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OBJECTIVE: Glutamine and arginine are both used as nutritional supplements in critically ill patients. Although glutamine has been shown to be beneficial for the metabolically stressed patient, considerations about arginine supplementation are not unanimously determined. Our aim is to review the current knowledge on the possible interplay between glutamine and arginine generation in the stressed patient and to elaborate on whether these amino acids may function as a common denominator. Because glutamine can be given by the parenteral and enteral routes, possible different actions on the metabolic fate (e.g., generation of citrulline) with both routes are analyzed. DATA SOURCE: A summary of data on the clinical effect of glutamine and arginine metabolism is given, incorporating data on glutamine and arginine supplementation. Differences between the route of administration, parenteral or enteral, and the molecular form of supplied glutamine, free or as dipeptide, on citrulline generation by the gut and production of arginine are discussed. RESULTS: Glutamine and arginine influence similar organ systems; however, they differ in their targets. For example, glutamine serves as fuel for the immune cells, increases human leukocyte antigen-DR expression on monocytes, enhances neutrophil phagocytosis, and increases heat shock protein expression. Arginine affects the immune system by stimulating direct or indirect proliferation of immune cells. This indirect effect is possibly mediated by nitric oxide, which also enhances macrophage cytotoxicity. Furthermore, glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Glutamine has shown to be beneficial in the surgical and critically ill patient, whereas arginine supplementation is still under debate. The route of glutamine administration (parenteral or enteral) determines the effect on citrulline and on the de novo arginine generation. There is a marked difference between the administration of free glutamine and dipeptide enterally or parenterally. Splanchnic extraction of the hydrolyzed glutamine in mice when administering the dipeptide enterally is higher compared with administering free glutamine from the enteral site. In patients, splanchnic extraction of the dipeptide given enterally is 100% when comparing supplementation of the dipeptide intravenously. CONCLUSIONS: The beneficial effects of free glutamine or dipeptide may depend on the route of administration but also on the metabolic fate of amino acids generated (e.g., citrulline, arginine). Glutamine serves as a substrate for de novo citrulline and arginine synthesis. More research needs to be done to establish the direct clinical relevance of the different metabolic pathways. Future perspectives might include combining enteral and parenteral routes of administrating free glutamine or dipeptide. [ABSTRACT FROM AUTHOR]

Background: Increased protein provision might ameliorate muscle wasting and improve long-term outcomes in critically ill patients. The aim of the PRECISe trial was to assess whether higher enteral protein provision (ie, 2·0 g/kg per day) would improve health-related quality of life and functional outcomes in critically ill patients who were mechanically ventilated compared with standard enteral protein provision (ie, 1·3 g/kg per day)., Methods: The PRECISe trial was an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in five Dutch hospitals and five Belgian hospitals. Inclusion criteria were initiation of invasive mechanical ventilation within 24 h of intensive care unit (ICU) admission and an expected duration of invasive ventilation of 3 days or longer. Exclusion criteria were contraindications for enteral nutrition, moribund condition, BMI less than 18 kg/m 2 , kidney failure with a no dialysis code, or hepatic encephalopathy. Patients were randomly assigned to one of four randomisation labels, corresponding with two study groups (ie, standard or high protein; two labels per group) in a 1:1:1:1 ratio through an interactive web-response system. Randomisation was done via random permuted-block randomisation in varying block sizes of eight and 12, stratified by centre. Participants, care providers, investigators, outcome assessors, data analysts, and the independent data safety monitoring board were all blinded to group allocation. Patients received isocaloric enteral feeds that contained 1·3 kcal/mL and 0·06 g of protein/mL (ie, standard protein) or 1·3 kcal/mL and 0·10 g of protein/mL (ie, high protein). The study-nutrition intervention was limited to the time period during the patient's ICU stay in which they required enteral feeding, with a maximum of 90 days. The primary outcome was EuroQoL 5-Dimension 5-level (EQ-5D-5L) health utility score at 30 days, 90 days, and 180 days after randomisation, adjusted for baseline EQ-5D-5L health utility score. This trial was registered with ClinicalTrials.gov (NCT04633421) and is closed to new participants., Findings: Between Nov 19, 2020, and April 14, 2023, 935 patients were randomly assigned. 335 (35·8%) of 935 patients were female and 600 (64·2%) were male. 465 (49·7%) of 935 were assigned to the standard protein group and 470 (50·3%) were assigned to the high protein group. 430 (92·5%) of 465 patients in the standard protein group and 419 (89·1%) of 470 patients in the high protein group were assessed for the primary outcome. The primary outcome, EQ-5D-5L health utility score during 180 days after randomisation (assessed at 30 days, 90 days, and 180 days), was lower in patients allocated to the high protein group than in those allocated to the standard protein group, with a mean difference of -0·05 (95% CI -0·10 to -0·01; p=0·031). Regarding safety outcomes, the probability of mortality during the entire follow-up was 0·38 (SE 0·02) in the standard protein group and 0·42 (0·02) in the high protein group (hazard ratio 1·14, 95% CI 0·92 to 1·40; p=0·22). There was a higher incidence of symptoms of gastrointestinal intolerance in patients in the high protein group (odds ratio 1·76, 95% CI 1·06 to 2·92; p=0·030). Incidence of other adverse events did not differ between groups., Interpretation: High enteral protein provision compared with standard enteral protein provision resulted in worse health-related quality of life in critically ill patients and did not improve functional outcomes during 180 days after ICU admission., Funding: Netherlands Organisation for Healthcare Research and Development and Belgian Health Care Knowledge Centre., Competing Interests: Declaration of interests EDW receives honoraria for scientific lectures from Baxter Healthcare, Nutricia–Danone, and Nestlé. ARHvZ receives grants from AOP Pharma, Nutricia–Danone, Fresenius Kabi, PAION, and Rousselot; receives consulting fees from AOP Pharma, Medcaptain, and PAION; receives honoraria for lectures from Abbott, AOP Pharma, Baxter, Nestlé, Nutricia–Danone, Fresenius Kabi, GE Healthcare, and Dutch Medical Food; receives support for travel from Nutricia–Danone and Dutch Medical Food; is a member of the adult intensive care unit patient nutrition guideline committee of the European Society for Clinical Nutrition and Metabolism, the executive team of SepsisNet Netherlands, and the executive team of the Netherlands Society for Parenteral and Enteral Nutrition; and is the European Society of Intensive Care Medicine Section Feeding, Rehabilitation Endocrinology and Metabolism chair. ZP receives grants from Fresenius Kabi, Nestlé, and Baxter; receives consulting fees from Fresenius Kabi, Nestlé, Baxter, Faraday Pharmaceuticals, and Bioage Pharmaceuticals; and receives honoraria for lectures from Baxter, Nestlé, Fresenius Kabi, and Nutricia. MCGvdP receives grants from the Netherlands Organisation of Health Research and Development and the Belgian Health Care Knowledge Centre; receives in-kind support from Nutricia; receives consulting fees from Nutricia and Nestlé; and receives honoraria for lectures and support for travel from Nutricia. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence., Methods: A systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated., Results: Three randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73-3.32) with a mean absolute risk difference of 8.7% (- 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79-3.71) with a mean absolute risk difference of 10.8% (95%CrI - 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively., Conclusion: The current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials., Registration: INPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060 )., (© 2024. The Author(s).)

