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      Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

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          Abstract

          Background

          In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits.

          Methods

          In a secondary analysis of the PEPaNIC RCT ( N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators.

          Results

          In the matched cohort ( n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1–5 ( P < 0.0001), maximally on PICU day 2. Also, blood glucose ( P < 0.001) and plasma insulin ( P < 0.0001), but not glucagon, were affected. In the total cohort ( n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04–0.04] mmol/L to 0.75 [0.04–2.03] mmol/L ( P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation ( P = 0.0002) and on time to live PICU discharge ( P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings.

          Conclusion

          Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

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          Most cited references 24

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          The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study.

          The objective of this study was to examine the relationship between the amount of energy and protein administered and clinical outcomes, and the extent to which pre-morbid nutritional status influenced this relationship. We conducted an observational cohort study of nutrition practices in 167 intensive care units (ICUs) across 21 [corrected] countries. Patient demographics were collected, and the type and amount of nutrition received were recorded daily for a maximum of 12 days. Patients were followed prospectively to determine 60-day mortality and ventilator-free days (VFDs). We used body mass index (BMI, kg/m2) as a marker of nutritional status prior to ICU admission. Regression models were developed to evaluate the relationship between nutrition received and 60-day mortality and VFDs, and to examine how BMI modifies this relationship. Data were collected on 2,772 mechanically ventilated patients who received an average of 1,034 kcal/day and 47 g protein/day. An increase of 1,000 cal per day was associated with reduced mortality [odds ratio for 60-day mortality 0.76; 95% confidence intervals (CI) 0.61-0.95, p = 0.014] and an increased number of VFDs (3.5 VFD, 95% CI 1.2-5.9, p = 0.003). The effect of increased calories associated with lower mortality was observed in patients with a BMI or =35 with no benefit for patients with a BMI 25 to or =35.
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            Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial.

            Enteral nutrition (EN) is recommended for patients in the intensive-care unit (ICU), but it does not consistently achieve nutritional goals. We assessed whether delivery of 100% of the energy target from days 4 to 8 in the ICU with EN plus supplemental parenteral nutrition (SPN) could optimise clinical outcome. This randomised controlled trial was undertaken in two centres in Switzerland. We enrolled patients on day 3 of admission to the ICU who had received less than 60% of their energy target from EN, were expected to stay for longer than 5 days, and to survive for longer than 7 days. We calculated energy targets with indirect calorimetry on day 3, or if not possible, set targets as 25 and 30 kcal per kg of ideal bodyweight a day for women and men, respectively. Patients were randomly assigned (1:1) by a computer-generated randomisation sequence to receive EN or SPN. The primary outcome was occurrence of nosocomial infection after cessation of intervention (day 8), measured until end of follow-up (day 28), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00802503. We randomly assigned 153 patients to SPN and 152 to EN. 30 patients discontinued before the study end. Mean energy delivery between day 4 and 8 was 28 kcal/kg per day (SD 5) for the SPN group (103% [SD 18%] of energy target), compared with 20 kcal/kg per day (7) for the EN group (77% [27%]). Between days 9 and 28, 41 (27%) of 153 patients in the SPN group had a nosocomial infection compared with 58 (38%) of 152 patients in the EN group (hazard ratio 0·65, 95% CI 0·43-0·97; p=0·0338), and the SPN group had a lower mean number of nosocomial infections per patient (-0·42 [-0·79 to -0·05]; p=0·0248). Individually optimised energy supplementation with SPN starting 4 days after ICU admission could reduce nosocomial infections and should be considered as a strategy to improve clinical outcome in patients in the ICU for whom EN is insufficient. Foundation Nutrition 2000Plus, ICU Quality Funds, Baxter, and Fresenius Kabi. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial.

