes for use at 30 and 90 days post-randomisation, in nutritional and metabolic clinical research in critically ill adults., (© 2022. The Author(s).)

Background: We sought to determine whether peaks in essential amino acid (EAA) concentration associated with intermittent feeding may provide anabolic advantages when compared with continuous feeding regimens in critical care., Methods: We performed a secondary analysis of data from a multicenter trial of UK intensive care patients randomly assigned to intermittent or continuous feeding. A linear mixed-effects model was developed to assess differences in urea-creatinine ratio (raised values of which can be a marker of muscle wasting) between arms. To investigate metabolic phenotypes, we performed k-means urea-to-creatinine ratio trajectory clustering. Amino acid concentrations were also modeled against urea-to-creatinine ratio from day 1 to day 7. The main outcome measure was serum urea-to-creatinine ratio (millimole per millimole) from day 0 to the end of the 10-day study period., Results: Urea-to-creatinine ratio trajectory differed between feeding regimens (coefficient -.245; P = .002). Patients receiving intermittent feeding demonstrated a flatter urea-to-creatinine ratio trajectory. With k-means analysis, the cluster with the largest proportion of continuously fed patients demonstrated the steepest rise in urea-to-creatinine ratio. Neither protein intake per se nor serum concentrations of EAA concentrations were correlated with urea-to-creatinine ratio (coefficient = .088 [P = .506] and coefficient <.001 [P = .122], respectively)., Conclusion: Intermittent feeding can mitigate the rise in urea-to-creatinine ratio otherwise seen in those continuously fed, suggesting that catabolism may have been, to some degree, prevented., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Purpose of Review: Patients hospitalised with COVID-19 are at high nutrition risk and a significant number are likely to require ongoing nutrition rehabilitation. Here, we summarise guideline recommendations for nutritional rehabilitation in postacute COVID-19 infection, outline the rationale for nutrition rehabilitation for survivors of postacute COVID-19 in patients admitted to both the hospital ward and intensive care unit and discuss current evidence for interventions., Recent Findings: Several guidelines exist outlining recommendations for nutrition care in hospital, critical care and the community setting. All have common themes pertaining to the importance of nutrition screening, nutrition assessment, appropriate choice of intervention and continuity of care across settings. While a plethora of data exists highlighting the high nutrition risk and prevalence of malnutrition in this population, minimal interventional studies have been published., Summary: Patients hospitalised with COVID-19 are at high nutrition risk. Future studies should focus on nutrition interventions for the rehabilitation period and determine whether nutrition needs differ between COVID-19 and non-COVID-19 survivors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Skeletal muscle wasting is a serious consequence of critical illness, which may impact on long term physical and functional disability. To date, no intervention has been proven to reduce skeletal muscle wasting. Leucine and it's metabolite β-hydroxy-β-methylbutyrate (HMB) have been proposed as interventions. This review details the mechanism of action of both leucine and HMB, discusses the most recent research for both leucine and HMB and lastly discusses considerations for future research., Recent Findings: Only one study of leucine in critical illness has recently been published. This was a feasibility study where the physiological and muscle related outcomes were not reported to be feasible. Three studies on HMB have been reported recently with no effect seen on either muscle mass or strength. The main limitation in our understanding of the potential use of leucine or HMB on skeletal muscle wasting is the lack of mechanistic studies available in this population., Summary: Mechanistic studies should be a priority before embarking on further randomized controlled trials related to this topic., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To investigate the prevalence of low skeletal muscle index (area normalized for height) and density, their trajectory of change, and to determine associations with clinical outcome in adults with severe respiratory failure requiring venovenous extracorporeal membrane oxygenation., Design: Prospective observational study., Patients: Adults receiving venovenous extracorporeal membrane oxygenation for a minimum of 72 hours and a maximum of 6 months between September 2010 and June 2017, who had a CT scan which included the third lumbar vertebra., Intervention: None., Measurements and Main Results: Skeletal muscle index and density was determined using Slice-O-Matic V5.0 (TomoVision, Montreal, QC, Canada). Low skeletal muscle index and density were defined using published criteria. Regression models were used to assess for associations between muscle index and density and clinical outcome. Two-hundred fifteen patients, median (interquartile range) age 46 years (35.0-57.0 yr) were included. Forty-five