Aims: When out-of-hospital cardiac arrest (OHCA) becomes refractory, extracorporeal cardiopulmonary resuscitation (ECPR) is a potential option to restore circulation and improve the patient's outcome. However, ECPR requires specific materials and highly skilled personnel, and it is unclear whether increased survival and health-related quality of life (HRQOL) justify these costs., Methods and Results: This cost-effectiveness study was part of the INCEPTION study, a multi-centre, pragmatic randomized trial comparing hospital-based ECPR to conventional CPR (CCPR) in patients with refractory OHCA in 10 cardiosurgical centres in the Netherlands. We analysed healthcare costs in the first year and measured HRQOL using the EQ-5D-5L at 1, 3, 6, and 12 months. Incremental cost-effectiveness ratios (ICERs), cost-effectiveness planes, and acceptability curves were calculated. Sensitivity analyses were performed for per-protocol and as-treated subgroups as well as imputed productivity loss in deceased patients. In total, 132 patients were enrolled: 62 in the CCPR and 70 in the ECPR group. The difference in mean costs after 1 year was €5109 (95% confidence interval -7264 to 15 764). Mean quality-adjusted life year (QALY) after 1 year was 0.15 in the ECPR group and 0.11 in the CCPR group, resulting in an ICER of €121 643 per additional QALY gained. The acceptability curve shows that at a willingness-to-pay threshold of €80.000, the probability of ECPR being cost-effective compared with CCPR is 36%. Sensitivity analysis showed increasing ICER in the per-protocol and as-treated groups and lower probabilities of acceptance., Conclusion: Hospital-based ECPR in refractory OHCA has a low probability of being cost-effective in a trial-based economic evaluation., Competing Interests: Conflict of interest: R.L. reports support from ABIOMED for consulting lecture work and consultancy on the Medical Advisory Board of Xenios., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Prospective, trial-based data comparing health-related quality of life (HRQoL) in patients surviving out-of-hospital cardiac arrest (OHCA) through extracorporeal cardiopulmonary resuscitation (ECPR) or conventional CPR (CCPR) are scarce. We aimed to determine HRQoL during 1-year after refractory OHCA in patients treated with ECPR and CCPR., Methods: We present a secondary analysis of the multicenter INCEPTION-trial, which studied the effectiveness of ECPR versus CCPR in patients with refractory OHCA. HRQoL was prospectively assessed using the EQ-5D-5L questionnaire. Poor HRQoL was pragmatically defined as an EQ-5D-5L health utility index (HUI) > 1 SD below the age-adjusted norm. We used mixed linear models to assess the difference in HRQoL over time and univariable analyses to assess factors potentially associated with poor HRQoL., Results: A total of 134 patients were enrolled, and hospital survival was 20% (27 patients). EQ-5D-5L data were available for 25 patients (5 ECPR and 20 CCPR). One year after OHCA, the estimated mean HUI was 0.73 (0.05) in all patients, 0.84 (0.12) in ECPR survivors, and 0.71 (0.05) in CCPR survivors (p-value 0.31). Eight (32%) survivors had a poor HRQoL. HRQoL was good in 17 (68%) patients, with 100% in ECPR survivors versus 60% in CCPR survivors (p-value 0.14)., Conclusion: One year after refractory OHCA, 68% of the survivors had a good HRQoL. We found no statistically significant difference in HRQoL one year after OHCA in patients treated with ECPR compared to CCPR. However, numerical differences may be clinically relevant in favor of ECPR., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly used as a supportive treatment for refractory out-of-hospital cardiac arrest (OHCA). Still, there is a paucity of data evaluating favorable and unfavorable prognostic characteristics in patients considered for ECPR., Methods: We performed a previously unplanned post-hoc analysis of the multicenter randomized controlled INCEPTION-trial. The study group consisted of patients receiving ECPR, irrespective of initial group randomization. The patients were divided into favorable survivors (cerebral performance category [CPC] 1-2) and unfavorable or non-survivors (CPC 3-5)., Results: In the initial INCEPTION-trial, 134 patients were randomized. ECPR treatment was started in 46 (66%) of 70 patients in the ECPR treatment arm and 3 (4%) of 74 patients in the conventional treatment arm. No statistically significant differences in baseline characteristics, medical history, or causes of arrest were observed between survivors ( n  = 5) and non-survivors ( n  = 44). More patients in the surviving group had a shockable rhythm at the time of cannulation (60% vs. 14%, p  = 0.037), underwent more defibrillation attempts (13 vs. 6, p  = 0.002), and received higher dosages of amiodarone (450 mg vs 375 mg, p  = 0.047) despite similar durations of resuscitation maneuvers. Furthermore, non-survivors more frequently had post-ECPR implantation adverse events., Conclusion: The persistence of ventricular arrhythmia is a favorable prognostic factor in patients with refractory OHCA undergoing an ECPR-based treatment. Future studies are warranted to confirm this finding and to establish additional prognostic factors. Clinical trial Registration: clinicaltrials.gov registration number NCT03101787., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Roberto Lorusso reports consulting fees from Medtronic, LivaNova, Getinge, and Abiomed and participates in an advisory board of Eurosets and Xenios, which are not related to this work. All other authors report no conflicts of interest.’., (© 2024 The Author(s).)

Cardiac arrest (CA) is a common and potentially avoidable cause of death, while constituting a substantial public health burden. Although survival rates for out-of-hospital cardiac arrest (OHCA) have improved in recent decades, the prognosis for refractory OHCA remains poor. The use of veno-arterial extracorporeal membrane oxygenation during cardiopulmonary resuscitation (ECPR) is increasingly being considered to support rescue measures when conventional cardiopulmonary resuscitation (CPR) fails. ECPR enables immediate haemodynamic and respiratory stabilisation of patients with CA who are refractory to conventional CPR and thereby reduces the low-flow time, promoting favourable neurological outcomes. In the case of refractory OHCA, multiple studies have shown beneficial effects in specific patient categories. However, ECPR might be more effective if it is implemented in the pre-hospital setting to reduce the low-flow time, thereby limiting permanent brain damage. The ongoing ON-SCENE trial might provide a definitive answer regarding the effectiveness of ECPR. The aim of this narrative review is to present the most recent literature available on ECPR and its current developments., (© 2024. The Author(s).)