              Systematic reviews suggest adult patients in intensive care units (ICUs) with relative contraindications to early enteral nutrition (EN) may benefit from parenteral nutrition (PN) provided within 24 hours of ICU admission. To determine whether providing early PN to critically ill adults with relative contraindications to early EN alters outcomes. Multicenter, randomized, single-blind clinical trial conducted between October 2006 and June 2011 in ICUs of 31 community and tertiary hospitals in Australia and New Zealand. Participants were critically ill adults with relative contraindications to early EN who were expected to remain in the ICU longer than 2 days. Random allocation to pragmatic standard care or early PN. Day-60 mortality; quality of life, infections, and body composition. A total of 1372 patients were randomized (686 to standard care, 686 to early PN). Of 682 patients receiving standard care, 199 patients (29.2%) initially commenced EN, 186 patients (27.3%) initially commenced PN, and 278 patients (40.8%) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days (95% CI, 2.3 to 3.4). Patients receiving early PN commenced PN a mean of 44 minutes after enrollment (95% CI, 36 to 55). Day-60 mortality did not differ significantly (22.8% for standard care vs 21.5% for early PN; risk difference, -1.26%; 95% CI, -6.6 to 4.1; P = .60). Early PN patients rated day-60 quality of life (RAND-36 General Health Status) statistically, but not clinically meaningfully, higher (45.5 for standard care vs 49.8 for early PN; mean difference, 4.3; 95% CI, 0.95 to 7.58; P = .01). Early PN patients required fewer days of invasive ventilation (7.73 vs 7.26 days per 10 patient × ICU days, risk difference, -0.47; 95% CI, -0.82 to -0.11; P = .01) and, based on Subjective Global Assessment, experienced less muscle wasting (0.43 vs 0.27 score increase per week; mean difference, -0.16; 95% CI, -0.28 to -0.038; P = .01) and fat loss (0.44 vs 0.31 score increase per week; mean difference, -0.13; 95% CI, -0.25 to -0.01; P = .04). The provision of early PN to critically ill adults with relative contraindications to early EN, compared with standard care, did not result in a difference in day-60 mortality. The early PN strategy resulted in significantly fewer days of invasive ventilation but not significantly shorter ICU or hospital stays. anzctr.org.au Identifier: ACTRN012605000704695.
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                Author and article information

                Contributors
                greet.vandenberghe@kuleuven.be
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                31 August 2020
                31 August 2020
                2020
                : 24
                Affiliations
                [1 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, , KU Leuven, ; 3000 Leuven, Belgium
                [2 ]GRID grid.17089.37, Department of Paediatrics, Intensive Care Unit, , University of Alberta, Stollery Children’s Hospital, ; Edmonton, AB Canada
                [3 ]GRID grid.416135.4, Intensive Care Unit, Department of Paediatrics and Paediatric Surgery, , Erasmus Medical Centre-Sophia Children’s Hospital, ; Rotterdam, Netherlands
                Article
                3256
                10.1186/s13054-020-03256-z
                7456767
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: Horizon 2020 Programme
                Award ID: AdvG-2017-785809
                Funded by: Methusalem programme of the Flemish Government
                Award ID: METH14/06
                Award ID: METH14/06
                Award Recipient :
                Funded by: Agentschap voor Innovatie door Wetenschap en Technologie (BE)
                Award ID: IWT/070695/TBM
                Funded by: Research Foundation Flanders
                Award ID: G.0C78.17N
                Award ID: G.0C78.17N
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100010648, Universitaire Ziekenhuizen Leuven, KU Leuven;
                Award ID: Postdoctoral research fellowship
                Award Recipient :
                Funded by: Sophia Children's Hospital Foundation
                Funded by: Stichting Agis Zorginnovatie
                Funded by: FundRef http://dx.doi.org/10.13039/501100005797, Vereniging Trustfonds Erasmus Universiteit Rotterdam;
                Funded by: European Society for Parenteral and Enteral Nutrition
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Emergency medicine & Trauma

                parenteral nutrition, intensive care, ketogenesis, ketone body, recovery

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