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Context Muscle expresses and secretes several myokines that bring about benefits in distant organs. Objective We investigated the impact of critical illness on muscular expression of irisin, kynurenine aminotransferases, and amylase; association with clinical outcome; and impact of interventions that attenuate muscle wasting/weakness. Methods We studied critically ill patients who participated in 2 randomized controlled trials (EPaNIC/NESCI) and documented time profiles in critically ill mice. Included in the study were 174 intensive care unit (ICU) patients (day 8 ± 1) vs 19 matched controls, and 60 mice subjected to surgery/sepsis vs 60 pair-fed healthy mice. Interventions studied included 7-day neuromuscular electrical stimulation (NMES), and withholding parenteral nutrition (PN) in the first ICU week (late PN) vs early PN. The main outcome measures were FNDC5 (irisin- precursor), KYAT1, KYAT3 , and amylase mRNA expression in skeletal muscle. Results Critically ill patients showed 34% to 80% lower mRNA expression of FNDC5 , KYAT1 , and amylases than controls (P <.0001). Critically ill mice showed time-dependent reductions in all mRNAs compared with healthy mice (P ≤.04). The lower FNDC5 expression in patients was independently associated with a higher ICU mortality (P =.015) and ICU-acquired weakness (P =.012), whereas the lower amylase expression in ICU survivors was independently associated with a longer ICU stay (P =.0060). Lower amylase expression was independently associated with a lower risk of death (P =.048), and lower KYAT1 expression with a lower risk of weakness (P =.022). NMES increased FNDC5 expression compared with unstimulated muscle (P =.016), and late PN patients had a higher KYAT1 expression than early PN patients (P =.022). Conclusion Expression of the studied myokines was affected by critical illness and associated with clinical outcomes, with limited effects of interventions that attenuate muscle wasting or weakness. [ABSTRACT FROM AUTHOR] more...

Purpose: Withholding parenteral nutrition (PN) early in critical illness, late-PN, has shown to prevent infections despite a higher peak C-reactive protein (CRP). We investigated whether the accentuated CRP rise was caused by a systemic inflammatory effect mediated by cytokines or arose as a consequence of the different feeding regimens, and whether it related to improved outcome with late-PN. Methods: This secondary analysis of the EPaNIC-RCT first investigated, with multivariable linear regression analyses, determinants of late-PN-induced CRP rise and its association with cytokine responses (IL-6, IL-10, TNF-α) in matched early-PN and late-PN patients requiring intensive care for ≥ 3 days. Secondly, with multivariable logistic regression and Cox proportional-hazard analyses, we investigated whether late-PN-induced CRP rises mediated infection prevention and enhanced recovery or reflected an adverse effect counteracting such benefits of late-PN. Results: CRP peaked on day 3, higher with late-PN [216(152–274)mg/l] (n = 946) than with early-PN [181(122–239)mg/l] (n = 946) (p < 0.0001). Independent determinants of higher CRP rise were lower carbohydrate and protein intakes (p ≤ 0.04) with late-PN, besides higher blood glucose and serum insulin concentrations (p ≤ 0.01). Late-PN did not affect cytokines. Higher CRP rises were independently associated with more infections and lower likelihood of early ICU discharge (p ≤ 0.002), and the effect size of late-PN versus early-PN on these outcomes was increased rather than reduced after adjusting for CRP rise, not confirming a mediating role. Conclusions: The higher CRP rise with late-PN, explained by the early macronutrient deficits, did not relate to cytokine responses and thus did not reflect more systemic inflammation. Instead of mediating clinical benefit on infection or recovery, the accentuated CRP rise appeared an adverse effect reducing such late-PN benefits. [ABSTRACT FROM AUTHOR] more...

