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Purpose: Muscle wasting deteriorates life quality after critical illness and increases mortality. Wasting starts upon admission to intensive care unit (ICU). We aimed to determine whether β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine, can attenuate this process., Methods: Prospective randomized, placebo-controlled double blind trial., Inclusion Criteria: ICU patients depending on mechanical ventilation on day 3 having a functional gastrointestinal tract. They were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on for 30 days., Primary Outcome: magnitude of loss of skeletal muscle area (SMA) of the quadriceps femoris measured by ultrasound at days 4 and 15., Secondary Outcomes: body composition, change in protein metabolism assessed by amino acids tracer pulse, and global health at 60 days. Data are mean [95% CI]. Statistics by ANCOVA with correction for confounders sex, age and/or BMI., Results: Thirty patients completed the trial, aged 65 [59, 71] years, SAPS2 score 48 [43, 52] and SOFA 8.5 [7.4, 9.7]. The loss of total SMA was 11% between days 4 and 15 (p < 0.001), but not different between the groups (p = 0.86). In the HMB group, net protein breakdown (Δ Estimate HMB-Placebo: -153 [-242, -63]; p = 0.0021) and production of several amino acid was significantly reduced, while phase angle increased more (0.66 [0.09, 1.24]; p = 0.0247), and SF-12 global health improved more (Δ Estimate HMB-Placebo: 27.39 [1.594, 53.19], p = 0.04)., Conclusion: HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle and better global health. CLINICALTRIALS., Gov Identifier: NCT03628365., Competing Interests: Conflict of interest MBB: no COI related to the present study. MMB receives honoraria for lectures from ABBOTT, Baxter, BBraun, DSM, Fresenius Kabi, Nestlé, Nutricia. NEPD receives honoraria for lectures from ABBOTT Nutrition., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p < 0.00001), and higher CRP (p < 0.0001). Most AA concentrations were lower in ICU patients (p < 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p < 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p < 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365)., Competing Interests: Conflicts of interest The authors have no conflict of interest to declare., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Critically ill patients with body mass index (BMI) < 20 kg/m 2 have worse outcomes than normal/overweight patients possibly because underweight is a marker of malnutrition. To assess the effects of nutrition therapy in this population during the first week of an ICU stay., Methods: Prospective, 2-centre, observational study. Nutritional evaluations were performed between days 2 and 3 (first) and between days 5 and 7 (second) of ICU admission. In the first evaluation, patients were divided into non-fed (without nutritional support) and early-fed (those already receiving nutritional support) groups. In the second evaluation, patients were divided according to caloric intake (≥or<20 kcal/kg) and protein intake (≥or<1.3 g of protein/kg)., Results: Of the 4236 patients screened and 342 were included in the cohort. Mortality was 58.5% (median 21 [11-38.25] days of follow-up). Unadjusted patient survival was worse in the non-fed group than in the early-fed group (HR 1.66; 95%CI, 1.18 to 2.32). There was no difference in mortality between groups after adjusting for the SOFA score on the day of the evaluation. At the second evaluation, unadjusted analysis showed better in-hospital survival in patients with higher caloric (HR0.58; 95%CI, 0.40 to 0.86) and protein intake (HR0.59; 95%CI, 0.42 to 0.82); there was no association between mortality and caloric or protein intake after adjusting for the SOFA score on the day of the evaluation., Conclusion: Nutritional therapy in the first week of ICU stay did not affect vital outcome after adjusting for the SOFA score on the day of the evaluation in underweight critically ill patients., Clinical Trial Registry: ClinicalTrials.gov number NCT03398343., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)