patients (21.1%) had low skeletal muscle index, and 48 (22.3%) had low skeletal muscle density on commencement of venovenous extracorporeal membrane oxygenation. Low skeletal muscle index was more prevalent in males (28.8% vs 11.6%; χ2 = 9.4; p = 0.002) and was associated with a longer duration of venovenous extracorporeal membrane oxygenation (B = 5.0; 95% CI, 0.2-9.9; p = 0.042). Higher skeletal muscle density was independently associated with ICU survival (odds ratio 1.6 per 10 Hounsfield units; 95% CI, 1.1-2.5; p = 0.025). No relationship was observed between skeletal muscle index nor density and physical function. Adequacy of energy and protein did not influence change in skeletal muscle index or density., Conclusions: Low skeletal muscle index at the commencement of venovenous extracorporeal membrane oxygenation was associated with a longer duration of venovenous extracorporeal membrane oxygenation, whereas preserved skeletal muscle density was associated with improved survival., Competing Interests: Dr. Connolly’s institution received funding from an NIHR Postdoctoral Fellowship (PDF-2015-08-015). Dr. Hart received funding from Philips and Resmed with the funds held and managed by Guy’s & St Thomas’ NHS Foundation Trust; he received financial support from Philips for development of the MYOTRACE technology that has patent approved in Europe (U.S. pending) outside the area of work commented on here; and he received personal fees from Philips-Respironics, Philips, Resmed, and Fisher-Paykel. 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 & Aims: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration., Methods: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members., Results: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%) respondents reported to monitor micronutrient deficiencies through clinical signs and/or laboratory abnormalities, and 148 (44.3%) reportedly measure blood micronutrient concentrations on a routine basis. Two hundred ninety-two (87.4%) participants provided specific data on parenteral micronutrient supplementation, of whom 150 (51.4%) reported early administration of combined multivitamin and trace element preparations at least in selected patients. Among specific parenteral micronutrient preparations, thiamine (146 [50.0%]) was reported to be the most frequently administered micronutrient, followed by vitamin B complex (104 [35.6%]) and folic acid (86 [29.5%]). One hundred twenty (35.9%) and 113 (33.8%) participants reported to perform daily measurements of phosphate and magnesium, respectively, whereas 173 (59.2%) and 185 (63.4%) reported to routinely supplement these minerals parenterally., Conclusion: The survey revealed a wide variation in current practices of micronutrient, phosphate and magnesium measurement and parenteral administration, suggesting a risk of insufficient prevention, diagnosis and treatment of deficiencies. These results provide the context for future comparative studies, and identify areas for knowledge translation and recommendations., Competing Interests: Conflicts of interest Dr. Amrein reports grants, personal fees and other from Fresenius Kabi (Austria), personal fees from Vifor Pharma (Austria), personal fees from Shire now part of Takeda (Austria), outside the submitted work. Dr. Bear reports personal fees from Nutricia (United Kingdom), personal fees from Baxter Healthcare (Global, based in USA), personal fees from Fresenius Kabi (Global, based in Germany), personal fees from Cardinal Health (USA), personal fees from AVANOS (USA), outside the submitted work. Dr. lasocki reports grants and personal fees from VIFOR PHARMA (France), personal fees from PFIZER (France), personal fees and non-financial support from MASIMO (France), non-financial support from PHARMACOSMOS (Denmark), outside the submitted work. Dr. Reintam Blaser reports grants from Fresenius Kabi (Germany), personal fees from Fresenius Kabi (Germany), personal fees from Nestlé (Switzerland), outside the submitted work. Rousseau reports non-financial support from Fresenius (Belgium), personal fees and non-financial support from Baxter (Belgium), non-financial support from Nutricia (Belgium), non-financial support from Nestlé (Belgium), outside the submitted work. Dr. van Zanten reports grants, personal fees and non-financial support from Nutricia Danone (Netherlands), grants from Mermaid (Denmark), personal fees and non-financial support from Fresenius Kabi (Belgium and Netherlands), grants and non-financial support from Cardinal Health (USA), personal fees from Nestle (USA), grants and personal fees from Amomed (Netherlands and Austria), grants and personal fees from Lyric (USA), personal fees from Baxter (Belgium), outside the submitted work. Dr. Casaer reports personal fees from Fresenius Kabi, (Belgium) outside the submitted work. MPC holds a postdoctoral research fellowship supported by the Research Foundation Flanders (1832817N). Gunst J holds a postdoctoral research fellowship supported by the Clinical Research and Education Council of the University Hospitals Leuven (Belgium). The other authors reported no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: The interest in the use of beta-hydroxy-beta-methylbutyrate (HMB) as an intervention