Aims: Previously, we performed the multicentre INCEPTION trial, randomizing patients with refractory out-of-hospital cardiac arrest (OHCA) to extracorporeal cardiopulmonary resuscitation (ECPR) or conventional cardiopulmonary resuscitation (CCPR). Frequentist analysis showed no statistically significant treatment effect for the primary outcome; 30-day survival with a favourable neurologic outcome (cerebral performance category score of 1-2). To facilitate a probabilistic interpretation of the results, we present a Bayesian re-analysis of the INCEPTION trial., Methods and Results: We analysed survival with a favourable neurologic outcome at 30 days and 6 months under a minimally informative prior in the intention-to-treat population. Effect sizes are presented as absolute risk differences (ARDs) and relative risks (RRs), with 95% credible intervals (CrIs). We estimated posterior probabilities at various thresholds, including the minimal clinically important difference (MCID) (5% ARD), based on expert consensus, and performed sensitivity analyses under sceptical and literature-based priors. The mean ARD for 30-day survival with a favourable neurologic outcome was 3.6% (95% CrI -9.5-16.7%), favouring ECPR, with a median RR of 1.22 (95% CrI 0.59-2.51). The posterior probability of an MCID was 42% at 30 days and 42% at 6 months, in favour of ECPR., Conclusion: Bayesian re-analysis of the INCEPTION trial estimated a 42% probability of an MCID between ECPR and CCPR in refractory OHCA in terms of 30-day survival with a favourable neurologic outcome., Trial Registration: Clinicaltrials.gov (NCT03101787, registered 5 April 2017)., Competing Interests: Conflict of interest: R.L. reports consulting fees from Abiomed and participates in an advisory board of Xenios not related to this work. All other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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: 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: Evidence for extracorporeal cardiopulmonary resuscitation (CPR) in refractory out-of-hospital cardiac arrest (OHCA) remains inconclusive. Recently, the INCEPTION-trial, comparing extracorporeal with conventional CPR, found no statistically significant difference in neurologically favorable survival. Since protocol deviations were anticipated, a pre-specified per-protocol analysis was foreseen., Methods: The per-protocol analysis of the INCEPTION trial excluded patients not meeting inclusion or exclusion criteria, amongst which time-to-cannulation of >60 minutes, and achieving a return of spontaneous circulation before hospital arrival. Crossovers were excluded as well. The primary outcome (30-day survival in a neurologically favorable condition; cerebral performance category [CPC] 1-2) was primarily analyzed under a frequentist statistical framework. In addition, Bayesian analysis under a minimally informative prior was performed., Results: Eighty-one patients were included in the per-protocol analysis (extracorporeal CPR n = 33, conventional CPR n = 48). Thirty-day survival with CPC1-2 was 15% in the extracorporeal CPR group versus 9% in the conventional CPR group (adjusted OR 1.9; 95% CI 0.4-9.3; p-value 0.393). Bayesian analysis showed an 84% posterior probability of any ECPR benefit and a 61% posterior probability of a 5% absolute risk reduction for the primary outcome., Conclusion: A pre-planned, pre-specified per-protocol analysis of the INCEPTION-trial, found a higher survival with favorable neurological in patients undergoing ECPR versus CCPR for refractory shockable OHCA. This difference did not reach statistical significance, but results should be interpreted with care, in the light of the small remaining sample size., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Lorusso reports consulting fees from Abiomed, and participates in an advisory board of Xenios, not related to this work. All other authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The metabolic course during and after critical illness is unclear. We performed repeated indirect calorimetry (IC) measurements during ICU- and post-ICU hospitalization to determine resting energy expenditure (REE)., Methods: Prospective observational design. In ventilated ICU patients, IC measurements were performed every three days until hospital discharge. Measured REE as predicted by the Harris-Benedict equation (HBE-REE) and 25 kcal/adjusted body weight/day (25-REE) were compared., Results: In 56 patients (38% females, 71[13]years, BMI 29(27;31)kg/m2), 189 ICU IC measurements were performed. Measured REE did not differ from HBE-REE at ICU admission, but was lower than 25-REE. Measured REE was increased compared to baseline on ICU-admission-day four (29(29-30)kcal/kg/day; mean difference 3.1(1.4-4.9)kcal/kg/day, p < 0.001) and thereafter during ICU admission. During post-ICU ward stay, 44 measurements were performed in 23 patients, showing a higher mean REE than during ICU stay (33(31-35)kcal/kg/day; mean difference 2.6(1.2-3.9)kcal/kg/day, p < 0.001). The REE in the ICU and ward was >110% of HBE-REE from day four onwards., Conclusions: Critically ill mechanically ventilated patients were shown to have a resting energy expenditure (REE) > 110% of predicted REE on ICU admission day four and thereafter. Indirect calorimetry measurements suggest that the mean energy requirements during post-ICU hospitalization are higher than those in the ICU., Competing Interests: Declaration of Competing Interest Prof. Dr. Van Zanten reported receiving honoraria for advisory board meetings, lectures, research, and travel expenses from AOP Pharma, Baxter, Cardinal Health, Danone-Nutricia, DIM3, Fresenius Kabi, GE Healthcare, Mermaid, Rousselot, and Lyric. Dr. Van de Poll reported receiving honoraria for advisory board meetings, lectures, research, and travel expenses from Danone-Nutricia, Fresenius Kabi, Nestle and COSMED, the Netherlands. The other authors have nothing to declare., (Copyright © 2023. Published by Elsevier Inc.)

Purpose of Review: Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging treatment for refractory cardiac arrest. In recent years, several randomized controlled trials have been published that aimed to address the efficacy and effectiveness of ECPR for out-of-hospital cardiac arrest (OHCA). Despite the lack of high-quality evidence concerning clinical effectiveness and cost-effectiveness, ECPR is increasingly implemented throughout the world. In this review, we aim to provide an overview of the current status of ECPR for OHCA., Recent Findings: Randomized controlled trials showed diverging results, largely due to differences in selection criteria and study design. Single-center studies, performed in centers with extraordinary expertise and dedication consistently achieve a low-flow time of around 60 min, but such achievements are rarely reproduced outside these centers. Strict patient selection can improve outcome but simultaneously limits the caseload. Preliminary data suggest that outcome may also be improved by avoiding hyperoxia postresuscitation., Summary: The potential of ECPR to increase survival in selected patients in highly dedicated systems seems to be proven, the question remains whether ECPR for OHCA can be widely implemented successfully and can develop into a sustainable, commonplace resource-effective treatment., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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).)