Background: In two recent randomized controlled trials, withholding parenteral nutrition early in critical illness improved outcome as compared to early up-to-calculated-target nutrition, which may be explained by beneficial effects of fasting. Outside critical care, fasting-mimicking diets were found to maintain fasting-induced benefits while avoiding prolonged starvation. It is unclear whether critically ill patients can develop a fasting response after a short-term nutrient interruption. In this randomized crossover pilot study, we investigated whether 12-h nutrient interruption initiates a metabolic fasting response in prolonged critically ill patients. As a secondary objective, we studied the feasibility of monitoring autophagy in blood samples.Methods: In a single-center study in 70 prolonged critically ill patients, 12-h up-to-calculated-target feeding was alternated with 12-h fasting on day 8 ± 1 in ICU, in random order. Blood samples were obtained at the start of the study, at the crossover point, and at the end of the 24-h study period. Primary endpoints were a fasting-induced increase in serum bilirubin and decrease in insulin requirements to maintain normoglycemia. Secondary outcomes included serum insulin-like growth factor I (IGF-I), serum urea, plasma beta-hydroxybutyrate (BOH), and mRNA and protein markers of autophagy in whole blood and isolated white blood cells. To obtain a healthy reference, mRNA and protein markers of autophagy were assessed in whole blood and isolated white blood cells of 23 matched healthy subjects in fed and fasted conditions. Data were analyzed using repeated-measures ANOVA, Fisher's exact test, or Mann-Whitney U test, as appropriate.Results: A 12-h nutrient interruption significantly increased serum bilirubin and BOH and decreased insulin requirements and serum IGF-I (all p ≤ 0.001). Urea was not affected. BOH was already increased from 4 h fasting onwards. Autophagic markers in blood samples were largely unaffected by fasting in patients and healthy subjects.Conclusions: A 12-h nutrient interruption initiated a metabolic fasting response in prolonged critically ill patients, which opens perspectives for the development of a fasting-mimicking diet. Blood samples may not be a good readout of autophagy at the tissue level.Trial Registration: ISRCTN, ISRCTN98404761. Registered 3 May 2017. [ABSTRACT FROM AUTHOR] more...

Purpose: Early diagnosis of acute kidney injury (AKI) remains a major challenge. We developed and validated AKI prediction models in adult ICU patients and made these models available via an online prognostic calculator. We compared predictive performance against serum neutrophil gelatinase-associated lipocalin (NGAL) levels at ICU admission.Methods: Analysis of the large multicenter EPaNIC database. Model development (n = 2123) and validation (n = 2367) were based on clinical information available (1) before and (2) upon ICU admission, (3) after 1 day in ICU and (4) including additional monitoring data from the first 24 h. The primary outcome was a comparison of the predictive performance between models and NGAL for the development of any AKI (AKI-123) and AKI stages 2 or 3 (AKI-23) during the first week of ICU stay.Results: Validation cohort prevalence was 29% for AKI-123 and 15% for AKI-23. The AKI-123 model before ICU admission included age, baseline serum creatinine, diabetes and type of admission (medical/surgical, emergency/planned) and had an AUC of 0.75 (95% CI 0.75-0.75). The AKI-23 model additionally included height and weight (AUC 0.77 (95% CI 0.77-0.77)). Performance consistently improved with progressive data availability to AUCs of 0.82 (95% CI 0.82-0.82) for AKI-123 and 0.84 (95% CI 0.83-0.84) for AKI-23 after 24 h. NGAL was less discriminant with AUCs of 0.74 (95% CI 0.74-0.74) for AKI-123 and 0.79 (95% CI 0.79-0.79) for AKI-23.Conclusions: AKI can be predicted early with models that only use routinely collected clinical information and outperform NGAL measured at ICU admission. The AKI-123 models are available at http://akipredictor.com/ . Trial registration Clinical Trials.gov NCT00512122. [ABSTRACT FROM AUTHOR] more...

Background: For critically ill patients treated in intensive care units (ICU), two feeding strategies are currently being advocated, one by American/Canadian and the other by European expert guidelines. These guidelines differ particularly in the timing of initiating parenteral nutrition (PN) in patients for whom enteral nutrition (EN) does not reach caloric targets. Methods/Design: The EPaNIC trial is an investigator-initiated, non-commercial, multi-center, randomized, controlled, clinical trial with a parallel group design. This study compares early (European guideline) versus late (American/Canadian guideline) initiation of PN when EN fails to reach a caloric target. In the early PN group, PN is initiated within 24-48 hours after ICU admission to complete early enteral nutrition (EN) up to a calculated nutritional target. In the late PN group, PN completing EN is initiated when the target is not reached on day 8. In both groups, the same early EN protocol is applied. The study is designed to compare clinical outcome (morbidity and mortality) in the 2 study arms as well as to address several mechanistical questions. We here describe the EPaNIC study protocol and the statistical analysis plan for the primary report of the clinical results. Discussion: The study has been initiated as planned on august 01 2007. One interim analysis advised continuation of the trial. The study will be completed in February 2011. Trial Registration: ClinicalTrials (NCT): NCT00512122 [ABSTRACT FROM AUTHOR] more...

Background: Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake.Methods: In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied.Results: GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p < 0.0001). Upon-admission GDF15 did not interact with randomization to early PN versus late PN for its outcome effects, but higher GDF15 independently related to worse outcomes (p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p < 0.0001) and a steeper drop in GDF15 with more oral intake after ICU discharge (p = 0.05).Conclusion: In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as "ready-to-feed indicator" appears limited.Trial Registration: ClinicalTrials.gov , NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial). [ABSTRACT FROM AUTHOR] more...