to prevent and treat sarcopenia has increased over recent years. The purpose of this review is to explore recent evidence pertaining to the mechanism of action of HMB and how this may influence changes in lean mass and strength in older persons who are both hospitalized and living in the community., Recent Findings: No new studies have been published over the last 2 years investigating the effect of HMB in older persons who are hospitalized, aside from one posthoc analysis of a randomized controlled trial exploring the effect of a high protein oral nutrition supplement containing HMB on handgrip strength and nutritional status. Three studies recruiting community-dwelling older adults have been published, but results are influenced by suboptimal methodological quality., Summary: Recent data suggest the need for high-quality studies investigating the effectiveness of HMB to improve outcomes related to sarcopenia in both hospitalized and community-dwelling older persons.

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.

Background: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it., Research Question: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients?, Study Design and Methods: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones., Results: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 μM [44-98 μM]; P = .547) and trial day 10 (239 μM [33-444 μM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups., Interpretation: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe., Trial Registry: ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov., (Copyright © 2020 American College of Chest Physicians. Published by 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.

Objective: Executive functioning encompasses interactive cognitive processes such as planning, organization, set-shifting, inhibition, self-monitoring, working memory, and initiating and sustaining motor and mental activity. Researchers therefore typically assess executive functioning with multiple tests, each yielding multiple scores. A single composite score of executive functioning, which summarizes deficits across a battery of tests, would be useful in research and clinical trials. This study examines multiple candidate composite scores of executive functioning using tests from the Delis-Kaplan Executive Function System (D-KEFS)., Method: Participants were 875 adults between the ages of 20 and 89 years from the D-KEFS standardization sample. Seven Total Achievement scores were used from three tests (i.e., Trail Making, Verbal Fluency, and Color-Word Interference) to form eight composite scores that were compared based on their psychometric properties and association with intelligence (IQ)., Results: The distributions of most composite scores were mildly to severely skewed, and some had a pronounced ceiling effect. The composite scores all showed a medium positive correlation with IQ. The composite scores were highly intercorrelated in the total sample and in four IQ subgroups (i.e., IQ <89, 90-99, 100-109, 110+), with some being so highly correlated that they appear redundant., Conclusions: This study is part of a larger research program developing a cognition endpoint for research and clinical trials with sound psychometric properties and utility across discrepant test batteries. Future research is needed to examine the reliability and ecological validity of these composite scores., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: Previous researchers have examined the frequency at which healthy participants obtain one or more low scores on neuropsychological test batteries, proposing five psychometric principles of multivariate base rates: (a) low scores are common, with their frequency contingent on (b) the low score cutoff used, (c) the number of tests administered/interpreted, and (d) the demographic characteristics and (e) intelligence of participants. The current study explored whether these principles applied to high scores as well, using the Delis-Kaplan Executive Function System (D-KEFS)., Method: Multivariate base rates of high scores (≥75th, ≥84th, ≥91st, ≥95th, and ≥98th percentiles) were derived for a three-test, four-test, and full D-KEFS battery, using the adult portion of the normative sample (aged 16-89 years; N = 1050) stratified by education and intelligence. The full D-KEFS battery provides 16 total achievement scores (primary indicators of executive function)., Results: High scores occurred commonly for all batteries. For the three-test battery, 24.1% and 12.4% had 1 or more scores ≥95th percentile and ≥98th percentile, respectively. High scores occurred more often for longer batteries: 61.6%, 72.9%, and 87.8% obtained 1 or more scores ≥84th percentile for the three-test, four-test, and full batteries, respectively. The frequency of high scores increased with more education and higher intelligence., Conclusions: The principles of multivariate base rates also applied to high D-KEFS scores: high scores were common and contingent on the cutoff used, number of tests administered/interpreted, and education/intelligence of examinees. Base rates of high scores may help clinicians identify true cognitive strengths and detect cognitive deficits in high functioning people.