Introduction: The association between obesity and outcome in critical illness is unclear. Since the amount of visceral adipose tissue(VAT) rather than BMI mediates the health effects of obesity we aimed to investigate the association between visceral obesity, BMI and 90-day mortality in critically ill patients., Method: In 555 critically ill patients (68% male), the VAT Index(VATI) was measured using Computed Tomography scans on the level of vertebra L3. The association between visceral obesity, BMI and 90-day mortality was investigated using univariable and multivariable analyses, correcting for age, sex, APACHE II score, sarcopenia and muscle quality., Results: Visceral obesity was present in 48.1% of the patients and its prevalence was similar in males and females. Mortality was similar amongst patients with and without visceral obesity (27.7% vs 24.0%, p = 0.31). The corrected odds ratio of 90-day mortality for visceral obesity was 0.667 (95%CI 0.424-1.049, p = 0.080). Using normal BMI as reference, the corrected odds ratio for overweight was 0.721 (95%CI 0.447-1.164 p = 0.181) and for obesity 0.462 (95%CI 0.208-1.027, p = 0.058)., Conclusion: No significant association of visceral obesity and BMI with 90-day mortality was observed in critically ill patients, although obesity and visceral obesity tended to be associated with improved 90-day mortality., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: During Intensive Care Unit (ICU) admission, patients demonstrate up to 15% muscle loss per week, contributing to neuromuscular weakness, complicating recovery and delaying return to daily life. Biomarkers for muscle loss could aid in early detection of patients at risk and help guide resources to mitigate muscle loss, e.g. physical therapy and protein supplementation., Aims: To explore serum biomarkers for muscle mass and muscle loss in ICU patients using a metabolomics approach., Methods: Mechanically ventilated patients with an unplanned ICU admission between June and December 2021 were prospectively studied. The cross-sectional area of the rectus femoris muscle was assessed using ultrasound (RF csa ) and 188 serum metabolites were assessed using the Biocrates™ AbsoluteIDQ p180 kit for targeted metabolomics. Patients were eligible for analysis when a serum sample drawn within 5 days of ICU admission and at least 1 RF csa were available. In patients with sequential RF csa measurements, muscle loss was defined as the negative slope of the regression line fitted to the RF csa measurements per patient in the first 10 days of ICU admission. Correlations between baseline metabolite concentrations and baseline muscle mass, as well as between baseline metabolite concentrations and muscle loss were assessed using Pearson's test for correlations. To correct for multiple testing, the Benjamini-Hochberg procedure was used., Results: Seventeen patients were eligible for analysis. Mean age was 62 (SD ± 9) years and the cohort was predominantly male (76%). Four metabolites correlated with baseline muscle mass: creatinine (R = 0.5, p = 0.041), glycerophospholipid PC&#95;ae&#95;C30&#95;0 (R = 0.5, p = 0.034) and two acylcarnitines: C14&#95;2 (R = 0.5, p = 0.042) and C10&#95;2 (R = 0.5, p = 0.049). For muscle loss, significant associations were found for histidine (R = -0.8, p = 0.002) and three glycerophospholipids; PC&#95;aa&#95;C40&#95;2 (R = 0.7, p = 0.015), PC&#95;ae&#95;C40&#95;1 (R = 0.6, p = 0.032) and PC&#95;aa&#95;C42&#95;1 (R = 0.6, p = 0.037). After correction for multiple testing, no significant associations remained., Conclusions: This exploratory analysis found certain metabolites to be associated with muscle mass and muscle loss. Future research, specifically addressing these metabolites is necessary to confirm or refute an association with muscle loss and determine their role as potential muscle loss marker., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Extracorporeal cardiopulmonary resuscitation is a promising treatment for refractory out-of-hospital cardiac arrest. Three recent randomized trials (ARREST trial, Prague OHCA study, and INCEPTION trial) that addressed the clinical benefit of extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest yielded seemingly diverging results. The evidence for extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest, derived from three recent randomized controlled trials, is not contradictory but rather complementary. Excellent results can be achieved with a very high level of dedication, provided that strict selection criteria are applied. However, pragmatic implementation of extracorporeal cardiopulmonary resuscitation does not necessarily lead to improved outcome of refractory out-of-hospital cardiac arrest. Centres that are performing extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest or aspire to do so should critically evaluate whether they are able to meet the pre-requisites that are needed to conduct an effective extracorporeal cardiopulmonary resuscitation programme., Competing Interests: Conflict of interest: R.L. reports a relationship with Medtronic, Getinge, and LivaNova that includes: consulting; and is an Advisory Board Member of Eurosets (honoraria paid as research funding). J.B. reports a relationship with Getinge, Abiomed, Xenios and Medtronic that includes consulting. The remaining authors declare that there is no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose of Review: Gastrointestinal (GI) dysfunction is common among critically ill patients and is associated with poor outcomes. In particular, nutrient delivery can be impaired in patients with GI dysfunction and pose a significant challenge to clinicians in daily clinical practice. This review aims to summarize the impact of GI dysfunction on nutrition therapy during critical illness and provide an update on recent advances in nutritional strategies during gastrointestinal dysfunction., Recent Findings: Although prognostic gastrointestinal dysfunction scoring systems exist, a lack of clear, uniform definitions of GI dysfunction limits diagnosis and subsequent adequate treatment. Recent studies have further investigated separate components of GI dysfunction in ICU patients, including the role of altered GI motility, nutrient digestion and absorption and the metabolic consequences of gut dysfunction. Various strategies to improve nutrient delivery are discussed. However, the evidence supporting their routine use is sometimes lacking., Summary: GI dysfunction frequently occurs during critical illness and negatively affects nutrition therapy. Strategies to improve nutrient delivery during GI dysfunction are available, though more research into the diagnosis and pathophysiology of GI dysfunction will likely further improve patient outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Critically ill patients are subject to severe skeletal muscle wasting during intensive care unit (ICU) stay, resulting in impaired short- and long-term functional outcomes and health-related quality of life. Increased protein provision may improve functional outcomes in ICU patients by attenuating skeletal muscle breakdown. Supporting evidence is limited however and results in great variety in recommended protein targets., Methods: The PRECISe trial is an investigator-initiated, bi-national, multi-center, quadruple-blinded randomized controlled trial with a parallel group design. In 935 patients, we will compare provision of isocaloric enteral nutrition with either a standard or high protein content, providing 1.3 or 2.0 g of protein/kg/day, respectively, when fed on target. All unplanned ICU admissions with initiation of invasive mechanical ventilation within 24 h of admission and an expected stay on ventilator support of at least 3 days are eligible. The study is designed to assess the effect of the intervention on functional recovery at 1, 3, and 6 months following ICU admission, including health-related quality of life, measures of muscle strength, physical function, and mental health. The primary endpoint of the trial is health-related quality of life as measured by the Euro-QoL-5D-5-level questionnaire Health Utility Score. Overall between-group differences will be assessed over the three time points using linear mixed-effects models., Discussion: The PRECISe trial will evaluate the effect of protein on functional recovery including both patient-centered and muscle-related outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT04633421 . Registered on November 18, 2020. First patient in (FPI) on November 19, 2020. Expected last patient last visit (LPLV) in October 2023., (© 2023. The Author(s).)