Malnutrition is common in patients with acute kidney injury (AKI) and the risk of mortality is high, especially if renal replacement therapy is needed. Between April 2013 through April 2014, we recruited critically ill adult patients (≥18 years) with severe AKI in two University hospitals in London, UK, and measured serial plasma concentrations of vitamin B 1 , B 6 , B 12 , C and D, folate, selenium, zinc, copper, iron, carnitine and 22 amino acids for six consecutive days. In patients receiving continuous renal replacement therapy (CRRT), the concentrations of the same nutrients in the effluent were also determined. CRRT patients (n = 31) had lower plasma concentrations of citrulline, glutamic acid and carnitine at 24 hrs after enrolment and significantly lower plasma glutamic acid concentrations (74.4 versus 98.2 μmol/L) at day 6 compared to non-CRRT patients (n = 24). All amino acids, trace elements, vitamin C and folate were detectable in effluent fluid. In >30% of CRRT and non-CRRT patients, the plasma nutrient concentrations of zinc, iron, selenium, vitamin D 3 , vitamin C, trytophan, taurine, histidine and hydroxyproline were below the reference range throughout the 6-day period. In conclusion, altered micronutrient status is common in patients with severe AKI regardless of treatment with CRRT.

Recent definitions of malnutrition include low muscle mass within its diagnostic criteria. In fact, malnutrition is one of the main risk factors of skeletal muscle loss contributing to the onset of sarcopenia. However, differences in the screening and diagnosis of skeletal muscle loss, especially as a result of malnutrition in clinical and community settings, still occur mainly as techniques and thresholds used vary in clinical practice. The objectives of this position paper are firstly to emphasize the link between skeletal muscle loss and malnutrition-related conditions and secondly to raise awareness for the timely identification of loss of skeletal muscle mass and function in high risk populations. Thirdly to recognize the need to implement appropriate nutritional strategies for prevention and treatment of skeletal muscle loss and malnutrition across the healthcare continuum. Malnutrition needs to be addressed clinically as a muscle-related disorder and clinicians should integrate nutritional assessment with muscle mass measurements for optimal evaluation of these two interrelated entities to tailor interventions appropriately. The design of monitoring/evaluation and discharge plans need to include multimodal interventions with nutrition and physical exercise that are key to preserve patient's muscle mass and function in clinical and community settings., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

This study provides observed base rates of low executive functioning test scores among healthy children and adolescents, stratifies those base rates by narrow intellectual functioning and age groupings, and provides normative classification ranges to aid the interpretation of performances on the Delis-Kaplan Executive Function System (D-KEFS) in clinical practice and research. Participants included 875 children and adolescents between 8 and 19 years old from the D-KEFS normative sample (48% male; 52% female). Among these participants, 838 had complete data and were included in the current study. The racial/ethnic composition of the sample was: White (73.7%), African American (12.4%), Hispanic (11.1%), and other racial/ethnic backgrounds (2.7%). The Overall Test Battery Mean (OTBM) and the prevalence of low scores at various clinical cut-offs were calculated for the 13 primary scores from the D-KEFS Trail Making Test, Verbal Fluency Test, and Color-Word Interference Test. The OTBM and base rates were also calculated separately for those scores reflecting executive functioning (n = 7) and processing speed (n = 6). Healthy children and adolescents commonly obtained low scores on the D-KEFS tests considered here. Younger age, lower estimated full-scale intelligence quotient, and more test scores interpreted were associated with a greater frequency of low scores. Clinicians and researchers are encouraged to consider these multivariate base rates when assessing and attempting to identify executive functioning impairment among children and adolescents with the D-KEFS.

Background: Loss of skeletal muscle mass and muscle weakness are common in a variety of clinical conditions with both wasting and weakness associated with an impairment of physical function. β-Hydroxy-β-methylbutyrate (HMB) is a nutrition supplement that has been shown to favorably influence muscle protein turnover and thus potentially plays a role in ameliorating skeletal muscle wasting and weakness., Objectives: The aim of this study was to investigate the efficacy of HMB alone, or supplements containing HMB, on skeletal muscle mass and physical function in a variety of clinical conditions characterized by loss of skeletal muscle mass and weakness., Methods: A systematic review and meta-analysis of randomized controlled trials reporting outcomes of muscle mass, strength, and physical function was performed. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment. Outcome data were synthesized through meta-analysis with the use of a random-effects model and data presented as standardized mean differences (SMDs)., Results: Fifteen randomized controlled trials were included, involving 2137 patients. Meta-analysis revealed some evidence to support the effect of HMB alone, or supplements containing HMB, on increasing skeletal muscle mass (SMD = 0.25; 95% CI: -0.00, 0.50; z = 1.93; P = 0.05; I2 = 58%) and strong evidence to support improving muscle strength (SMD = 0.31; 95% CI: 0.12, 0.50; z = 3.25; P = 0.001; I2 = 0%). Effect sizes were small. No effect on bodyweight (SMD = 0.16; 95% CI: -0.08, 0.41; z = 1.34; P = 0.18; I2 = 67%) or any other outcome was found. No study was considered to have low risk of bias in all categories., Conclusion: HMB, and supplements containing HMB, increased muscle mass and strength in a variety of clinical conditions, although the effect size was small. Given the bias associated with many of the included studies, further high-quality studies should be undertaken to enable interpretation and translation into clinical practice. The trial was registered on PROSPERO as CRD42017058517., (Copyright © American Society for Nutrition 2019.)

Background: The use of veno-venous extracorporeal membrane oxygenation (vv-ECMO) is increasing in adults with severe respiratory failure. Observational data suggest that there are significant challenges to providing adequate nutrition support for patients on vv-ECMO. We aimed to describe firstly the nutrition support practices in a large single-centre providing vv-ECMO to adults and secondly any association with clinical outcome., Methods: We conducted a retrospective review of patients receiving vv-ECMO on the Intensive Care Unit (ICU) of a large London teaching hospital. Adult patients admitted to the ICU with severe respiratory failure between December 2010 and December 2015 were included. Daily energy and protein delivery were compared with estimated targets and reasons for feeding interruptions were collected from electronic medical records. Adequate feeding was defined as 80-110% of estimated targets., Results: We analysed 203 eligible patients. Median duration of ICU stay was 21.0 (IQR, 15.0-33.0) days and vv-ECMO 10.0 (IQR, 7.0-16.0) days. Although median energy (89.8% (IQR, 80.5-96.0%)) and protein (84.7% (IQR, 74.0-96.7%)) delivery was adequate, underfeeding of either energy or protein occurred on nearly one third (28.3%) of nutrition support days. A higher admission severity of illness score was associated with inadequate protein delivery (p = 0.040). Patients with more severe organ dysfunction on the first day of vv-ECMO received inadequate energy (p = 0.026). The most common reasons for interrupted feeding were medical procedures (39.1%) followed by poor gastric motility (22.8%)., Conclusion: Adequate energy and protein delivery during vv-ECMO is possible but underfeeding is still common, especially in those who are more severely ill or who have more severe organ dysfunction. Patients with inadequate energy or protein delivery did not differ in ICU and 6-month survival. Prospective studies investigating optimal feeding in this patient cohort are required., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Preserving muscle is not only crucial for maintaining proper physical movement, but also for its many metabolic and homeostatic roles. Low muscle mass