Purpose of Review: In critically ill patients, optimal protein provision remains a challenge given the wide range in recommended protein delivery in international guidelines and the lack of robust, high quality evidence. As patients are confronted with poor functional outcomes after admission, often attributed to muscle wasting and persisting for multiple years, there is a pressing need for optimal nutritional strategies in the ICU, particularly including protein. This review will discuss the recent literature with regard to purpose, timing and mode of protein delivery., Recent Findings: Recent studies on the effect of dose and timing of protein on clinical and functional outcomes are largely observational in nature and the protein delivery considered as "high" still often only nears the lower end of current recommendations. The majority of trials observed no effect of protein supplementation on mortality, muscle strength or function, though some report attenuation of muscle volume loss, especially when combined with muscle activation. There is no strong evidence that ICU patients should receive supplementation with any specific amino acids., Summary: Though adequate protein provision is likely important, it is difficult to come to a uniform conclusion regarding dosing and timing due to conflicting results in mostly observational studies as well as different cut-off values for high, moderate and low protein intake. This topic is currently subject to large clinical trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Extracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxygenation in a patient who does not have spontaneous circulation. The evidence with regard to the effect of extracorporeal CPR on survival with a favorable neurologic outcome in refractory out-of-hospital cardiac arrest is inconclusive., Methods: In this multicenter, randomized, controlled trial conducted in the Netherlands, we assigned patients with an out-of-hospital cardiac arrest to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, had an initial ventricular arrhythmia, and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 (range, 1 to 5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis., Results: Of the 160 patients who underwent randomization, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR; 26 patients who did not meet the inclusion criteria at hospital admission were excluded. At 30 days, 14 patients (20%) in the extracorporeal-CPR group were alive with a favorable neurologic outcome, as compared with 10 patients (16%) in the conventional-CPR group (odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P = 0.52). The number of serious adverse events per patient was similar in the two groups., Conclusions: In patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR and conventional CPR had similar effects on survival with a favorable neurologic outcome. (Funded by the Netherlands Organization for Health Research and Development and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.gov number, NCT03101787.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Glycocalyx shedding and subsequent endothelial dysfunction occur in many conditions, such as in sepsis, in critical illness, and during major surgery such as in coronary artery bypass grafting (CABG) where it has been shown to associate with organ dysfunction. Hitherto, there is no consensus about the golden standard in measuring glycocalyx properties in humans. The objective of this study was to compare different indices of glycocalyx shedding and dysfunction. To this end, we studied patients undergoing elective CABG surgery, which is a known cause of glycocalyx shedding., Materials and Methods: Sublingual glycocalyx thickness was measured in 23 patients by: 1) determining the perfused boundary region (PBR)-an inverse measure of glycocalyx thickness-by means of sidestream dark field imaging technique. This is stated double, 2) measuring plasma levels of the glycocalyx shedding products syndecan-1, hyaluronan, and heparan sulfate and 3) measuring plasma markers of impaired glycocalyx function and endothelial activation (Ang-2, Tie-2, E-selectin, and thrombomodulin). Measurements were performed directly after induction, directly after onset of cardiopulmonary bypass (CPB), and directly after cessation of CPB. We assessed changes over time as well as correlations between the various markers., Results: The PBR increased from 1.81 ± 0.21 μm after induction of anesthesia to 2.27 ± 0.25 μm ( p < 0.0001) directly after CPB was initiated and did not change further during CPB. A similar pattern was seen for syndecan-1, hyaluronan, heparan sulfate, Ang-2, Tie-2, and thrombomodulin. E-selectin levels also increased between induction and the start of CPB and increased further during CPB. The PBR correlated moderately with heparan sulfate, E-selectin, and thrombomodulin and weakly with Syndecan-1, hyaluronan, and Tie-2. Shedding markers syndecan-1 and hyaluronan correlated with all functional markers. Shedding marker heparan sulfate only correlated with Tie-2, thrombomodulin, and E-selectin. Thrombomodulin correlated with all shedding markers., Conclusion: Our results show that glycocalyx thinning, illustrated by increased sublingual PBR and increased levels of shedding markers, is paralleled with impaired glycocalyx function and increased endothelial activation in CABG surgery with CPB. As correlations between different markers were limited, no single marker could be identified to represent the glycocalyx in its full complexity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bol, Huckriede, van de Pas, Delhaas, Lorusso, Nicolaes, Sels and van de Poll.)

Reliable assessment of the microcirculation is important to investigate microcirculatory properties in various disease states. The GlycoCheck system automatically analyzes sublingual sidestream dark field images to determine the perfused boundary region (PBR; a measure of glycocalyx thickness), red blood cell filling percentage, and microvascular vessel density. Although GlycoCheck has been used to study the microcirculation in patients, little is known about the reproducibility of measurements in healthy volunteers. We assessed intra- and interobserver agreement by having two experienced observers perform three consecutive microcirculation measurements with the GlycoCheck system in 49 healthy volunteers. Intraobserver agreement of single measurements were poor (intraclass correlation coefficients (ICCs) < 0.4) for PBR, red blood cell filling percentage and microvascular vessel density. ICCs increased to values > 0.6 (indicating good reproducibility) for all parameters when performing and averaging three consecutive measurements. No systematic differences were observed between observers for any parameter. Interobserver variability was fair for PBR (ICC = 0.53) and red blood cell filling percentage (ICC = 0.58) and poor for perfused vessel density (ICC = 0.20). In conclusion, GlycoCheck software can be used with acceptable reliability and reproducibility for microcirculation measurements on a population level when averaging three consecutive measurements. Repeated measurements are preferably performed by the same observer., (© 2022. The Author(s).)