has been shown to adversely affect health outcomes in a variety of disease states (eg, chronic obstructive pulmonary disease, cancer, cardiovascular disease) and leads to an increased risk for readmission and mortality in hospitalized patients. Low muscle mass is now included in the most recent diagnostic criteria for malnutrition. Current management strategies for malnutrition may not prioritize the maintenance and restoration of muscle mass. This likely reflects the challenge of identifying and measuring this body composition compartment in clinical practice and the lack of awareness by health care professionals of the importance that muscle plays in patient health outcomes. As such, we provide a review of current approaches and make recommendations for managing low muscle mass and preventing muscle loss in clinical practice. Recommendations to assist the clinician in the optimal management of patients at risk of low muscle mass include the following: (1) place muscle mass at the core of nutritional assessment and management strategies; (2) identify and assess low muscle mass; (3) develop a management pathway for patients at risk of low muscle mass; (4) optimize nutrition to focus on muscle mass gain versus weight gain alone; and (5) promote exercise and/or rehabilitation therapy to help maintain and build muscle mass. The need to raise awareness of the importance of screening and managing 'at risk' patients so it becomes routine is imperative for change to occur. Health systems need to drive clinicians to treat patients with this focused approach, and the economic benefits need to be communicated to payers. Lastly, further focused research in the area of managing patients with low muscle mass is warranted., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

The use of extracorporeal membrane oxygenation (ECMO) for both severe respiratory and cardiac failure is increasing. Because these patients are some of the sickest in the intensive care unit, a multidisciplinary approach to their treatment, including appropriate nutrition therapy, is warranted. Currently, limited data exist on the optimal timing, type, and amount of nutrition to be provided. This review focuses on describing the current nutrition practices in patients receiving ECMO, details research that is currently being undertaken, and lists important research questions that require exploration in this field. Observational data suggest that early enteral nutrition is safe and that although nutrition targets can be met, underfeeding is still common. Until further research is available, these patients should be fed according to guidelines for the general critically unwell population., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Purpose of Review: Mortality has long been the gold-standard outcome measure for intensive care clinical trials. However, as the critical care community begins to understand and accept that survivorship is associated with functional disability and a health and socioeconomic burden, the clinical and research focus has begun to shift towards long-term physical function RECENT FINDINGS: To use mortality as a primary outcome measure, one would either have to choose an improbable effect (e.g. a difference of 5-10% in mortality as a result of a single intervention) or recruit a larger number of patients, the latter being unfeasible for most critical care trials.Outcome measures will need to match interventions. As an example, amino acids, or intermittent feeding, can stimulate muscle protein synthesis, and so prevention of muscle wasting may seem an appropriate outcome measure when assessing the effectiveness of these interventions. Testing the effectiveness of these interventions requires the development of novel outcome measures that are targeted and acceptable to patients. We describe advancements in dual-energy X-ray absorptiometry scanning, bio-impedence analysis, MRI and muscle ultrasound in this patient group that are beginning to address this development need., Summary: New approaches to outcome assessment are beginning to appear in post-ICU research, which promise to improve our understanding of nutrition and exercise interventions on skeletal muscle structure, composition and function, without causing undue suffering to the patient.