Objectives: To investigate national mortality trends over a 12-year period for patients with severe acute pancreatitis (SAP) admitted to Dutch ICUs. Additionally, an assessment of outcome in SAP was undertaken to differentiate between early (< 14 d of ICU admission) and late (> 14 d of ICU admission) mortality., Design: Data from the Dutch National Intensive Care Evaluation and health insurance companies' databases were extracted. Outcomes included 14-day, ICU, hospital, and 1-year mortality. Mortality before and after 2010 was compared using mixed logistic regression and mixed Cox proportional-hazards models. Sensitivity analyses, excluding early mortality, were performed to assess trends in late mortality., Setting: Not applicable., Patients: Consecutive adult patients with SAP admitted to all 81 Dutch ICUs between 2007 and 2018., Interventions: Not applicable., Measurements and Main Results: Among 4,160 patients treated in 81 ICUs, 14-day mortality was 17%, ICU mortality 17%, hospital mortality 23%, and 1-year mortality 33%. After 2010 in-hospital mortality adjusted for age, sex, modified Marshall, and Acute Physiology and Chronic Health Evaluation III scores were lower (odds ratio [OR], 0.76; 95% CI, 0.61-0.94) than before 2010. There was no change in ICU and 1-year mortality. Sensitivity analyses excluding patients with early mortality demonstrated a decreased ICU mortality (OR, 0.45; 95% CI, 0.32-0.64), decreased in-hospital (OR, 0.48; 95% CI, 0.36-0.63), and decreased 1-year mortality (hazard ratio, 0.81; 95% CI, 0.68-0.96) after 2010 compared with 2007-2010., Conclusions: Over the 12-year period examined, mortality in patients with SAP admitted to Dutch ICUs did not change, although after 2010 late mortality decreased. Novel therapies should focus on preventing early mortality in SAP., Competing Interests: Drs. Termorshuizen’s and de Keizer’s institutions received funding from the National Intensive Care Evaluation Foundation. Dr. Termorshuizen’s institution received funding from the Rivierduinen Institute for Mental Health Care. Dr. de Keizer’s institution received funding from the Ministry of Health and Welfare. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1-3 after intubation, 66 from day 4-6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO 2 /FiO 2 -ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (p = 0.017) and PEEP was 11.8 (SD 2.8) cmH 2 O vs. 11.3 (SD 3.4) cmH 2 O, (p = 0.475), for ICU survivors and non-survivors. At day 1-3, compliance was ~ 55 mL/cmH 2 O vs. ~ 45 mL/cmH 2 O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12-13 cmH 2 O. At day 4-6 compliance changed to ~ 50 mL/cmH 2 O vs. ~ 38 mL/cmH 2 O. At day 7 and beyond, compliance was ~ 38 mL/cmH 2 O with the intersection at a PEEP of ~ 9 cmH 2 O vs. ~ 25 mL/cmH 2 O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH 2 O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups., (© 2022. The Author(s).)

Background: Electrical impedance tomography (EIT) visualises alveolar overdistension and alveolar collapse and enables optimisation of ventilator settings by using the best balance between alveolar overdistension and collapse (ODCL). Besides, the global inhomogeneity index (GI), measured by EIT, may also be of added value in determining PEEP. Optimal PEEP is often determined based on the best dynamic compliance without EIT at the bedside. This study aimed to assess the effect of a PEEP trial on ODCL, GI and dynamic compliance in patients with and without ARDS. Secondly, PEEP levels from "optimal PEEP" approaches by ODCL, GI and dynamic compliance are compared., Methods: In 2015-2016, we included patients with ARDS using postoperative cardiothoracic surgery patients as a reference group. A PEEP trial was performed with four consecutive incremental followed by four decremental PEEP steps of 2 cmH 2 O. Primary outcomes at each step were GI, ODCL and best dynamic compliance. In addition, the agreement between ODCL, GI, and dynamic compliance was determined for the individual patient., Results: Twenty-eight ARDS and 17 postoperative cardiothoracic surgery patients were included. The mean optimal PEEP, according to best compliance, was 10.3 (±2.9) cmH 2 O in ARDS compared to 9.8 (±2.5) cmH 2 O in cardiothoracic surgery patients. Optimal PEEP according to ODCL was 10.9 (±2.5) in ARDS and 9.6 (±1.6) in cardiothoracic surgery patients. Optimal PEEP according to GI was 17.1 (±3.9) in ARDS compared to 14.2 (±3.4) in cardiothoracic surgery patients., Conclusions: Currently, no golden standard to titrate PEEP is available. We showed that when using the GI, PEEP requirements are higher compared to ODCL and best dynamic compliance during a PEEP trial in patients with and without ARDS., (© 2022. The Author(s).)

Introduction: Concern for loss of physical performance and Health-Related Quality of Life (HRQoL) may raise doubts regarding the meaningfulness of an Intensive Care (ICU) admission in elderly patients. We evaluated self-perceived long-term recovery and satisfaction in elderly surviving an abdominal sepsis related ICU-admission and related this to objective measures of HRQoL., Methods: A cross-sectional survey study was performed in all ICU-survivors with age ≥70 admitted with abdominal sepsis. HRQoL, frailty and self-perceived long-term recovery were measured using the EQ-5D-3L, Groningen Frailty Indicator, and a self-developed questionnaire, respectively., Results: Of 144 patients admitted, 48 were alive at follow up (2.42 [0.92; 3.83] years), and 29 (60%) returned the survey. Eleven patients out of 29 (38%) recovered to baseline functioning, and reported higher HRQoL compared to unrecovered patients (0.861 [0.807; 1.000] and 0.753 [0.499; 0.779] respectively, p=0.005). Of the unrecovered patients, 53% were satisfied with their functioning, and 94% were willing to return to ICU., Conclusions: Mortality in elderly patients with abdominal sepsis is high and ICU-admission should be weighed carefully. However, despite substantial functional decline in survivors, it does not necessarily cause self-perceived unsatisfactory functioning, poor HRQoL and unwillingness to receive life-sustaining therapy again. Caution is advised to use an anticipated loss of functioning as an argument to deny an ICU-admission.

Background: Visceral obesity is associated with the metabolic syndrome. The metabolic risk differs per ethnicity, but reference values for visceral obesity for body composition analyses using Computed Tomography (CT) scans in the Caucasian population are lacking. Therefore, the aim of this study was to define gender specific reference values for visceral obesity in a Caucasian cohort based upon the association between the amount of visceral adipose tissue (VAT) and markers of increased metabolic risk., Methods: Visceral Adipose Tissue Area Index (VATI cm 2 /m 2 ) at the level of vertebra L3 was analyzed using CT scans of 416 healthy living kidney donor candidates. The use of antihypertensive drugs and/or statins was used as an indicator for increased metabolic risk. Gender specific cut-off values for VATI with a sensitivity ≥80% were calculated using receiver operating characteristic (ROC) curves., Results: In both men and women who used antihypertensive drugs, statins or both, VATI was higher than in those who did not use these drugs (p ≤ 0.013). In males and females respectively, a value of VATI of ≥38.7 cm 2 /m 2 and ≥24.9 cm 2 /m 2 was associated with increased metabolic risk with a sensitivity of 80%. ROC analysis showed that VATI was a better predictor of increased metabolic risk than BMI (area under ROC curve (AUC) = 0.702 vs AUC = 0.556 in males and AUC = 0.757 vs AUC = 0.630 in females)., Conclusion: Gender and ethnicity specific cut-off values for visceral obesity are important in body composition research, although further validation is needed. This study also showed that quantification of VATI is a better predictor for metabolic risk than BMI., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries., Design: Multicenter observational cohort study., Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany., Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave., Interventions: None., Measurements and Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications., Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: The rate of protein digestion and amino acid absorption determines the postprandial rise in circulating amino acids and modulates postprandial muscle protein synthesis rates., Objective: We sought to compare protein digestion, amino acid absorption kinetics, and the postprandial muscle protein synthetic response following ingestion of intact milk protein or an equivalent amount of free amino acids., Methods: Twenty-four healthy, young participants (mean ± SD age: 22 ± 3 y and BMI 23 ± 2 kg/m2; sex: 12 male and 12 female participants) received a primed continuous infusion of l-[ring-2H5]-phenylalanine and l-[ring-3,5-2H2]-tyrosine, after which they ingested either 30 g intrinsically l-[1-13C]-phenylalanine-labeled milk protein or an equivalent amount of free amino acids labeled with l-[1-13C]-phenylalanine. Blood samples and muscle biopsies were obtained to assess protein digestion and amino acid absorption kinetics (secondary outcome), whole-body protein net balance (secondary outcome), and mixed muscle protein synthesis rates (primary outcome) throughout the 6-h postprandial period., Results: Postprandial plasma amino acid concentrations increased after ingestion of intact milk protein and free amino acids (both P < 0.001), with a greater increase following ingestion of the free amino acids than following ingestion of intact milk protein (P-time × treatment < 0.001). Exogenous phenylalanine release into plasma, assessed over the 6-h postprandial period, was greater with free amino acid ingestion (76 ± 9%) than with milk protein treatment (59 ± 10%; P < 0.001). Ingestion of free amino acids and intact milk protein increased mixed muscle protein synthesis rates (P-time < 0.001), with no differences between treatments (from 0.037 ± 0.015%/h to 0.053 ± 0.014%/h and 0.039 ± 0.016%/h to 0.051 ± 0.010%/h, respectively; P-time × treatment = 0.629)., Conclusions: Ingestion of a bolus of free amino acids leads to more rapid amino acid absorption and greater postprandial plasma amino acid availability than ingestion of an equivalent amount of intact milk protein. Ingestion of free amino acids may be preferred over ingestion of intact protein in conditions where protein digestion and amino acid absorption are compromised., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Postprandial rise of plasma essential amino acids (EAAs) determines the anabolic effect of dietary protein. Disturbed gastrointestinal function could impair the anabolic response in critically ill patients. Aim was to investigate the postprandial EAA response in critically ill patients and its relation to small-intestinal function., Methods: Twenty-one mechanically ventilated patients and 9 healthy controls received a bolus containing 100 ml of a formula feed (Ensure) and 2 g of 3-O-Methyl-d-glucose (3-OMG) via postpyloric feeding tube. Fasting and postprandial plasma concentrations of EAAs, 3-OMG, total bile salts, and the gut-released hormone fibroblast growth factor 19 (FGF19) were measured over a 4-hour period. Changes over time and between groups were assessed with linear mixed-effects analysis. Early (0-60 minutes) and total postprandial responses are summarized as the incremental area under the curve (iAUC)., Results: At baseline, fasting EAA levels were similar in both groups: 1181 (1055-1276) vs 1150 (1065-1334) μmol·L-1, P = .87. The early postprandial rise in EAA was not apparent in critically ill patients compared with healthy controls (iAUC 60 , -4858 [-6859 to 2886] vs 5406 [3099-16,853] µmol·L -1 ·60 minutes; P = .039). Impaired EAA response did not correlate with impaired 3-OMG response (Spearman ρ 0.32, P = .09). There was a limited increase in total bile salts but no relevant FGF19 response in either group., Conclusion: Postprandial rise of EAA is blunted in critically ill patients and unrelated to glucose absorption measured with 3-OMG. Future studies should aim to delineate governing mechanisms of macronutrient malabsorption., (© 2021 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

The design of emergency medicine trials can raise several ethical concerns - risks may be greater, and randomisation may have to occur before consent. Research in emergency medicine is thus an illuminating context to explore the interplay between risk and randomisation, and the consequences for consent. Using a currently running trial, we describe possible concerns, considerations, and solutions to reconcile the conflicting interests of scientific inquiry, ethical principles, and clinical reality in emergency medicine research., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: We performed a comprehensive health assessment in mechanically ventilated coronavirus disease 2019 survivors to assess the impact of respiratory and skeletal muscle injury sustained during ICU stay on physical performance at 3 months following hospital discharge., Design: Preregistered prospective observational cohort study., Setting: University hospital ICU., Patients: All mechanically ventilated coronavirus disease 2019 patients admitted to our ICU during the first European pandemic wave., Measurements and Main Results: At 3 months after hospital discharge, 46 survivors underwent a comprehensive physical assessment (6-min walking distance, Medical Research Council sum score and handgrip strength), a full pulmonary function test, and a chest CT scan which was used to analyze skeletal muscle architecture. In addition, patient-reported outcomes measures were collected. Physical performance assessed by 6-minute walking distance was below 80% of predicted in 48% of patients. Patients with impaired physical performance had more muscle weakness (Medical Research Council sum score 53 [51-56] vs 59 [56-60]; p < 0.001), lower lung diffusing capacity (54% [44-66%] vs 68% of predicted [61-72% of predicted]; p = 0.002), and higher intermuscular adipose tissue area (p = 0.037). Reduced lung diffusing capacity and increased intermuscular adipose tissue were independently associated with physical performance., Conclusions: Physical disability is common at 3 months in severe coronavirus disease 2019 survivors. Lung diffusing capacity and intermuscular adipose tissue assessed on CT were independently associated with walking distance, suggesting a key role for pulmonary function and muscle quality in functional disability., Competing Interests: Dr. Posthuma received funding from Medtalk Health. 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.)

Objectives: Changes in muscle mass and quality are important targets for nutritional intervention in critical illness. Effects of such interventions may be assessed using sequential computed tomography (CT) scans. However, fluid and lipid infiltration potentially affects muscle area measurements. The aim of this study was to evaluate changes in muscle mass and quality in critical illness with special emphasis on the influence of edema on this assessment., Methods: Changes in skeletal muscle area index (SMI) and radiation attenuation (RA) at the level of vertebra L3 were analyzed using sequential CT scans of 77 patients with abdominal sepsis. Additionally, the relation between these changes and disease severity using the maximum Sequential Organ Failure Assessment (SOFA) score and change in edema were studied., Results: SMI declined on average 0.35%/d (±1.22%; P = 0.013). However, SMI increased in 41.6% of the study population. Increasing edema formation was significantly associated with increased SMI and with a higher SOFA score. Muscle RA decreased during critical illness, but was not significantly associated with changes in SMI or changes in edema., Conclusion: In critically ill patients, edema affects skeletal muscle area measurements, which leads to an overestimation of skeletal muscle area. A higher SOFA score was associated with edema formation. Because both edema and fat infiltration may affect muscle RA, the separate effects of these on muscle quality are difficult to distinguish. When using abdominal CT scans to changes in muscle mass and quality in critically ill patients, researchers must be aware and careful with the interpretation of the results., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo., Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially., Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group., Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention., (© 2021 The Author(s).)

Background: The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ failure during ICU admission as driver for outcome remains to be investigated yet., Design and Setting: Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection., Participants and Methods: 94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models., Results: Survivors improved one SOFA score point more per 5 days (95% CI: 4-8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk factors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043)., Conclusions: The decrease in SOFA score associated with survival suggests multi-organ failure involvement during mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than surviving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sepsis is a global health care problem with a high mortality. Early death seems common; however, data are sparse. The objective of the present study was to report causes and influencing factors of early death in sepsis and septic shock., Methods: All septic ICU patients were included from 2012 to 2017. Early death was predefined as occurring within 48 h. Causes and factors leading up to death were reported by a panel of four intensivists, independently reviewing the medical files. Following factors were assessed: (1) delay in ICU admission; (2) futile ICU treatment; (3) missed diagnosis or inadequate treatment on the ICU. Fleiss kappa was used to assess inter-observer agreement., Results: 1107 septic patients (APACHE II score 25 ± 8) were included. 344 patients died of which 97 (28%) within 48 h. In 33% an autopsy was performed. Primary causes of early death were multiple organ failure, mesenteric ischaemia and death after cardio-pulmonary resuscitation (CPR). Delay in ICU admission was scored in 32% of early deaths with slight agreement (κ = 0.180), futile ICU treatment in 29% with moderate agreement (κ = 0.415) and missed diagnosis or treatment in 7% of cases with slight agreement (κ = 0.122)., Conclusions: Early death after ICU admission in sepsis is common and primarily caused by multiple organ failure, mesenteric ischaemia and death after unsuccessful CPR. Influencing factors were delay in ICU admission and futile ICU admission. Fleiss kappa indicates substantial variability in clinical judgement between intensivists, strengthening the necessity for shared decision making.

Background: Postoperative outcome prediction in elderly is based on preoperative physical status but its predictive value is uncertain. The goal was to evaluate the value of risk assessment performed perioperatively in predicting outcome in case of admission to an intensive care unit (ICU)., Methods: A total of 108 postsurgical patients were retrospectively selected from a prospectively recorded database of 144 elderly septic patients (>70 years) admitted to the ICU department after elective or emergency abdominal surgery between 2012 and 2017. Perioperative risk assessment scores including Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality (P-POSSUM) and American Society of Anaesthesiologists Physical Status classification (ASA) were determined. Acute Physiology and Chronic Health Evaluation IV (APACHE IV) was obtained at ICU admission., Results: In-hospital mortality was 48.9% in elderly requiring ICU admission after elective surgery (n = 45), compared to 49.2% after emergency surgery (n = 63). APACHE IV significantly predicted in-hospital mortality after complicated elective surgery [area under the curve 0.935 (p < 0.001)] where outpatient ASA physical status and P-POSSUM did not. In contrast, P-POSSUM and APACHE IV significantly predicted in-hospital mortality when based on current physical state in elderly requiring emergency surgery (AUC 0.769 (p = 0.002) and 0.736 (p = 0.006), respectively)., Conclusions: Perioperative risk assessment reflecting premorbid physical status of elderly loses its value when complications occur requiring unplanned ICU admission. Risks in elderly should be re-assessed based on current clinical condition prior to ICU admission, because outcome prediction is more reliable then.

Purpose: We aimed to describe epidemiology of diarrhea and cholestasis in critically ill patients and explore associations between these two conditions., Material and Methods: We performed a retrospective study including all consecutive patients who stayed in the ICU for at least 3 days and in whom plasma measurements of liver enzymes/cholestasis parameters were performed. Diarrhea was defined as 3 or more loose or liquid stools per day and cholestasis as increase of alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) 1.5 times above the upper limit of normality., Results: Diarrhea was observed in 26.1% and cholestasis in 27.9% of study patients, about one third of the cases in both diarrhea and cholestasis occurred beyond the first week of patient's ICU stay. Cholestasis occurred in 45.6% of patients with diarrhea vs 28.0% of patients without diarrhea (p < 0.001). In 94 patients (13.1%) both diarrhea and cholestasis occurred, cholestasis was more commonly (2/3 of cases) documented before manifestation of diarrhea., Conclusions: Cholestasis is more common in patients with diarrhea and vice versa. Diarrhea and cholestasis both occur in approximately one quarter of ICU patients, with significant proportion manifesting beyond the first week in the ICU., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest regarding this manuscript. ARB received speaker fees from Fresenius Kabi and Nestlé, none related to this study. University of Tartu received a study grant from Fresenius Kabi, not related to this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19., Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO 2 /FiO 2 ) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO 2 /FiO 2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420)., Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO 2 /FiO 2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO 2 /FiO 2 (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO 2 /FiO 2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group., Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint., Funding: InflaRx., (© 2020 Elsevier Ltd. All rights reserved.)